U.S. patent application number 10/023282 was filed with the patent office on 2003-05-15 for secreted protein hemae80.
This patent application is currently assigned to Human Genome Sciences, Inc.. Invention is credited to Brewer, Laurie A., Carter, Kenneth C., Dillon, Patrick J., Ebner, Reinhard, Endress, Gregory A., Fan, Ping, Feng, Ping, Ferrie, Ann M., Fischer, Carrie L., Florence, Charles, Florence, Kimberly, Greene, John M., Hu, Jing-Shan, Kyaw, Hla, Lafleur, David W., Li, Yi, Moore, Paul A., Ni, Jian, Olsen, Henrik S., Rosen, Craig A., Ruben, Steven M., Shi, Yanggu, Soppet, Daniel R., Wei, Ying-Fei, Young, Paul, Yu, Guo-Liang, Zeng, Zhizhen.
Application Number | 20030092893 10/023282 |
Document ID | / |
Family ID | 27587077 |
Filed Date | 2003-05-15 |
United States Patent
Application |
20030092893 |
Kind Code |
A1 |
Young, Paul ; et
al. |
May 15, 2003 |
Secreted protein HEMAE80
Abstract
The present invention relates to novel human secreted proteins
and isolated nucleic acids containing the coding regions of the
genes encoding such proteins. Also provided are vectors, host
cells, antibodies, and recombinant methods for producing human
secreted proteins. The invention further relates to diagnostic and
therapeutic methods useful for diagnosing and treating disorders
related to these novel human secreted proteins.
Inventors: |
Young, Paul; (Gaithersburg,
MD) ; Greene, John M.; (Gaithersburg, MD) ;
Ferrie, Ann M.; (Painted Post, NY) ; Ruben, Steven
M.; (Olney, MD) ; Rosen, Craig A.;
(Laytonsville, MD) ; Hu, Jing-Shan; (Mountain
View, CA) ; Olsen, Henrik S.; (Gaithersburg, MD)
; Ebner, Reinhard; (Gaithersburg, MD) ; Brewer,
Laurie A.; (St. Paul, MN) ; Moore, Paul A.;
(Germantown, MD) ; Shi, Yanggu; (Gaithersburg,
MD) ; Florence, Charles; (Rockville, MD) ;
Florence, Kimberly; (Rockville, MD) ; Lafleur, David
W.; (Washington, DC) ; Ni, Jian; (Germantown,
MD) ; Fan, Ping; (Potomac, MD) ; Wei,
Ying-Fei; (Berkeley, CA) ; Fischer, Carrie L.;
(Burke, VA) ; Soppet, Daniel R.; (Centerville,
VA) ; Li, Yi; (Sunnyvale, CA) ; Zeng,
Zhizhen; (Lansdale, PA) ; Kyaw, Hla;
(Frederick, MD) ; Yu, Guo-Liang; (Berkeley,
CA) ; Feng, Ping; (Gaithersburg, MD) ; Dillon,
Patrick J.; (Carlsbad, CA) ; Endress, Gregory A.;
(Florence, MA) ; Carter, Kenneth C.; (North
Potomac, MD) |
Correspondence
Address: |
HUMAN GENOME SCIENCES INC
9410 KEY WEST AVENUE
ROCKVILLE
MD
20850
|
Assignee: |
Human Genome Sciences, Inc.
9410 Key West Avenue
Rockville
MD
20850
|
Family ID: |
27587077 |
Appl. No.: |
10/023282 |
Filed: |
December 20, 2001 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10023282 |
Dec 20, 2001 |
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09205258 |
Dec 4, 1998 |
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09205258 |
Dec 4, 1998 |
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PCT/US98/11422 |
Jun 4, 1998 |
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60048885 |
Jun 6, 1997 |
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60049375 |
Jun 6, 1997 |
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60048881 |
Jun 6, 1997 |
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60048971 |
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60048882 |
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60092921 |
Jul 15, 1998 |
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60094657 |
Jul 30, 1998 |
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Current U.S.
Class: |
530/388.1 |
Current CPC
Class: |
C07K 14/4702 20130101;
G01N 33/68 20130101; C07K 2319/00 20130101; C07K 14/4718 20130101;
A61K 48/00 20130101; C12N 15/11 20130101; C07K 14/47 20130101; C12N
2799/026 20130101; A61K 38/00 20130101; C07K 2319/02 20130101 |
Class at
Publication: |
530/388.1 |
International
Class: |
C07K 016/00 |
Claims
1. An isolated antibody or fragment thereof that specifically binds
to a protein selected from the group consisting of: (a) a protein
consisting of amino acid residues 1 to 136 of SEQ ID NO:310; (b) a
protein consisting of amino acid residues 25 to 136 of SEQ ID
NO:310; (c) a protein consisting of a portion of SEQ ID NO:310,
wherein said portion comprises at least 30 contiguous amino acid
residues of SEQ ID NO:310; and (d) a protein consisting of a
portion of SEQ ID NO:310, wherein said portion comprises at least
50 contiguous amino acid residues of SEQ ID NO:310.
2. The antibody or fragment thereof of claim 1 that specifically
binds protein (a).
3. The antibody or fragment thereof of claim 1 that specifically
binds protein (b).
4. The antibody or fragment thereof of claim 1 that specifically
binds protein (c).
5. The antibody or fragment thereof of claim 1 that specifically
binds protein (d).
6. The antibody or fragment thereof of claim 2 that specifically
binds protein (b).
7. The antibody or fragment thereof of claim 3, wherein said
protein bound by said antibody or fragment thereof is
glycosylated.
8. The antibody or fragment thereof of claim 3 which is a human
antibody.
9. The antibody or fragment thereof of claim 3 which is a
polyclonal antibody.
10. The antibody or fragment thereof of claim 3 which is selected
from the group consisting of: (a) a chimeric antibody; (b) a
humanized antibody; (c) a single chain antibody; and (d) a Fab
fragment.
11. The antibody or fragment thereof of claim 3 which is
labeled.
12. The antibody or fragment thereof of claim 11, wherein the label
is selected from the group consisting of: (a) an enzyme; (b) a
radioisotope; and (c) a fluorescent label.
13. The antibody or fragment thereof of claim 3, wherein said
antibody or fragment thereof specifically binds to said protein in
a Western blot.
14. The antibody or fragment thereof of claim 3, wherein said
antibody or fragment thereof specifically binds to said protein in
an ELISA.
15. An isolated cell that produces the antibody or fragment thereof
of claim 3.
16. A hybridoma that produces the antibody or fragment thereof of
claim 3.
17. An isolated antibody or fragment thereof obtained from an
animal that has been immunized with a protein selected from the
group consisting of: (a) a protein comprising the amino acid
sequence of amino acid residues 1 to 136 of SEQ ID NO:310; and (b)
a protein comprising the amino acid sequence of amino acid residues
25 to 136 of SEQ ID NO:310; (c) a protein comprising the amino acid
sequence of at least 30 contiguous amino acid residues of SEQ ID
NO:310; and (d) a protein comprising the amino acid sequence of at
least 50 contiguous amino acid residues of SEQ ID NO:310; wherein
said antibody or fragment thereof specifically binds to said amino
acid sequence.
18. The antibody or fragment thereof of claim 17 obtained from an
animal immunized with protein (a).
19. The antibody or fragment thereof of claim 17 obtained from an
animal immunized with protein (b).
20. The antibody or fragment thereof of claim 17 obtained from an
animal immunized with protein (c).
21. The antibody or fragment thereof of claim 17 obtained from an
animal immunized with protein (d).
22. The antibody or fragment thereof of claim 17 which is a
monoclonal antibody.
23. The antibody or fragment thereof of claim 17 which is selected
from the group consisting of: (a) a chimeric antibody; (b) a
polyclonal antibody; (c) a humanized antibody; (d) a single chain
antibody; and (e) a Fab fragment.
24. An isolated monoclonal antibody or fragment thereof that
specifically binds to a protein selected from the group consisting
of: (a) a protein consisting of amino acid residues 1 to 136 of SEQ
ID NO:310; (b) a protein consisting of amino acid residues 25 to
136 of SEQ ID NO:310; (c) a protein consisting of a portion of SEQ
ID NO:310, wherein said portion comprises at least 30 contiguous
amino acid residues of SEQ ID NO:310; and (d) a protein consisting
of a portion of SEQ ID NO:310, wherein said portion comprises at
least 50 contiguous amino acid residues of SEQ ID NO:310.
25. The antibody or fragment thereof of claim 24 that specifically
binds protein (a).
26. The antibody or fragment thereof of claim 24 that specifically
binds protein (b).
27. The antibody or fragment thereof of claim 24 that specifically
binds protein (c).
28. The antibody or fragment thereof of claim 24 that specifically
binds protein (d).
29. The antibody or fragment thereof of claim 26, wherein said
protein bound by said antibody or fragment thereof is
glycosylated.
30. The antibody or fragment thereof of claim 26 which is a human
antibody.
31. The antibody or fragment thereof of claim 26 which is selected
from the group consisting of: (a) a chimeric antibody; (b) a
humanized antibody; (c) a single chain antibody; and (d) a Fab
fragment.
32. The antibody or fragment thereof of claim 26 which is
labeled.
33. The antibody or fragment thereof of claim 32, wherein the label
is selected from the group consisting of: (a) an enzyme; (b) a
radioisotope; and (c) a fluorescent label.
34. The antibody or fragment thereof of claim 26, wherein said
antibody or fragment thereof specifically binds to said protein in
a Western blot.
35. The antibody or fragment thereof of claim 26, wherein said
antibody or fragment thereof specifically binds to said protein in
an ELISA.
36. An isolated cell that produces the antibody or fragment thereof
of claim 26.
37. A hybridoma that produces the antibody or fragment thereof of
claim 26.
38. An isolated antibody or fragment thereof that specifically
binds to a protein selected from the group consisting of: (a) a
protein consisting of the full-length polypeptide encoded by the
HEMAE80 cDNA contained in ATCC Deposit Number 97975; (b) a protein
consisting of the mature form of the polypeptide encoded by the
HEMAE80 cDNA contained in ATCC Deposit Number 97975; (c) a protein
consisting of a portion of the polypeptide encoded by the HEMAE80
cDNA contained in ATCC Deposit Number 97975, wherein said portion
comprises at least 30 contiguous amino acid residues of the
polypeptide encoded by the HEMAE80 cDNA contained in ATCC Deposit
Number 97975; and (d) a protein consisting of a portion of the
polypeptide encoded by the HEMAE80 cDNA contained in ATCC Deposit
Number 97975, wherein said portion comprises at least 50 contiguous
amino acid residues of the polypeptide encoded by the HEMAE80 cDNA
contained in ATCC Deposit Number 97975.
39. The antibody or fragment thereof of claim 38 that specifically
binds protein (a).
40. The antibody or fragment thereof of claim 38 that specifically
binds protein (b).
41. The antibody or fragment thereof of claim 38 that specifically
binds protein (c).
42. The antibody or fragment thereof of claim 38 that specifically
binds protein (d).
43. The antibody or fragment thereof of claim 39 that specifically
binds protein (b).
44. The antibody or fragment thereof of claim 40, wherein said
protein bound by said antibody or fragment thereof is
glycosylated.
45. The antibody or fragment thereof of claim 40 which is a human
antibody.
46. The antibody or fragment thereof of claim 40 which is a
polyclonal antibody.
47. The antibody or fragment thereof of claim 40 which is selected
from the group consisting of: (a) a chimeric antibody; (b) a
humanized antibody; (c) a single chain antibody; and (d) a Fab
fragment.
48. The antibody or fragment thereof of claim 40 which is
labeled.
49. The antibody or fragment thereof of claim 48, wherein the label
is selected from the group consisting of: (a) an enzyme; (b) a
radioisotope; and (c) a fluorescent label.
50. The antibody or fragment thereof of claim 40, wherein said
antibody or fragment thereof specifically binds to said protein in
a Western blot.
51. The antibody or fragment thereof of claim 40, wherein said
antibody or fragment thereof specifically binds to said protein in
an ELISA.
52. An isolated cell that produces the antibody or fragment thereof
of claim 40.
53. A hybridoma that produces the antibody or fragment thereof of
claim 40.
54. An isolated antibody or fragment thereof obtained from an
animal that has been immunized with a protein selected from the
group consisting of: (a) a protein comprising the amino acid
sequence of the full-length polypeptide encoded by the HEMAE80 cDNA
contained in ATCC Deposit Number 97975; (b) a protein comprising
the amino acid sequence of the mature form of the polypeptide
encoded by the HEMAE80 cDNA contained in ATCC Deposit Number 97975;
(c) a protein comprising the amino acid sequence of at least 30
contiguous amino acid residues of the polypeptide encoded by the
HEMAE80 cDNA contained in ATCC Deposit Number 97975; and (d) a
protein comprising the amino acid sequence of at least 50
contiguous amino acid residues the polypeptide encoded by the
HEMAE80 cDNA contained in ATCC Deposit Number 97975; wherein said
antibody or fragment thereof specifically binds to said amino acid
sequence.
55. The antibody or fragment thereof of claim 54 obtained from an
animal immunized with protein (a).
56. The antibody or fragment thereof of claim 54 obtained from an
animal immunized with protein (b).
57. The antibody or fragment thereof of claim 54 obtained from an
animal immunized with protein (c).
58. The antibody or fragment thereof of claim 54 obtained from an
animal immunized with protein (d).
59. The antibody or fragment thereof of claim 54 which is a
monoclonal antibody.
60. The antibody or fragment thereof of claim 54 which is selected
from the group consisting of: (a) a chimeric antibody; (b) a
polyclonal antibody; (c) a humanized antibody; (d) a single chain
antibody; and (e) a Fab fragment.
61. An isolated monoclonal antibody or fragment thereof that
specifically binds to a protein selected from the group consisting
of: (a) a protein consisting of the full-length polypeptide encoded
by the HEMAE80 cDNA contained in ATCC Deposit Number 97975; (b) a
protein consisting of the mature form of the polypeptide encoded by
the HEMAE80 cDNA contained in ATCC Deposit Number 97975; (c) a
protein consisting of a portion of the polypeptide encoded by the
HEMAE80 cDNA contained in ATCC Deposit Number 97975, wherein said
portion comprises at least 30 contiguous amino acid residues of the
polypeptide encoded by the HEMAE80 cDNA contained in ATCC Deposit
Number 97975; and (d) a protein consisting of a portion of the
polypeptide encoded by the HEMAE80 cDNA contained in ATCC Deposit
Number 97975, wherein said portion comprises at least 50 contiguous
amino acid residues of the polypeptide encoded by the HEMAE80 cDNA
contained in ATCC Deposit Number 97975.
62. The antibody or fragment thereof of claim 61 that specifically
binds protein (a).
63. The antibody or fragment thereof of claim 61 that specifically
binds protein (b).
64. The antibody or fragment thereof of claim 61 that specifically
binds protein (c).
65. The antibody or fragment thereof of claim 61 that specifically
binds protein (d).
66. The antibody or fragment thereof of claim 62 that specifically
binds protein (b).
67. The antibody or fragment thereof of claim 63, wherein said
protein bound by said antibody or fragment thereof is
glycosylated.
68. The antibody or fragment thereof of claim 63 which is a human
antibody.
69. The antibody or fragment thereof of claim 63 which is selected
from the group consisting of: (a) a chimeric antibody; (b) a
humanized antibody; (c) a single chain antibody; and (d) a Fab
fragment.
70. The antibody or fragment thereof of claim 63 which is
labeled.
71. The antibody or fragment thereof of claim 70, wherein the label
is selected from the group consisting of: (a) an enzyme; (b) a
radioisotope; and (c) a fluorescent label.
72. The antibody or fragment thereof of claim 63, wherein said
antibody or fragment thereof specifically binds to said protein in
a Western blot.
73. The antibody or fragment thereof of claim 63, wherein said
antibody or fragment thereof specifically binds to said protein in
an ELISA.
74. An isolated cell that produces the antibody or fragment thereof
of claim 63.
75. A hybridoma that produces the antibody or fragment thereof of
claim 63.
Description
[0001] This application claims benefit under 35 U.S.C. 119(e) from
U.S. Provisional Patent Application Serial Nos. 60/070,923;
60/092,921 and 60/094,657, and this application is a
continuation-in-part of, and claims benefit under 35 U.S.C.
.sctn.120 of copending U.S. patent application Ser. No:
PCT/US98/11422, filed Jun. 4, 1998, which is hereby incorporated
herein by reference, which claims benefit under 35 U.S.C.
.sctn.119(e) based on U.S. Provisional Applications:
1 Filing Date Appln No. 1. 06-Jun-1997 60/048,885 2. 06-Jun-1997
60/049,375 3. 06-Jun-1997 60/048,881 4. 06-Jun-1997 60/048,880 5.
06-Jun-1997 60/048,896 6. 06-Jun-1997 60/049,020 7. 06-Jun-1997
60/048,876 8. 06-Jun-1997 60/048,895 9. 06-Jun-1997 60/048,884 10.
06-Jun-1997 60/048,894 11. 06-Jun-1997 60/048,971 12. 06-Jun-1997
60/048,964 13. 06-Jun-1997 60/048,882 14. 06-Jun-1997 60/048,899
15. 06-Jun-1997 60/048,893 16. 06-Jun-1997 60/048,900 17.
06-Jun-1997 60/048,901 18. 06-Jun-1997 60/048,892 19. 06-Jun-1997
60/048,915 20. 06-Jun-1997 60/049,019 21. 06-Jun-1997 60/048,970
22. 06-Jun-1997 60/048,972 23. 06-Jun-1997 60/048,916 24.
06-Jun-1997 60/049,373 25. 06-Jun-1997 60/048,875 26. 06-Jun-1997
60/049,374 27. 06-Jun-1997 60/048,917 28. 06-Jun-1997 60/048,949
29. 06-Jun-1997 60/048,974 30. 06-Jun-1997 60/048,883 31.
06-Jun-1997 60/048.897 32. 06-Jun-1997 60/048,898 33. 06-Jun-1997
60/048,962 34. 06-Jun-1997 60/048,963 35. 06-Jun-1997 60/048,877
36. 06-Jun-1997 60/048,878 37. 05-Sep-1997 60/057,645 38.
05-Sep-1997 60/057,642 39. 05-Sep-1997 60/057,668 40. 05-Sep-1997
60/057,635 41. 05-Sep-1997 60/057,627 42. 05-Sep-1997 60/057,667
43. 05-Sep-1997 60/057,666 44. 05-Sep-1997 60/057,764 45.
05-Sep-1997 60/057,643 46. 05-Sep-1997 60/057,769 47. 05-Sep-1997
60/057,763 48. 05-Sep-1997 60/057,650 49. 05-Sep-1997 60/057,584
50. 05-Sep-1997 60/057,647 51. 05-Sep-1997 60/057,661 52.
05-Sep-1997 60/057,662 53. 05-Sep-1997 60/057,646 54. 05-Sep-1997
60/057,654 55. 05-Sep-1997 60/057,651 56. 05-Sep-1997 60/057,644
57. 05-Sep-1997 60/057,765 58. 05-Sep-1997 60/057,762 59.
05-Sep-1997 60/057,775 60. 05-Sep-1997 60/057,648 61. 05-Sep-1997
60/057,774 62. 05-Sep-1997 60/057,649 63. 05-Sep-1997 60/057,770
64. 05-Sep-1997 60/057,771 65. 05-Sep-1997 60/057,761 66.
05-Sep-1997 60/057,760 67. 05-Sep-1997 60/057,776 68. 05-Sep-1997
60/057,778 69. 05-Sep-1997 60/057,629 70. 05-Sep-1997 60/057,628
71. 05-Sep-1997 60/057,777 72. 05-Sep-1997 60/057,634 73.
18-Dec-1997 60/070,923 74. 15-Jul-1998 60/092,921 75. 30-Jul-1998
60/094,657
FIELD OF THE INVENTION
[0002] This invention relates to newly identified polynucleotides
and the polypeptides encoded by these polynucleotides, uses of such
polynucleotides and polypeptides, and their production.
BACKGROUND OF THE INVENTION
[0003] Unlike bacterium, which exist as a single compartment
surrounded by a membrane, human cells and other eucaryotes are
subdivided by membranes into many functionally distinct
compartments. Each membrane-bounded compartment, or organelle,
contains different-proteins essential for the function of the
organelle. The cell uses "sorting signals," which are amino acid
motifs located within the protein, to target proteins to particular
cellular organelles.
[0004] One type of sorting signal, called a signal sequence, a
signal peptide, or a leader sequence, directs a class of proteins
to an organelle called the endoplasmic reticulum (ER). The ER
separates the membrane-bounded proteins from all other types of
proteins. Once localized to the ER, both groups of proteins can be
further directed to another organelle called the Golgi apparatus.
Here, the Golgi distributes the proteins to vesicles, including
secretory vesicles, the cell membrane, lysosomes, and the other
organelles.
[0005] Proteins targeted to the ER by a signal sequence can be
released into the extracellular space as a secreted protein. For
example, vesicles containing secreted proteins can fuse with the
cell membrane and release their contents into the extracellular
space--a process called exocytosis. Exocytosis can occur
constitutively or after receipt of a triggering signal. In the
latter case, the proteins are stored in secretory vesicles (or
secretory granules) until exocytosis is triggered. Similarly,
proteins residing on the cell membrane can also be secreted into
the extracellular space by proteolytic cleavage of a "linker"
holding the protein to the membrane.
[0006] Despite the great progress made in recent years, only a
small number of genes encoding human secreted proteins have been
identified. These secreted proteins include the commercially
valuable human insulin, interferon, Factor VIII, human growth
hormone, tissue plasminogen activator, and erythropoeitin. Thus, in
light of the pervasive role of secreted proteins in human
physiology, a need exists for identifying and characterizing novel
human secreted proteins and the genes that encode them. This
knowledge will allow one to detect, to treat, and to prevent
medical disorders by using secreted proteins or the genes that
encode them.
SUMMARY OF THE INVENTION
[0007] The present invention relates to novel polynucleotides and
the encoded polypeptides. Moreover, the present invention relates
to vectors, host cells, antibodies, and recombinant methods for
producing the polypeptides and polynucleotides. Also provided are
diagnostic methods for detecting disorders related to the
polypeptides, and therapeutic methods for treating such disorders.
The invention further relates to screening methods for identifying
binding partners of the polypeptides.
DETAILED DESCRIPTION
[0008] Definitions
[0009] The following definitions are provided to facilitate
understanding of certain terms used throughout this
specification.
[0010] In the present invention, "isolated" refers to material
removed from its original environment (e.g., the natural
environment if it is naturally occurring), and thus is altered "by
the hand of man" from its natural state. For example, an isolated
polynucleotide could be part of a yector or a composition of
matter, or could be contained within a cell, and still be
"isolated" because that vector, composition of matter, or
particular cell is not the original environment of the
polynucleotide.
[0011] In the present invention, a "secreted" protein refers to
those proteins capable of being directed to the ER, secretory
vesicles, or the extracellular space as a result of a signal
sequence, as well as those proteins released into the extracellular
space without necessarily containing a signal sequence. If the
secreted protein is released into the extracellular space, the
secreted protein can undergo extracellular processing to produce a
"mature" protein. Release into the extracellular space can occur by
many mechanisms, including exocytosis and proteolytic cleavage.
[0012] As used herein, a "polynucleotide" refers to a molecule
having a nucleic acid sequence contained in SEQ ID NO:X or the cDNA
contained within the clone deposited with the ATCC. For example,
the polynucleotide can contain the nucleotide sequence of the full
length cDNA sequence, including the 5' and 3' untranslated
sequences, the coding region, with or without the signal sequence,
the secreted protein coding region, as well as fragments, epitopes,
domains, and variants of the nucleic acid sequence. Moreover, as
used herein, a "polypeptide" refers to a molecule having the
translated amino acid sequence generated from the polynucleotide as
broadly defined.
[0013] In the present invention, the full length sequence
identified as SEQ ID NO:X was often generated by overlapping
sequences contained in multiple clones (contig analysis). A
representative clone containing all or most of the sequence for SEQ
ID NO:X was deposited with the American Type Culture Collection
("ATCC"). As shown in Table 1, each clone is identified by a cDNA
Clone ID (Identifier) and the ATCC Deposit Number. The ATCC is
located at 10801 University Boulevard, Manassas, Va. 20110-2209,
USA. The ATCC deposit was made pursuant to the terms of the
Budapest Treaty on the international recognition of the deposit of
Microorganisms for purposes of patent procedure.
[0014] A "polynucleotide" of the present invention also includes
those polynucleotides capable of hybridizing, under stringent
hybridization conditions, to sequences contained in SEQ ID NO:X,
the complement thereof, or the cDNA within the clone deposited with
the ATCC. "Stringent hybridization conditions" refers to an
overnight incubation at 42.degree. C. in a solution comprising 50%
formamide, 5.times. SSC (750 mM NaCl, 75 mM sodium citrate), 50 mM
sodium phosphate (pH 7.6), 5.times. Denhardt's solution, 10%
dextran sulfate, and 20 .mu.g/ml denatured, sheared salmon sperm
DNA, followed by washing the filters in 0.1.times. SSC at about
65.degree. C.
[0015] Also contemplated are nucleic acid molecules that hybridize
to the polynucleotides of the present invention at lower stringency
hybridization conditions. Changes in the stringency of
hybridization and signal detection are primarily accomplished
through the manipulation of formamide concentration (lower
percentages of formamide result in lowered stringency); salt
conditions, or temperature. For example, lower stringency
conditions include an overnight incubation at 37.degree. C. in a
solution comprising 6.times. SSPE (20.times. SSPE=3M NaCl; 0.2M
NaH.sub.2PO.sub.4; 0.02M EDTA, pH 7.4), 0.5% SDS, 30% formamide,
100 ug/mil salmon sperm blocking DNA; followed by washes at
50.degree. C. with 1.times. SSPE, 0.1% SDS. In addition, to achieve
even lower stringency, washes performed following stringent
hybridization can be done at higher salt concentrations (e.g.
5.times. SSC).
[0016] Note that variations in the above conditions may be
accomplished through the inclusion and/or substitution of alternate
blocking reagents used to suppress background in hybridization
experiments. Typical blocking reagents include Denhardt's reagent,
BLOTTO, heparin, denatured salmon sperm DNA, and commercially
available proprietary formulations. The inclusion of specific
blocking reagents may require modification of the hybridization
conditions described above, due to problems with compatibility.
[0017] Of course, a polynucleotide which hybridizes only to polyA+
sequences (such as any 3' terminal polyA+ tract of a cDNA shown in
the sequence listing), or to a complementary stretch of T (or U)
residues, would not be included in the definition of
"polynucleotide," since such a polynucleotide would hybridize to
any nucleic acid molecule containing a poly (A) stretch or the
complement thereof (e.g., practically any double-stranded cDNA
clone).
[0018] The polynucleotide of the present invention can be composed
of any polyribonucleotide or polydeoxribonucleotide, which may be
unmodified RLNA or DNA or modified RNA or DNA. For example,
polynucleotides can be composed of single- and double-stranded DNA,
DNA that is a mixture of single- and double-stranded regions,
single- and double-stranded RNA, and RNA that is mixture of single-
and double-stranded regions, hybrid molecules comprising DNA and
RNA that may be single-stranded or, more typically, double-stranded
or a mixture of single- and double-stranded regions. In addition,
the polynucleotide can be composed of triple-stranded regions
comprising RNA or DNA or both RNA and DNA. A polynucleotide may
also contain one or more modified bases or DNA or RNA backbones
modified for stability or for other reasons. "Modified" bases
include, for example, tritylated bases and unusual bases such as
inosine. A variety of modifications can be made to DNA and RNA;
thus, "polynucleotide" embraces chemically, enzymatically, or
metabolically modified forms.
[0019] The polypeptide of the present invention can be composed of
amino acids joined to each other by peptide bonds or modified
peptide bonds, i.e., peptide isosteres, and may contain amino acids
other than the 20 gene-encoded amino acids. The polypeptides may be
modified by either natural processes, such as posttranslational
processing, or by chemical modification techniques which are well
known in the art. Such modifications are well described in basic
texts and in more detailed monographs, as well as in a voluminous
research literature. Modifications can occur anywhere in a
polypeptide, including the peptide backbone, the amino acid
side-chains and the amino or carboxyl termini. It will be
appreciated that the same type of modification may be present in
the same or varying degrees at several sites in a given
polypeptide. Also, a given polypeptide may contain many types of
modifications. Polypeptides may be branched, for example, as a
result of ubiquitination, and they may be cyclic, with or without
branching. Cyclic, branched, and branched cyclic polypeptides may
result from posttranslation natural processes or may be made by
synthetic methods. Modifications include acetylation, acylation,
ADP-ribosylation, amidation, covalent attachment of flavin,
covalent attachment of a heme moiety, covalent attachment of a
nucleotide or nucleotide derivative, covalent attachment of a lipid
or lipid derivative, covalent attachment of phosphotidylinositol,
cross-linking, cyclization, disulfide bond formation,
demethylation, formation of covalent cross-links, formation of
cysteine, formation of pyroglutamate, formylation,
gamma-carboxylation, glycosylation, GPI anchor formation,
hydroxylation, iodination, methylation, myristoylation, oxidation,
pegylation, proteolytic processing, phosphorylation, prenylation,
racerization, selenoylation, sulfation, transfer-RNA mediated
addition of amino acids to proteins such as arginylation, and
ubiquitination. (See, for instance, PROTEINS--STRUCTURE AND
MOLECULAR PROPERTIES, 2nd Ed., T. E. Creighton, W. H. Freeman and
Company, New York (1993); POSTTRANSLATIONAL COVALENT MODIFICATION
OF PROTEINS, B. C. Johnson, Ed., Academic Press, New York, pgs.
1-12 (1983); Seifter et al., Meth Enzymol 182:626-646 (1990);
Rattan et al., Ann NY Acad Sci 663:48-62 (1992).)
[0020] "SEQ ID NO:X" refers to a polynucleotide sequence while "SEQ
ID NO:Y" refers to a polypeptide sequence, both sequences
identified by an integer specified in Table 1.
[0021] "A polypeptide having biological activity" refers to
polypeptides exhibiting activity similar, but not necessarily
identical to, an activity of a polypeptide of the present
invention, including mature forms, as measured in a particular
biological assay, with or without dose dependency. In the case
where dose dependency does exist, it need not be identical to that
of the polypeptide, but rather substantially similar to the
dose-dependence in a given activity as compared to the polypeptide
of the present invention (i.e., the candidate polypeptide will
exhibit greater activity or not more than about 25-fold less and,
preferably, not more than about tenfold less activity, and most
preferably, not more than about three-fold less activity relative
to the polypeptide of the present invention.)
[0022] Polynucleotides and Polypeptides of the Invention
[0023] Features of Protein Encoded by Gene No: 1
[0024] This gene is expressed primarily in melanocytes and, to a
lesser extent, in testes, ovary, kidney and other tissues.
[0025] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include; but are not
limited to, disorders of neural crest derived cells including
pigmentation defects, melanoma, reproductive organ defects, and
defects of the kidney . Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the skin, reproductive, and renal
systems, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g. melanocytes, testes, ovary, kidney, cancerous and wounded
tissues) or bodily fluids (e.g., lymph, serum, plasma, urine,
synovial fluid and spinal fluid) or another tissue or cell sample
taken from an individual having such a disorder, relative to the
standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0026] The tissue distribution in melanocytes indicates that the
protein product of this gene is useful for treating disorders that
arise from alterations in the number or fate of neural crest
derived cells including cancers such as melanoma and defects of the
developing reproductive system.
[0027] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:11 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 2512 of SEQ ID NO:11, b is an integer
of 15 to 2526, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:11, and where b is greater
than or equal to a+14.
[0028] Features of Protein Encoded by Gene No: 2
[0029] One embodiment of this invention is a polypeptide comprising
the following amino acid sequence: ENMICVKCLPQYPEHSKHV (SEQ ID
NO:487). An additional embodiment is the polynucleotides encoding
these polypeptides.
[0030] This gene is expressed primarily in infant brain and fetal
lung.
[0031] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, developmental disorders of the brain or lung.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the central nervous and pulmonary systems, expression of this gene
at significantly higher or lower levels may be routinely detected
in certain tissues or cell types (e.g. brain, lung, cancerous and
wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0032] The tissue distribution in infant brain and fetal lung
indicates that the protein product of this gene is useful for
treating or diagnosing disorders associated with abnormal
proliferation of cells in the Central nervous system and developing
lung. Furthermore, the protein product of this gene is useful for
the detection/treatment of neurodegenerative disease states and
behavioural disorders such as Alzheimers Disease, Parkinsons
Disease, Huntingtons Disease, Tourette Syndrome, schizophrenia,
mania, dementia, paranoia, obsessive compulsive disorder, panic
disorder, learning disabilities, ALS, psychoses, autism, and
altered bahaviors, including disorders in feeding, sleep patterns,
balance, and perception. In addition, the gene or gene product may
also play a role in the treatment and/or detection of developmental
disorders associated with the developing embryo, or sexually-linked
disorders. Protein, as well as, antibodies directed against the
protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[0033] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:12 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1117 of SEQ ID NO:12, b is an integer
of 15 to 1131, where-both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:12, and where b is greater
than or equal to a+14.
[0034] Features of Protein Encoded by Gene No: 3
[0035] One embodiment of this invention is a polypeptide the
following amino acid sequence: ARVAFHLICRYILPTVYCHV (SEQ ID
NO:488). An additional embodiment is the polynucleotides encoding
these polypeptides.
[0036] This gene is expressed primarily in breast lymph node, and
to a lesser extent, in ovarian cancer and chondrosarcoma.
[0037] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune responses such as inflammation or immune
surveillance for tumors. This gene may be important for
inflammatory responses associated with tumors. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the immune
system, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g. lymph nodes, cancerous and wounded tissues) or bodily fluids
(e.g. lymph, serum, plasma, urine, synovial fluid and spinal fluid)
or another tissue or cell sample taken from an individual having
such a disorder, relative to the standard gene expression level,
i.e., the expression level in healthy tissue or bodily fluid from
an individual not having the disorder.
[0038] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 251 as residues: Lys-45 to Val-50, and/or Lys-69 to
Arg-76.
[0039] The tissue distribution in breast lymph node indicates that
the protein product of this gene is useful for the treatment or
diagnosis of immune responses, including those associated with
tumor-induced inflammation. Furthermore, given the tissue
distribution, the gene product may also be involved in
lymphopoiesis. In a case such as this, it can be used in immune
disorders such as infection, inflammation, allergy,
immunodeficiency etc. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0040] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:13 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 927 of SEQ ID NO:13, b is an integer
of 15 to 941, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:13, and where b is greater
than or equal to a+14.
[0041] Features of Protein Encoded by Gene No: 4
[0042] One embodiment of this invention is a polypeptide comprising
the following amino acid sequence: ELVESPGAAGNSARSGNVVC (SEQ ID
NO:489). An additional embodiment is the polynucleotides encoding
these polypeptides.
[0043] This gene is expressed primarily in T-cells and T-cell
lymphomas.
[0044] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immunological diseases involving T-cells such as
inflammation, autoimmunity, and cancers including T-cell lymphomas.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
T-cells and other cells of the immune system, expression of this
gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g. immune, cancerous
and wounded tissues) or bodily fluids (e.g. lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0045] The tissue distribution in T-cells and T-cell lymphomas
indicates that the protein product of this gene is useful for
diagnosing and treating T-cell based disorders such as inflammatory
diseases, autoimmune disease and tumors including T-cell lymphomas.
Furthermore, the tissue distribution indicates that the
polypeptides or polynucleotides are useful for the treatment,
prophylaxis, and diagnosis of immune and autoirnmune diseases, such
as lupus, transplant rejection, allergic reactions, arthritis,
asthma, immunodeficiency diseases, leukemia, and AIDS.
Additionally, expression of this gene product in T cells also
strongly indicates a role for this protein in immune function and
immune surveillance. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy tagets for the above listed tissues.
[0046] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:14 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 829 of SEQ ID NO:14, b is an integer
of 15 to 843, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:14, and where b is greater
than or equal to a+14.
[0047] Features of Protein Encoded by Gene No: 5
[0048] This gene is expressed primarily in activated monocytes.
[0049] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, inflammation, autoimmunity, infection, or disorders
involving activation of monocytes. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the immune system, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g. immune, cancerous
and wounded tissues) or bodily fluids (e.g. lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0050] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 253 as residues: Asp-19 to Arg-31.
[0051] The tissue distribution indicates that the protein product
of this gene is useful for diagnosing or treating diseases that
result in activation of monocytes including infections,
inflammatory responses or autoimmune diseases. Furthermore,
expression of this gene product in monocytes also strongly
indicates a role for this protein in immune function and immune
surveillance.
[0052] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:15 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1004 of SEQ ID NO:15, b is an integer
of 15 to 1018, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:15, and where b is greater
than or equal to a+14.
[0053] Features of Protein Encoded by Gene No: 6
[0054] The translation product of this gene shares sequence
homology with terminal deoxynucleotidyltransferase which is thought
to be important in catalyzing the elongation of oligo- or
polydeoxynucleotide chains. One embodiment of this invention is a
polypeptide comprising the following amino acid sequence:
FKKLVNPRXQGIRHEEEAVSWQERR (SEQ ID NO:490). An additional embodiment
is the polynucleotides encoding these polypeptides.
[0055] This gene is expressed primarily in activated human
neutrophils, and to a lesser extent in T-cells, primary dendritic
cells and bone marrow cells.
[0056] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, cancers, particularly those of the blood such as
leukemia and deficiencies in neutrophils such as neutropenia, and
immune system disorders. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification_of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the cardiovascular and immune
systems, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g. immune, cancerous and wounded tissues) or bodily fluids (e.g.
lymph, serum, plasma, urine, synovial fluid and spinal fluid) or
another tissue or cell sample taken from an individual having such
a disorder, relative to the standard gene expression level, i.e.,
the expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0057] The tissue distribution in neutrophils and other immune
cells, combined with the homology to terminal
deoxynucleotidyltransferase indicates that the protein product of
this gene is useful for the treatment and differential diagnosis of
acute leukemias. Alternatively, this gene may function in the
proliferation of neutrophils and be useful as a treatment for
neutropenia, for example, following neutropenia as a result of
chemotherapy. Additionally, the tissue distribution indicates that
the protein product of this gene is useful for the diagnosis and/or
treatment of hematopoietic disorders. This gene product is
primarily expressed in hematopoietic cells and tissues, suggesting
that it plays a role in the survival, proliferation, and/or
differentiation of hematopoieitic lineages. This is particularly
supported by the expression of this gene product in bone marrow,
which is a primary site of definitive hematopoiesis. Expression of
this gene product in T cells and primary dendritic cells also
strongly indicates a role for this protein in immune function and
immune surveillance.
[0058] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:16 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 647 of SEQ ID NO:16, b is an integer
of 15 to 661, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:16, and where b is greater
than or equal to a+14.
[0059] Features of Protein Encoded by Gene No: 7
[0060] The translation product of this gene exhibits a reasonable
homology to the human chorionic gonadotropic (HCG) analogue-GT
beta-subunit as disclosed in U.S. Pat. No. 5,508,261 and PCT
Publication No. WO 92/22568. There is a high degree of conservation
of the structurally important cysteine residues between these
proteins.
[0061] This gene is expressed primarily in IL-1 and LPS induced
neutrophils.
[0062] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, diseases of the immune system, including inflammatory
diseases and allergies. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the immune system, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g., immune, cancerous
and wounded tissues) or bodily fluids (e.g. lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0063] The tissue distribution in neutrophils indicates that the
protein product of this gene is useful for the treatment/diagnosis
of diseases of the immune system, since expression is primarily in
neutrophils, and thus the translation product of this gene may be
useful as a growth factor for the differentiation and/or
proliferation of neutrophils for the treatment of neutropenia, for
example following chemotherapy.
[0064] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:17 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 539 of SEQ ID NO:17, b is an integer
of 15 to 553, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:17, and where b is greater
than or equal to a+14.
[0065] Features of Protein Encoded by Gene No: 8
[0066] This gene is expressed primarily in IL-1 and LPS-induced
neutrophils.
[0067] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, diseases of the immune system, including inflammatory
diseases and allergies. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the immune system, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g., immune, cancerous
and wounded tissues) or bodily fluids (e.g. lymph, serim, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0068] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 256 as residues: Ser-14 to Pro-22, and/or Leu-43 to
Val-53.
[0069] The tissue distribution in neutrophils indicates that the
protein product of this gene is useful for the treatment and
diagnosis of diseases of the immune system, since expression is
primarily in neutrophils, and thus the translation product of this
gene may be useful as a growth factor for the differentiation
and/or proliferation of neutrophils for the treatment of
neutropenia, for example following chemotherapy.
[0070] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:18 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 855 of SEQ ID NO:18, b is an integer
of 15 to 869, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:18, and where b is greater
than or equal to a+14.
[0071] Features of Protein Encoded by Gene No: 9
[0072] When tested against Jurkat cell lines, supernatants removed
from cells expressing this gene activated the NF-kB transcription
factor. Thus, it is likely that the protein encoded by this gene
activates Jurkat cells by activating a transcriptional factor found
within these cells. Nuclear factor kB is a transcription factor
activated by a wide variety of agents, leading to cell activation,
differentiation, or apoptosis. Reporter constructs utilizing the
NF-kB promoter element are used to screen supernatants for such
activity.
[0073] This gene is expressed primarily in IL-1 and LPS induced
neutrophils.
[0074] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, diseases of the immune system, including inflammatory
diseases and allergies. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunnological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the immune system, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g., irrjmune,
cancerous and wounded tissues) or bodily fluids (e.g. lymph, serum,
plasma, urine, synovial fluid and spinal fluid) or another tissue
or cell sample taken from an individual having such a disorder,
relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0075] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 257 as residues: Tyr-22 to His-35.
[0076] The tissue distribution in neutrophils, combined with the
biological activity data suggest that the protein product of this
gene is useful for the treatment and/or diagnosis of diseases of
the immune system, since expression is primarily in neutrophils,
and thus the translation product of this gene may be useful as a
growth factor for the differentiation and/or proliferation of
neutrophils for the treatment of neutropenia, for example following
chemotherapy.
[0077] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:19 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 945 of SEQ ID NO:19, b is an integer
of 15 to 959, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:19, and where b is greater
than or equal to a+14,
[0078] Features of Protein Encoded by Gene No: 10
[0079] This gene is expressed primarily in activated T-cells and to
a lesser extent in endothelial cells.
[0080] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune dysfunctions including cancer of the T
lymphocytes and autoimmune disorders and inflammation. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the immune
system, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g. immune, cancerous and wounded tissues) or bodily fluids (e.g.
lymph, serum, plasma, urine, synovial fluid and spinal fluid) or
another tissue or cell sample taken from an individual having such
a disorder, relative to the standard gene expression level, i.e.,
the expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0081] The tissue distribution in activated T-cells indicates that
the protein product of this gene is useful for the treatment and/or
diagnosis of immune disorders, particularly of T-cell origin, and
may act as a growth factor for particular subsets of T-cells such
as CD4 positive cells, which would make this a useful therapeutic
for the treatment of HIV and other immune compromising illnesses.
Furthermore, this gene product may be involved in the regulation of
cytokine production, antigen presentation, or other processes that
may also suggest a usefulness in the treatment of AIDS or other
immune compromising diseases (e.g. by boosting immune
responses).
[0082] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:20 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1432 of SEQ ID NO:20, b is an integer
of 15 to 1446, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:20, and where b is greater
than or equal to a+14.
[0083] Features of Protein Encoded by Gene No: 11
[0084] The gene encoding the disclosed cDNA is thought to reside on
chromosome 3. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
3.
[0085] This gene is expressed primarily in fetal tissues, such as
liver/spleen and brain, as well as in placental tissue.
[0086] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
the diagnosis of many developmental abnormalities. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
developing fetus, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g. fetal, placental, cancerous and wounded tissues)
or bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0087] The tissue distribution in fetal tissues indicates that the
protein product of this gene is useful as a growth factor or
differentiation factor for particular cell types in the developing
fetus and may be useful in replacement or other types of therapy in
cases where the gene is expressed aberrantly. Furthermore, the
tissue distribution indicates that the protein product of this gene
is useful for the diagnosis and/or treatment of disorders of the
placenta. Specific expression within the placenta indicates that
this gene product may play a role in the proper establishment and
maintenance of placental function. Alternately, this gene product
may be produced by the placenta and then transported to the embryo,
where it may play a crucial role in the development and/or survival
of the developing embryo or fetus. Expression of this gene product
in a vascular-rich tissue such as the placenta also indicates that
this gene product may be produced more generally in endothelial
cells or within the circulation. In such instances, it may play
more generalized roles in vascular function, such as in
angiogenesis. It may also be produced in the vasculature and have
effects on other cells within the circulation, such as
hematopoietic cells. It may serve to promote the proliferation,
survival, activation, and/or differentiation of hematopoietic
cells, as well as other cells throughout the body.
[0088] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:21 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1457 of SEQ ID NO:21, b is an integer
of 15 to 1471, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:21, and where b is greater
than or equal to a+14.
[0089] Features of Protein Encoded by Gene No: 12
[0090] One embodiment of this invention is a polypeptide comprising
one or more of the following amino acid sequences:
ISVLXYPHCVVHELPELTAESLEAAGDSN- QFCWRNLFSCINLLRILNKLTKWKHS
RTMMLVVFKSAPULKRALKVKQAMMQLYVLKLLKVQTKYLGRQWRKS- NMKT
MSAIYQKVRHRLNDDWAYGNDLDARPWDFQAEECALRANIERFNARRYDRAH
SNPDFLPVDNCLQSVLGQRVDLPEDFQMNYDLWLEREVFSKPISWEELL (SEQ ID NO:491),
MRAASPPASASDLIEQQQKRGRREHKALIKQDNLDAFNERD
PYKADDSREEEEENDDDNSLEGETFPLERDE- VMPPPLQHPQTDRLXCPKGLPW
XPKVREKDIEMFLESSRSKFIGYTLGSDTNTVVGLPRPIHESIKTLKQHKY- TSLA
EVQAQMEEEYLRSPLSGGEEEVEQVPAETLYQGLLPSLPQYMIALLKILLAAAPT
SKAKTDSINILADVLPEEMPTTVLQSMKLGVDVNRHKEVIVKAISAVLLLLLKH
FKLNHVYQFEYMAQHLVFANCIPLILKFFNQNIMSYITAKNSISVLDYPHCVVH
ELPELTAESLEAGDSNQFCWRNLFSCINLLRILNKLTKWKHSRTMMLVVFKSA
PILKRALKVKQAMMQLYVLKLLKVQTKYLGRQWRKSNMKTMSAIYQKVRHR
LNDDWAYGNDLDARPWDFQAEECALRANIERFNARRYDRAHSNPDFLPVDNC
LQSVLGQRVDLPEDFQMNYDLWLEREVFSKPISWEELLQ (SEQ ID NO:492),
MRAASPPASASDLIEQQQKRGRREHKALIKQDNLDAFNERDPYKADDSRE (SEQ ID NO:493),
EEEENDDDNSLEGETFPLERDEVMPPPLQHPQTDRLX CPKGLPWX (SEQ ID NO:494),
PKVREKDIEMFLESSRSKFIGYTLGSDTNTV VGLPRPIHESIKTLKQHKYT (SEQ ID
NO:495), SIAEVQAQMEEEYLRSPLSGG EEEVEQVPAETLYQGLLPSLPQYMIA (SEQ ID
NO:496), LLKILLAAAPTSKAK TDSINILADVLPEEMPTTVLQSMKLGVDVNRHK (SEQ ID
NO:497), EVIVKA ISAVLLLLLKHFKLNHVYQFEYMAQHLVFANCIPLILKFFNQNI (SEQ
ID NO:498), MSYITAKNSISVLDYPHCVVHELPELTAESLEAGDSNQFCWRNLFSCI (SEQ
ID NO:499), NLLRILNKLTKWKHSRTMMLVVFKSAPILKRALKVKQ AMMQLYVLKL (SEQ
ID NO:500), LKVQTKYLGRQWRKSNMKTMSAIYQKVRH RLNDDWAYGNDLDARP (SEQ ID
NO:501), WDFQAEECALRANIERFNARRYDR AHSNPDFLPVDNCLQSVLGQRVDL (SEQ ID
NO:502), and PEDFQMNYDLWLE REVFSKPISWEELLQ (SEQ ID NO:503). An
additional embodiment is the polynucleotides encoding these
polypeptides. The translation product of this gene shares sequence
homology with a C. elegans protein (gi.vertline.1086830 coded for
by C. elegans cDNA yk20f8.5).
[0091] This gene is expressed primarily in T-cells, and to a lesser
extent in tumor tissue including glioblastoma, meningioma, and
Wilm's tumor.
[0092] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, diseases of the immune system, including autoimmune
conditions such as rheumatoid arthritis, inflammatory disorders and
cancer. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune system, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g. immune, cancerous and wounded tissues) or bodily
fluids (e.g. lymph, serum, plasma, urine, synovial fluid and spinal
fluid) or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[0093] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 260 as residues: Thr-9 to Ser-14.
[0094] The tissue distribution in T-cells indicates that the
protein product of this gene is useful for the diagnosis and/or
modulation of immune function disorders, including rheumatoid
arthritis and inflammatory responses. Furthermore, this gene
product may be involved in the regulation of cytokine production,
antigen presentation, or other processes that may also suggest a
usefulness in the treatment of cancer (e.g. by boosting immune
responses). Since the gene is expressed in cells of lymphoid
origin, the gene or protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues. Expression of
this gene product in T cells also strongly indicates a role for
this protein in immune function and immune surveillance.
[0095] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:22 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1388 of SEQ ID NO:22, b is an integer
of 15 to 1402, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:22, and where b is greater
than or equal to a+14.
[0096] Features of Protein Encoded by Gene No: 13
[0097] This gene is expressed primarily in placenta, and to a
lesser extent in fetal liver and bone marrow.
[0098] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
the diagnosis of hematological disorders. Similarly, polypeptides
and antibodies directed to these polypeptides are useful in
providing immunological probes for differential identification of
the tissue(s) or cell type(s). For a number of disorders of the
above tissues or cells, particularly of the hematological and
immune systems, expression of this gene at significantly higher or
lower levels may be routinely detected in certain tissues or cell
types (e.g. placental, immune, cancerous and wounded tissues) or
bodily fluids (e.g. lymph, serum, plasma, urine, synovial fluid and
spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0099] The tissue distribution in fetal liver, and bone marrow
indicates that the protein product of this gene is useful as a
growth factor for hematapoietic stem cells or progenitor cells in
the treatment of chemotherapy patients or kidney disease.
Furthermore, the tissue distribution in placenta indicates that the
protein product of this gene is useful for the diagnosis and/or
treatment of vascular or reproductive disorders. Specific
expression within the placenta indicates that this gene product may
play a role in the proper establishment and maintenance of
placental function. Alternately, this gene product may be produced
by the placenta and then transported to the embryo, where it may
play a crucial role in the development and/or survival of the
developing embryo or fetus. Expression of this gene product in a
vascular-rich tissue such as the placenta also indicates that this
gene product may be produced-more generally in endothelial cells or
within the circulation. In such instances, it may play more
generalized roles in vascular function, such as in angiogenesis. It
may also be produced in the vasculature and have effects on other
cells within the circulation, such as hematopoietic cells. It may
serve to promote the proliferation, survival, activation, and/or
differentiation of hematopoietic cells, as well as other cells
throughout the body.
[0100] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:23 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1033 of SEQ ID NO:23, b is an integer
of 15 to 1047, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:23, and where b is greater
than or equal to a+14.
[0101] Features of Protein Encoded by Gene No: 14
[0102] This gene is expressed primarily in stromal cells.
[0103] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of hematapoietic disorders including cancer, neutropenia,
anemia, and thrombocytopenia. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the hematapoietic and immune
systems, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g. immune, cancerous and wounded tissues) or bodily fluids (e.g.
lymph, serum, plasma, urine, synovial fluid and spinal fluid) or
another tissue or cell sample taken from an individual having such
a disorder, relative to the standard gene expression level, i.e.,
the expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0104] The tissue distribution in stromal cells indicates that the
protein product of this gene is useful as a growth factor for
hematapoietic stem cells or progenitor cells, in particular
following chemotherapy treatment. Furthermore, the tissue
distribution indicates that the protein product of this gene is
useful for the treatment and diagnosis of hematopoetic related
disorders such as anemia, pancytopenia, leukopenia,
thrombocytopenia or leukemia, since stromal cells are important in
the production of cells of hematopoietic lineages. The uses include
bone marrow cell ex vivo culture, bone marrow transplantation, bone
marrow reconstitution, radiotherapy or chemotherapy of neoplasia.
The gene product may also be involved in lymphopoiesis, therefore,
it can be used in immune disorders such as infection, inflammation,
allergy, immunodeficiency etc. In addition, this gene product may
have commercial utility in the expansion of stem cells and
committed progenitors of various blood lineages, and in the
differentiation and/or proliferation of various cell types.
[0105] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:24 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 976 of SEQ ID NO:24, b is an integer
of 15 to 990, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:24, and where b is greater
than or equal to a+14.
[0106] Features of Protein Encoded by Gene No: 15
[0107] The translation product of this gene shares sequence
homology with epsilon-COP from Bos taurus, which is thought to be
important as a component of coatomer, a complex of seven proteins,
that is the major component of the non-clathrin membrane coat. One
embodiment of this invention is a polypeptide comprising one or
more of the following amino acid sequences:
MAPPAPGPASGGSGEVDELFDVKNAFYIGSYQQCINEAXXVKLSSPERDVERD
VFLYRAYLAQRKFGVVLDEIKPSSAPELQAVRMFADYLAHESRRDSIVAELDRE
MSRSXDVINTTFLLMAASIYLHDQNPDAALRALHQGDSLECTAMTVQILLKLD
RLDLARKELKRMQDLDEDATLTQLATAWVSLATGGEKLQDAYYIFQEMADKCS
PTLLLLNGQAACHMAQGRWEAAEGLLQEALDKDSGYPETLVNLIVLSQHLGKP
PEVTNRYLSQLKDAHRSHPFIKEYQAKENDFDRLVLQYAPSAEAGPELSGP (SEQ ID
NO:504), RDVERDVFLYRAYLAQRKFGVVLDEIKPSSAPELQAVR
MFADYLAHESRRDSIVAELDREMSRSXDVTNTTF- LLMAASIYLHDQNPDAALRA
LHQGDSLECTAMTVQILLKLDRLDLARKELKRMQDLDEDATLTQLATAWVSLA
TGGEKLQDAYYIFQEMADKCSPTLLLLNGQAACHMAQGRWEAAEGLLQEALD
KDSGYPETLVNLIVLSQHLGKPPEVTNRYLSQLKDAHRSHPFIKEYQAKENDFD RLVLQYAPSA
(SEQ ID NO:505), MAPPAPGPASGGSGEVDELFDVKNAFYIGSY QQCINEAXXVKLSSPER
(SEQ ID NO:506), DVERDVFLYRAYLAQRKFGVVLD EIKPSSAPELQAVRMFADYLAHES
(SEQ ID NO:507), RRDSIVAELDREMSRSX DVTNTTFLLMAASIYLHDQNPDAALRALHQG
(SEQ ID NO:508), DSLECTAMTV QILLKLDRLDLARKELKRMQDLDEDATLTQLATAWVS
(SEQ ID NO:509), LATG GEKLQDAYYIFQEMADKCSPTLLLLNGQAACHMAQGRWEAAEG
(SEQ ID NO:510), LLQEALDKDSGYPETLVNLIVLSQHLGKPPEVTNRYLSQLKDAHR SHP
(SEQ ID NO:511), FIKEYQAKENDFDRLVLQYAPSAEAGPELSGP (SEQ ID NO:512),
RDVERDVFLYRAYLAQRKFGVVLDEIKPSSAPELGAVRMFADYLAHE (SEQ ID NO:513),
SRRDSIVAELDREMSRSXDVTNTTFLLMAASIYLHDQNP DAALRALHQ (SEQ ID NO:514),
GDSLECTAMTVQILLKLDRLDLARKELKRMQ DLDEDATLTGLATAWV (SEQ ID NO:515),
SLATGGEKLQDAYYIFQEMADKCS PTLLLLNGQAACHMAQGRWEAAE (SEQ ID NO:516),
GLLQEALDKDSG YPETLVNLIVLSQHLGKPPEVTNRYL (SEQ ID NO:517),
SQLKDAHRSHPFIK EYQAKENDFDRLVLQYAPSA (SEQ ID NO:518), or
NRYYRESWSLQVPVRNSGS THASERNGASGPRPGLRRLRGGRRAVRRKERLLHRQLPAVHKR
(SEQ ID NO:519). An additional embodiment is the polynucleotides
encoding these polypeptides. The gene encoding the disclosed cDNA
is thought to reside on chromosome 19. Accordingly, polynucleotides
of the invention are useful as a marker in linkage analysis for
chromosome 19.
[0108] This gene is expressed primarily in activated monocytes and
T-cells.
[0109] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immunomodulation, specifically relating to transport
problems in these cells. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
inmmunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the immune system, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g. immune, cancerous
and wounded tissues) or bodily fluids (e.g. lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0110] The tissue distribution in activated monocytes and T-cells
combined with the homology to epsilon-COP indicates that the
protein product of this gene is useful for treating and/or
diagnosing problems with the cellular transport of proteins that
may result in immunologic dysfunction. Furthermore, this gene
product may be involved in the regulation of cytokine production,
antigen presentation, or other processes that may also suggest a
usefulness in the treatment of cancer (e.g. by boosting immune
responses). Since the gene is expressed in cells of lymphoid
origin, the gene or protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0111] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:25 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
as any integer between 1 to 1194 of SEQ ID NO:25, b is an integer
of 15 to 1208, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:25, and where b is greater
than or equal to a+14.
[0112] Features of Protein Encoded by Gene No: 16
[0113] The translation product, of this gene shares sequence
homology with an RNA helicase which is thought to be important in
polynucleotide metabolism. The translation product of this contig
exhibits good homology to the LbeIF4A antigen of Leishmania
braziliensis. The LbeIF4A antigen, or immunogenic portions of it,
can be used to induce protective immunity against leishmaniasis,
specifically L. donovani, L. chagasi, L. infantum, L. major, L.
braziliensis, L. panamensis, L. tropica and L. guyanensis. It can
also be used diagnostically to detect Leishmania infection or to
stimulate a cellular and/or humoral immune response or to stimulate
the production of interleukin-12. The gene encoding the disclosed
cDNA is thought to reside on chromosome 7. Accordingly,
polynucleotides related to this invention are useful as a marker in
linkage analysis for chromosome 7.
[0114] This gene is expressed primarily in colon cancer, and to a
lesser extent, in pituitary.
[0115] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of cancers particularly of the colon. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
gastrointestinal system, expression of this gene at significantly
higher or lower levels may be routinely detected in certain tissues
or cell types (e.g. colon, pituitary, cancerous and wounded
tissues) or bodily fluids (e.g. lymph, serum, plasma, urine,
synovial fluid and spinal fluid) or another tissue or cell sample
taken from an individual having such a disorder, relative to the
standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0116] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 264 as residues: Glu-93 to Ala-98, Gln-150 to
Leu-156, Leu-220 to Leu-231, Leu-268 to Arg-273, Val-324 to
Pro-341, Arg-372 to Asn-380, Ser-405 to Gly-410, Phe-426 to
Ala-433, Glu-458 to Asp-470, and/or Arg-506 to Ser-547.
[0117] The tissue distribution in colon cancer, combined with the
homology to RNA helicase indicates that the protein product of this
gene is useful for the development of diagnostic tests for colon
cancer or other gastrointestinal or metabolic disorders. Protein,
as well as, antibodies directed against the protein may show
utility as a tissue-specific marker and/or immunotherapy target for
the above listed tissues.
[0118] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:26 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1908 of SEQ ID NO:26, b is an integer
of 15 to 1922, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:26, and where b is greater
than or equal to a+14.
[0119] Features of Protein Encoded by Gene No: 17
[0120] The translation product of this contig has sequence homology
to a cytoplasmic protein that binds specifically to JNK, designated
the JNK interacting protein-1 or JIP-1 in Mus musculus. JIP-1
caused cytoplasmic retention of JNK and inhibition of JNK-regulated
gene expression. The gene encoding the disclosed cDNA is thought to
reside on chromosome 11. Accordingly, polynucleotides related to
this invention are useful as a marker in linkage analysis for
chromosome 11. An embodiment of the invention is a polypeptide
comprising one or more of the following amino acid sequences:
APGXGWRGSLGEPPPPPRASLSSDTSALSYDSVKYTLVVDEHAQLELVSLRRAS ETTVTRVTLPPS
(SEQ ID NO:520), APGXGWRGSLGEPPPPPRASLSSDTSALSY (SEQ ID NO:521), or
DSVKYTLVVDEHAQLELVSLRRASETTVTRVTLPPS (SEQ ID NO:522). An additional
embodiment is the polynucleotides encoding these polypeptides.
[0121] This gene is expressed primarily in brain, including
pituitary, cerebellum, frontal cortex, and fetal brain, and to a
lesser extent in the cortex or the kidney.
[0122] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of the central nervous system disorders including
ischemia, epilepsy, Parkinson's disease, and schizophrenia.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the central nervous system, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. brain, kidney, cancerous and
wounded tissues) or bodily fluids (e.g. lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder. Furthermore, the translation product of this contig may
suppress the effects of the JNK signaling pathway on cellular
proliferation, including transformation by the Bcr-Ab1
oncogene.
[0123] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 265 as residues: Pro-6 to Ser-26, Ala-30 to Asp-41,
Gly-55 to Ser-61, Gly-74 to Thr-80, Tyr-117 to Ala-123, Tyr-167 to
Asp-172, Ala-212 to Cys-223, and/or Pro-239 to Tyr-244.
[0124] The tissue distribution in brain indicates that the protein
product of this gene is useful for the enhanced survivial and/or
differentiation of neurons as a treatment for neurodegenerative
disease. Furthermore, the tissue distribution indicates that the
translation product of this gene may be involved in neuronal
survival; synapse formation; conductance; neural differentiation,
etc. Such involvement may impact many processes, such as learning
and cognition. It may also be useful in the treatment of such
neurodegenerative disorders as schizophrenia; ALS; or
Alzheimer's.
[0125] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:27 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1937 of SEQ ID NO:27, b is an integer
of 15 to 1951, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:27, and where b is greater
than or equal to a+14.
[0126] Features of Protein Encoded by Gene No: 18
[0127] The translation product of this gene shares sequence
homology with a liver stage antigen from a protozoan parasite.
[0128] This gene is expressed primarily in fetal tissue, and to a
lesser extent, in activated T-cells and other immune cells.
[0129] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, developmental abnormalities and diseases of immune
function. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune system, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g. immune, cancerous and wounded tissues) or bodily
fluids (e.g. lymph, serum, plasma, urine, synovial fluid and spinal
fluid) or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[0130] The tissue distribution in T-cells, combined with the
homology to a protozoan antigen indicates that the protein product
of this gene is useful for the treatment and/or immune modulation
of parasitic infections. Furthermore, expression of this gene
product in T cells also strongly indicates a role for this protein
in immune function and immune surveillance.
[0131] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:28 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 3975 of SEQ ID NO:28, b is an integer
of 15 to 3989, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:28, and where b is greater
than or equal to a+14.
[0132] Features of Protein Encoded by Gene No: 19
[0133] One embodiment of the invention is a polypeptide comprising
one or more of the following amino acid sequences:
MKAIGIEPSLATYHHHRLFDQPGDPLKRS- SFIIYDIMNELMGKRFSPKDPDDDK
FFQSAMSICSSLRDLELAYQVHGLLKTGDNWKFIGPDQHRNFYYSKFF- DLICL
MEQIDVTLKWYEDLIPSAYFPHSQTMIHLLQALDVANRLEVIPKIWER (SEQ ID NO:523),
KDSKEYGHTFRSDLREEILMLMARDKHPPELQVAFADCAADIKS
AYESQPIRQTAQDWPATSLNCIAILFLR- AGRTQEAWKMLGLFRKHNKIPRSELL
NELMDSAKVSNSPSQAIEVVELASAFSLPICEGLTQRVMSDFAINQE- QKEALSNL
TALTSDSDTDSSSDSDSDTSEGK (SEQ ID NO:524), MKAIGIEPSLATYHHIIR
LFDQPGDPLKRSSFIIYDIMNELMGKRFSPK (SEQ ID NO:525), DPDDDKFFQSA
MSICSSLRDLELAYQVHGLLKTGDNWKFIGPDQHRNFY (SEQ ID NO:526),
YSKFFDLICLMEQIDVTLKWYEDLIPSA (SEQ ID NO:527), YFPHSQTMIHLLQ
ALDVANRLEVIPKIWER (SEQ ID NO:528), KDSKEYGHTFRSDLREEILML
MARDKHPPELQVAFADCAADIKSAY (SEQ ID NO:529), ESQPIRQTAQDWP
ATSLNCIAILFLRAGRTQEAWKMLGLFRKHNKIPRSE (SEQ ID NO:530),
LLNELMDSAKVSNSPSQAIEVVELASAFSLPECEGLTQRVMSDFAIN (SEQ ID NO:531), or
QEQKEALSNLTALTSDSDTDSSSDSDSDTSEGK (SEQ ID NO:532). An additional
embodiment is the polynucleotides encoding these polypeptides. The
gene encoding the disclosed cDNA is thought to reside on chromosome
2. Accordingly, polynucleotides related to this invention are
useful as a marker in linkage analysis for chromosome 2.
[0134] This gene is expressed primarily in stromal and CD34
depleted bone marrow cells, and to a lesser extent in tissues of
embryonic origin.
[0135] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, diseases of hematologic origin including cancers and
immune dysfunction. Similarly, polypeptides and antibodies directed
to these polypeptides are useful in providing immunological probes
for differential identification of the tissue(s) or cell type(s).
For a number of disorders of the above tissues or cells,
particularly of the hematapoietic and immune systems, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g. immune, cancerous
and wounded tissues) or bodily fluids (e.g. lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0136] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 267 as residues: Ser-28 to Gln-34.
[0137] The tissue distribution in stromal and CD34 depleted bone
marrow cells indicates that the protein product of this gene is
useful as a growth factor for hematopoietic stem cells or
progenitor cells which may be useful in the treatment of
chemotherapy patients suffering from neutropenia. Furthermore, the
tissue distribution indicates that the protein product of this gene
is useful for the treatment and diagnosis of hematopoetic related
disorders such as anemia, pancytopenia, leukopenia,
thrombocytopenia or leukemia, since stromal cells are important in
the production of cells of hematopoietic lineages. The uses include
bone marrow cell ex vivo culture, bone marrow transplantation, bone
marrow reconstitution, radiotherapy or chemotherapy of neoplasia.
The gene product may also be involved in lymphopoiesis, therefore,
it can be used in immune disorders such as infection, inflammation,
allergy, immunodeficiency etc. In addition, this gene product may
have commercial utility in the expansion of stem cells and
committed progenitors of various blood lineages, and in the
differentiation and/or proliferation of various cell types.
[0138] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:29 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 3721 of SEQ ID NO:29, b is an integer
of 15 to 3735, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:29, and where b is greater
than or equal to a+14.
[0139] Features of Protein Encoded by Gene No: 20
[0140] One embodiment of this invention is a polypeptide comprising
one or more of the following amino acid sequences:
MSSDNESDIEDEDLKLELRRLRDKHLKEI- QDLQSRQKHEIESLYTKLGKVPPAVI
IPPAAPLSGRRRRPTKSKGSKSSRSSSLGNKSPQLSGNLSGQSAASV- LHP
QQTLHPPGNIPESGQNQLLQPLKPSPSSDNLYSAFTSDGAISVPSLSAPGQGTSS
TNTVGATVNSQAAQAQPPAMTSSRKGTFTDDLHKLVDNWARDAMNLSGRRG
SKGHMNYEGPGMARKFSAPGQLCISMTSNLGGSAPISAASATSLGHFTKSMC
PPQQYGFPATPFGAQWSGTGGPAPQPLGQFQPVGTASLQNFNISNLQK SISNPPGSNLRTT (SEQ
ID NO:533), IQDLQSRQKHEIESLYTKLGKVPPAVIIP
PAAPLSGRRRRPTKSKGSKSSRSSSLGNKSPQLS- GNLSGQSAASVLHP
QQTLHPPGNIPESGQNQLLQPLKPSPSSDNLYSAFTSDGAISVPSLSAPGQGT SST (SEQ ID
NO:534), TSDGAISVPSLSAPGQGTSSTNTVGATVNSQAAQAQ PPAMTSSRKGTFTDDLH
(SEQ ID NO:535), KGHMNYEGPGMARKFSAPGQL CISMTSNLGGSAPISAASATSLGHFTK
(SEQ ID NO:536), QPLKPSPSSDNL YSAFTSDGAISVPSLSAPG (SEQ ID NO:537),
MSSDNESEIEDEDLKLELRRLRD KHLKEIQDLQSRQKHEIESLYTKLGKVP (SEQ ID
NO:538), PAVIIPPAAPL SGRRRRPTKSKGSKSSRSSSLGNKSPQLSGNLSGQS (SEQ ID
NO:539), AASVLHPQQTLHPPGNIPESGQNQLLQPLKPSPSSDNLYSAFTSDGAISV (SEQ ID
NO:540), PSLSAPGQGTSSTNTVGATVNSQAAQAQPPAMTSSRKGTFTDDL (SEQ ID
NO:541), HKLVDNWARDAMNLSGRRGSKGHMNYEGPGMARKFS APGQLCISMT (SEQ ID
NO:542), SNLGGSAPISAASATSLGHFTKSMCPPQQY GFPATPFGAQWSGTGG (SEQ ID
NO:543), and PAPQPLGQFQPVGTSALQNF NISNLQKSISNPPGSNLRTT (SEQ ID
NO:544). Additional embodiments is the polynucleotides encoding
these polypeptides.
[0141] This gene is expressed in fetal liver and tissues associated
with the CNS.
[0142] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, liver and CNS diseases. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the liver and CNS, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g. liver, cancerous
and wounded tissues) or bodily fluids (e.g. lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0143] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 268 as residues: Gln-26 to Lys-34.
[0144] The tissue distribution in fetal liver and neural tissues
indicates that the protein product of this gene is useful for the
diagnosis and treatment for liver diseases such as hepatocellular
carcinomas and diseases of the CNS. Furthermore, the tissue
distribution indicates that the protein product of this gene is
useful for the detection and treatment of liver disorders and
cancers (e.g. hepatoblastoma, jaundice, hepatitis, liver metabolic
diseases and conditions that are attributable to the
differentiation of hepatocyte progenitor cells), as well as the
detection and treatment of neurodegenerative disease states and
behavioural disorders such as Alzheimers Disease, Parkinsons
Disease, Huntingtons Disease, Tourette Syndrome, schizophrenia,
mania, dementia, paranoia, obsessive compulsive disorder, panic
disorder, learning disabilities, ALS, psychoses, autism, and
altered bahaviors, including disorders in feeding, sleep patterns,
balance, and perception.
[0145] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:30 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1653 of SEQ ID NO:30, b is an integer
of 15 to 1667, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:30, and where b is greater
than or equal to a+14.
[0146] Features of Protein Encoded by Gene No: 21
[0147] The translation product of this gene shows sequence homology
to two recently gened genes, karyopherin beta 3 and Ran_GTP binding
protein 5. (See Genbank Accession Nos. gi.vertline.2 102696 and
gnl.vertline.PID.vertline.e328731.) The Ran_GTP binding protein is
related to importin-beta, the key mediator of nuclear localization
signal (NLS)-dependent nuclear transport. Based on homology, it is
likely that this gene may demonstrate activity similar to the
RAN_GTP binding protein. One embodiment of this invention is a
polypeptide comprising the following amino acid sequence:
VRVAAAESMXLLLECAXVRGPEYLTQMWHFMCDALIKAIGTE- PDSDVLSEIMHSFAK (SEQ ID
NO:545). An additional embodiment is the polynucleotides encoding
these polypeptides.
[0148] This gene is expressed in thymus tissue, and to a lesser
extent in stromal cells.
[0149] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune disorders. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the immune system, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g. immune, thymus,
cancerous and wounded tissues) or bodily fluids (e.g. lymph, serum,
plasma, urine, synovial fluid and spinal fluid) or another tissue
or cell sample taken from an individual having such a disorder,
relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0150] The tissue distribution in thymus indicates that the protein
product of this gene is useful for the diagnosis and treatment for
immune disorders. Furthermore, the polypeptides or polynucleotides
of the present invention are also useful in the treatment,
prophlaxis, and detection of thymus disorders, such as Graves
Disease, lymphocytic thyroiditis, hyperthyroidism, and
hypothyroidism. Additionally, the tissue distribution indicates
that the protein product of this gene is useful for the treatment
and diagnosis of hematopoetic related disorders such as anemia,
pancytopenia, leukopenia, thrombocytopenia or leukemia, since
stromal cells are important in the production of cells of
hematopoietic lineages. The uses include bone marrow cell ex vivo
culture, bone marrow transplantation, bone marrow reconstitution,
radiotherapy or chemotherapy of neoplasia. The gene product may
also be involved in lymphopoiesis, therefore, it can be used in
immune disorders such as infection, inflammation, allergy,
immunodeficiency etc. In addition, this gene product may have
commercial utility in the expansion of stem cells and committed
progenitors of various blood lineages, and in the differentiation
and/or proliferation of various cell types.
[0151] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:31 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1394 of SEQ ID NO:31, b is an integer
of 15 to 1408, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:31, and where b is greater
than or equal to a+14.
[0152] Features of Protein Encoded by Gene No: 22
[0153] The translation product of this gene shares sequence
homology with a natural resistance-associated macrophage protein 2
from Homo sapiens (gi.vertline.3152690 (AF064484)), which is
thought to function as a macrophage-specific membrane transport
protein. This gene is expressed primarily in prostate and
osteoclastoma tissues. One embodiment of this invention is a
polypeptide comprising one ore more of the following amino acid
sequences: MEINNQNCFIVIDLVRTVMENGVEGLLIFGAFLPESWLIGVRCSSEPPKALLLIL
AHSQKRRLDGWSFIRHLRVHYCVSLTIHFS (SEQ ID NO:546), GGREANKXFF
IESCIALFVSFIINVFVVSVEAEXFFGXTNEQVVEVCTNTSSPHAGLFPKDNSTL
AVDIYKGGVVLGCYFGPAALYIWAVGILAAGQSST (SEQ ID NO:547), GGREA
NKXFFIESCIALFVSFIINVFVVSVFAEXFFGXTNEQVVE (SEQ ID NO:548), and/or
VCTNTSSPHAGLFPKDNSTLAVDIYKGGVVLGCYFGPAALYIWAVGILAAGQSST (SEQ ID
NO:549). Additional embodiments is the polynucleotides encoding
these polypeptides. The gene encoding the disclosed cDNA is thought
to reside on chromosome 12. Accordingly, polynucleotides related to
this invention are useful as a marker in linkage analysis for
chromosome 12.
[0154] This gene is expressed primarily in fetal liver/spleen,
fetal brain, and to a lesser extent in placenta.
[0155] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune, developmental, hepatic, or bone and prostate
diseases, and cancers, particularly of the bone and prostate.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the bone and prostate systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. bone, prostate, cancerous and
wounded tissues) or bodily fluids (e.g. lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0156] The tissue distribution in bone indicates that the protein
product of this gene is useful for the diagnosis and treatment of
bone and prostate disorders, especially cancers of those systems.
Elevated levels of expression of this gene product in osteoclastoma
indicates that it may play a role in the survival, proliferation,
and/or growth of osteoclasts. Therefore, it may be useful in
influencing bone mass in such conditions as osteoporosis. Moreover,
the protein product of this gene is useful for the treatment and
diagnosis of hematopoietic related disorders such as anemia,
pancytopenia, leukopenia, thrombocytopenia or leukemia since
stromal cells are important in the production of cells of
hematopoietic lineages. The uses include bone marrow cell ex vivo
culture, bone marrow transplantation, bone marrow reconstitution,
radiotherapy or chemotherapy of neoplasia. The gene product may
also be involved in lymphopoiesis, therefore, it can be used in
immune disorders such as infection, inflammation, allergy,
immunodeficiency etc. In addition, this gene product may have
commercial utility in the expansion of stem cells and committed
progenitors of various blood lineages, and in the differentiation
and/or proliferation of various cell types. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[0157] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:32 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 3172 of SEQ ID NO:32, b is an integer
of 15 to 3186, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:32, and where b is greater
than or equal to a+14.
[0158] Features of Protein Encoded by Gene No: 23
[0159] This gene shares sequence homology with the FK506-binding
protein (FKBP-13) family, a known cytosolic receptor for the
immunosuppressants FK506 and rapamycin. Recently, another group has
gened a very similar gene, recognizing the homology to the
FK506-binding protein family, calling their gene FKBP23 (See
Genbank Accession No. 2827255.). Contact of cells with supernatant
expressing the product of this gene increases the permeability of
both prostate stromal cells and dermal fibroblasts to calcium.
Thus, it is likely that the product of this gene is involved in a
signal transduction pathway that is initiated when the product of
this gene binds receptors on the surface of stromal cells and
dermal fibroblast cells. Thus, polynucleotides and polypeptides
have uses which include, but are not limited to, activating stromal
and fibroblast cells.
[0160] This gene is expressed primarily in lymphoid tissues and
stromal cells.
[0161] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample,
especially for those susceptible to immune suppressant therapies
and for diagnosis of diseases and conditions which include, but are
not limited to, immune suppresant disorders. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immnunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the immune
system, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g. immune, cancerous and wounded tissues) or bodily fluids (e.g.
lymph, serum, plasma, urine, synovial fluid and spinal fluid) or
another tissue or cell sample taken from an individual having such
a disorder, relative to the standard gene expression level, i.e.,
the expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0162] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 271 as residues: Ala-19 to Val-31, Arg-38 to Gly-49,
Ala-61 to Lys-66, Tyr-68 to Pro-78, Gly-116 to Ala-121, Asp-154 to
Ser-162, Glu-173 to Gln-186, Phe-194 to Gly-203, and/or Pro-207 to
Val-212.
[0163] The tissue distribution in lymphoid tissues and stromal
cells, the biological activity data, combined with the homology to
FKBP-12 and -13 indicates that the protein product of this gene is
useful for the diagnosis and treatment of immune suppressant
disorders.
[0164] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:33 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 957 of SEQ ED NO:33, b is an integer
of 15 to 971, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:33, and where b is greater
than or equal to a+14.
[0165] Features of Protein Encoded by Gene No: 24
[0166] The gene encoding the disclosed cDNA is thought to reside on
chromosome 8. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
8.
[0167] This gene is expressed primarily in the brain and in the
retina.
[0168] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neurological and ocular associated disease states.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the disorders of the central nervous system, expression of this
gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g. brain, cancerous
and wounded tissues) or bodily fluids (e.g. lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0169] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 272 as residues: Cys-34 to Asp-40.
[0170] The tissue distribution in retina indicates that the protein
product of this gene is useful for the treatment and/or detection
of eye disorders including blindness, color blindness, impaired
vision, short and long sightedness, retinitis pigmentosa, retinitis
proliferans, and retinoblastoma. Expression in the brain indicates
a role in the is useful for the detection/treatment of
neurodegenerative disease states and behavioural disorders such as
Alzheimer's Disease, Parkinson's Disease, Huntington's Disease,
schizophrenia, mania, dementia, paranoia, obsessive compulsive
disorder and panic disorder.
[0171] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:34 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1778 of SEQ ID NO:34, b is an integer
of 15 to 1792, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:34, and where b is greater
than or equal to a+14.
[0172] Features of Protein Encoded by Gene No: 25
[0173] This gene shows sequence homology to a newly identified
class of proteins expressed in the nervous system, called stathmin
family. (See Genbank Accession No. 2585991; see also Eur. J.
Biochem. 248 (3), 794-806 (1997).) The stathmin family appears to
be an ubiquitous phosphoprotein involved as a relay integrating
various intracellular signaling pathways. These pathways affect
cell proliferation and differentiation. One embodiment of the
invention is a polypeptide comprising one or both of the following
amino acid sequences: QDKHAEEVRKNKELKEEASR (SEQ ID NO:550),
QQDLSPWAAPVGCP
LXXASXTCHXLPLSGCLRRQSXSLPVVAXLCFWFSCPLASLFVPGQPCVTCPF
PSLPFQDKHAEEVRKNKELKEEASR (SEQ ID NO:551). An additional embodiment
is the polynucleotides encoding these polypeptides.
[0174] This gene is expressed highly in brain tissues.
[0175] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neurological disorders. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the central nervous system,
expression of this gene at significantly higher or lower levels may
be routinely detected in certain tissues or cell types (e.g. brain,
cancerous and wounded tissues) or bodily fluids (e.g. lymph, serum,
plasma, urine, synovial fluid and spinal fluid) or another tissue
or cell sample taken from an individual having such a disorder,
relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0176] The tissue distribution in brain indicates that the protein
product of this gene is useful for the detection/treatment of
neurodegenerative disease states and behavioural disorders such as
Alzheimers Disease, Parkinsons Disease, Huntintons Disease,
schizophrenia, mania, dementia, paranoia, obsessive compulsive
disorder and panic disorder.
[0177] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:35 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 882 of SEQ ID NO:35, b is an integer
of 15 to 896, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:35, and where b is greater
than or equal to a+14.
[0178] Features of Protein Encoded by Gene No: 26
[0179] The polynucleotide sequence of this gene contains a domain
similar to a Flt3 ligand peptide. One embodiment of the invention
is a polypeptide comprising the following amino acid sequence:
PTRCCTTQPCRSSARRPCWVPMVPSPEGREXQPTCPS (SEQ ID NO:552). An
additional embodiment is the polynucleotides encoding these
polypeptides. Thus, this gene may have activity as binding to Flt3
receptors, a process known to promote angiogenesis and/or
lymphangiogenesis.
[0180] This gene is expressed in human tonsil, and to a lesser
extent in teratocarcinoma, placenta, colon carcinoma, and fetal
kidney.
[0181] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for identification of the tissue(s) or cell
type(s) present in a biological sample and for diagnosis of
diseases and conditions which include, but are not limited to,
diseases of the tonsil, as well as cancers, such as colon,
reproductive, and kidney cancers. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the tonsils, colon, reproductive
organs, and kidneys, expression of this gene at significantly
higher or lower levels may be routinely detected in certain tissues
or cell types (e.g. immune, tonsils, colon, kidney, cancerous and
wounded tissues) or bodily fluids (e.g. lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0182] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 274 as residues: Pro-22 to Glu-33.
[0183] The tissue distribution in tonsils, several cancers, and
fetal tissues indicates that the protein product of this gene is
useful for the diagnosis and treatment of diseases of the tonsil or
colon, such as tonsilitis, inflammatory diseases involving nose and
paranasal sinuses, especially during the infection of influenza,
adenoviruses, parainfluenza, or rhinoviruses, for example. The gene
may also be useful in the diagnosis and treatment of neoplasms of
nasopharynx or colon origins. Protein, as well as, antibodies
directed against the protein may show utility as a tumor marker
and/or immunotherapy targets for the above listed tissues.
[0184] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:36 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 898 of SEQ ID NO:36, b is an integer
of 15 to 912, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:36, and where b is greater
than or equal to a+14.
[0185] Features of Protein Encoded by Gene No: 27
[0186] One embodiment of the invention is a polypeptide comprising
one or of the following amino acid sequences:
MKRSLNENSARSTAGCLPVPLFNQKKRN
RQPLTSNPLKDDSGISTPSDNYDFPPLPTDWAWEAVNPEXAPVMKTVDTGQI
PHSVSRPLRSQDSVFNSIQSNTGRSQGGWSYRDGNKNTSLKTWXKNDF
KPQCKRTNLVANDGKNSCPMSSGA- QQQKQLR TPEPPNLSRNKETELL
RPTHSSKISGCTMRGLDKNSALQTLKPNFQQNQYKXQMLDDIPEDNT
LKETSLYQLQFKEKASSLRIISAVIESMKYWREHAQKTVLLFEVLAVLDSAV
TPGPYYSKTFLMRDGKNTLPCVFYEIDRELPRLIRGRVHRCVGNYDQ
KKNIFQCVSVRPASVSEQKTFQAFV- KIADVEMQYYINVMNET (SEQ ID NO:553),
SQDSVFNSIQSNTGRSQGGWSYRDGNKNTSLKTWXKNDF- KPQCKR (SEQ ID NO:554),
NKETELLRQTHSSKISGCTMRGLDKNSALQTLKPNF (SEQ ID NO:555),
SSLRIISAVIESMKYWREHAQKTVLLFEVLAVLDSAVTPGPYYSK TFLM (SEQ ID NO:556),
and/or PRLIRGRVHRCVGNYDQKKNIFQCVSVRPASV SEQKTFQAFV (SEQ ID NO:557).
An additional embodiment is the polynucleotides encoding these
polypeptides.
[0187] This gene is expressed primarily in human testes.
[0188] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, male reproductive disorders, including cancer.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the male reproductive system, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. testes, cancerous and wounded
tissues) or bodily fluids (e.g. lymph, serum, seminal fluid,
plasma, urine, synovial fluid and spinal fluid) or another tissue
or cell sample taken from an individual having such a disorder,
relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0189] The tissue distribution in human testes indicates that the
protein product of this gene is useful as a hormone with
reproductive or other systemic functions; contraceptive
development; male infertility of testicular causes, such as
Kleinfelter's syndrome, varicocele, orchitis; male sexual
dysfunctions; testicular neoplasms; and inflammatory disorders such
as epididymitis. Furthermore, this gene product is useful in the
treatment of male infertility and/or impotence. This gene product
is also useful in assays designed to identify binding agents as
such agents (antagonists) are useful as male contraceptive agents.
Similarly, the protein is believed to by useful in the treatment
and/or diagnosis of testicular cancer. The testes are also a site
of active gene expression of transcripts that may be expressed,
particularly at low levels, in other tissues of the body.
Therefore, this gene product may be expressed in other specific
tissues or organs where it may play related functional roles in
other processes, such as hematopoiesis, inflammation, bone
formation, and kidney function, to name a few possible target
indications.
[0190] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:37 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1368 of SEQ ID NO:37, b is an integer
of 15 to 1382, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:37, and where b is greater
than or equal to a+14.
[0191] Features of Protein Encoded by Gene No: 28
[0192] This gene is expressed primarily in apoptotic T-cell.
[0193] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, diseases relating to T cells, as well as cancer in
general. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the disorders of the immune system, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. immune, cancerous and wounded
tissues) or bodily fluids (e.g. lymph, serum, plasma, urine,
synovial fluid and spinal fluid) or another tissue or cell sample
taken from an individual having such a disorder, relative to the
standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0194] The tissue distribution in apoptotic T-cells indicates that
the protein product of this gene is useful for the detection and/or
treatment of disorders of the immune system. Moreover, since the
gene was isolated from an apoptotic cell, and based on the
understanding of the relationship of apoptosis and cancer, it is
likely that this gene may play a role in the genesis of cancer.
Furthermore, expression of this gene product in T cells also
strongly indicates a role for this protein in immune function and
immune surveillance.
[0195] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:38 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 858 of SEQ ID NO:38, b is an integer
of 15 to 872, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:38, and where b is greater
than or equal to a+14.
[0196] Features of Protein Encoded by Gene No: 29
[0197] This gene is expressed primarily in human tonsils.
[0198] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, gastrointestinal and immune disorders. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
gastrointestinal and immune system, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. immune, gastrointestinal,
cancerous and wounded tissues) or bodily fluids (e.g. lymph, serum,
plasma, urine, synovial fluid and spinal fluid) or another tissue
or cell sample taken from an individual having such a disorder,
relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0199] The tissue distribution in human tonsils indicates that the
protein product of this gene is useful for the diagnosis and
treatment of gastrointestinal diseases. Alternatively, the tissue
distribution indicates that the protein product of this gene is
useful for the diagnosis and treatment of a variety of immune
system disorders. Expression of this gene product in tonsils
indicates a role in the regulation of the proliferation; survival;
differentiation; and/or activation of potentially all hematopoietic
cell lineages, including blood stem cells. This gene product may be
involved in the regulation of cytokine production, antigen
presentation, or other processes that may also suggest a usefulness
in the treatment of cancer (e.g. by boosting immune responses).
Since the gene is expressed in cells of lymphoid origin, the gene
or protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues. Therefore it may be also used as an agent for
immunological disorders including arthritis, asthma, immune
deficiency diseases such as AIDS, leukemia, rheumatoid arthritis,
inflammatory bowel disease, sepsis, acne, and psoriasis. In
addition, this gene product may have commercial utility in the
expansion of stem cells and committed progenitors of various blood
lineages, and in the differentiation and/or proliferation of
various cell types. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0200] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:39 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 798 of SEQ ID NO:39, b is an integer
of 15 to 812, where both a and b correspond to the positions of
nucleotide residues shown in 20 SEQ ID NO:39, and where b is
greater than or equal to a+14.
[0201] Features of Protein Encoded by Gene No: 30
[0202] The translation product of this gene shares sequence
homology with C44C1.2 gene product of Caenorhabditis elegans. One
embodiment of the invention is a polypeptide comprising one or more
of the following amino acid sequences:
GVFRPCVCGRPASLTCSPLDPEVGPYCDTPTMRTLFNLLWLALACSPVHTTLSK
SDAKKAASKTLLEKSQFSDKPVQDRGLVVTDLKAESVVLEHRSYCSAKARDR
HFAGDVLGYVTPWNSHGYDVTKVFGSKFTQISPVWLQLKRRGREMFEVTGL
HDVDQGWMRAVRKHAKGLHIVPRLLFEDWTYDDFRNVLDSEDEIEELSKTVV
QVAKNQHFDGFVVEVWNQLLSQKRVGLIHMLTHLAEALHQARLLALLVIP
PAITPGTDQLGMFTHKEFEQLAPVLDGFSLMTYDYSTAHQPGPNAPLSWVRAC
VQVLKPKXKWRTKSSWGSTSMXWTXRXPXDARXPVVGXRXIQXLKDH XPRMVLDSKPQ (SEQ ID
NO:558), TCSPLDPEVGPYCDTPTMRTLFNLLW LALACSPVHTTLS (SEQ ID NO:559),
LVVTDLKAESVVLEHRSYCSAKARDRH FAGDVLGYVTPWNSHGYDVTKVFGSKF (SEQ ID
NO:560), REMFEVTGL HDVDQGWMRAVRKHAKGLHIVPRLLFEDWTYDDFRNVLDSESE (SEQ
ID NO:561), HFDGFVVEVWNQLLSQKRVGLIHMLTHLAEALHQARLLALLVIP
PAITPGTDQLGM (SEQ ID NO:562), and/or DGFSLMTYDYSTAHQPGPNAPL
SWVRACVQVLDPKXKWRTKSSWGST (SEQ ID NO:563). An additional embodiment
is the polynucleotides encoding these polypeptides. The gene
encoding the disclosed cDNA is thought to reside on chromosome 11.
Accordingly, polynucleotides related to this invention are useful
as a marker in linkage analysis for chromosome 11. When tested
against Jurkat cell lines, supernatants removed from cells
containing this gene activated the NF-kB transcription factor.
Thus, it is likely that this gene activates Jurkat cells by
activating a transcriptional factor found within these cells.
Nuclear factor kB is a transcription factor activated by a wide
variety of agents, leading to cell activation, differentiation, or
apoptosis. Reporter constructs utilizing the NF-kB promoter element
are used to screen supernatants for such activity.
[0203] This gene is expressed primarily in human T-cells, and to a
lesser extent, in human colon carcinoma.
[0204] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune and gastrointestinal disorders and cancer.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune and gastrointestinal systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. immune, cancerous and wounded
tissues) or bodily fluids (e.g. lymph, serum, plasma, urine,
synovial fluid and spinal fluid) or another tissue or cell sample
taken from an individual having such a disorder, relative to the
standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0205] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 278 as residues: Leu-21 to Ala-30, Ser-38 to Asp-47,
Pro-87 to Asp-94, Leu-197 to Thr-204, Pro-256 to Ser-262, Thr-277
to Arg-282, and/or Thr-293 to Trp-303.
[0206] The tissue distribution in human T-cells and human colon
carcinoma indicates that the protein product of this gene is useful
for the diagnosis and treatment of immune disorders and
gastrointestinal diseases. Furthermore, this gene product may be
involved in the regulation of cytokine production, antigen
presentation, or other processes that may also suggest a usefulness
in the treatment of cancer (e.g. by boosting immune responses).
Since the gene is expressed in cells of lymphoid origin, the gene
or protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues. Expression of this gene product in T cells
also strongly indicates a role for this protein in immune function
and immune surveillance.
[0207] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:40 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1501 of SEQ ID NO:40, b is an integer
of 15 to 1515, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:40, and where b is greater
than or equal to a+14.
[0208] Features of Protein Encoded by Gene No: 31
[0209] The translation product of this gene shares sequence
homology with Ribosomal protein L11 of Caenorhabditis elegans. (See
Genbank Accession No. 156201.) One embodiment of the invention is a
polypeptide comprising one or more of the following amino acid
sequences: ERGVSINQFCKEFNERTKDIKEGIPLPTKILVKPDRTFEIKIGQPTVSYFLKAAAG
IEKGARQTGKEVAGLVTLKHVYEIARIKAQDEAFALQDVPLSSVVRSIIG
SARSLGIRVVKDLSSEELAAFQKERAIFLAAQKEADLAAQEEAAKK (SEQ ID NO:564),
ERGVSINQFCKEFNERTKDIKEGIPLPTDILVKPDRTFEIKIGQ PTVSYFL (SEQ ID
NO:565), KAAAGIEKGARQTGKEVAGLVTLKHVYEIARIK AQDEAFALQDVPLSSV (SEQ ID
NO:566), and/or VRSIIGSARSLGIRVVK
DLSSEELAAFQKERAIFLAAQKEADLAAQEEAAKK (SEQ ID NO:567). An additional
embodiment is the polynucleotides encoding these polypeptides. The
gene encoding the disclosed cDNA is thought to reside on chromosome
11. Accordingly, polynucleotides related to this invention are
useful as a marker in linkage analysis for chromosome 11.
[0210] This gene is expressed in human embryo tissue, and to a
lesser extent, in human epithelloid sarcoma.
[0211] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for identification of the tissue(s) or cell
type(s) present in a biological sample and for diagnosis of
diseases and conditions which include, but are not limited to,
development disorders and epithelial cell cancer. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
embryonic and epithelial cell systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. embryonic, cancerous and
wounded tissues) or bodily fluids (e.g. lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0212] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 279 as residues: Lys-34 to Gly-40.
[0213] The tissue distribution in human embryo indicates that the
protein product of this gene is useful for the diagnosis and
treatment of developmental disorders and epithelial cancer.
Furthermore, expression within embryonic tissue and other cellular
sources marked by proliferating cells indicates that this protein
may play a role in the regulation of cellular division, and may
show utility in the diagnosis and treatment of cancer and other
proliferative disorders. Similarly, embryonic development also
involves decisions involving cell differentiation and/or apoptosis
in pattern formation. Thus this protein may also be involved in
apoptosis or tissue differentiation and could again be useful in
cancer therapy. Protein, as well as, antibodies directed against
the protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[0214] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:41 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 690 of SEQ ID NO:41, b is an integer
of 15 to 704, where both a and b correspond to the positions of
nucleotide-residues shown in SEQ ID NO:41, and where b is greater
than or equal to a+14.
[0215] Features of Protein Encoded by Gene No: 32
[0216] This gene is expressed primarily in resting T-cells.
[0217] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, inflammatory and general immune disorders. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the immune
system, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g. immune, cancerous and wounded tissues) or bodily fluids (e.g.
lymph, serum, plasma, urine, synovial fluid and spinal fluid) or
another tissue or cell sample taken from an individual having such
a disorder, relative to the standard gene expression level, i.e.,
the expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0218] The tissue distribution in T-cells indicates that the
protein product of this gene is useful for the diagnosis and
treatment of disorders of the immune system. Furthermore, this gene
product may be involved in the regulation of cytokine production.
antigen presentation, or other processes that may also suggest a
usefulness in the treatment of cancer (e.g. by boosting immune
responses). Since the gene is expressed in cells of lymphoid
origin, the gene or protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues. Expression of
this gene product in T cells also strongly indicates a role for
this protein in immune function and immune surveillance.
[0219] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:42 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1080 of SEQ ID NO:42, b is an integer
of 15 to 1094, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:42, and where b is greater
than or equal to a+14.
[0220] Features of Protein Encoded by Gene No: 33
[0221] This gene is believed to reside on chromosome 1.
Accordingly, polynucleotides derived from this gene are useful in
linkage analysis as chromosome 1 markers.
[0222] This gene is expressed primarily in prostate, and to a
lesser extent in soares adult brain, human umbilical vein
endothelial cells, and amniotic cells.
[0223] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, prostate-related disorders. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the urinary system and nervous
system expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g. prostate, cancerous and wounded tissues) or bodily fluids
(e.g. lymph, serum, plasma, urine, synovial fluid and spinal fluid)
or another tissue or cell sample taken from an individual having
such a disorder, relative to the standard gene expression level,
i.e., the expression level in healthy tissue or bodily fluid from
an individual not having the disorder.
[0224] The tissue distribution in prostate indicates that the
protein products of this gene are useful for the diagnosis and
treatment of disorders of the urinary and nervous systems.
Furthermore, the tissue distribution indicates that the protein
product of this gene is useful for the detection/treatment of
neurodegenerative disease states and behavioural disorders such as
Alzheimers Disease, Parkinsons Disease, Huntingtons Disease,
Tourette Syndrome, schizophrenia, mania, dementia, paranoia,
obsessive compulsive disorder, panic disorder, learning
disabilities, ALS, psychoses, autism, and altered bahaviors,
including disorders in feeding, sleep patterns, balance, and
perception. Protein, as well as, antibodies directed against the
protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[0225] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:43 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1807 of SEQ ID NO:43, b is an integer
of 15 to 1821, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:43, and where b is greater
than or equal to a+14.
[0226] Features of Protein Encoded by Gene No: 34
[0227] This gene shares sequence homology with R05G6.4 gene
product. (See Genbank Accession No. gi.vertline.1326338.) This gene
also shares sequence homology with the cyclophilin-like protein
CyP-60. (See Genbank Accession No. 1199598, see also Biochem. J.
314 (1), 313-319 (1996).) One embodiment of the invention is a
polypeptide comprising one or more of the following amino acid
sequences:
2 AVYTYHEKKKDTAASGYGTQNIRLSR (SEQ ID NO:568), DAVKDFDCCCLSLQPCHD
PVVTPDG YLYEREAILEYILHQKKEIARQMKAY EKQRGTRREEQKELQRAASQDHVRGF
LEKESAIVSRPLNPFTAKALSGTSPD DVQPGPSVGPPSKDKDKVLPSFWIPS
LTPEAKATKLEKPSRTVTCPMSGKPL RMS DLTPVHFTPLDSSVDRVGLITR
SERYVCAVTRDSLSNATPCAVLRPSG AVVTLECVEKLIRKDMVDPVTGDKLT DRDIIVLQRGGT
YLYEREAILEYILHQKKEIARQMKAY (SEQ ID NO:569),
EKQRGTRREEQKELQRAASQDHVRGF LE FTAKALSGTSPDDVQPGPSVGPPSKD (SEQ ID
NO:570), KDKVLPSFWIPSLTPEAKATKLEKPS RTVTCPMSGKPL
VHFTPLDSSVDRVGLITRSERYVCAV (SEQ ID NO:571), and/or
TRDSLSNATPCAVLRPSGAVVTLECV EKLI MSDLTPVHFTPLDSSVDRVGLITRSE (SEQ ID
NO:572). RYVCAVTRDSLSNATPCAVLRPSGAV VTLECVEKLIRKDM
[0228] An additional embodiment is the polynucleotides encoding
these polypeptides.
[0229] This gene is expressed primarily in human testis, and to a
lesser extent in activated T-cells.
[0230] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, male reproductive disorders and in particular
testicular cancer. Similarly, polypeptides and antibodies directed
to these polypeptides are useful in providing immunological probes
for differential identification of the tissue(s) or cell type(s).
For a number of disorders of the above tissues or cells,
particularly of the reproductive and immune systems, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g. testes, immune,
cancerous and wounded tissues) or bodily fluids (e.g. lymph, serum,
plasma, urine, synovial fluid and spinal fluid) or another tissue
or cell sample taken from an individual having such a disorder,
relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0231] The tissue distribution in human testis indicates that the
protein product of this gene is useful for the diagnosis and
treatment of disorders of the male reproductive system, and in
particular of testicular cancer. Furthermore, this gene is useful
for the treatment and diagnosis of conditions concerning proper
testicular function (e.g. endocrine function, sperm maturation), as
well as cancer. Therefore, this gene product is useful in the
treatment of male infertility and/or impotence. This gene product
is also useful in assays designed to identify binding agents as
such agents (antagonists) are useful as male contraceptive agents.
Similarly, the protein is believed to by useful in the treatment
and/or diagnosis of testicular cancer. The testes are also a site
of active gene expression of transcripts that may be expressed,
particularly at low levels, in other tissues of the body.
Therefore, this gene product may be expressed in other specific
tissues or organs where it may play related functional roles in
other processes, such as hematopoiesis, inflammation, bone
formation, and kidney function, to name a few possible target
indications. Protein, as well as, antibodies directed against the
protein may show utility as a tissue-specific marker and/or
immunotherapy target for the above listed tissues.
[0232] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:44 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1010 of SEQ ID NO:44, b is an integer
of 15 to 1024, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:44, and where b is greater
than or equal to a+14.
[0233] Features of Protein Encoded by Gene No: 35
[0234] The translation product of this gene shares sequence
homology with Lpe5p of Saccharomyces cerevisiae, which is thought
to be important in the metabolism of phospholipids. The gene
encoding the disclosed cDNA is thought to reside on chromosome 8.
Accordingly, polynucleotides related to this invention are useful
as a marker in linkage analysis for chromosome 8.
[0235] This gene is expressed primarily in liver and brain.
[0236] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and coriditions which include, but are not
limited to, metabolic disorders. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the metabolic and nervous systems
expression of this gene at significantly higher or lower levels may
be routinely detected in certain tissues or cell types (e.g. liver,
brain, cancerous and wounded tissues) or bodily fluids (e.g. lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0237] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 283 as residues: Pro-14 to Leu-20, Lys-28 to Asn-38,
Arg-109 to Arg-114, Lys-119 to Asn-124, Glu-152 to Leu-157, or
Pro-172 to Val-180.
[0238] The tissue distribution in liver and brain, combined with
the homology to Lpe5p of Saccharomyces cerevisiae indicates that
the protein product of this gene is useful for the diagnosis and
treatment of metabolic and nervous disorders. Additionally, the
tissue distribution indicates that the protein product of this gene
is useful for the detection and treatment of liver disorders and
cancers (e.g. hepatoblastoma, jaundice, hepatitis, liver metabolic
diseases and conditions that are attributable to the
differentiation of hepatocyte progenitor cells). Protein, as well
as, antibodies directed against the protein may show utility as a
tumor marker and/or immunotherapy targets for the above listed
tissues.
[0239] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:45 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 969 of SEQ ID NO:45, b is an integer
of 15 to 983, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:45, and where b is greater
than or equal to a+14.
[0240] Features of Protein Encoded by Gene No: 36
[0241] This gene shares sequence homology with the nuclear
ribonucleoprotein U (HNRNP U), encoded by C. elegans (See Genbank
Accesion gi.vertline.1703576.) One embodiment of the invention is a
polypeptide comprising one or more of the following amino acid
sequences:
3 MDTSENRPENDVPEPPMPIADQVSND DR (SEQ ID NO:573), PEGSVEDEEK
KESSLPKSFKRKISV V SATKGVPAGNSDTEGGQPGRKRRWGASTA TTQKKPSISITTE
SLKSLIPD IKPLAG QEAVVDLHADDSRISEDETERNGDDGTHD
KGLKICRTVTQVVPAEGQENGQREEEE E EKEPEAEPPVPPQVSVEVALPPPAEHEVK
KVTLGDTLTRRSI SQQKSGVSITIDDPV RTAQVPSPPRGK ISNIVHISNLVRPFTL GQLKELL
GRTGTL VEEAFWIDKIKSHC FVTYSTVEEAVATRTALHGVKWPQSNP K FLCA
DYAEQDELDYHRGLLVDRPSETKT EEQGIPRPLHPPPPPPVQPPQHPRAEQRE QERAVREQWAER
EREMERRERTRSEREW DRDKvVREGPRSRSRSRXRRRK ERA KS
KEKKSEKKEKAQEEPPAKLLDDLFRKTKA APCIYWLPLTDWQIVQKEAERA ERAKER
EKRRKEQEEEEQKEREKEAERERNRQLER EKRREHSRERDR ERE RERERDRGDRDR
DRERDRERGRERDRRDTKRHSRSRSRSTP VRDRGGR ENDVPEPPMPIADQVSNDDRPEGSVEDEE
(SEQ ID NO:574), KKESSLPKSFKR KISVVSA VDLHADDSRISEDETERNGDDGTHDKGLK
(SEQ ID NO:575), ICRT VTQV PQVSVEVALPPPAEHEVKKVTLGDTLTRR (SEQ ID
NO:576), SISQQ KSGVSITIDDPVRTAQVPSPP LKELLGRTGTLVEEAF WIDKIKSHCFVT
(SEQ ID NO:577), YSTVEEAVATRTALHGVKWPQSNPKFL
VDRPSETKTEEQGIPRPLHPPPPPPVQPP (SEQ ID NO:578),
QHPRAEQREQERAVREQWAERERE EWDRDKVREGPRSRSRSRXRRRKERAKSK (SEQ ID
NO:579), EKKSEKKEK AQEEPPAKLLDDLFRKTKA AP LDVPLASRSPEFPLPLMT
QSELPRCPPH (SEQ ID NO:581), PGAR LATLSISPIWSVLSL (SEQ ID NO:582),
and PLTDSQIVQKEAERAERAKEREKRRKEQE (SEQ ID NO:580).
EEEQKEREKEAERERNR QLEREKRREHS RERDRER
[0242] An additional embodiment is the polynucleotides encoding
these polypeptides. The gene encoding the disclosed cDNA is thought
to reside on chromosome 14. Accordingly, polynucleotides related to
this invention are useful as a marker in linkage analysis for
chromosome 14.
[0243] This gene is expressed primarily in epididymus, and to a
lesser extent in testes.
[0244] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, diseases of the male reproductive system. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the male
reproductive system, expression of this gene at significantly
higher or lower levels may be routinely detected in certain tissues
or cell types (e.g. epididymus, testes, cancerous and wounded
tissues) or bodily fluids (e.g. lymph, serum, plasma, urine,
synovial fluid and spinal fluid) or another tissue or cell sample
taken from an individual having such a disorder, relative to the
standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0245] The tissue distribution in epididymus and testes indicates
that the protein product of this gene is useful for the diagnosis
and treatment of male reproductive disorders. Furthermore, the
protein product of this gene is useful for the treatment and
diagnosis of conditions concerning proper reproductive and
testicular function (e.g. endocrine function, sperm maturation), as
well as cancer. Therefore, this gene product is useful in the
treatment of male infertility and/or impotence. This gene product
is also useful in assays designed to identify binding agents as
such agents (antagonists) are useful as male contraceptive agents.
Similarly, the protein is believed to by useful in the treatment
and/or diagnosis of testicular cancer. The testes are also a site
of active gene expression of transcripts that may be expressed,
particularly at low levels, in other tissues of the body.
Therefore, this gene product may be expressed in other specific
tissues or organs where it may play related functional roles in
other processes, such as hematopoiesis, inflammation, bone
formation, and kidney function, to name a few possible target
indications.
[0246] Features of Protein Encoded by Gene No: 37
[0247] This gene is expressed primarily in amygdala.
[0248] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, inflanmmatory diseases and reproductive disorders.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the amygdala, expression of this gene at significantly higher or
lower levels may be routinely detected in certain tissues or cell
types (e.g. brain, cancerous and wounded tissues) or bodily fluids
(e.g. lymph, serum, plasma, urine, synovial fluid and spinal fluid)
or another tissue or cell sample taken from an individual having
such a disorder, relative to the standard gene expression level,
i.e., the expression level in healthy tissue or bodily fluid from
an individual not having the disorder.
[0249] The tissue distribution in amygdala indicates that the
protein product of this gene is useful for the diagnosis and
treatment of inflammatory diseases and neural disorders. The
amygdala processes sensory information and relays this to other
areas of the brain including the endocrine and autonomic domains of
the hypothalamus and the brain stem. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[0250] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:47 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 826 of SEQ ID NO:47, b is an integer
of 15 to 840, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:47, and where b is greater
than or equal to a+14.
[0251] Features of Protein Encoded by Gene No: 38
[0252] This gene shares sequence homology with human opsonin
protein P35 fragment. (See Genbank Accession No. R94181.) The
opsonin protein activates the phagocytosis of pathogenic microbes
by phagocytic cells which indicates that the protein product of
this gene may be useful in the treatment and/or prevention of a
variety of immune conditions, particularly bacterial infections and
antigen presentation. Preferred polypeptide fragments comprise the
amino acid sequence:
4 GCDSCPPHLPREAFAQDTQAEGECSS (SEQ ID NO:583),
RAERADMCPDAPPSQEVPEGPGAAP RGWLPSSCLSCALRV CPDSSSTQAM (SEQ ID
NO:584), and/or GMLLAFWLPGASWQEAARGQYSEDED
TDTDEYKEAKASINPVTGRVEEKPPN PMEGMTEE QKEHEA
TQAMGMLLAFWLPGASWQEAARGQYS (SEQ ID NO:585). E
[0253] Also preferred are polynucleotide fragments encoding these
polypeptide fragments.
[0254] This gene is expressed in immune-related tissues such as
thymus, macrophage, and T cells.
[0255] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune disorders and infectious diseases. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the immune
system, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g., immune, hematopoietic, and cancerous and wounded tissues) or
bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0256] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 286 as residues: Lys-9 to Arg-14, or Met-38 to
Asp-51.
[0257] The tissue distribution in immune tissues, particularly
macrophages, combined with the homology to a conserved human
opsonin protein indicates that the protein product of this gene is
useful for diagnosis and treatment of immune disorders, as well as
the treatment and/or diagnosis of infectious disease. Moreover, the
gene product may be involved in the regulation of cytokine
production, antigen presentation, or other processes that may also
suggest a usefulness in the treatment of cancer (e.g. by boosting
immune responses). Since the gene is expressed in cells of lymphoid
origin, the natural gene product may be involved in immune
functions. Therefore it may be also used as an agent for
immunological disorders including arthritis, asthma,
immunodeficiency diseases such as AIDS, leukemia, rheumatoid
arthritis, granulomatous disease, inflammatory bowel disease,
sepsis, acne, neutropenia, neutrophilia, psoriasis,
hypersensitivities, such as T-cell mediated cytotoxicity; immune
reactions to transplanted organs and tissues, such as
host-versus-graft and graft-versus-host diseases, or autoimmunity
disorders, such as autoimmune infertility, lense tissue injury,
demyelination, systemic lupus erythematosis, drug induced hemolytic
anemia, rheumatoid arthritis, Sjogren's disease, scleroderma and
tissues. In addition, this gene product may have commercial utility
in the expansion of stem cells and committed progenitors of various
blood lineages, and in the differentiation and/or proliferation of
various cell types. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0258] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:48 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 2418 of SEQ ID NO:48, b is an integer
of 15 to 2432, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:48, and where b is greater
than or equal to a+14.
[0259] Features of Protein Encoded by Gene No: 39
[0260] The translation product of this gene shares sequence
homology with alpha-2 type I collagen which is thought to be
important in tissue repair. (See, e.g., Genbank Accession No.
211607.) Preferred polypeptide fragments comprise the amino acid
sequence:
5 PQLPSCGRPWPGTASVFQSHTQGPRE (SEQ ID NO:586),
DPDPCRAQGSAGTHCPISLSPPRQ KTHPRALWSAGPSCALCPGGSGXTSP (SEQ ID
NO:587), PQGAPRGIXWDRCPQIQVLEGQRVR FPSQPQHPSHLAPRGGCGWRPDSRPL
LPTPSGLSSFFPLDAQCWPWRTVSWR AGAPGQQARLQYLLSFQGEGAPHEXG (SEQ ID
NO:588), ATGEGGDGAWEACXCXRCLLNWQAGG WGLQLSLMWL HRGPLRPPGVRWTPW
AFLEACSWGPALSLLGSGHSLPGTHE QAAWSRGCGQHGQSPTQKCKSSKEPL AQA
PPWDSPAAPPHQGFADVLERPT LEPFGVLAPPVPSALVEAAXQVLLRE
PQGGFXGTAAHRSRCWKGSG MQLLFLLPHPSPQLHASLPHSA ALP (SEQ ID NO:589),
CPRGESLTTASPAGAAGRXDAVPRCR HQAGRGWV PRGPCERGGGDRGKPRA
VAWDXGSLRWAVWSAR AGQGRSSEP APLASRRGYSTCCLSRGKGLPMRXGR
RGRGVMVPGKPACAXGAC QHPSHLAPRGGCGWRPDSRPLLPTPS (SEQ ID NO:590),
GLSSFFPL GVRWTPWAFLEACSWGPALSLLGSGH (SEQ ID NO:591), SLPG
WDSPAAPPHQGFADVLERPTLEPFGV (SEQ ID NO:592), and/or LA
RSSEPAPLASRRGYSTCCLSRGKGLP (SEQ ID NO:593). MR
[0261] Also preferred are the polynucleotide sequences encoding
these polypeptide sequences.
[0262] This gene is expressed primarily in the brain, and to a
lesser extent, in the kidney and thymus
[0263] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, brain, kidney, endocrine, hematopoietic, and immune
disorders. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the brain, kidney, and immune disorders, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., neural, urogenital, renal,
immune, hematopoietic, and cancerous and wounded tissues) or bodily
fluids (e.g., lymph, serum, plasma, urine, synovial fluid and
spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0264] The tissue distribution in brain and thymus, combined with
the homology to an alpha-2 type I collagen protein indicates that
the protein product of this gene is useful for the diagnosis and
treatment of tissue repair, and brain, kidney, immune disorders.
Moreover, this protein may also be important in the diagnosis or
treatment of various autoimmune disorders such as rheumatoid
arthritis, lupus, scleroderma, and dermatomyositis as well as
dwarfism, spinal deformation, and specific joint abnormalities as
well as chondrodysplasias i.e. spondyloepiphyseal dysplasia
congenita, familial osteoarthritis, Atelosteogenesis type II,
metaphyseal chondrodysplasia type Schmid. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[0265] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:49 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1728 of SEQ ID NO:49, b is an integer
of 15 to 1742, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:49, and where b is greater
than or equal to a+14.
[0266] Features of Protein Encoded by Gene No: 40
[0267] The translation product of this gene shares sequence
homology with mini-collagen which is thought to be important in
tissue repair and tumor metastasis, and potentially in cellular
migration, attachment, and/or chemotaxis. (See Genbank Accession
No. gnl.vertline.PID.vertline.d1006976- .) Preferred polypeptide
fragments comprise the amino acid sequence:
PGFRGPSGSLGCSFFPRSLGRVLPPGCQRPGAHADSSPPPTP (SEQ ID NO:594). Also
preferred are polynucleotides encoding this polypeptide fragment.
The gene encoding the disclosed cDNA is believed to reside on
chromosome 16. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
16.
[0268] This gene is expressed in ovarian cancer, and to a lesser
extent, in dendritic cells and smooth muscle.
[0269] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, tumor metastasis, tissue repair, integumentary,
reproductive, and/or immune disorders, particularly cancers.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the tumor metastasis and tissue repair, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., integumentary, immune,
hematopoietic, reproductive, ovarian, and cancerous and wounded
tissues) or bodily fluids (e.g., lymph, serum, plasma, urine,
synovial fluid and spinal fluid) or another tissue or cell sample
taken from an individual having such a disorder, relative to the
standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0270] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 288 as residues: Asn-2 to His-11.
[0271] The tissue distribution in dendritic cells, combined with
the homology to the mini-collagen gene indicates that the protein
product of this gene is useful for diagnosis and treatment of tumor
metastasis and tissue repair. Alternatively, this protein may also
be important in the diagnosis or treatment of various autoimmune
disorders such as rheumatoid arthritis, lupus, scleroderma, and
dermatomyositis as well as dwarfism, spinal deformation, and
specific joint abnormalities as well as chondrodysplasias ie.
spondyloepiphyseal dysplasia congenita, familial osteoarthritis,
Atelosteogenesis type II, metaphyseal chondrodysplasia type Schmid.
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[0272] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:50 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1473 of SEQ ID NO:50, b is an integer
of 15 to 1487, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:50, and where b is greater
than or equal to a+14.
[0273] Features of Protein Encoded by Gene No: 41
[0274] This gene shares sequence homology with the HIV TAT protein.
(See Genbank Accession No. 328416.) Preferred polypeptide fragments
comprise the amino acid sequence:
6 EDLKKPDPASLRAASCGEGKKRKACK (SEQ ID NO:595);
NCTCGLAEELEKEKSREQMSSQPKSA CGNCYLGDAFRCASCPYLGMPAFKPG EKVLLS
EDLKKPDPASLRAASCGEGKKRKACK (SEQ ID NO:596);
NCTCGLAEELEKEKSREQMSSQPKSA CGNCYLGDAFRCASCPYLGMPAFKPG EKVLLSDSNLHD
CGNCYLGDAFRCASCPYLGMPAFKPG (SEQ ID NO:597); EKVLLSDS
SCGEGKKRKACKNCTCGLAEELEKE (SEQ ID NO:598), SQPKSACGNCYLGDAFRCASC
(SEQ ID NO:599); CCCVSKDQGIMGPGFR (SEQ ID NO:601),
HSVTELQTPALSLISAMLPPSCLSEL (SEQ ID NO:602),
LVYSILCDTSQVAHNLLRAPEDSLTG CCDDIQCPSAPFHP QPHLTVALHLC
PVVIYVNLQVLNLLHILTYLEILHVL LLVYSILCDTSQVAHNLLRAPEDS (SEQ ID
NO:603), LTVALHLCPVVIYVNLQVLNLLHILT (SEQ ID NO:604), and/or
REAGQNSERQYVSLSRDP (SEQ ID NO:600).
[0275] Also preferred are polynucleotide fragnents encoding these
polypeptide fragments.
[0276] This gene is expressed primarily in the infant brain, and to
a lesser extent, in the breast and testes.
[0277] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neural, developmental, reproductive, brain, testes and
breast disorders. Similarly, polypeptides and antibodies directed
to these polypeptides are useful in providing immunological probes
for differential identification of the tissue(s) or cell type(s).
For a number of disorders of the above tissues or cells,
particularly of the brain, testes and breast disorders, expression
of this gene at significantly higher or lower levels may be
routinely detected in certain tissues or cell types (e.g., neural,
developmental, reproductive, testicular, breast, and cancerous and
wounded tissues) or bodily fluids (e.g., seminal fluid, amniotic
fluid, lymph, serum, plasma, urine, synovial fluid and spinal
fluid) or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[0278] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 289 as residues: Pro-7 to Val-15.
[0279] The tissue distribution in infant brain tissue indicates
that the protein product of this gene is useful for diagnosis and
treatment of neural and other related disorders. Similarly the
protein product of this gene is useful for the detectionl/treatment
of neurodegenerative disease states, behavioural disorders, or
inflamatory conditions such as Alzheimers Disease, Parkinsons
Disease, Huntingtons Disease, Tourette Syndrome, meningitis,
encephalitis, demyelinating diseases, peripheral neuropathies,
neoplasia, trauma, congenital malformations, spinal cord injuries,
ischemia and infarction, aneurysms, hemorrhages, schizophrenia,
mania, dementia, paranoia, obsessive compulsive disorder, panic
disorder, learning disabilities, ALS, psychoses, autism, and
altered behaviors, including disorders in feeding, sleep patterns,
balance, and perception. In addition, elevated expression of this
gene product in regions of the brain indicates that it plays a role
in normal neural function. Potentially, this gene product is
involved in synapse formation, neurotransmission, learning,
cognition, homeostasis, or neuronal differentiation or survival.
Moreover, the gene or gene product may also play a role in the
treatment and/or detection of developmental disorders associated
with the developing embryo, sexually-linked disorders, or disorders
of the cardiovascular or reproductive system. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[0280] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:51 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1314 of SEQ ID NO:51, b is an integer
of 15 to 1328, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:51, and where b is greater
than or equal to a+14.
[0281] Features of Protein Encoded by Gene No: 42
[0282] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
FFNALYVFRKPQAIFDSEKENKRKNPTKYNNPLRYIYFKVKL- IFQFIPLANYKIK (SEQ ID
NO:605). Polynucleotides encoding these polypeptides are also
encompassed by the invention. The gene encoding the disclosed cDNA
is believed to reside on chromosome 3. Accordingly,
polynuLcleotides related to this invention are useful as a marker
in linkage analysis for chromosome 3.
[0283] This gene is expressed primarily in the infant brain, human
cerebellum, and to a lesser extent, in medulloblastoma.
[0284] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, brain related disorders, such as neurodegenerative
conditions, medulloblastoma, and other cancers or proliferative
conditions. Similarly, polypeptides and antibodies directed to
these polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the brain related disorders and brain cancers, including
medulloblastoma, expression of this gene at significantly higher or
lower levels may be routinely detected in certain tissues or cell
types (e.g., neural, developmental, and cancerous and wounded
tissues) or bodily fluids (e.g., lymph, amniotic fluid, serum,
plasma, urine, synovial fluid and spinal fluid) or another tissue
or cell sample taken from an individual having such a disorder,
relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0285] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 290 as residues: Thr-41 to Glu-47.
[0286] The tissue distribution in infant brain and medulloblastoma
indicates that the protein product of this gene is useful for
diagnosis and treatment of human brain related disorders, brain
cancers, and medulloblastoma. Similarly, the protein product of
this gene is useful for the detection/treatment of
neurodegenerative disease states, behavioural disorders, or
inflamatory conditions such as Alzheimers Disease, Parkinsons
Disease, Huntingtons Disease, Tourette Syndrome, meningitis,
encephalitis, demyelinating diseases, peripheral neuropathies,
neoplasia, trauma, congenital malformations, spinal cord injuries,
ischemia and infarction, aneurysms, hemorrhages, schizophrenia,
mania, dementia, paranoia, obsessive compulsive disorder, panic
disorder, learning disabilities, ALS, psychoses, autism, and
altered behaviors, including disorders in feeding, sleep patterns,
balance, and perception. In addition, elevated expression of this
gene product in regions of the brain indicates that it plays a role
in normal neural function. Potentially, this gene product is
involved in synapse formation, neurotransmission, learning,
cognition, homeostasis, or neuronal differentiation or survival.
Moreover, the gene or gene product may also play a role in the
treatment and/or detection of developmental disorders associated
with the developing embryo, sexually-linked disorders, or disorders
of the cardiovascular system. Protein, as well as, antibodies
directed against the protein may show utility as a tumor marker
and/or immunotherapy targets for the above listed tissues.
[0287] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:52 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1842 of SEQ ID NO:52, b is an integer
of 15 to 1856, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:52, and where b is greater
than or equal to a+14.
[0288] Features of Protein Encoded by Gene No: 43
[0289] The translation product of this gene shares sequence
homology with a phosphotyrosine-indepepdent ligand for the lck SH2
domain which is thought to be important in signal transduction
related to phosphotyrosine-independent ligand for the lck SH2
domain, which may implicate this protein as playing an essential
role in regulating key cellular processes such as cellular
division, and potentially in male fertility. (See Genbank Accession
No. gi.vertline.1184951.) Preferred polypeptide fragments comprise
the amino acid sequence:
7 ESSGQARTLADPGPGWPRQQGMCFGS (SEQ ID NO:606),
LTGLSTTPHGFLTVSAEADPRLIESL SQMLSMGFSDEGGWLTRLLQTKNYDI GAALDTIQYSKH
YSMVYIYHIFFIHSLLDGQLGWFHIF (SEQ ID NO:607), AIVSCAAPDI
IFNSFAFSTYISKSC SFYLQNVSCIHSSLSIFNLFQCPIIS CMEECNNWLTGLFLHFKIKRCDR
LSPSPRCCPWASLMKAAGSPGSCRPR (SEQ ID NO:608),
TMTSERLWTPSSIQSIPRRCDHFC P PLLRAPLLSHSCVKLA
GWPRQQGMCFGSLTGLSTTPHGFLTV (SEQ ID NO:609), SAEADPRL
LGWFHIFAIVSCAAPDI IFNSFAFS (SEQ ID NO:610), TYISKSCS
SLSIFNLFQCPIISCMEECNNWLTG (SEQ ID NO:611), and/or
LMKAAGSPGSCRPRTMTSERLWTPSS (SEQ ID NO:612). IQSI
[0290] Also preferred are polynucleotide fragments encoding this
polypeptide fragment. It is likely that this gene is a new member
of a family of phosphotyrosine-independent ligands for the lck SH2
domains.
[0291] This gene is expressed primarily in the placenta, and to a
lesser extent, in endothelial cells and neutrophils.
[0292] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, reproductive, cardiovascular, immune, and infectious
diseases. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the cardiovascular, reproductive, and immune system, and infectious
diseases, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g., reproductive, cardiovascular, immune, hematopoietic, and
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
amniotic fluid, seminal fluid, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0293] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 291 as residues: Ile-93 to Arg-98.
[0294] The tissue distribution in placenta and endothelial tissues,
combined with the homology to a phosphotyrosine-independent ligand
for the lck SH2 domain indicates that the protein product of this
gene is useful for diagnosis and treatment of cardiovascular,
reproductive, and immune system diseases, as well as infectious
diseases. Moreover, the polypeptide of this gene may be able to
modulate T or B cell development and/or T or B cell activation
(e.g. by modulation of Lck activity). It may also be capable of
modulating degradation of cellular proteins (e.g. cell cycle
regulatory proteins stimulating expression of cell cycle dependent
kinase inhibitors and arresting cell cycle progression at specific
boundaries to thereby modulate cell proliferation). p62 acts to
boost B cell response and may be used to treat disorders where this
is beneficial, e.g. infections by pathogenic microorganisms, e.g.
bacteria, viruses and protozoans. p62 can be used to expand T cell
populations for treating infectious diseases or cancer, e.g. the
resulting cells may be transduced to render them resistant to HIV
infection. Inhibitors of p62 can be used to reduce B or T cell
responses and may be used to treat a variety of autoimmune
diseases, e.g. diabetes mellitus, arthritis, multiple sclerosis
allergic reactions, Crohn's diseases etc. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[0295] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:53 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1544 of SEQ ID NO:53, b is an integer
of 15 to 1558, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:53, and where b is greater
than or equal to a+14.
[0296] Features of Protein Encoded by Gene No: 44
[0297] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
8 SSSSPRRPRELLGSLKTPLVRPHSAP (SEQ ID NO:613), and/or
LDLPGSFCXHTADPMGALHTRFWGRQ TWIHRKL RLHGTSRLASKXGIQFLR
NPSKTHTPRDAAFRDPGQTPDPQSLQ APSPSKCSAPNRATSVWSLKPRLLYK
HRPSSDKTPPPGRQAPLLFFSAG FLRNPSKTHTPRDAAFRDPGQTPDPQ (SEQ ID NO:614).
SLQA
[0298] Polynucleotides encoding these polypeptides are also
encompassed by the invention.
[0299] This gene is expressed primarily in the fetal brain,
cerebellum, and to a lesser extent, in the placenta.
[0300] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neural, developmental, or reproductive disorders,
particularly cancers. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the neuronal cell related
disorders, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g., neural, reproductive, vascular, and cancerous and wounded
tissues) or bodily fluids (e.g., lymph, amniotic fluid, serum,
plasma, urine, synovial fluid and spinal fluid) or another tissue
or cell sample taken from an individual having such a disorder,
relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0301] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO. 292 as residues: Thr-20 to Gly-28.
[0302] The tissue distribution in fetal brain, combined with the
homology to proline-rich protein genes indicates that the protein
product of this gene is useful for diagnosis and treatment of
neuronal cell related disorders. Similarly, the protein product of
this gene is useful for the detection/treatment of
neurodegenerative disease states, behavioural disorders, or
inflamatory conditions such as Alzheimers Disease, Parkinsons
Disease, Huntingtons Disease, Tourette Syndrome, meningitis,
encephalitis, demyelinating diseases, peripheral neuropathies,
neoplasia, trauma, congenital malformations, spinal cord injuries,
ischemia and infarction, aneurysms, hemorrhages, schizophrenia,
mania, dementia, paranoia, obsessive compulsive disorder, panic
disorder, learning disabilities, ALS, psychoses, autism, and
altered behaviors, including disorders in feeding, sleep patterns,
balance, and perception. In addition, elevated expression of this
gene product in regions of the brain indicates that it plays a role
in normal neural function. Potentially, this gene product is
involved in synapse formation, neurotransmission, learning,
cognition, homeostasis, or neuronal differentiation or survival.
Moreover, the gene or gene product may also play a role in the
treatment and/or detection of developmental disorders associated
with the developing embryo, sexually-linked disorders, or disorders
of the cardiovascular system. Moreover, expression within fetal
tissue and other cellular sources marked by proliferating cells
indicates that this protein may play a role in the regulation of
cellular division, and may show utility in the diagnosis and
treatment of cancer and other proliferative disorders. Similarly,
developmental tissues rely on decisions involving cell
differentiation and/or apoptosis in pattern formation. Thus this
protein may also be involved in apoptosis or tissue differentiation
and could again be useful in cancer therapy. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[0303] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:54 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 934 of SEQ ID NO:54, b is an integer
of 15 to 948, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:54, and where b is greater
than or equal to a+14.
[0304] Features of Protein Encoded by Gene No: 45
[0305] The translation product of this gene shares sequence
homology with precerebellin precerebellin of human, which is
thought to be important in synaptic physiology. (See Genbank
Accession No. gi.vertline.180251.) The cerebellum contains a
hexadecapeptide, termed cerebellin, that is conserved in sequence
from human to chicken. Three independent, overlapping cDNA genes
have been isolated from a human cerebellum cDNA library that encode
the cerebellin sequence. The longest gene codes for a protein of
193 amino acids that we term precerebellin. This protein has a
significant similarity (31.3% identity, 52.2% similarity) to the
globular (non-collagen-like) region of the B chain of human
complement component C1q. The region of relatedness extends over
approximately 145 amino acids located in the carboxyl terminus of
both proteins. Unlike C1q B chain, no collagen-like motifs are
present in the amino-terminal regions of precerebellin. The amino
terminus of precerebellin contains three possible N-linked
glycosylation sites. Although hydrophobic amino acids are clustered
at the amino terminus, they do not conform to the classical
signal-peptide motif, and no other obvious membrane-spanning
domains are predicted from the cDNA sequence. The cDNA predicts
that the cerebellin peptide is flanked by Val-Arg and Glu-Pro
residues. Therefore, cerebeliin is not liberated from precerebellin
by the classical dibasic amino acid proteolytic-cleavage mechanism
seen in many neuropeptide precursors. In Northern (RNA) blots,
precerebellin transcripts, with four distinct sizes (1.8, 2.3, 2.7,
and 3.0 kilobases), are abundant in cerebellum. These transcripts
are present at either very low or undetectable levels in other
brain areas and extraneural structures. A similar pattern of
cerebellin precursor transcripts are seen in rat, mouse, and human
cerebellum. Furthermore, a partial genomic fragment from mouse
shows the same bands in Northern blots as the human cDNA gene.
During rat development, precerebellin transcripts mirror the level
of cerebellin peptide. Low levels of precerebellin mRNA are seen at
birth. Levels increase modestly from postpartum day 1 to 8, then
increase more dramatically between day 5 and 15, and eventually
reach peak values between day 21 and 56. It has been observed that
cerebellin-like immunoreactivity is associated with Purkinje cell
postsynaptic structures. Thus, it is likely that this gene also
have synaptic activity. Northern analysis showed a brain-specific
2.4 kb message. This is consistant with the current insert size we
have, suggesting our gene is full-length and is brain-specific.
Preferred polypeptide fragments comprise the amino acid
sequence:
9 QEGSEPVLLEGECLVVCEPGRAAAGG (SEQ ID NO:615), PGGAALGEAPPGRVAFXA
VRSHHHE PAGETGNGTSGAIYFDQVL VNEGGG FDRASGSFVAPVRGVYSFRFHVVKVY
NRQTVQVSLMLN TWPVISAFANDPD VTREAATSSVLLPLDPGDRVSLR LR RGXSTGW
GETGNGTSGAIYFDQVLVNEGGGFDR (SEQ ID NO:616), ASG SFVAPV
NDPDVTREAATSSVLLPLDPGDRVS (SEQ ID NO:617), FHVVKVYNRQT (SEQ ID
NO:618), IYFDQVLVN (SEQ ID NO:619), ESRERSGNRRGAEDRGTCGLQSPSA (SEQ
ID NO:620), EMPQFYFFLKLGCLAQVPMQRGGIGA (SEQ ID NO:621),
RGSXXPAXAVXGAREGRRKLSGAGFL CLKDLGPSEREDEEARET
MPQFYFFLKLGCLAQVPMQRGGIGAR (SEQ ID NO:622), G
QATCSASGSPGQFGGCTPSPHGTG S (SEQ ID NO:623),
CRHPGQGLRRSQRPGQSHRPRSPGPG RSRWPHWCHCRFPLLAHGGGFGPQQM
PLAQGVPLPGLLPRAPL QQLGQAHR PPGTPPPAGRALTPPGPTRPPGPEAP
EPRAARDCVGDLVASVAWLPTWLRGS ATHKCPGLLP LFCFRSSPWILTAGT LIVCPL
GCTPSPHGTGSCRHPGQGLRRSQRP (SEQ ID NO:624),
SRWPHWCHCRFPLLAHGGGFGPQQMP (SEQ ID NO:625),
DCVGDLVASVAWLPTWLRGSATHKCP (SEQ ID NO:626), GL
DDRPRVQHQAHLDSLAVVHLHHMEP (SEQ ID NO:627), EAVDTPDRGYEGARGPVKATALV-
HQD LVEVDGPTGAIAGFPCWLMVVASDRX KCHSPRGCLSQGCSPGPP CSSSARL
TDHQALPLQQDGL YEGARGPVKATALVHQDLVEVDGPTG (SEQ ID NO:628), AIAGF
MAPLVPLPVSPAGSWWWLRTAXNATR (SEQ ID NO:629), PGGASPRAAPPGPP
AAARPGSQTTR HSPSSRTGSDPSWAHPAPRARST- RTK GSPGLCRGPGSQCGLAPNMAEGLCNP
QVPRSSA PLLFPLLSLDSHRRHPDS LPSLGSLNPLSIPVSQLCPASHSYSC CHCSS
SSRTGSDPSWAHPAPRARSTRTKGSP (SEQ ID NO:630), and/or GLC
RRHPDSLPSLGSLNPLSIPVSQLCPA (SEQ ID NO:631). S
[0306] Also preferred are polynucleotide fragments encoding these
polypeptide fragments.
[0307] This gene is expressed primarily in cerebellum and infant
brain. By Northern analysis, a single transcript of 2.4 kb was
observed in brain tissues.
[0308] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neural and developmental disorders, particularly
neuronal cell signal transduction, synaptic physiology, or
proliferative conditions such as cancer. Similarly, polypeptides
and antibodies directed to these polypeptides are useful in
providing immunological probes for differential identification of
the tissue(s) or cell type(s). For a number of disorders of the
above tissues or cells, particularly of the neuronal cell signal
transduction and synaptic physiology expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., neural, developmental, and
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
amniotic fluid, serum, plasma, urine, synovial fluid and spinal
fluid) or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[0309] The tissue distribution in cerebellum and infant brain,
combined with the homology to the conserved precerebellin gene or
gene family indicates that the protein product of this gene is
useful for diagnosis and treatment of neuronal cell related
disorders. Furthermore, the protein product of this gene is useful
for the detection/treatment of neurodegenerative disease states,
behavioural disorders, or inflamatory conditions such as Alzheimers
Disease, Parkinsons Disease, Huntingtons Disease, Tourette
Syndrome, meningitis, encephalitis, demyelinating diseases,
peripheral neuropathies, neoplasia, trauma, congenital
malformations, spinal cord injuries, ischemia and infarction,
aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia,
obsessive compulsive disorder, panic disorder, learning
disabilities, ALS, psychoses, autism, and altered behaviors,
including disorders in feeding, sleep patterns, balance, and
perception. In addition, elevated expression of this gene product
in regions of the brain indicates that it plays a role in normal
neural function. Potentially, this gene product is involved in
synapse formation, neurotransmission, learning, cognition,
homeostasis, or neuronal differentiation or survival. Moreover, the
gene or gene product may also play a role in the treatment and/or
detection of developmental disorders associated with the developing
embryo, sexually-linked disorders, or disorders of the
cardiovascular system. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0310] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:55 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 976 of SEQ ID NO:55, b is an integer
of 15 to 990, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:55, and where b is greater
than or equal to a+14.
[0311] Features of Protein Encoded by Gene No: 46
[0312] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
10 STHASGPPAPERLCLPERGTAPWGRR (SEQ ID NO:632), ANDAA
VRRWWLRTMGAAAHCT PEQRRPRRP (SEQ ID NO:633), and/or
ATILGMDTQNILHTRLSLCSLSWVSL ASSFXXLAXRRKAIVVQQKQSKISKK KKVEKXXLN
DSVNENSDTVGQIVHY IMKNEANADVLKAMVADNSLYDPESP
VTPSTPGSPPVSPGLCHQGGRQGSTS VA IICIRWAVXSRGMCVIGVGTSGG TL
IMKNEANADVLKAMVADNSLYDPESP (SEQ ID NO:634). VTP
[0313] Polynucleotides encoding these polypeptides are also
encompassed by the invention.
[0314] This gene is expressed in fetal liver and spleen, and to a
lesser extent in bone marrow, umbilical vein, and T cells.
[0315] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, disorders of the immune system, particularly
hematopoiesis. Similarly, polypeptides and antibodies directed to
these polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the hematopoiesis and immune disorders, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., immune, hematopoietic,
developmental, and cancerous and wounded tissues) or bodily fluids
(e.g., lymph, amniotic fluid, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0316] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 294 as residues: Asp-30 to Glu-57.
[0317] The tissue distribution in fetal liver/spleen and bone
marrow indicates that the protein product of this gene is useful
for diagnosis and treatment of hematopoietic and immune disorders.
Moreover, the protein product of this gene is useful for the
treatment and diagnosis of hematopoetic related disorders such as
anemia, pancytopenia, leukopenia, thrombocytopenia or leukemia
since stromal cells are important in the production of cells of
hematopoietic lineages. The uses include bone marrow cell ex vivo
culture, bone marrow transplantation, bone marrow reconstitution,
radiotherapy or chemotherapy of neoplasia. The gene product may
also be involved in lymphopoiesis, therefore, it can be used in
immune disorders such as infection, inflammation, allergy,
immunodeficiency etc. In addition, this gene product may have
commercial utility in the expansion of stem cells and committed
progenitors of various blood lineages, and in the differentiation
and/or proliferation of various cell types. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[0318] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:56 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1589 of SEQ ID NO:56, b is an integer
of 15 to 1603, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:56, and where b is greater
than or equal to a+14.
[0319] Features of Protein Encoded by Gene No: 47
[0320] The translation product of this gene shares sequence
homology with a 12 kD nucleic acid binding protein of Feline
calcivirus which is thought to be important in viral replication
and may implicate this protein as playing an integral role in the
development of host-viral inhibitors and/or novel vaccines. (See
Genbank Accession No. 59264). In specific embodiments, polypeptides
of the invention comprise the following amino acid sequence:
11 HCHLWASGSCLACFFPGGLTRDAAQQ (SEQ ID NO:635),
HVTKSYSPPYLSQTSHSCLVFQPVLW PEYTFWNLFEA ILQFQMNHSVLQQX
GPRHVCRGAEEAAAGEGPGYSDRAAA ARGAPSQWGRPAPKDTLAQTLGQTGR ASPR
LPAGLGTQAS PAPKDTLAQTLGQTGRASPR LPAGL (SEQ ID NO:636), GTQ
TIACFSXKARD MYAEERKRQQLERD (SEQ ID NO:637), and/or
QATVTEQLLREGLQASGDAQLRRTRL HKLSARREERVQG FLQALELKRADW LARLGTASA
LRRTRLHKLSARREERVQG FLQALE (SEQ ID NO:638). LKR
[0321] Polynucleotides encoding these polypeptides are also
encompassed by the invention.
[0322] This gene is expressed primarily in human cardiomyopathy
tissue, and to a lesser extent, in T helper cells, fetal brain and
synovial sarcoma.
[0323] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, cardiovascular, immune, or developmental disorders,
particularly cardiomyopathy which occur secondary to viral
infections. Similarly, polypeptides and antibodies directed to
these polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the cardiovascular system, expression of this gene at significantly
higher or lower levels may be routinely detected in certain tissues
or cell types (e.g., cardiovascular, neural, developmental,
skeletal, immune cancerous and wounded tissues) or bodily fluids
(e.g., lymph, amniotic fluid, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0324] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 295 as residues: Trp-20 to Cys-26.
[0325] The tissue distribution in cardiomyopathy tissue, combined
with the homology to a viral 12 kD nucleic acid binding protein
indicates that the protein product of this gene is useful for
diagnosis and intervention of cardiomyopathy, including those
caused by ischemic, hypertensive, congenital, valvular, or
pericardial abnormalities. The gene expression pattern may be the
consequence or the cause for these conditions. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[0326] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:57 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1038 of SEQ ID NO:57, b is an integer
of 15 to 1052, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:57, and where b is greater
than or equal to a+14.
[0327] Features of Protein Encoded by Gene No: 48
[0328] The translation product of this gene shares sequence
homology with tumor necrosis factor related gene product, which is
thought to be important in tumor necrosis, bacterial and viral
infection, immune diseases and irnmunoreactions. In specific
embodiments, polypeptides of the invention comprise the following
amino acid sequence:
KMNSIPWQIPKETPXLDANLVIVECKPLWFCIGTIKQLKLWNQVFMGFKSMFF
RIGKLNYLFTIPYCYLFIDNILGIFYSILGAQGIKYNFYIQRIFTCLLNLNLKIHS NLA (SEQ
ID NO:639), LWFCIGTIKQLKLWNQVFMGFKSMFFR (SEQ ID NO:640),
YSILGAQGIKYNFYIQRIFTCLLNLN (SEQ ID NO:641), and/or TFKLVRFLE (SEQ
ID NO:642). Polynucleotides encoding these polypeptides are also
encompassed by the invention. The gene encoding the disclosed cDNA
is believed to reside on chromosome 10. Accordingly,
polynucleotides related to this invention are useful as a marker in
linkage analysis for chromosome 10.
[0329] This gene is expressed primarily in colon, and to a lesser
extent, in ovarian and breast cancers.
[0330] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, gastrointestinal, reproductive, colon, ovarian, breast
disorders, particularly cancers. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the colon, ovary and breast,
expression of this gene at significantly higher or lower levels may
be routinely detected in certain tissues or cell types (e.g.,
gastrointestinal, reproductive, colon, ovarian, breast, and
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
breast milk, bile, serum, plasma, urine, synovial fluid and spinal
fluid) or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[0331] The tissue distribution in colon tissue, combined with the
homology to tumor necrosis factors indicates that the protein
product of this gene is useful for the intervention of cancers of
the col6n, ovary and breast, particularly because TNF family
members are known to be involved in the tumor development. Protein,
as well as, antibodies directed against the protein may show
utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[0332] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:58 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 800 of SEQ ID NO:58, b is an integer
of 15 to 814, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:58, and where b is greater
than or equal to a+14.
[0333] Features of Protein Encoded by Gene No: 49
[0334] The translation product of this gene shares sequence
homology with mucins, such as epithelial mucin, which are thought
to be important in extracellular matrix functions such as
protection, lubrication and cell adhesion, which are important in a
variety of functions, particularly immune chemotaxis and
infiltration (See for example Genbank Accession No. R68002).
Preferred polypeptide fragments comprise the following amino acid
sequence: PRSRPALRPGRQRPPSHSATSGVLRPRKKPDP (SEQ ID NO:643), RKSFAK
PVLWTNAIQAGRGRVLCYTRPPPASSSFSALVPDGNRMEGLRTYFLNAFD
PGTDYLYLFPFSFTVTFQHCLTVRWAFESLQVPQNRPERWASHPLPTHXP AYLPDNQVXMSASG
(SEQ ID NO:644), GNRMEGLRTYFLNAFDPGTDYL YLF (SEQ ID NO:645) and/or
FQHCLTVRWAFESLQVPQNRPERWASHPLP (SEQ ID NO:646). Also preferred are
polynucleotide fragments encoding these polypeptide fragments.
Moreover, this gene maps to chromosome 22q11.2-qter, and therefore,
can be used as a marker in linkage analysis for chromosome 22.
[0335] This gene is expressed primarily in corpus colosum.
[0336] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, tumors, especially of the corpus colosum, as well as
metastatic lesions, autoimmune conditions, and integumentary
disorders. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the corpus colosum and other solid tissues, expression of this gene
at significantly higher or lower levels may be routinely detected
in certain tissues or cell types (e.g., integumentary, autoimmune,
neural, and cancerous and wounded tissues) or bodily fluids (e.g.,
lymph, serum, plasma, urine, synovial fluid and spinal fluid) or
another tissue or cell sample taken from an individual having such
a disorder, relative to the standard gene expression level, i.e.,
the expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0337] The tissue distribution in corpus colosum, combined with the
homology to mucins indicates that the protein product of this gene
is useful for serum tumor markers or immunotherapy targets because
tumor cells have greatly elevated levels of mucin expression and
shed the molecules into the epithelial tissues. Moreover, the
protein product of this gene is useful for the treatment,
diagnosis, and/or prevention of various skin disorders including
congenital disorders (i.e. nevi, moles, freckles, Mongolian spots,
hemangiomas, port-wine syndrome), integumentary tumors (i.e.
keratoses, Bowen's disease, basal cell carcinoma, squamous cell
carcinoma, malignant melanoma, Paget's disease, mycosis fungoides,
and Kaposi's sarcoma), injuries and inflammation of the skin (i.e.
wounds, rashes, prickly heat disorder, psoriasis, dermatitis),
atherosclerosis, uticaria, eczema, photosensitivity, autoimmune
disorders (i.e. lupus erythematosus, vitiligo, dermatomyositis,
morphea, scleroderma, pemphigoid, and pemphigus), keloids, striae,
erythema, petechiae, purpura, and xanthelasma. In addition, such
disorders may predispose increased susceptibility to viral and
bacterial infections of the skin (i.e. cold sores, warts,
chickenpox, molluscum contagiosum, herpes zoster, boils,
cellulitis, erysipelas, impetigo, tinea, althletes foot, and
ringworm). Moreover, the protein product of this gene may also be
useful for the treatment or diagnosis of various connective tissue
disorders such as arthritis, trauma, tendonitis, chrondomalacia and
inflammation, autoimmune disorders such as rheumatoid arthritis,
lupus, scleroderma, and dermatomyositis as well as dwarfism, spinal
deformation, and specific joint abnormalities as well as
chondrodysplasias (ie. spondyloepiphyseal dysplasia congenita,
familial osteoarthritis, Atelosteogenesis type II, metaphyseal
chondrodysplasia type Schmid). Protein, as well as, antibodies
directed against the protein may show utility as a tumor marker
and/or immunotherapy targets for the above listed tissues.
[0338] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:59 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1201 of SEQ ID NO:59, b is an integer
of 15 to 1215, where both a and b correspond to the positions of
nucteotide residues shown in SEQ ID NO:59, and where b is greater
than or equal to a+14.
[0339] Features of Protein Encoded by Gene No: 50
[0340] This gene is expressed primarily in CD34 depleted buffy coat
cord blood and primary dendritic cells.
[0341] Therefore, polynucleotides and polypeptides of the invention
are useful as reaaents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, hematopoietic disorders and immunological disorders,
particularly those related to developmental or reproductive
conditions. Similarly, polypeptides and antibodies directed to
these polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the hematopoietic and immune systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., developmental, immune,
hematopoietic, and cancerous and wounded tissues) or bodily fluids
(e.g., lymph, amniotic fluid, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0342] The tissue distribution in CD34 depleted buffy coat cord
blood and primary dendritic cells indicates that the protein
product of this gene is useful for the diagnosis and treatment of
hematopoietic and immune disorders. Secreted or cell surface
proteins in the above tissue distribution often are involved in
cell activation (e.g. cytokines) or molecules involved in cell
surface activation. Moreover, the protein product of this gene is
useful for the treatment and diagnosis of hematopoetic related
disorders such as anemia, pancytopenia, leukopenia,
thrombocytopenia or leukemia since stromal cells are important in
the production of cells of hematopoietic lineages. The uses include
bone marrow cell ex vivo culture, bone marrow transplantation, bone
marrow reconstitution, radiotherapy or chemotherapy of neoplasia.
The gene product may also be involved in lymphopoiesis, therefore,
it can be used in immune disorders such as infection, inflammation,
allergy, immunodeficiency etc. In addition, this gene product may
have commercial utility in the expansion of stem cells and
committed progenitors of various blood lineages, and in the
differentiation and/or proliferation of various cell types.
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[0343] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:60 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 464 of SEQ ID NO:60, b is an integer
of 15 to 478, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:60, and where b is greater
than or equal to a+14.
[0344] Features of Protein Encoded by Gene No: 51
[0345] The translation product of this gene shares sequence
homology with Interferon induced 1-8 gene encoded polypeptide,
which is thought to be important in binding to retroviral rev
responsive elements and may be beneficial in the development of
novel inhibitors of host-viral interactions leading to effective
viral vaccines. Preferred polypeptide fragment comprise the
following amino acid sequences: MTLITPSXKLTFXKGNKSWSSRACSSTLVDP
(SEQ ID NO:647), FLFLHAVDPW PSNG (SEQ ID NO:648),
WSCQSGVFLVFTGCSVLCQMLSGAVVVWRRSAP EDSAVWQASINKPRGKGRHGIKGENTSV (SEQ
ID NO:649), and/or LVFTGC SVLCQMLSGAVVVWRRSAPEDSAVWQASI (SEQ ID
NO:650). Also preferred are polynucleotide fragments encoding these
polypeptide fragments.
[0346] This gene is expressed primarily in CD34 positive cells and
neutrophils.
[0347] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, viral infection, such as AIDS, and other immune or
hematopoietic disorders. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the immune system, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g., immune,
hematopoietic, and cancerous and wounded tissues) or bodily fluids
(e.g., lymph, amniotic fluid, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0348] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 299 as residues: Gln-51 to Trp-62.
[0349] The tissue distribution in neutrophils and CD34 positive
cells, combined with the homology to interferon induced gene 1-8
indicates that the protein product of this gene is useful for the
intervention of retroviral infection including HIV. The factor may
be involved in viral stability or viral entry into the cells.
Alternatively, the virus/factor complex may elicit the cellular
immune reaction and could possibly play a beneficial role in the
develpoment of effective inhibitors of host-viral interactions,
such as exists for novel viral vaccines. Moreover, this gene
product may be involved in the regulation of cytokine production,
antigen presentation, or other processes that may also suggest a
usefulness in the treatment of cancer (e.g. by boosting immune
responses). Since the gene is expressed in cells of lymphoid
origin, the natural gene product may be involved in immune
functions. Therefore it may be also used as an agent for
immunological disorders including arthritis, asthma,
immunodeficiency diseases such as AIDS, leukemia, rheumatoid
arthritis, granulomatous disease, inflammatory bowel disease,
sepsis, acne, neutropenia, neutrophilia, psoriasis,
hypersensitivities, such as T-cell mediated cytotoxicity; immune
reactions to transplanted organs and tissues, such as
host-versus-graft and graft-versus-host diseases, or autoimmunity
disorders, such as autoimmune infertility, lense tissue injury,
demyelination, systemic lupus erythematosis, drug induced hemolytic
anemia, rheumatoid arthritis, Sjogren's disease, scleroderma and
tissues. In addition, this gene product may have commercial utility
in the expansion of stem cells and committed progenitors of various
blood lineages, and in the differentiation and/or proliferation of
various cell types. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0350] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:61 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 604 of SEQ ID NO:61, b is an integer
of 15 to 618, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:61, and where b is greater
than or equal to a+14.
[0351] Features of Protein Encoded by Gene No: 52
[0352] This gene shares sequence homology to immunoglobulin lambda
chain (See Genbank Accession No. 2865484). Therefore it is likely
that this gene has activity similar to an immunoglobulin lambda
chain and may play a benefical role in the development of effective
immunotherapy-based toxins. Preferred polypeptide fragments
comprise the following amino acid sequence:
GHPSPALSIAPSDGSQLPCDEVPYGEAHVTRYCKKPLTNSHLETEAQSSSL (SEQ ID
NO:651), NNKHYLSFCGSGFCPVYLGFTGLASIIQAVKVLVVAV
IIPRQDRERICLQAQVGRIHLRGCWT- GPPFLDGYWSEAFYNTLSRGPLHRA
PHHMATGFHQREQWKEQEKGDQGRHRSLLVASPQKRCYFCCILXVRSE- SLGP GVEFYXGVNGRR
(SEQ ID NO:652), ERICLQAQVGRIHLRGCWTGPPELDGY WSEAF (SEQ ID NO:653),
SDGSQLPCDEVPYGEAHVTRYCKKPL (SEQ ID NO:654), and/or
HQREQWKEQEKGDQGRHRSLLVASPQK (SEQ ID NO:655). Also preferred are
polynucleotide fragments encoding these polypeptide fragments.
[0353] This gene is expressed primarily in Hodgkin's lymphoma.
[0354] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, Hodgkin's lymphoma and other immune or hematopoietic
disorders. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune system, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g., immune, hematopoietic, and cancerous and wounded
tissues) or bodily fluids (eg., lymph, serum, plasma, urine,
synovial fluid and spinal fluid) or another tissue or cell sample
taken from an individual having such a disorder, relative to the
standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0355] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 300 as residues: Pro-27 to Thr-32.
[0356] The tissue distribution in Hodgkin's lymphoma, combined with
the sequence homology to immunoglobulin lambda chain protein
indicates that the protein product of this gene is useful for the
diagnosis of Hodgkin's lymphoma, since the elevated expression and
secretion by the tumor mass may be indicative of tumors of this
type. Additionally the gene product may be used as a target in the
immunotherapy of the cancer. Because the gene is expressed in cells
of lymphoid origin, the natural gene product may be involved in
immune functions. Therefore it may be also used as an agent for
immunological disorders including arthritis, asthma, immune
deficiency diseases such as AIDS, and leukemia. Protein, as well
as, antibodies directed against the protein may show utility as a
tumor marker and/or immunotherapy targets for the above listed
tissues.
[0357] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:62 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 737 of SEQ ID NO:62, b is an integer
of 15 to 751, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:62, and where b is greater
than or equal to a+14.
[0358] Features of Protein Encoded by Gene No: 53
[0359] This gene has extensive homology to cDNA for Homo sapiens
mRNA for the ISLR gene(See Genbank Accession No. AB003184). This
protein is considered to be a new member of the Ig superfamily and
contains a leucine-rich repeat (LRR) with conserved flanking
sequences and a C2-type immunoglobulin (Ig)-like domain. These
domains are important for protein-protein interaction or cell
adhesion, and therefore it is possible that the novel protein ISLR
may also interact with other proteins or cells. The ISLR gene was
mapped on human chromosome 15q23-q24 by fluorescence in situ
hybridization (See Medline Article No. 97468140). Homology to the
ISLR gene has been confirmed by another independent group as well
(See Genbank Accession No. Hs.102171).
[0360] This gene is expressed in a number of tissues including
human retina, heart, skeletal muscle, prostate, ovary, small
intestine, thyroid, adrenal cortex, testis, stomach, spinal cord,
fetal lung and fetal kidney tissues, colon, tonsil and stomach
cancer, and to a lesser extent in endometrial stromal cells treated
with estradiol, breast tissue, synovium, lymphoma, and number of
other tumors.
[0361] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, tumors of colon, ovary, breast, and integumentary or
immune origins. However, due to the wide range of expression in
various tissues, protein may play a vital role in the development
of cancer in other tissues as well, not just those mentioned above.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the colon, ovary and breast, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., immune, integumentary,
reproductive, developmental, and cancerous and wounded tissues) or
bodily fluids (e.g., lymph, amniotic fluid, breast milk, seminal
fluid, bile, serum, plasma, urine, synovial fluid and spinal fluid)
or another tissue or cell sample taken from an individual having
such a disorder, relative to the standard gene expression level,
i.e., the expression level in healthy tissue or bodily fluid from
an individual not having the disorder. Additionally, this gene maps
to chromosome 15q23-q24, and therefore, can be used as a marker in
linkage analysis for chromosome 15.
[0362] The tissue distribution in tumors of colon, ovary, and
breast origins indicates that the protein product of this gene is
useful for the diagnosis and intervention of these tumors, in
addition to other tumors where expression has been indicated. The
secreted protein can also be used to determine biological activity,
to raise antibodies, as tissue markers, to isolate cognate ligands
or receptors, to identify agents that modulate their interactions
and as nutritional supplements. It may also have a very wide range
of biological acitivities. Typical of these are cytokine, cell
proliferation/differentiation modulating activity or induction of
other cytokines; immunostimulating/immunosuppressant activities
(e.g. for treating human immunodeficiency virus infection, cancer,
autoimmune diseases and allergy); regulation of hematopoiesis (e.g.
for treating anaemnia or as adjunct to chemotherapy); stimulation
or growth of bone, cartilage, tendons, ligaments and/or nerves
(e.g. for treating wounds); stimulation of follicle stimulating
hormone (for control of fertility); chemotactic and chemokinetic
activities (e.g. for treating infections, tumors); hemostatic or
thrombolytic activity (e.g. for treating haemophilia, cardiac
infarction, etc.); anti-inflammatory activity (e.g. for treating
septic shock, Crohn's disease); as antimicrobials; for treating
psoriasis or other hyperproliferative diseases; for regulation of
metabolism, and behaviour. Also contemplated is the use of the
corresponding nucleic acid in gene therapy procedures. Protein, as
well as, antibodies directed against the protein may show utility
as a tumnor marker and/or immunotherapy targets for the above
listed tissues.
[0363] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:63 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 766 of SEQ ID NO:63, b is an integer
of 15 to 780, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:63, and where b is greater
than or equal to a+14.
[0364] Features of Protein Encoded by Gene No: 54
[0365] Gene has homology to a multidrug resistence gene 1 (See
Genbank Accession No. P06795). Preferred polynucleotide fragments
comprise the following sequence:
gcttcgtgtccaaccctcttgcccttcgcctgtgtgcctggagccagtcccac-
cacgctcgcgtttcctcctgtag
tgctcacaggtcccagcaccgatggcattccctttgccctgagtctgcag-
cgggtcccttttgtgcttccttcccctcaggta gcctctctceccctgggccac
tcccgggggtgagggggttaccccttcccagtgttttttattcctgtggggctcaccccaaagtattaaaagt-
agctttgtaa (SEQ ID NO:656),
gcttcgtgtccaaccctcttgcccttcgcctgtgtgcctggagc
cagtcccaccacgctcgcgtttcctcctgtagtgctcacaggtcccagcaccgatggcattccctttgccctg-
agtctgcag
cgggtcccttttgtgcttccttcccctcaggtagcctctctccccctgggccactcccrggggg-
tgaggggottaccccttcccagtgttttttattcctgtggggctcacccca
aagtattaaaagtagctttgtaa (SEQ ID NO:657), gcttcgtgtccaac
cctcttarcccttcocctgytagctgoagccagtcccaccacgctcgcgtttcctcctgtagtgctcacaggt-
cccagcacegat ggcattccctttgccctgagt
ctgcagcgggtcccttttgtgcttccttcccctcaggta- gcctctctceccctgggccac
tcccgggggtgagggoattaccccttcccagtgttttttattcctgtggggc- tcacccca
aagtattaaaagtagctttgtaa (SEQ ID NO:658). Also preferred are
polypeptides comprising one or more of the fragments encoded by
these polynucleotide fragments. Moreover, In specific embodiments,
polypeptides of the invention comprise the following amino acid
sequence: FRINRLTIGXAVAMTRGNQRELARQKNMKKQSDSVKGKRRDDGLSAAARKQ RDSEI
(SEQ ID NO:659), AVAMTRGNQRELARQKNMKKQSDSVKGKR (SEQ ID NO:660),
KSRATRLRESAEMTGFLLPPASRGTRRSCSRSRKRQTRRRRNPSSF
VASCPTLLPFACVPGASPTTLAFPPV- VLTGPSTDGIPFALSLQRVPFVLPSPQVAS LPLGHSRG
(SEQ ID NO:661), LRESAEMTGFLLPPASRGTRRSCSRS (SEQ ID NO:662), and/or
VVLTGPSTDGIPFALSLQRVPFVLPSPQVA (SEQ ID NO:663). Polynucleotides
encoding these polypeptides are also encompassed by the
invention.
[0366] This gene is expressed primarily in lung, esophagus,
leukemia (Jurkat cells), breast cancers and to a lesser extent, in
macrophages treated with GM-CSF fetal tissues.
[0367] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune, developmental, or pulmonary disorders,
particularly cancers. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the solid tumors, lung and
leukemia, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g., immune, developmental, pulmonary, and cancerous and wounded
tissues) or bodily fluids (e.g., lymph, pulmonary surfactant and
sputum, amniotic fluid, serum, plasma, urine, synovial fluid and
spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
Furthermore, due to the high expression level in lung tissue and
the proposed function of the multidrug resistence protein 1 gene as
the efflux pump resposible for low-drug accumulation in
multidrug-resistent cells, protein as well mutants thereof, may
also be beneficial as a target for gene therapy, particularly for
the chronic patient.
[0368] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 302 as residues: Met-1 to Lys-16.
[0369] The tissue distribution cancers and fetal tissues indicates
that the protein product of this gene is useful for the detection
of cells in active proliferation, such as cancers. The gene
products may be used for cancer markers or immunotherapy target.
Similarly, the secreted protein can also be used to determine
biological activity, to raise antibodies, as tissue markers, to
isolate cognate ligands or receptors, to identify agents that
modulate their interactions and as nutritional supplements. It may
also have a very wide range of biological acitivities. Typical of
these are cytokine, cell proliferation/differentiation modulating
activity or induction of other cytokines;
immunostimulating/immunosuppres- sant activities (e.g. for treating
human immunodeficiency virus infection, cancer, autoimmune diseases
and allergy); regulation of hematopoiesis (e.g. for treating
anaemia or as adjunct to chemotherapy); stimulation or growth of
bone, cartilage, tendons, ligaments and/or nerves (e.g. for
treating wounds); stimulation of follicle stimulating hormone (for
control of fertility); chemotactic and chemokinetic activities
(e.g. for treating infections, tumors); hemostatic or thrombolytic
activity (e.g. for treating haemophilia, cardiac infarction, etc.);
anti-inflammatory activity (e.g. for treating septic shock, Crohn's
disease); as antimicrobials; for treating psoriasis or other
hyperproliferative diseases; for regulation of metabolism, and
behaviour. Also contemplated is the use of the corresponding
nucleic acid in gene therapy procedures. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[0370] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:64 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 574 of SEQ ID NO:64, b is an integer
of 15 to 588, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:64, and where b is greater
than or equal to a+14.
[0371] Features of Protein Encoded by Gene No: 55
[0372] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
LLSTSHLLTQSYSFNKRSHSFAWKNAHCILQSENNELQNSVY- IYVCIYVHF ICTFLCDI (SEQ
ID NO:664), and/or KRSHSFAWKNAHCILQSENNELQNSVYIYVC- I (SEQ ID
NO:665). Polynucleotides encoding these polypeptides are also
encompassed by the invention. The gene encoding the disclosed cDNA
is believed to reside on the X chromosome. Accordingly,
polynucleotides related to this invention are useful as a marker in
linkage analysis for the X chromosome.
[0373] This gene is expressed primarily in the brain, and to a
lesser extent, in the developing embryo.
[0374] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neurodegenerative disease states and developmental
disorders. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders, including X-linked disorders, of the above
tissues or cells, particularly of the neurological, developmental
systems, and cardiovascular system, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., neural, developmental, and
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
amniotic fluid, serum, plasma, urine, synovial fluid and spinal
fluid) or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[0375] The tissue distribution in neural tissue indicates that the
protein product of this gene is useful for the detection/treatment
of neurodegenerative disease states and behavioural disorders such
as Alzheimers Disease, Parkinsons Disease, Huntingtons Disease,
Klinefelter's, schizophrenia, mania, dementia, paranoia, obsessive
compulsive disorder and panic disorder. In addition, the gene or
gene product may also play a role in the treatment and/or detection
of developmental disorders associated with the developing embryo,
sexually- or X-linked disorders, or disorders of the cardiovascular
system. Protein, as well as, antibodies directed against the
protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[0376] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:65 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 931 of SEQ ID NO:65, b is an integer
of 15 to 945, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:65, and where b is greater
than or equal to a+14.
[0377] Features of Protein Encoded by Gene No: 56
[0378] The translation product of this gene shares sequence
homology with paxillin, which is thought to be important in
mediating signal transduction from growth factor receptors to the
cytoskeleton. Moreover, in normal hematopoietic cells and myeloid
cell lines, tyrosine phosphorylation of paxillin has been shown to
be rapidly and transiently induced by interleukin-3 and several
other hematopoietic growth factors. The predicted structure of
paxillin implicates this molecule in protein-protein interactions
involved in signal transduction from growth factor receptors and
the BCR/ABL oncogene fusion protein to the cytoskeleton. Preferred
polynucleotide fragments comprise the following sequence:
tggctcactgtcttacaatcactgctgtggaatcatgataccacttttagctctttgcat
cttccttcagtgtatttttgtttttcaagaggaagtagattttaactggacaactttgag
tactgacatcattgataaataaactggcttgtggtttcaa (SEQ ID NO:666). Also
preferred are polypeptide fragments encoded by these polynucleotide
fragments. More preferably, polypeptide fragments comprise the
amino acid sequence:
LDELMAHLTEMQAKVAVRADAGKKHLPDKQDHKASLDSMLGGLEQELQDLG
IATVPKGHCASCQKPIAGKVIHALGQSWHPEHFVCTHCKEEIGSSPFFER
SGLXYCPNDYHQLFSPRCAYCAAPILDKVLTAMNQTWHPEHFFCSHCGEVFG
AEGFHEKDKKPYCRKDFLAMFSPKCGGCNRPVLENYLSAMDTVWHPEC
FVCGDCFTSFSTGSFFELDGRPFC- ELHYHHRRGTLCHCCGQPITGRCISAM
GYKFHPEHFVCAFCLTQLSKGIFREQNDKTYCQPCFNKLF (SEQ ID NO:667),
KASLDSMLGGLEQELQDLGIATVPKGHCASCQKPIAGKVIHAL (SEQ ID NO:668),
CPNDYHQLFSPRCAYCAAPILDKVLTAMNQTWHPEHFFCS HCGEVFGAEG (SEQ ID
NO:669), DKKPYCRKDFLAMFSPKCGGCNRPVLEN
YLSAMDTVWHPECFVCGDCFTSFSTGSFFELDGRPFCEL (SEQ ID NO:670),
CGQPITGRCISAMGYKFHPEHFVCAFCLTQLSKGIFREQNDKTYCQ (SEQ ID NO:671),
HKSLAGAXVYTTNIQELNVYSEAQEPKESPPPSKTSAAAQLDEL
MAHLTEMQAKVAVRADAGKKHLPDKQDHKASLDSMLGGLEQELQDLGIA
TVPKGHCASCQKPIAGKVIHALG- QSWHPEHFVCTHCKEEIGSSPFFERSGL
XYCPNDYHQLFSPRCAYCAAPILDKVLTAMNQTWHPEHFFCSHCG- EVFGAEG
FHEKDKKPYCRKDFLAMFSPKCGGCNRPVLENYLSAMDTVWHPECFVCG
DCFTSFSTGSFFELDGRPFCELHYHHRRGTLCHGCGQPITGRCISAMGYKFH
PEHFVCAFCLTQLSKGIFREQNDKTYCQPCFNKLFPL (SEQ ID NO:672), NVY
DEAQEPKESPPPSKTSAAA (SEQ ID NO:673), DSMLGGLEQELQDLGIATVPKG HCAS
(SEQ ID NO:674), YLSAMDTVWHPECFVCGDCFTSFSTG (SEQ ID NO:675),
RCISAMGYKFHPEHFVCAFCLTQLSK (SEQ ID NO:676), PTRPVLFFS
TCQSCSSRPVRQEHLGCRTMEELDALLEELERSTLQDSDEYSNPAPLPLDQHSR
KETNLDETSEILSIQDNTSPLPAXSCILPISRSSMSTVKPKSQRNHHHLLKRQQ LLSWMSSWLT
(SEQ ID NO:677), PVRQEHLGCRTMEELDALLEELERSTLQ (SEQ ID NO:678),
SCILPISRSSMSTVKPKSQRN (SEQ ID NO:679), WHPEHFVC THC (SEQ ID
NO:680), LFSPRC (SEQ ID NO:681), PILDKV (SEQ ID NO:682), TWHPEHFF
(SEQ ID NO:683), EGFHEKD (SEQ ID NO:684), KFHPEHFVCAFCL (SEQ ID
NO:685), PITGRCI (SEQ ID NO:686), and/or HPEHFVC (SEQ ID NO:687).
Polynucleotide fragements encoding these preferred polypeptide
fragments are also contemplated. The gene encoding the disclosed
cDNA is believed to reside on chromosome 11. Accordingly,
polynucleotides related to this invention are useful as a marker in
linkage analysis for chromosome 11.
[0379] This gene is expressed primarily in brain, and to a lesser
extent in the developing embryo.
[0380] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neurological disease states and developmental
abnormalities. Similarly, polypeptides and antibodies directed to
these polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune and nervous systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., neural, developmental, immune,
hematopoieitic, and cancerous and wounded tissues) or bodily fluids
(e.g., lymph, amniotic fluid, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0381] The tissue distribution in brain, combined with the homology
to the conserved paxillin gene, indicates that the protein product
of this gene is useful for the treatment and or detection of
disease states associated with abnormal signal transduction in
brain and/or the developing embryo. This would include treatment or
detection of neurodegenerative disease states and behavioural
disorders such as Alzheimers Disease, Parkinsons Disease,
Huntintons Disease, schizophrenia, mania, dementia, paranoia,
obsessive compulsive disorder and panic disorder and also in the
treatment and or detection of embryonic development defects.
Moreover, expression within embryonic tissue and other cellular
sources marked by proliferating cells indicates that this protein
may play a role in the regulation of cellular division, and may
show utility in the diagnosis and treatment of cancer and other
proliferative disorders. Similarly, developmental tissues rely on
decisions involving cell differentiation and/or apoptosis in
pattern formation. Thus this protein may also be involved in
apoptosis or tissue differentiation and could again be useful in
cancer therapy. Protein, as well as, antibodies directed against
the protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[0382] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:66 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1852 of SEQ ID NO:66, b is an integer
of 15 to 1866, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NQ:66, and where b is greater
than or equal to a+14.
[0383] Features of Protein Encoded by Gene No: 57
[0384] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
RIYCSEDTFSPXAESGVSWQSSVSQLYQDYE (SEQ ID NO:688). Polynucleotides
encoding these polypeptides are also encompassed by the
invention.
[0385] This gene is expressed primarily in fetal spleen, brain, and
to a lesser extent, in six week old embryo.
[0386] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune disorders, neurological disorders, and
developmental abnormalities. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the immune and developmental
systems, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g., immune, neural, developmental, and cancerous and wounded
tissues) or bodily fluids (e.g., lymph, amniotic fluid, serum,
plasma, urine, synovial fluid and spinal fluid) or another tissue
or cell sample taken from an individual having such a disorder,
relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0387] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 305 as residues: Arg-28 to Gly-34.
[0388] The tissue distribution in fetal spleen indicates that the
protein product of this gene is useful for the treatment/detection
of immune disorders such as arthritis, asthma, immune deficiency
diseases such as AIDS, and leukemia. In addition the expression of
this gene in the early embryo, indicates a key role in embryo
development, and hence the gene or gene product could be used in
the treatment and or detection of embryonic developmental defects.
This would include treatment or detection of neurodegenerative
disease states and behavioural disorders such as AIzheimers
Disease, Parkinsons Disease, Huntintons Disease, schizophrenia,
Mrania, dementia, paranoia, obsessive compulsive disorder and panic
disorder and also in the treatment and or detection of embryonic
development defects. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0389] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:67 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1138 of SEQ ID NO:67, b is an integer
of 15 to 1152, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:67, and where b is greater
than or equal to a+14.
[0390] Features of Protein Encoded by Gene No: 58
[0391] The translation product of this gene shares sequence
homology with the gene disrupted in the neurodegenerative disease
dentatorubal-pallidoluysian atrophy. Moreover, the translation
product of this gene also shares homology with the GRASP65 protein,
a protein involved in the stacking of golgi cistemae (See Genbank
Accession No. AF015264). Preferred polypeptide fragments comprise
the following: MGSSQSVEIPGGGTEGYHVLRVQENSPGHRAGLEPFFDFIVSINGSRLNKDN
DTLKDLLKXNVEKPVKMLIYSSKTLELRETSVTPSNLWGGQGLLGVSIRFCSFD
GANENVWHVLEVESNSPAALAGLRPHSDYIIGADTVMNESEDLFSLIETH
EAKPLKLYVYNTDTDNCREVIITPNSAWGGEGSLGCGIGYGYLHRIPTRPFEE
GKKISLPGQMAGTPITPLKDGFTEVQLSSVNPPSLSPPGTTGIEQSLTGLSISST
PPAVSSVLSTGVPTVPLLPPQVNQSLTSVPPMNPATTLPGLMPLPAGLPNLPNL
NLNLPAPHIMPGVGLPELVNPGLPPLPSMPPRNLPGIAPLPLPSEFLPSFPL
VPESSSAASSGELLSSLPPTSNAPSDPATTTAKADAASSLTVDVTPPTAKAPIT
VEDRVGDSTPVSEKPVSAAVDANASESP (SEQ ID NO:689), SVEIPGGGTEGY
HVLRVQENSPGHRAGLEPFFDFIVSINGSRLNKDNDTLKDLLKXNVEKPVK
MLIYSSKTLELRETSVTPSNLWGGQGLLGVSIRFCSFDGANENVWH (SEQ ID NO:690),
ESNSPAALAGLRPHSDYIIGADTVMNESEDLFSLIETHEAKPLKLY
VYNTDTDNCREVIITPNSAWGGEGSL- GCGIGYGYLHRIPTRPFEEGKKISLPG
QMAGTPITPLKDGFTEVQLSSVNPPSLSPPGTTGIEQSLTGLSISS (SEQ ID NO:691),
ESNSPAALAGLRPHSDYIIGADTVMNESEDLFSLIETHEAKPLK
LYVYNTDTDNCREVIITPNSAWGGEGSLGCGIGYGYLHRIPTRPFEEGKKISL
PGQMAGTPITPLKDGFTEVQLSSVNPPSLSPPGTTGIEQSLTGLSISS (SEQ ID NO;692)
RIPTRPFEEGKKISLPGQMAGTPITPLKDGFTEVQLSSVNPPSLSP
PGTTGIEQSLTGLSISSTPPAVSSVL- STGVPTVPLLPPQVNQSLTSVPPMNPA
TTLPGLMPLPAGLPNLPNLNLNLPAPHLMPGVGLPELVNPGLPPLP- SMPPRN (SEQ ID
NO:693), PGLPPLPSMPPRNLPGIAPLPLPSEFLPSFPLVPESSSAASSG
ELLSSLPPTSNAPSDPATTTAKADAASSLTVDVTPPTAKAPTTVEDRVGDSTPV SEKPVSAAVDAN
(SEQ ID NO:694), AWGGEGSLGCGIGYGYLHRIPT (SEQ ID NO:695), SPAALAGLRP
(SEQ ID NO:696), and/or WGGQGLLG (SEQ ID NO:697). The gene encoding
the disclosed cDNA is believed to reside on chromosome 2.
Accordingly, polynucleotides related to this invention are useful
as a marker in linkage analysis for chromosome 2.
[0392] This gene is expressed primarily in prostate cancer, and to
a lesser extent, in the pineal glands and in fetal lung.
[0393] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neurological, endocrine, reproductive, pulmonary,
developmental disorders. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the nervous, pulmonary, and
endocrine systems, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g., neurological, endocrine, reproductive, pulmonary,
developmental, and cancerous and wounded tissues) or bodily fluids
(e.g., lymph, amniotic fluid, pulmonary surfactant and sputum,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0394] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 306 as residues: Asn-9 to Leu-14.
[0395] The abundance of this gene in the pineal gland and its
homology to a gene disrupted in the neurodegenerative disease state
Dentatorubral-pallidoluysian atrophy indicates that this gene may
be useful in the treatment and/or detection of other
neurodegenerative disease states and behavioural disorders such as
Alzheimers Disease, Parkinsons Disease, Huntingtons Disease,
schizophrenia, mania, dementia, paranoia, obsessive compulsive
disorder and panic disorder. Alternatively, the abundance of this
gene in fetal lung would suggest that misregulatlon of the
expression of this protein product in the adult could lead to
lymphoma or sarcoma formation, particularly in the lung; that it
may also be involved in predisposition to certain pulmonary defects
such as pulmonary edema and embolism, bronchitis and cystic
fibrosis; and thus the gene or the gene product encoded by the gene
could be used in the detection and/or treatment of these pulmonary
disorders. Protein, as well as, antibodies directed against the
protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[0396] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:68 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention, To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 2469 of SEQ ID NO:68, b is an integer
of 15 to 2483, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:68, and where b is greater
than or equal to a+14.
[0397] Features of Protein Encoded by Gene No: 59
[0398] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
RNGALLDKNFFNANSHFPVKGERIRRR (SEQ ID NO:698). Polynucleotides
encoding these polypeptides are also encompassed by the
invention.
[0399] This gene is expressed primarily in the developing
embryo.
[0400] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, developmental abnormalities. Similarly, polypeptides
and antibodies directed to these polypeptides are useful in
providing immunological probes for differential identification of
the tissue(s) or cell type(s). For a number of disorders of the
above tissues or cells, particularly of the developmental system,
expression of this gene at significantly higher or lower levels may
be routinely detected in certain tissues or cell types (e.g.,
developing, proliferating, and cancerous and wounded tissues) or
bodily fluids (e.g., mph, amniotic fluid, serum, plasma, urine,
synovial fluid and spinal fluid) or another tissue or cell sample
taken from an individual having such a disorder, relative to the
standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0401] The tissue distribution of this gene primarily in the embryo
indicates the gene plays a key role in embryo development, and that
the gene or the protein encoded by the gene could be used in the
treatment and or detection of developmental defects in the embryo
or in infants. Similarly, the relatively specific expression of
this gene product during embryogenesis indicates that it may be a
key player in the proliferation, maintenance, and/or
differentiation of various cell types during development. It may
also act as a morphogen to control cell and tissue type
specification. Because of potential roles in proliferation and
differentiation, this gene product may have applications in the
adult for tissue regeneration and the treatment of cancers.
Expression within embryonic tissue and other cellular sources
marked by proliferating cells indicates that this protein may play
a role in the regulation of cellular division, and may show utility
in the diagnosis and treatment of cancer and other proliferative
disorders. Similarly, developmental tissues rely on decisions
involving cell differentiation and/or apoptosis in pattern
formation. Thus, this protein may also be involved in apoptosis or
tissue differentiation and could again be useful in cancer therapy.
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[0402] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:69 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 522 of SEQ ID NO:69, b is an integer
of 15 to 536, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:69, and where b is greater
than or equal to a+14.
[0403] Features of Protein Encoded by Gene No: 60
[0404] This gene displays homology to nestin, an intermediate
filament protein, the expression of which correlates with the
proliferation of central nervous system progenitor cells and is
useful in the identification of brain tumors. In specific
embodiments, polypeptides of the invention comprise the following
amino acid sequence: RGSGFGWTSFPRPLPTELTCPGFHRERAFPPDGRVRGVRGWGIRR
GCRAVWGVGACGCSPGSSWRGSAHRAS- GPADLPVACRXEGGADSPSLLPSPP (SEQ ID
NO:699), AVWGVGACGCSPGSSWRGSAHRA (SEQ ID NO:700), YRP
TMEKMKQVVTQTRWMRPDAKRANRRHRRISGKIFAWNPLPKTRFSRLL
KAVSENTKRPEPSRPPWMVSHSVEAS (SEQ ID NO:701), and/or FAWNPLP
KTRFSRLLKAVSENTKRPEP (SEQ ID NO:702). Polynucleotides encoding
these polypeptides are also encompassed by the invention. The gene
encoding the disclosed cDNA is believed to reside on chromosome 1.
Accordingly, polynucleotides related to this invention are useful
as a marker in linkage analysis for chromosome 1.
[0405] This gene is expressed primarily in kidney, and to a lesser
extent, in brain.
[0406] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, renal disorders and neurodegenerative conditions.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the excretory and nervous systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., neural, urogenital, renal, and
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0407] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 308 as residues: Thr-130 to Asn-137.
[0408] The tissue distribution in brain and kidney, combined with
the homology to the conserved nestin protein, indicates that the
protein product of this gene is useful for the detection and/or
treatment of neurodegenerative disease states and behavioural
disorders such as Alzheimers Disease, Parkinsons Disease,
Huntingtons Disease, schizophrenia, mania, dementia, paranoia,
obsessive compulsive disorder and panic disorder. In addition, its
abundance in kidney indicates that it is useful in the treatment
and detection of acute renal failure and other disease states
associated with the kidney, such as nephritus, renal tubular
acidosis, proteinuria, pyuria, edema, pyelonephritis,
hydronephritis, nephrotic syndrome, crush syndrome,
glomerulonephritis, hematuria, renal colic and kidney stones, in
addition to Wilms Tumor Disease, and congenital kidney
abnormalities such as horseshoe kidney, polycystic kidney, and
Falconi's syndrome. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0409] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ED NO:70 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 560 of SEQ ID NO:70, b is an integer
of 15 to 574, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:70, and where b is greater
than or equal to a+14.
[0410] Features of Protein Encoded by Gene No: 61
[0411] This gene shares homology with the latrophilin-related
protein 1 precursor as well as the calcium-independent
alpha-latrotoxin receptor. alpha-Latrotoxin, a black widow spider
neurotoxin, can bind to high affinity receptors on the presynaptic
plasma membrane and stimulate massive neurotransmitter release in
the absence of Ca2+. Neurexins, previously isolated as
alpha-latrotoxin receptors, require Ca2+ for their interaction with
the toxin and, thus, may not participate in the Ca2+-independent
alpha-latrotoxin activity. However, latrophilin binds
alpha-Latrotoxin with high affinity in the presence of various
divalent cations (Ca2+, Mg2+, Ba2+, and Sr2+) as well as in EDTA.
This presumably membrane-bound protein is localized to and
differentially distributed among neuronal tissues, with about four
times more latrophilin expressed in the cerebral cortex than in the
cerebellum; subcellular fractionation showed that the protein is
highly enriched in synaptosomal plasma membranes. Preferred
polypeptide fragments comprise the following amino acid sequence:
IYKVFRHTAGLKPEVSCFENIRSCARXXXXXXXXXXXXWIFGVLHVVHASVV
TAYLFTVSNAFQGMFIFLFLCVLSRKIQEEYYRLFKNVPCC (SEQ ID NO:703),
WIFGVLHVVHASVVTAYLFTVSNAFQGMFIFLFLCVLSRKIQEEYYRLFKNVP CC (SEQ ID
NO:704), IYKVFRHTAGLKPEVSCFENIRSCAR (SEQ ID NO:705),
IIYKVFRHTAGLKPEVSCFENIRSCARGA- LALLFLLGTTWIFGVLHVVHASVVT
AYLFTVSNAFQG (SEQ ID NO:706), and/or EVSCFENIRSCARGALALLFLLG
TTWIFGVLH (SEQ ID NO:707). Also preferred are polynucleotide
fragments encoding these polypeptide fragments. (See Genbank
Accession No. 2213659) The translation product of this gene also
shares sequence homology with CD 97, a seven transmembrane bound
receptor. The gene encoding the disclosed cDNA is believed to
reside on chromosome 1. Accordingly, polynucleotides related to
this invention are useful as a marker in linkage analysis for
chromosome 1.
[0412] This gene is expressed primarily in infant brain and in
endothelial cells.
[0413] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neurological, vascular, and hematopoeitic disorders.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the neurological and hematopoeitic systems, expression of this gene
at significantly higher or lower levels may be routinely detected
in certain tissues or cell types (e.g., vascular, neural,
hematopoietic, and cancerous and wounded tissues) or bodily fluids
(e.g., lymph, serum, plasma, urine, synovial fluid and spinal
fluid) or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[0414] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 309 as residues: Lys-13 to Leu-21.
[0415] The tissue distribution in infant brain genes suggest that
the protein product may be useful in the detection and/or treatment
of neurodegenerative disease states and behavioural disorders such
as Alzheimers Disease, Parkinsons Disease, Huntingtons Disease,
schizophrenia, mania, dementia, paranoia, obsessive compulsive
disorder and panic disorder, while its expression in in
hematopoietic cell types indicates that the gene could be important
for the treatment or detection of immune or hematopoietic disorders
including arthritis, asthma and immunodeficiency diseases.
Moreover, the expression within endothelial tissue indicates that
the protein product of this gene may show utility in the treatment
and/or prevention of a variety of vascular disorders, which
include, but are not limited to microvascular disease,
atherosclerosis, stroke, embolism, and aneurysm. Furthermore,
expression within infant tissue indicates that this protein may
play a role in the regulation of cellular division, and may show
utility in the diagnosis and treatment of cancer and other
proliferative disorders. Similarly, developmental tissues rely on
decisions involving cell differentiation and/or apoptosis in
pattern formation. Thus, this protein may also be involved in
apoptosis or tissue differentiation and could again be useful in
cancer therapy. Protein, as well as, antibodies directed against
the protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[0416] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:71 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 918 of SEQ ID NO:71, b is an integer
of 15 to 932, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:7 1, and where b is greater
than or equal to a+14.
[0417] Features of Protein Encoded by Gene No: 62
[0418] In specific embodiments, polypepti des of the invention
comprise the following amino acid sequence:
TTILRTCTIVCFYYWFNGVMVLLFFLDRNLLTFNQASI- M
PFSNTDFLHCLSFKKKLMLLRYIFYVVLTGPTLSLKGDENQIKNLFT (SEQ ID NO:708),
IVCFYYWFNGVMVLLFFLDRNLL (SEQ ID NO:709), and/or
LLRYIFYVVLTGPTLSLKGDENQI (SEQ ID NO:710). Polynucleotides encoding,
these polypeptides are also encompassed by the invention. The gene
encoding the disclosed cDNA is believed to reside on chromosome 4.
Accordingly, polynucleotides related to this invention are useful
as a marker in linkage analysis for chromosome 4.
[0419] This gene is expressed primarily in fetal liver and fetal
spleen.
[0420] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include. but are not
limited to, hematopoietic, immunological, developmental, and/or
hepatic disorders. Similarly, polypeptides and antibodies directed
to these polypeptides are useful in providing immunological probes
for differential identification of the tissue(s) or cell type(s).
For a number of disorders of the above tissues or cells,
particularly of the immune and hematopoetic systems, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g., hematopoietic,
immune, hepatic, developmental, and cancerous and wounded tissues)
or bodily fluids (e.g., lymph, amniotic fluid, bile, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0421] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 310 as residues: Ser-91 to Lys-98.
[0422] The tissue distribution of this gene in fetal liver and
spleen indicates that the gene could be important for the treatment
or detection of immune or hematopoietic disorders including
arthritis, leukemia, and immunodeficiency diseases. Moreover, the
protein product of this gene is useful for the treatment and
diagnosis of hematopoetic related disorders such as anemia,
pancytopenia, leukopenia, thrombocytopenia or leukemia since
stromal cells are important in the production of cells of
hematopoietic lineages. The uses include bone marrow cell ex vivo
culture, bone marrow transplantation, bone marrow reconstitution,
radiotherapy or chemotherapy of neoplasia. The gene product may
also be involved in lymphopoiesis, therefore, it can be used in
immune disorders such as infection, inflammation, allergy,
immunodeficiency etc. In addition, this gene product may have
commercial utility in the expansion of stem cells and committed
progenitors of various blood lineages, and in the differentiation
and/or proliferation of various cell types. Moreover, expression
within fetal tissue indicates that this protein may play a role in
the regulation of cellular division, and may show utility in the
diagnosis and treatment of cancer and other proliferative
disorders. Similarly, developmental tissues rely on decisions
involving cell differentiation and/or apoptosis in pattern
formation. Thus, this protein may also be involved in apoptosis or
tissue differentiation and could again be useful in cancer therapy.
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[0423] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:72 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 982 of SEQ ID NO:72, b is an integer
of 15 to 996, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:72, and where b is greater
than or equal to a+14.
[0424] Features of Protein Encoded by Gene No: 63
[0425] This gene shares homology with human serum amyloid protein
(See Genbank Accession No. W13671). Preferred polypeptide fragments
comprise the following amino acid sequence:
ALTRIPPGDWVINVTAVSFAGKTTARFFHSSPPSLGDQ- ARTDPGHQRRD (SEQ ID
NO:711), SMLLLFPLQERPQQDSFIRLLLAWGTRLELTLDIKGGI (SEQ ID NO:712),
TGWADGFSSHIIPPLMSRVSSSLVPQARRRRMKESCCGLSCKGN
AANIDYPVTGRNSCERAPLCAFALHFQERTXITGXGEDPGPFQSXGRVTA
SRXTLACSHVAMTPAGCXQALGTPSSYCVRKAPRA (SEQ ID NO:713) and/or
QARRRRMKESCCGLSCKGNSSNIDYPVT (SEQ ID NO:714). Also preferred are
polynucleotide fragments encoding these polypeptide fragments The
gene encoding the disclosed cDNA is believed to reside on
chromosome 9. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
9.
[0426] This gene is expressed primarily in fetal liver and
spleen.
[0427] Therefore, polynucleotides and polypeptides of the invention
are useful as areagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, hematopoietic, immune, and/or developmental disorders.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the hematopoietic and immune systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., hematopoietic, immune,
developmental, and cancerous and wounded tissues) or bodily fluids
(e.g., lymph, amniotic fluid, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0428] The tissue distribution of this gene in fetal liver-spleen
indicates that the gene is important for the treatment or detection
of immune or hematopoietic disorders including arthritis, leukemia,
and immunodeficiency diseases. Moreover, the protein product of
this gene is useful for the treatment and diagnosis of hematopoetic
related disorders such as anemia, pancytopenia, leukopenia,
thrombocytopenia or leukemia since stromal cells are important in
the production of cells of hematopoietic lineages. The uses include
bone marrow cell ex vivo culture, bone marrow transplantation, bone
marrow reconstitution, radiotherapy or chemotherapy of neoplasia.
The gene product may also be involved in lymphopoiesis, therefore,
it can be used in immune disorders such as infection, inflammation,
allergy, immunodeficiency, etc. In addition, this gene product may
have commercial utility in the expansion of stem cells and
committed progenitors of various blood lineages, and in the
differentiation and/or proliferation of various cell types.
Furthermore, expression within fetal tissue indicates that this
protein may play a role in the regulation of cellular division, and
may show utility in the diagnosis and treatment of cancer and other
proliferative disorders. Similarly, developmental tissues rely on
decisions involving cell differentiation and/or apoptosis in
pattern formation. Thus, this protein may also be involved in
apoptosis or tissue differentiation and could again be useful in
cancer therapy. Protein, as well as, antibodies directed against
the protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[0429] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:73 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 771 of SEQ ID NO:73, b is an integer
of 15 to 785, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:73, and where b is greater
than or equal to a+14.
[0430] Features of Protein Encoded by Gene No: 64
[0431] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence: LWRSSGVER (SEQ ID
NO:715). Polynucleotides encoding these polypeptides are also
encompassed by the invention. The gene encoding the disclosed cDNA
is believed to reside on chromosome 3. Accordingly, polynucleotides
related to this invention are useful as a marker in linkage
analysis for chromosome 3.
[0432] This gene is expressed specifically in the brain.
[0433] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neural disorders, particularly neurodegenerative
disease states. Similarly, polypeptides and antibodies directed to
these polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the neurological systems, expression of this gene at significantly
higher or lower levels may be routinely detected in certain tissues
or cell types (e.g., neural, and cancerous and wounded tissues) or
bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0434] The tissue distribution in brain indicates that the protein
product of this gene is useful for the detection/treatment of
neurodegenerative disease states, behavioural disorders, or
inflamatory conditions such as Alzheimers Disease, Parkinsons
Disease, Huntingtons Disease, Tourette Syndrome, meningitis,
encephalitis, demyelinating diseases, peripheral neuropathies,
neoplasia, trauma, congenital malformations, spinal cord injuries,
ischemia and infarction, aneurysms, hemorrhages, schizophrenia,
mania, dementia, paranoia, obsessive compulsive disorder, panic
disorder, learning disabilities, ALS, psychoses, autism, and
altered behaviors, including disorders in feeding, sleep patterns,
balance, and perception. In addition, elevated expression of this
gene product in regions of the brain indicates that it plays a role
in normal neural function. Potentially, this gene product is
involved in synapse formation, neurotransmission, learning,
cognition, homeostasis, or neuronal differentiation or survival.
Moreover, the gene or gene product may also play a role in the
treatment and/or detection of developmental disorders associated
with the developing embryo, sexually-linked disorders, or disorders
of the cardiovascular system. Protein, as well as, antibodies
directed against the protein may show utility as a tumor marker
and/or immunotherapy targets for the above listed tissues.
[0435] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:74 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1055 of SEQ ID NO:74, b is an integer
of 15 to 1069, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:74, and where b is greater
than or equal to a+14.
[0436] Features of Protein Encoded by Gene No: 65
[0437] This gene shares homology with a yeast protein. Preferred
polypeptide fragments comprise the following amino acid sequence:
LQEVNITLPENSVWYERYKFDIPVFHL (SEQ ID NO:716). Also preferred are
polynucleotide fragments encoding these polypeptide fragments. (See
Genbank Accession No. 1332638)
[0438] This gene is expressed primarily in fetal tissue (fetus and
fetal liver).
[0439] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, hepatic, developmental, inmmune, and/or hematopoietic
disorders, including cancers (e.g. hepatoblastoma). Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
hepatic system, expression of this gene at significantly higher or
lower levels may be routinely detected in certain tissues or cell
types (e.g., hepatic, developmental, immune, hematopoietic, and
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
amniotic fluid, bile, serum, plasma, urine, synovial fluid and
spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0440] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 313 as residues: Asn-72 to Glu-77.
[0441] The tissue distribution in fetal liver indicates that the
protein product of this gene is useful for the detection and
treatment of liver disorders and cancers (e.g. hepatoblastoma,
jaundice, hepatitis, liver metabolic diseases and conditions that
are attributable to the differentiation of hepatocyte progenitor
cells). In addition the expression in fetus would suggest a useful
role for the protein product in developmental abnormalities, fetal
deficiencies, pre-natal disorders and various would-healing models
and/or tissue trauma. Moreover, the protein product of this gene is
useful for the treatment and diagnosis of hematopoetic related
disorders such as anemia, pancytopenia, leukopenia,
thrombocytopenia or leukemia since stromal cells are important in
the production of cells of hematopoietic lineages. The uses include
bone marrow cell ex vivo culture, bone marrow transplantation, bone
marrow reconstitution, radiotherapy or chemotherapy of neoplasia.
The gene product may also be involved in lymphopoiesis, therefore,
it can be used in immune disorders such as infection, inflammation,
allergy, immunodeficiency etc. In addition, this gene product may
have commercial utility in the expansion of stem cells and
committed progenitors of various blood lineages, and in the
differentiation and/or proliferation of various cell types.
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[0442] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:75 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 817 of SEQ ID NO:75, b is an integer
of 15 to 831, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:75, and where b is greater
than or equal to a+14.
[0443] Features of Protein Encoded by Gene No: 66
[0444] This gene has homology with a B-cell surface antigen which
may indicate that this gene plays a role in the immune response,
including, but not limited to disorders and infections of the
immune system. Preferred polynucleotide fragments comprise the
following sequence:
TAGCATGTAGCCAGTCGAATAACNTATAAGGACAAAGTGGAGTCCACGCGT
GCGGCCGTCTAGACTAGTGGATCCCCCGGCTGCAGGATTCGGCACGAG (SEQ ID NO:718).
Also preferred are polypeptides comprising polypeptide fragments
encoded by these polynucleotide fragments (See Genbank Accession
No.T94535). Additionally, this gene shares homology with an
interferon-gamma receptor. Preferred polypeptide fragments also
comprise the following amino acid sequence: MQGSGSQFRACLLCLCFSCP
CSPGGPRWNSRQGGRRFPKTCRAISQNLVFK- YKTFCPVRYMQPHRSSLCLHF
TSYVFILSTWGSLRTYSTDLKKKKKNSRGGPVPIRPKS (SEQ ID NO:717),
MQGSGSQFRACLLCLCFSCPCSPGGPRWNSRQGGRRFPKTCRAISQNLVFK (SEQ ID
NO:719), PVRYMQPHRSSLCLHFTSYVFILSTWGSLRTYSTDLKKK KKNSRGGPVPIRPKS
(SEQ ID NO:720), GEEQRDCSLGWRGVGMRATHCQ AARMFVLFSLPKYAGL (SEQ ID
NO:721), TSGSPGCRIRHELPGEEQRDCS LGWRGVGMRATHCQAAR (SEQ ID NO:722),
EPPIAKQQECSCFFPFQ
NMQGSGSQFRACLLCLCFSCPCSPGGPRWNSRQGGRRFPKTCRAISQNLVFK
YKTFCPVRYMQPHRSSLCLHFTSYVFILSTWGSLRTYSTDLKKKKKNSR GGPVPIRPKS (SEQ
ID NO:723), and/or QFRACLLCLCFSCPCSPGGPRWNS RQGGRRF (SEQ ID
NO:724). Also preferred are polynucleotide fragments encoding these
polypeptide fragments
[0445] This gene is expressed primarily in T-cells and gall
bladder.
[0446] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immunological disorders and conditions
(immunodeficiencies, cancer, leukemia, hematopoeisis), in addition
to metabolic, gastrointestinal, and/or digestive disorders.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immnunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune and digestive systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., immune, hematopoietic,
metabolic, gastrointestinal, digestive, and cancerous and wounded
tissues) or bodily fluids (e.g., lymph, serum, bile, plasma, urine,
synovial fluid and spinal fluid) or another tissue or cell sample
taken from an individual having such a disorder, relative to the
standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0447] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 314 as residues: Thr-41 to Gly-52.
[0448] The tissue distribution in T-cells indicates that the
protein product of this gene is useful for the treatment and
diagnosis of immune disorders including: leukemias, lymphomas,
auto-immune disorders, immuno-supressive (transplantation) and
immunodeficiencies (e.g. AIDS), inflammation and hematopoeitic
disorders. Moreover, the expression of this gene in gall bladder
would suggest a possible role for this gene product in digestive
disorders, particularly of the pancreas or liver. Protein, as well
as, antibodies directed against the protein may show utility as a
tumor marker and/or immunotherapy targets for the above listed
tissues.
[0449] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:76 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 576 of SEQ ID NO:76, b is an integer
of 15 to 590, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:76, and where b is greater
than or equal to a+14.
[0450] Features of Protein Encoded by Gene No: 67
[0451] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence: NQFTSCILFCDGGHWRELLFQSI
(SEQ ID NO:725), AMSSKLLNLLALLQYSVHDHCHPRRLLKRGARATLRHKGWGPSSLRGCE
SFQIVLIGWGPDLAVGFGRGKLL- SRSLPVRHGGVSEFCLPHRDVVRLEKVKK (SEQ ID
NO:726), and/or GPSSLRGCESFQIVLIGWGPDLAVGFGRGKLLS (SEQ ID NO:727).
Polynucleotides encoding these polypeptides are also encompassed by
the invention. The gene encoding the disclosed cDNA is believed to
reside on chromosome 11. Accordingly, polynucleotides related to
this invention are useful as a marker in linkage analysis for
chromosome 11.
[0452] This gene is expressed primarily in a variety of fetal and
developmental tissues (e.g. fetal spleen, infant brain).
[0453] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, developmental, immune or neurological abnormalities.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the developing immune and central nervous systems, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g., neural, immune,
hemaopoietic, hepatic, developmental, and cancerous and wounded
tissues) or bodily fluids (e.g., lymph, amniotic fluid, bile,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0454] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 315 as residues: Ser-38 to Ser-43.
[0455] The tissue distribution in fetal tissues indicates that the
protein product of this gene is useful for developmental
abnormalities or fetal deficiencies. The detection in infant brain
would suggest a role in neurological disorders (both developmental
and neurodegenerative conditions of the brain and nervous system,
behavioral disorders, depression, schizophrenia, Alzheimer's
disease, Parkinson's disease, Huntington's disease, mania,
dementia). In addition, the detection in spleen would similarly
suggest a role in the detection and treatment of immunologically
mediated disorders (e.g. immunodeficiency, inflammation, cancer,
wound healing, tissue repair, hematopoeisis). Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[0456] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:77 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1260 of SEQ ID NO:77, b is an integer
of 15 to 1274, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:77, and where b is greater
than or equal to a+14.
[0457] Features of Protein Encoded by Gene No: 68
[0458] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
TRKNIDFXETEKYYLFSFSNNVSFKNFWLKYN (SEQ ID NO:728). Polynucleotides
encoding these polypeptides are also encompassed by the
invention.
[0459] This gene is expressed primarily in spleen, T-cells, and
fetal heart.
[0460] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immunological or hematopoietic deficiencies or
disorders, including AIDS and cardiovascular or developmental
conditions. Similarly, polypeptides and antibodies directed to
these polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells. particularly of
the immune and cardiovascular systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., immune, hematopoietic,
cardiovascular, developmental, and cancerous and wounded tissues)
or bodily fluids (e.g., lymph, amniotic fluid, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0461] The tissue distribution in spleen and T-cells indicates that
the protein product of this gene is useful for the diagnosis and
treatment of immune disorders including: leukemias, lymphomas,
autoimmune disorders, immunodeficiencies (e.g. AIDS),
immuno-suppressive conditions (transplantation) and hematopoeitic
disorders. Moreover, the expression in fetal heart indicates that
the protein product of this gene is useful for the treatment and
diagnosis of cadiovascular disorders (e.g. heart disease,
restenosis, atherosclerosis, stoke, angina, thrombosis). Protein,
as well as, antibodies directed against the protein may show
utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[0462] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:78 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1119 of SEQ ID NO:78, b is an integer
of 15 to 1133, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:78, and where b is greater
than or equal to a+14.
[0463] Features of Protein Encoded by Gene No: 69
[0464] This gene shares homology with a human collagen protein.
Preferred polypeptide fragments comprise the following amino acid
sequence: MPRKTSKCRQLLCSGASRNADTAARQSTCSSHRPPGKIPSLGPRRXPGCXSVP
SSRGEQSTGSPAAPRCGRRDAHRGLPGGAAMTPGDTWASFNPRAGHSKSQ
GEGQESSGASRQDRHPVSHWVERQREAWGAPRSSSAGGVKVAATTEREPEFK IKTGKA (SEQ ID
NO:729), CSGASRNADTAARQSTCSSHRPPGKIPSLGPR
RXPGCXSVPSSRGEQSTGSPAAPRCGRRDAH- RGLPGGAAMTPGDTWASF NPRAGHS (SEQ ID
NO:730), QGEGQESSGASRQDRHPVSHWVERQREAWG
APRSSSAGGVKVAATTEREPEFKIKTGKA (SEQ ID NO:731), IRHEGKRML
NESRKPLSFASRLSSLYFKLGFPFCGRSNLYSTCTAAPGGSPGLPLPFYPVADG (SEQ ID
NO:732), TRAESLFPLLHAFPVFILNSGSLSVVAATFTPPALLLLGA
PQASLCLSTQWLTGCLSCLDAPLLSCPSPWLL- LCPALGLKLAHVSPGVMAA
PPGRPLCASRLPHLGAAGEPVLCSPRLLGTELQPGXLRGPRLGILPGGRWE
EQVLCLAAVSAFLDAPEHRSCRHFEVFLGMCQIT (SEQ ID NO:733), PALGLKL
AHVSPGVMAAPPGRPLCASRLP (SEQ ID NO:734), GGRWEEQVLCLAAV SAFLDAPEHR
(SEQ ID NO:735), SWPMCPPESWLLLLGGLCVRHVFHTW
GQLASPCSVPLGCLAQSCSLGXSVDPDWGFCQGGDGR- SRCFAWRLCLHFWT
PQSTEVAGTLRSSSACARLHE (SEQ ID NO:736), and/or GDGRSRCFAWRLC
LHFWTPQSTEVAGTLR (SEQ ID NO:737). Also preferred are polynucleotide
fragments encoding these polypeptide fragments
[0465] This gene is expressed primarily in fetal heart.
[0466] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, cardiovascular or developmental disorders, particularly
vascular conditions. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the cardiovascular system,
expression of this gene at significantly higher or lower levels may
be routinely detected in certain tissues or cell types (e.g.,
cardiovascular, developmental, skeletal, vascular, and cancerous
and wounded tissues) or bodily fluids (e.g., lymph, amniotic fluid,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0467] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 317 as residues: Pro-32 to Ser-39.
[0468] The tissue distribution in fetal heart indicates that the
protein product of this gene is useful for the treatment and
diagnosis of cadiovascular disorders (e.g. heart disease,
restenosis, atherosclerosis, stroke, angina, thrombosis), in
addition to vascular disorders, such as microvascular disease.
Expression within fetal tissue indicates that this protein may play
a role in the regulation of cellular division, and may show utility
in the diagnosis and treatment of cancer and other proliferative
disorders. Similarly, developmental tissues rely on decisions
involving cell differentiation and/or apoptosis in pattern
formation. Thus this protein may also be involved in apoptosis or
tissue differentiation and could again be useful in cancer therapy.
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[0469] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:79 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 647 of SEQ ID NO:79, b is an integer
of 15 to 661, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:79, and where b is greater
than or equal to a+14.
[0470] Features of Protein Encoded by Gene No: 70
[0471] The translation product of this gene shares sequence
homology with a chicken single-strand DNA-binding protein. The
promoter region of the chicken alpha2(I) collagen gene contains a
pyrimidine-rich element that is well conserved in different
mammalian species. This sequence can also form an unusual DNA
structure as shown by its sensitivity to SI nuclease in vitro and
it lies in a region that is DNase I-hypersensitive only when this
promoter is active. The high affinity of this protein for this
conserved pyrimidine-rich region indicates that it might be
involved in the transcriptional regulation of the alpha2(I)
collagen gene. Preferred polypeptide fragments comprise the
following amino acid sequence:
MSPRYPGGPRPPLRIPNQALGGVPGSQPLLPSGMDPTRQQGHPNMGGPMQ
RMTPPRGMVPLGPQNYGGAMRPPLNALGGPGMPGMNMGPGGGRPWPNPT
NANSIPYSSASPGNYVGPPGGGG- PPGTPIMPSPADSTNSGDNMYTLMNAVPPG
PNRPNFPMGPGSDGPMGGLGGMESHHMNGSLGSGDMDSISKNS- PNNMSLS
NQPGTPRDDGEMGGNFLNPFQSESYSPSMTMSV (SEQ ID NO:738), MSPRYPG
GPRPPLRIPNQALGGVPGSQPLLPSGMDPTRQQGHPNMGGPMQRMTPPRGMV PLGPQNYGG
AMRPPLNALGGPGMPGMNMGPGGGRPWPNPTNANS IPYSS ASPGNY (SEQ ID NO:739),
LNALGGPGMPGMNMGPGGGRPW PNPTNA NSI
PYSSASPGNYVGPPGGGGPPGTPIMPSPADSTNSGDNMY- TLMNAVPPGPN (SEQ ID
NO:740), GPMGGLGGMESHHMNGSLGSGDMDSISKNSPNNMSL
SNQPGTPRDDGEMGGNFLNPFQSESYSPSMTMSV (SEQ ID NO:741), TCEHSS EAKAFHDY
(SEQ ID NO:742), and/or RRETCEHSSEAKAFHDYPF (SEQ ID NO:743),. Also
preferred are polynucleotide fragments encoding these polypeptide
fragments. (See Genbank Accession No. 1562534)
[0472] This gene is expressed primarily in placenta, and to a
lesser extent, in fetal heart.
[0473] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, developmental abnormalities, fetal deficiencies, and
particularly of the cardiovascular system and/or vascular
conditions. Similarly, polypeptides and antibodies directed to
these polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the reproductive system, expression of this gene at significantly
higher or lower levels may be routinely detected in certain tissues
or cell types (e.g., developmental, vascular, cardiovascular,
reproductive, and cancerous and wounded tissues) or bodily fluids
(e.g., lymph, amniotic fluid, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0474] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 318 as residues: Met-1 to Leu-13, Gly-33 to Gly-46,
Pro-48 to Gly-57, Pro-63 to Gly-68, Pro-89 to Asn-102, Ser-108 to
Asn-113, Pro-118 to Pro-124, Pro-132 to Asn-141, Pro-151 to
Asn-157, Ile-191 to Met-199, Ser-202 to Gly-215, Phe-222 to
Pro-229.
[0475] The tissue distribution in fetal heart and placenta
indicates that the protein product of this gene is useful for the
detection and treatment of developmental abnormalities or fetal
deficiencies, ovarian and other endometrial cancers, reproductive
disfunction, cardiovascular disorders, and pre-natal disorders, in
particular vascular disorders, which include, but are not limited
to, stroke, angina, microvascular disease, atherosclerosis,
embolism, and aneurysm. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0476] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:80 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1364 of SEQ ID NO:80, b is an integer
of 15 to 1378, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:80, and where b is greater
than or equal to a+14.
[0477] Features of Protein Encoded by Gene No: 71
[0478] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence: TTTLFQSAWCFFSKYCTDFT
(SEQ ID NO:744), VRGCEDGGGGGIWGGWWPGQQMAPPWLSCPHRQFPHFHSGRQRRQSD
LLKEELPQPSGAAGRASGNKPYTPP- PASNSLTLRLLSFRFNAFNRSHPQ PSLNYKDRQ (SEQ
ID NO:745), PWLSCPHRQFPHFHSGRQRRQSDLL (SEQ ID NO:746), and/or
RLLSFRFNAFNRSHPQPSLN (SEQ ID NO:747). Polynucleotides encoding
these polypeptides are also encompassed by the invention. The gene
encoding the disclosed cDNA is believed to reside on chromosome 7.
Accordingly, polynucleotides related to this invention are useful
as a marker in linkage analysis for chromosome7.
[0479] This gene is expressed primarily in fetal liver, and to a
lesser extent, in the breast and testes.
[0480] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, hepatic disorders (including hepatoblastomas),
hematopoietic, immune, and/or reproductive disorders. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
hepatic and reproductive systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., hematopoietic, immune,
hepatic, reproductive, developmental, and cancerous and wounded
tissues) or bodily fluids (e.g., lymph, amniotic fluid, bile,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0481] The tissue distribution in fetal liver indicates that the
protein product of this gene is useful for the detection and
treatment of liver disorders and cancers (e.g. hepatoblastoma,
jaundice, hepatitis, liver metabolic diseases and conditions that
are attributable to the differentiation of hepatocyte progenitor
cells). The expression in testes and breast indicates that the
protein product of this gene is useful for the detection and
treatment of endocrine and reproductive disorders (e.g. sperm
maturation, milk production, testicular and breast cancers).
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[0482] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:81 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1426 of SEQ ID NO:81, b is an integer
of 15 to 1440, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:81, and where b is greater
than or equal to a+14.
[0483] Features of Protein Encoded by Gene No: 72
[0484] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
RDSSLWAAALSFRQQCSSLASCLVSMYSRPGRQHRAK AGAGSQTEQCWGRKVDAVV (SEQ ID
NO:748), CLVSMYSRPGRQHRAKA GAGSQTEQCW (SEQ ID NO:749),
PEHGFSSCDFWEGAPSSGPKEGGRSPPQL ACVWGMNLSSPPCLALLTNRACLAVNWHRVTLFP-
GIQVCNQNTGEEKLQDPC PHLSS (SEQ ID NO:750),
RSPPQLACVWGMNLSSPPCLALLTNRACLA (SEQ ID NO:751),
CERDSETSSIAMTCIKHKPPKQKKRLSLLPGFRSALPRVCRCHMITV
QREAFRTHTGCSTSVHLPSRGGFLPDF (SEQ ID NO:752), and/or KKRLSLLPG
FRSALPRVCRCHMITVQRE (SEQ ID NO:753). Polynucleotides encoding these
polypeptides are also encompassed by the invention. The gene
encoding the disclosed cDNA is believed to reside on chromosome 1.
Accordingly, polynucleotides related to this invention are useful
as a marker in linkage analysis for chromosome 1.
[0485] This gene is expressed primarily in smooth muscle, and to a
lesser extent, in brain.
[0486] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, cardiovascular and neurological disorders, particularly
embolism, atherosclerosis, stroke, aneurysm, and miscovascular
disease. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the cardiovascular and central nervous systems, expression of this
gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g., neural, vascular,
endothelial, smooth muscle, and cancerous and wounded tissues) or
bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0487] The tissue distribution in brain and smooth muscle indicates
that the protein product of this gene is useful for the detection
and treatment of restenosis, atherosclerosis, stroke, angina,
thrombosis, wound healing and other conditions of heart disease.
Moreover, the protein product of this gene is useful for the
detection and treatment of developmental, degenerative and
behavioral conditions of the brain and nervous system (e.g.
schizophrenia, depression, Alzheimer's disease, Parkinson's
disease, Huntington's disease, manria, dementia, paranoia,
addictive behavior and sleep disorders). Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[0488] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:82 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1367 of SEQ ID NO:82, b is an integer
of 15 to 1381, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:82, and where b is greater
than or equal to a+14.
[0489] Features of Protein Encoded by Gene No: 73
[0490] This gene shares homology with human stromalin-2, which is
believed to play an integral role in modulating cellular function
of hematopoletic cells and tissues, and may possibly serve as a
tumor suppressor. Preferred polypeptide fragments comprise the
following amino acid sequence:
QAFVLLSDLLLIFSPQMIVGGRDFLRPLVFFPEATLQSELASFLMDHVFIQPGDL GSGA (SEQ
ID NO:754), ACSYLLCNPEFTFFSRADFARSQLVDLLTDRFQQ ELEELLQVG (SEQ ID
NO:755), QKQLSSLRDRMVAFCELCQSCLSDVDT EIQEQVST (SEQ ID NO:756),
QVILPALTLVYFSILWTLTHISKSDAS (SEQ ID NO:757),
STHDLTRWELYEPCCQLLQKAVDTGXVP- HQV (SEQ ID NO:758),
TSFLFPLQAFVLLSDLLLIFSPQMIVGGRDFLRPLVFFPEATLQSELASFLMD- HVF
IQPGDLGSGA (SEQ ID NO:759), GWGACSYLLCNPEFTFFSRADFARS
QLVDLLTDRFQQELEELLQVGAGAGQWDTPNKGGRGCKTGDVD (SEQ ID NO:760),
VWVLDGIMGTEESVSSFFPFKPLCPQKQLSSLRDRMVAFCELCQ
SCLSDVDTEIQEQVSTDSSGSNKASIPA- PIPRRN (SEQ ID NO:761), NASLPST
SEWLSSSSPSRFYWCLWSWFPLFFSSITFPELPQSTHDLTRW- ELYEPCCQLL
QKAVDTGXVPHQVSGQARDGLGAGGLXFKDLRSRWPLGVSSLSAWSGQSEE
DQVGGGHLLHSSLRRWTLLPGSSWISWKPRIILRDSRRRRVN (SEQ ID NO:762),
VLGEMLLWIFFPSQSSFLDEDEVYNLAATLKRLSAFYK (SEQ ID NO:763),
PKPHFSNPLLLQVILPALTLVYFSILWTLTHISKSDASPGECGS (SEQ ID NO:764),
and/or HCQFLLG (SEQ ID NO:765). Also preferred are polynucleotide
fragments encoding these polypeptide fragments (See Genbank
Accession No.R65208) The gene encoding the disclosed cDNA is
believed to reside on chromosome 7. Accordingly, polynucleotides
related to this invention are useful as a marker in linkage
analysis for chromosome 7.
[0491] This gene is expressed primarily in the brain (infant brain,
adult brain, pituitary, cerebellum, hippocampus, schizophrenic
hypothalmus, amygdala).
[0492] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, developmental disorders and neurodegenerative diseases
of the brain and nervous system, in addition to immune or
hematopoietic disorders. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the central nervous system,
expression of this gene at significantly higher or lower levels may
be routinely detected in certain tissues or cell types (e.g.,
neural, developmental, immune, hematopoietic, and cancerous and
wounded tissues) or bodily fluids (e.g., lymph, amniotic fluid,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0493] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 321 as residues: Thr-25 to Lys-36, Lys-55 to
Ser-63.
[0494] The tissue distribution primarily in brain, combined with
the homology to the highly conserved SA-1 and SA-2 proteins,
indicates that the protein product of this gene is useful for the
detection and treatment of developmental, degenerative and
behavioral conditions of the brain and nervous system (e.g.
schizophrenia, depression, Alzheimer's disease, Parkinson's
disease, Huntington's disease, mania, dementia, paranoia, addictive
behavior and sleep disorders). Moreover, the protein product of
this gene is useful for the treatment and diagnosis of hematopoetic
related disorders such as anemia, pancytopenia, leukopenia,
thrombocytopenia or leukemia since stromal cells are important in
the production of cells of hematopoietic lineages. The uses include
bone marrow cell ex vivo culture, bone marrow transplantation, bone
marrow reconstitution, radiotherapy or chemotherapy of neoplasia.
The gene product may also be involved in lymphopoiesis, therefore,
it can be used in immune disorders such as infection, inflammation,
allergy, immunodeficiency etc. In addition, this gene product may
have commercial utility in the expansion of stem cells and
committed progenitors of various blood lineages, and in the
differentiation and/or proliferation of various cell types.
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[0495] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:83 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1692 of SEQ ID NO:83, b is an integer
of 15 to 1706, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:83, and where b is greater
than or equal to a+14.
[0496] Features of Protein Encoded by Gene No: 74
[0497] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
12 EFGTSLVALELHELLYHWETRAQPSLILYVVSDLRWMEFRTSCLLFDFVLFLE (SEQ ID
NO:766), TKPGMVGHVPIVPATKXAEAGGSPEPGSSTLQWPMIT (SEQ ID NO: 767),
and/or PCTPSWATEPDHVSEDE LLYHWETRAQPSLILYVV (SEQ ID NO:768).
SDLRWMEFRTSC
[0498] Polynucleotides encoding these polypeptides are also
encompassed by the invention.
[0499] This gene is expressed primarily in the hypothalamus of a
human suffering from schizophrenia.
[0500] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, disorders of the CNS, particularly schizophrenia.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the CNS, such as schizophrenia expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., neural, and cancerous and
wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0501] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 322 as residues: Gly-38 to Ala-44.
[0502] The tissue distribution in the hypothalamus indicates that
the protein products of this gene are useful for the study,
diagnosis and treatment of schizophrenia and other disorders
involving the CNS. Moreover, the protein product of this gene is
useful for the detection/treatment of neurodegenerative disease
states, behavioural disorders, or inflamatory conditions such as
Alzheimers Disease, Parkinsons Disease, Huntingtons Disease,
Tourette Syndrome, meningitis, encephalitis, demyelinating
diseases, peripheral neuropathies, neoplasia, trauma, congenital
malformations, spinal cord injuries, ischemia and infarction,
aneurysms, hemorrhages, mania, dementia, paranoia, obsessive
compulsive disorder, panic disorder, learning disabilities, ALS,
psychoses, autism, and altered behaviors, including disorders in
feeding, sleep patterns, balance, and perception. In addition,
elevated expression of this gene product in regions of the brain
indicates that it plays a role in normal neural function.
Potentially, this gene product is involved in synapse formation,
neurotransmission, learning, cognition, homeostasis, or neuronal
differentiation or survival. Moreover, the gene or gene product may
also play a role in the treatment and/or detection of developmental
disorders associated with the developing embryo, sexually-linked
disorders, or disorders of the cardiovascular system. Protein, as
well as, antibodies directed against the protein may show utility
as a tumor marker and/or immunotherapy targets for the above listed
tissues.
[0503] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:84 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 559 of SEQ ID NO:84, b is an integer
of 15 to 573, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:84, and where b is greater
than or equal to a+14.
[0504] Features of Protein Encoded by Gene No: 75
[0505] Preferred polypeptides of the invention comprise the
following amino acid sequence encoded by this gene:
13 LAVSTSFICCADISTALPLGSSRPAPAPRHREHEHGHQARPPRLLXTSLMPLSTP (SEQ ID
NO:769), AAAQLLWTQLTPMGGRPGGRHSPPTLHTGPRALPPGPPHPSLHVAALSLLR
APAVPHQPPGTESTSMGTKPGLPGCSXRPLCHYQHQ (SEQ ID NO:770),
LXPSYFGHSSPPWGAVLVGVTPHPRCTPAPGPCRLGLHTHPCTWQLCLC
CADISTALPLGSSRPAPAPRHREHEHGH (SEQ ID NO:771),
WTQLTPMGGRPGGRHSPPTLHTGPR (SEQ ID NO:772), and/or HQPPGTEST (SEQ ID
NO:773). SMGTKPGLPGC
[0506] Polynucleotides encoding such polypeptides are also
provided.
[0507] This gene is expressed primarily in endometrial tumors, and
to a lesser extent, in amniotic cells.
[0508] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, reproductive, developmental, and immune disorders,
particularly cancers of those systems. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the reproductive and immune
systems, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g., developmental, reproductive, and cancerous and wounded
tissues) or bodily fluids (e.g., lymph, amniotic fluid, serum,
plasma, urine, synovial fluid and spinal fluid) or another tissue
or cell sample taken from an individual having such a disorder,
relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0509] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 323 as residues: Ser-3 to Arg-9.
[0510] The tissue distribution in endometrium and amniotic cells
indicates that the protein products of this gene are useful for the
study and treatment of developmental, reproductive, and immune
disorders, particularly cancers of those systems. Moreover, the
expression within embryonic tissue and other cellular sources
marked by proliferating cells indicates that this protein may play
a role in the regulation of cellular division, and may show utility
in the diagnosis and treatment of cancer and other proliferative
disorders. Similarly, developmental tissues rely on decisions
involving cell differentiation and/or apoptosis in pattern
formation. Thus this protein may also be involved in apoptosis or
tissue differentiation and could again be useful in cancer therapy.
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[0511] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:85 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 670 of SEQ ID NO:85, b is an integer
of 15 to 684, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:85, and where b is greater
than or equal to a+14.
[0512] Features of Protein Encoded by Gene No: 76
[0513] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
14 SRGSLLPPHPHRVVVRVHRGAKSLKALRQYIGAAHLQLPWDGKDPARPLGI (SEQ ID
NO:774), TLCLQMEIQVLG CCSFGFYYMVGSDTAEKQGPIPGSQTQ (SEQ ID NO:775),
EGPWLSRHTHSPRAVPESSTAPAQPLLLPLPAPQARRWASNANGWGWDHQR
EGQANYPYSARPAPHNLHPQYLNLHLQTQCYAQGSGWVLPIPGQLKVGGP
YILPEGLQGLCSSVHPHNNPVR HRGAKSLKALRQYIGAA (SEQ ID NO:776), HLQLPWDG
PAPQARRWASNANGWGWDHQR (SEQ ID NO:777), and/or
HPQYLNLHLQTQCYAQGSGWVLP (SEQ ID NO:778).
[0514] Polynucleotides encoding these polypeptides are also
encompassed by the invention. The gene encoding the disclosed cDNA
is believed to reside on chromosome 22. Accordingly,
polynucleotides related to this invention are useful as a marker in
linkage analysis for chromosome 22.
[0515] This gene is expressed primarily in kidney cortex, and to a
lesser extent, in early stage human brain.
[0516] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, renal disorders such as renal cancer, developmental, or
neural disorders, particularly cancers. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the kidney expression of this
gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g., developmental,
neural, renal, urogenital, endothelial, vascular, and cancerous and
wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0517] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 324 as residues: Gly-38 to Gly-45, Gly-47 to Gly-52,
Pro-92 to Lys-110.
[0518] The tissue distribution in kidney cortex indicates that the
protein products of this gene are useful for the study, treatment
and diagnosis of renal diseases, including renal failure,
nephritus, renal tubular acidosis, proteinuria, pyuria, edema,
pyelonephritis, hydronephritis, nephrotic syndrome, crush syndrome,
glomerulonephritis, hematuria, renal colic and kidney stones, in
addition to Wilms Tumor Disease, and congenital kidney
abnormalities such as horseshoe kidney, polycystic kidney, and
Falconi's syndrome. Moreover, the expression within human brain
indicates that the protein product of this gene is useful for the
detection/treatment of neurodegenerative disease states,
behavioural disorders, or inflamatory conditions such as Alzheimers
Disease, Parkinsons Disease, Huntingtons Disease, Tourette
Syndrome, meningitis, encephalitis, demyelinating diseases,
peripheral neuropathies, neoplasia, trauma, congenital
malformations, spinal cord injuries, ischemia and infarction,
aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia,
obsessive compulsive disorder, panic disorder, learning
disabilities, ALS, psychoses, autism, and altered behaviors,
including disorders in feeding, sleep patterns, balance, and
perception. In addition, elevated expression of this gene product
in regions of the brain indicates that it plays a role in normal
neural function. Potentially, this gene product is involved in
synapse formation, neurotransmission, learning, cognition,
homeostasis, or neuronal differentiation or survival. Moreover, the
gene or gene product may also play a role in the treatment and/or
detection of developmental disorders associated with the developing
embryo, sexually-linked disorders, or disorders of the
cardiovascular system. Furthermore, the protein product may also
show utility in the treament and/or prevention of a variety of
vascular disorders, particularly embolism, aneurysm, stroke,
atherosclerosis, or microvascular disease. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[0519] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:86 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1022 of SEQ ID NO:86, b is an integer
of 15 to 1036, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:86, and where b is greater
than or equal to a+14.
[0520] Features of Protein Encoded by Gene No: 77
[0521] In specific embodiments, polypeptides of the invention
comprise-the following amino acid sequence:
15 TNGIMQYVTFCVWLILFSIMFLRFIQAVACISTSFLAEYYSIIWIYNSFTYSSF (SEQ ID
NO:779), VSAVWLL YNFMFNFSKNCQKVFHSGCIIYIPTGNVQGFL- F (SEQ ID
NO:780), FHILALTNTSFXXXFCFFIIATLVDVKWHLIVLICISLMTNDIILCAY- GSK
VFPWRNVPSSPLPFQNLVICLLLFSFKKFWPGAVAHL
CVTQARVQWRDLGSLQPPPPGFKRFSCLSLLSRXDYMHLPPRPANFCIFSKMG (SEQ ID
NO:781), FHHVGQAGLEVLXSSDLPALASQSAXITGEPLRLARIS (SEQ ID NO:783),
and/or LILFSIMFLRFIQAVACISTSFLF LPPRPANFCTFSK (SEQ ID NO:784).
MGFHHVGQAGLE
[0522] Polynucleotides encoding these polypeptides are also
encompassed by the invention.
[0523] This gene is expressed primarily in kidney medulla.
[0524] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, metabolic and renal disorders. Similarly, polypeptides
and antibodies directed to these polypeptides are useful in
providing immunological probes for differential identification of
the tissue(s) or cell type(s). For a number of disorders of the
above tissues or cells, particularly of the metabolic and renal
systems, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g., renal, urogenital, endocrine, and cancerous and wounded
tissues) or bodily fluids (e.g., lymph, serum, plasma, urine,
synovial fluid and spinal fluid) or another tissue or cell sample
taken from an individual having such a disorder, relative to the
standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0525] The tissue distribution in kidney tissue indicates that the
protein products of this gene are useful for study, treatment and
diagnosis of metabolic and renal diseases and disorders. Moreover,
this gene or gene product could be used in the treatment and/or
detection renal failure, nephritus, renal tubular acidosis,
proteinuria, pyuria, edema, pyelonephritis, hydronephritis,
nephrotic syndrome, crush syndrome, glomerulonephritis, hematuria,
renal colic and kidney stones, in addition to Wilms Tumor Disease,
and congenital kidney abnormalities such as horseshoe kidney,
polycystic kidney, and Falconi's syndrome. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[0526] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:87 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 894 of SEQ ID NO:87, b is an integer
of 15 to 908, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:87, and where b is greater
than or equal to a+14.
[0527] Features of Protein Encoded by Gene No: 78
[0528] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
16 ALVPSPQQILPSCFSLMWQVTTKSALVFFKCIYIPFLSAPSLPRLENCLIFCSLDV (SEQ ID
NO:784), and/or QSQLVFLSSPPVAGVLFFFLLSPLGSKSCSTVEX
APSLPRLENCLIFCSLDVQSQLVFLS (SEQ ID NO:785).
[0529] Polynucleotides encoding these polypeptides are also
encompassed by the invention.
[0530] This gene is expressed in chronic synovitis and
microvascular endothelium.
[0531] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, skeletal or vascualar disorders, such as arthritis and
atherosclerosis. Similarly, polypeptides and antibodies directed to
these polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the vascular and skeletal systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., skeletal, synovium,
endothelial cells, vascular, and cancerous and wounded tissues) or
bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0532] The tissue distribution in synovium and microvascular
endothelium indicates that the protein products of this gene are
useful for study, diagnosis and treatment of arthritic and other
inflammatory diseases as well as cardiovascular diseases. Moreover,
the expression of this gene product in synovium would suggest a
role in the detection and treatment of disorders and conditions
affecting the skeletal system, in particular osteoporosis, bone
cancer, as well as, disorders afflicting connective tissues (e.g.
arthritis, trauma, tendonitis, chrondomalacia and inflammation),
such as in the diagnosis or treatment of various autoimmune
disorders such as rheumatoid arthritis, lupus, scleroderma, and
dermatomyositis as well as dwarfism, spinal deformation, and
specific joint abnormalities as well as chondrodysplasias (ie.
spondyloepiphyseal dysplasia congenita, familial osteoarthritis,
Atelosteogenesis type II, metaphyseal chondrodysplasia type
Schmid). In addition the protein would also be useful in the
treatment and/or prevention of a variety of vascular disorders,
which include, but are not limited to, miscorvascular disease,
embolism, thrombosis, aneurysm, stroke, or atherosclerosis.
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[0533] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:88 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 641 of SEQ ID NO:88, b is an integer
of 15 to 655, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:88, and-where b is greater
than or equal to a+14.
[0534] Features of Protein Encoded by Gene No: 79
[0535] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
17 SSPSRVRLRHTPG (SEQ ID NO:786), and/or SNTNYCFMFF (SEQ ID
NO:787). YFPVKVLVPFKNCYILSLLILPCCICGHQFPRXQACTFCLHTLGGFSFS- XLFL
VLLSFYVQTGFSV
[0536] Polynucleotides encoding these polypeptides are also
encompassed by the invention.
[0537] This gene is expressed in resting T-cells and activated
monocytes.
[0538] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune or hematopoietic disorders. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the immune
system, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g., immune, hematpoietic, and cancerous and wounded tissues) or
bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0539] The tissue distribution in T-cells and monocytes indicates
that the protein products of this gene are useful for the study and
treatment of immune diseases such as inflammatory conditions. This
gene product may be involved in the regulation of cytokine
production, antigen presentation, or other processes that may also
suggest a usefulness in the treatment of cancer (e.g. by boosting
immune responses). Since the gene is expressed in cells of lymphoid
origin, the natural gene product may be involved in immune
functions. Therefore it may be also used as an agent for
immunological disorders including arthritis, asthma,
immunodeficiency diseases such as AIDS, leukemia, rheumatoid
arthritis, granulomatous disease, inflammatory bowel disease,
sepsis, acne, neutropenia, neutrophilia, psoriasis,
hypersensitivities, such as T-cell mediated cytotoxicity; immune
reactions to transplanted organs and tissues, such as
host-versus-graft and graft-versus-host diseases, or autoimmunity
disorders, such as autoimmune infertility, lense tissue injury,
demyelination, systemic lupus erythematosis, drug induced hemolytic
anemia, rheumatoid arthritis, Sjogren's disease, scleroderma and
tissues. In addition, this gene product may have commercial utility
in the expansion of stem cells and committed progenitors of various
blood lineages, and in the differentiation and/or proliferation of
various cell types. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0540] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:89 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1088 of SEQ ID NO:89, b is an integer
of 15 to 1102, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:89, and where b is greater
than or equal to a+14.
[0541] Features of Protein Encoded by Gene No: 80
[0542] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
18 GTSRHGQRPIAPGTPWQREPRVEVMDPAGGPRGVLPRPCRXLVLLNPRGGKG (SEQ ID
NO:788), and/or KALQLFRSHVQPLLAEAEISFTMLTERRNHARELVRSEELGRWXALVVM-
XGD GLMHEVVNGLHGAA RPIAPGTPWQREPRVEVMDPA (SEQ ID NO:789). GGP
[0543] Polynucleotides encoding these polypeptides are also
encompassed by the invention. The gene encoding the disclosed cDNA
is believed to reside on chromosome 17. Accordingly,
polynucleotides related to this invention are useful as a marker in
linkage analysis for chromosome 17.
[0544] This gene is expressed in a variety of immune system
tissues, e.g., neutrophils, T-cells, and TNF induced epithelial and
endothelial cells.
[0545] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, infectious and immune or hematopoietic disorders.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune and vascular systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., immune, hematopoietic, and
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0546] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 328 as residues: Met-1 to Trp-6.
[0547] The tissue distribution in immune tissues and cells
indicates that the protein products of this gene are useful for the
study and treatment of infectious diseases, immune and vascular
disorders. Moreover, this gene product may be involved in the
regulation of cytokine production, antigen presentation, or other
processes that may also suggest a usefulness in the treatment of
cancer (e.g. by boosting immune responses). Since the gene is
expressed in cells of lymphoid origin, the natural gene product may
be involved in immune functions. Therefore it may be also used as
an agent for immunological disorders including arthritis, asthma,
immunodeficiency diseases such as AIDS, leukemia, rheumatoid
arthritis, granulomatous disease, inflammatory bowel disease,
sepsis, acne, neutropenia, neutrophilia, psoriasis,
hypersensitivities, such as T-cell mediated cytotoxicity; immune
reactions to transplanted organs and tissues, such as
host-versus-graft and graft-versus-host diseases, or autoimmunity
disorders, such as autoimmune infertility, lense tissue injury,
demyelination, systemic lupus erythematosis, drug induced hemolytic
anemia, rheumatoid arthritis, Sjogren's disease, scleroderma and
tissues. In addition, this gene product may have commercial utility
in the expansion of stem cells and committed progenitors of various
blood lineages, and in the differentiation and/or proliferation of
various cell types. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0548] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:90 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1519 of SEQ ID NO:90, b is an integer
of 15 to 1533, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:90, and where b is greater
than or equal to a+14.
[0549] Features of Protein Encoded by Gene No: 81
[0550] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence: ASGPLMGXAVLKIFE (SEQ ID
NO:790). Polynucleotides encoding these polypeptides are also
encompassed by the invention.
[0551] This gene is expressed in activated neutrophils.
[0552] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, inflammation and other immune or hematopoietic
conditions. Similarly, polypeptides and antibodies directed to
these polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune system, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g., immune, hematopoietic, and cancerous and wounded
tissues) or bodily fluids (e.g., lymph, serum, plasma, urine,
synovial fluid and spinal fluid) or another tissue or cell sample
taken from an individual having such a disorder, relative to the
standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0553] The tissue distribution in neutrophils indicates that the
protein products of this gene are useful for the study and
treatment of immune disorders. Moreover, this gene product may be
involved in the regulation of cytokine production, antigen
presentation, or other processes that may also suggest a usefulness
in the treatment of cancer (e.g. by boosting immune responses).
Since the gene is expressed in cells of lymphoid origin, the
natural gene product may be involved in immune functions. Therefore
it may be also used as an agent for immunological disorders
including arthritis, asthma, immunodeficiency diseases such as
AIDS, leukemia, rheumatoid arthritis, granulomatous disease,
inflammatory bowel disease, sepsis, acne, neutropenia,
neutrophilia, psoriasis, hypersensitivities, such as T-cell
mediated cytotoxicity; immune reactions to transplanted organs and
tissues, such as host-versus-graft and graft-versus-host diseases,
or autoimmunity disorders, such as autoimmune infertility, lense
tissue injury, demyelination, systemic lupus erythematosis, drug
induced hemolytic anemia, rheumatoid arthritis, Sjogren's disease,
scleroderma and tissues. In addition, this gene product may have
commercial utility in the expansion of stem cells and committed
progenitors of various blood lineages, and in the differentiation
and/or proliferation of various cell types. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[0554] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ED NO:91 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 561 of SEQ ID NO:91, b is an integer
of 15 to 575, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:91, and where b is greater
than or equal to a+14.
[0555] Features of Protein Encoded by Gene No: 82
[0556] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
19 LLRSALXSPHLPTPVPLV (SEQ ID NO:791),
QXRNLAQEAFKWIPQDRPTVRSRXRMGLSIRLPILASNCCALPFXXPTSPLQ (SEQ ID
NO:792), CLWSCHCSFQANTGLAS QMTQEPPTSVRAHGIAAWGN (SEQ ID NO:793),
and/or GCRDKNTKRLIQYWPESCSGMTKGTGVGRWGEXRAERSS (SEQ ID NO:794).
HGIAAWGNGCRDKNTKRLIQY
[0557] Polynucleotides encoding these polypeptides are also
encompassed by the invention.
[0558] This gene is expressed in neutrophils.
[0559] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, inflammatory and other immune or hematopoietic
conditions. Similarly, polypeptides and antibodies directed to
these polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune system, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g., immune, hematopoietic, and cancerous and wounded
tissues) or bodily fluids (e.g., lymph, serum, plasma, urine,
synovial fluid and spinal fluid) or another tissue or cell sample
taken from an individual having such a disorder, relative to the
standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0560] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 330 as residues: Ala-83 to Thr-91.
[0561] The tissue distribution in neutrophils indicates that the
protein products of this gene are useful for the study and
treatment of immune disorders. Moreover, the expression of this
gene product in neutrophils indicates a role in the regulation of
the proliferation; survival; differentiation; and/or activation of
hematopoietic cell lineages, including blood stem cells. This gene
product may be involved in the regulation of cytokine production,
antigen presentation, or other processes that may also suggest a
usefulness in the treatment of cancer (e.g. by boosting immune
responses). Since the gene is expressed in cells of lymphoid
origin, the natural gene product may be involved in immune
functions. Therefore it may be also used as an agent for
immunological disorders including arthritis, asthma,
immunodeficiency diseases such as AIDS, leukemia, rheumatoid
arthritis, granulomatdus disease, inflammatory bowel disease,
sepsis, acne, neutropenia, neutrophilia, psoriasis,
hypersensitivities, such as T-cell mediated cytotoxicity; immune
reactions to transplanted organs and tissues, such as
host-versus-graft and graft-versus-host diseases, or autoimmunity
disorders, such as autoimmune infertility, lense tissue injury,
demyelination, systemic lupus erythematosis, drug induced hemolytic
anemia, rheumatoid arthritis, Sjogren's disease, scleroderma and
tissues. In addition, this gene product may have commercial utility
in the expansion of stem cells and committed progenitors of various
blood lineages, and in the differentiation and/or proliferation of
various cell types. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0562] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:92 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded: from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 625 of SEQ ID NO:92, b is an integer
of 15 to 639, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:92, and where b is greater
than or equal to a+14.
[0563] Features of Protein Encoded by Gene No: 83
[0564] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
20 CERSGYTRMAMDT (SEQ ID NO:795), TGSILAVGKKYSL (SEQ ID NO:796),
GSYSRGDWHMRVVGLRGLGASTLQGLLIGIKPNKPQGRGKLQGRSSRKDTVL
WPSPEHPHMVSMAILVYPDLSHYSNPHSTPAALLGCWPPFREGEILGLQRP
GQWPEERCDRPWLPPC GSYSRGDWHMRVVGLRGLGAST (SEQ ID NO:797), and/or
LQGLLIG, STPAALLGCWPPFREGEILGLQRPGQW (SEQ ID NO:798),
[0565] Polynucleotides encoding these polypeptides are also
encompassed by the invention.
[0566] This gene is expressed in human neutrophils.
[0567] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, inflammation and immune or hematopoletic disorders.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune and inflammatory system, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., immune, hematopoietic, and
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0568] The tissue distribution in neutrophils indicates that the
protein products of this gene are useful for diagnosis and
treatment of disorders of the inflammatory and imunune systems.
Moreover, expression of this gene product in neutrophils indicates
a role in the regulation of the proliferation; survival;
differentiation; and/or activation of hematopoietic cell lineages,
including blood stem cells. This gene product may be involved in
the regulation of cytokine production, antigen presentation, or
other processes that may also suggest a usefulness in the treatment
of cancer (e.g. by boosting immune responses). Since the gene is
expressed in cells of lymphoid origin, the natural gene product may
be involved in immune functions. Therefore it may be also used as
an agent for immunological disorders including arthritis, asthma,
immunodeficiency diseases such as AIDS, leukemia, rheumatoid
arthritis, granulomatous disease, inflammatory bowel disease,
sepsis, acne, neutropenia, neutrophilia, psoriasis,
hypersensitivities, such as T-cell mediated cytotoxicity; immune
reactions to transplanted organs and tissues, such as
host-versus-graft and graft-versus-host diseases, or autoimmunity
disorders, such as autoimmune infertility, lense tissue injury,
demyelination, systemic lupus erythematosis, drug induced hemolytic
anemia, rheumatoid arthritis, Sjogren's disease, scleroderma and
tissues. In addition, this gene product may have commercial utility
in the expansion of stem cells and committed progenitors of various
blood lineages, and in the differentiation and/or proliferation of
various cell types. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0569] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:93 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 844 of SEQ ID NO:93, b is an integer
of 15 to 858, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:93, and where b is greater
than or equal to a+14.
[0570] Features of Protein Encoded by Gene No: 84
[0571] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
21 TMGTWVDWLTTNTAHTPAIAAAICAEDFPQRHCGSVERSPDQAC (SEQ ID NO:799),
and/or TNTAHTPAIAAAICAEDFPQRHC (SEQ ID NO:800).
[0572] Polynucleotides encoding these polypeptides are also
encompassed by the invention.
[0573] This gene is expressed in human neutrophils.
[0574] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, inflammatory and immune or hematopoietic disorders.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the inflammatory and immune systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., immune, hematopoietic, and
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0575] The tissue distribution in neutrophils indicates that the
protein products of this gene are useful for diagnosis and
treatment of disorders of the immune and inflammatory systems.
Moreover, the expression of this gene product indicates a role in
the regulation of the proliferation; survival; differentiation;
and/or activation of hematopoietic cell lineages, including blood
stem cells. This gene product may be involved in the regulation of
cytokine production, antigen presentation, or other processes that
may also suggest a usefulness in the treatment of cancer (e.g. by
boosting immune responses). Since the gene is expressed in cells of
lymphoid origin, the natural gene product may be involved in immune
functions. Therefore it may be also used as an agent for
immunological disorders including arthritis, asthma,
immunodeficiency diseases such as AIDS, leukemia, rheumatoid
arthritis, granulomatous disease, inflammatory bowel disease,
sepsis, acne, neutropenia, neutrophilia, psoriasis,
hypersensitivities, such as T-cell mediated cytotoxicity; immune
reactions to transplanted organs and tissues, such as
host-versus-graft and graft-versus-host diseases, or autoimmunity
disorders, such as autoimmune infertility, lense tissue injury,
demyelination, systemic lupus erythematosis, drug induced hemolytic
anemia, rheumatoid arthritis, Sjogren's disease, scleroderma and
tissues. In addition, this gene product may have commercial utility
in the expansion of stem cells and committed progenitors of various
blood lineages, and in the differentiation and/or proliferation of
various cell types. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0576] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:94 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 512 of SEQ ID NO:94, b is an integer
of 15 to 526, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:94, and where b is greater
than or equal to a+14.
[0577] Features of Protein Encoded by Gene No: 85
[0578] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
22 MSPETKGKGRSFPLK (SEQ ID NO:801),
CQNKCSETTCGRTRRESNKQARAMAFIFKGKDLPFPFVSGDIQPKSSGSM
APDQQGLCYLGSWRSHLYCRLLPMDQVSPALC (SEQ ID NO:802), KPSPGLAYCSLSW
SFHMLFLNICSGITIPVILSSGPSHLSTLSLAVSPR RPGTWVKACSCWCP (SEQ ID
NO:803), NKQARAMAFIFKGKDLPFPFVSGDI (SEQ ID NO:804),
YLGSWRSHLYCRLLPMDQVSP (SEQ ID NO:805), and/or
GITIPVILSSGPSHLSTLSLAVSPR (SEQ ID NO:806).
[0579] Polynucleotides encoding these polypeptides are also
encompassed by the invention.
[0580] This gene is expressed in activated neutrophils.
[0581] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, inflammation and immune or hematopoietic diseases.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune system and inflammatory system, expression of this gene
at significantly higher or lower levels may be routinely detected
in certain tissues or cell types (e.g., immune, hematopoietic, and
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0582] The tissue distribution in neutrophils indicates that the
protein products of this gene are useful for diagnosis and
treatment of diseases of the inflammatory and immune systems.
Moreover, the expression of this gene product indicates a role in
the regulation of the proliferation; survival; differentiation;
and/or activation of hematopoietic cell lineages, including blood
stern cells. This gene product may be involved in the regulation of
cytokine production, antigen presentation, or other processes that
may also suggest a usefulness in the treatment of cancer (e.g. by
boosting immune responses). Since the gene is expressed in cells of
lymphoid origin, the natural gene product may be involved in immune
functions. Therefore it may be also used as an agent for
immunological disorders including arthritis, asthma,
immunodeficiency diseases such as AIDS, leukemia, rheumatoid
arthritis, granulomatous disease, inflammatory bowel disease,
sepsis, acne, neutropenia, neutrophilia, psoriasis,
hypersensitivities, such as T-cell mediated cytotoxicity; immune
reactions to transplanted organs and tissues, such as
host-versus-graft and graft-versus-host diseases, or autoimmunity
disorders, such as autoimmune infertility, lense tissue injury,
demyelination, systemic lupus erythematosis, drug induced hemolytic
anemia, rheumatoid arthritis, Sjogren's disease, scleroderma and
tissues. In addition, this gene product may have commercial utility
in the expansion of stem cells and committed progenitors of various
blood lineages, and in the differentiation and/or proliferation of
various cell types. Protein as well as, antibodies directed against
the protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[0583] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:95 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 412 of SEQ ID NO:95, b is an integer
of 15 to 426, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:95, and where b is greater
than or equal to a+14.
[0584] Features of Protein Encoded by Gene No: 86
[0585] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
23 LERLGVGRGLE (SEQ ID NO:807), DLPPCWTTLKEHQCF (SEQ ID NO:808),
and/or MQYQLFTIQCKVVEQTICEDERKMESTCLTLAX- PESVRQXCPATLWSSMN
ICTNRVXLSWRKEEQRIMGRTETGAKDKGRDFLERGSRGW- QLYTGAADTE EV (SEQ ID
NO:809).
[0586] Polynucleotides encoding these polypeptides are also
encompassed by the invention.
[0587] This gene is expressed in activated neutrophils.
[0588] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, inflammation and immune system disorders. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
inflammatory and immune system, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., immune, hematopoietic, and
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0589] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 334 as residues: Met-1 to Gly-6, Gly-32 to Pro-43,
Leu-55 to Gln-60.
[0590] The tissue distribution in neutrophils indicates that the
protein products of this gene are useful for diagnosis and
treatment of disorders of the immune and inflammatory system.
Moreover, the expression of this gene product indicates a role in
the regulation of the proliferation; survival; differentiation;
and/or activation of hematopoietic cell lineages, including blood
stem cells. This gene product may be involved in the regulation of
cytokine production, antigen presentation, or other processes that
may also suggest a usefulness in the treatment of cancer (e.g. by
boosting immune responses). Since the gene is expressed in cells of
lymphoid origin, the natural gene product may be involved in immune
functions. Therefore it may be also used as an agent for
immunological disorders including arthritis, asthma,
immunodeficiency diseases such as AIDS, leukemia, rheumatoid
arthritis, granulomatous disease, inflammatory bowel disease,
sepsis, acne, neutropenia, neutrophilia, psoriasis,
hypersensitivities, such as T-cell mediated cytotoxicity; immune
reactions to transplanted organs and tissues, such as
host-versus-graft and graft-versus-host diseases, or autoimmunity
disorders, such as autoimmune infertility, lense tissue injury,
demyelination, systemic lupus erythematosis, drug induced hemolytic
anemia, rheumatoid arthritis, Sjogren's disease, scleroderma and
tissues. In addition, this gene product may have commercial utility
in the expansion of stem cells and committed progenitors of various
blood lineages, and in the differentiation and/or proliferation of
various cell types. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0591] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:96 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 830 of SEQ ID NO:96, b is an integer
of 15 to 844, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:96, and where b is greater
than or equal to a+14.
[0592] Features of Protein Encoded by Gene No: 87
[0593] In specific embodiments, polypeptides of the invention
comprise the sequence:
24 EQVLALLWPRFELILEMNVQSVRSTDPQRLGGLDTRPHYITRRYAEFSSA
LVSINQTIPNERTMQLLGQLQVEVENFVLRVAAEFSSRKEQLVFLINNYD
MMLGVLMERAADDSKEVESFQQLLNARTQEFIEELLSPPFGGLVAFVKEA
EALIERGQAERLRGEEARVTQLIRGFGSSWKSSVESLSQDVMRSFTNFRN GTSIIQG (SEQ ID
NO:810), ALLKYRFFYQFLLGNERATAKEIRDEYVETLS- KIYLSYYRSYL GRLMKV
QYEEVAEKDDLMGVEDTAKKGFXSKPSLRSRNTIFTLGT- RGSVISPTELE APILVPHTAQR
(SEQ ID NO:811), EQRYPFEALFRSQHYXLLDNSCREYLFICEFFVVSGPXAHDLFHAVMGRT
LSMTLKHLDSYLADCYDAIAVFLCIHIVLRFRNIAAKRDVPALDRYW (SEQ ID NO:812),
GGLDTRPHYITRRYAEFSSALVSINQ (SEQ ID NO:813), SRKEQLVFLIINNYDMMLGVL
(SEQ ID NO:814), ALLKYRFEYQFLLGNERATAKEIRDEYVIETLSKIYLSYYRSYLGRLMKV
QYEEVAEKDDLMGVEDTAKKGFXSKPSLRSRNTIFTLGTRGSVISPTELE
APILVPUTAQRXEQRYPEEALFRSQHYXLLDNSCREYLFICEFFVVSGPX
AHDLEHAVMGRTLSMTLKHLDSYLADCYDAIAVFLCIHIVLRFRNIAAKR
DVPALDRYWEQVLALLWPREELILEMNVQSVRSTDPQRLGGLDTRPHYIT
RRYAEFSSALVSTNQTIPNERTMQLLGQLQVEVENFVLRVAAEFSSRKEQ
LVFLTNNYDMMLGVLMERAADDSKEVESFQQLLNARTQEFIEELLSPPFG
GLVAFVKENEALIERGQAERLRGEEARVTQLIRGFGSSWKSSVESLSQDV MRSETNFRNGTS
(SEQ ID NO:815), PADLRAVSGTSEVGLMLLELHH KVVNVDELSPGREGSELRLGQHPVEAM
IELDQLGQRSLNDTGAISEVGETPHYILT- QRFH (SEQ ID NO:816), and/or
GPBPGASHSAAXEQRYPFEALFRSQHYXLLDNSCREYLFIC EFFVVSGP
XAHDLFHAVMGRTLSMTLKHLDSYLADCYDAIAVFLCIHIVLRFRNIAAK RDVPALDRYWGT
GACLAMATV (SEQ ID NO:817).
[0594] Polynucleotides encoding these polypeptides are also
encompassed by the invention. The translation product of this gene
shares sequence homology with a suppressor of actin mutation which
is thought to be important in mutation suppression.
[0595] This gene is expressed primarily in fetal liver.
[0596] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, hepatic or metabolic conditions. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the liver
or cancer, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g., hepatic, metabolic, and cancerous and wounded tissues) or
bodily fluids (e.g., lymph, bile, serum, plasma, urine, synovial
fluid and spinal fluid) or another tissue or cell sample taken from
an individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0597] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 335 as residues: Val-53 to Arg-60, Thr-88 to Thr-94,
Ala-142 to Ser-150, Gly-188 to Glu-196, Gly-208 to Ser-214, Thr-227
to Gly-232, Lys-279 to Phe-285.
[0598] The tissue distribution in liver, combined with the homology
to a highly conserved suppressor of actin mutation, suggest that
the protein product of this gene is useful for dianosis and
treament of liver disorders or cancer. Similarly, the protein
product of this gene is useful for the detection and treatment of
hepatoblastoma, jaundice, hepatitis, liver metabolic diseases and
conditions that are attributable to the differentiation of
hepatocyte progenitor cells. In addition the expression in fetus
would suggest a useful role for the protein product in
developmental abnormalities, fetal deficiencies, pre-natal
disorders and various would-healing models and/or tissue trauma.
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[0599] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:97 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1971 of SEQ ID NO:97, b is an integer
of 15 to 1985, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:97, and where b is greater
than or equal to a+14.
[0600] Features of Protein Encoded by Gene No: 88
[0601] In specific embodiments, polypeptides of the invention
comprise the sequence:
25 YEGKBFDYVFSIDVNEGGPSYKLPYNTSDDPWLTAYNFLQKNDLNPMFLD
QVAKFIIDNTKGQMLGLGNPSESDPFTGGGRYVPGSSGSSNTLPTADPFT
GAGRYVPGSASMGTTMAGVDPFTGNSAYRSAASKTMNIYFPKKEAVTFDQ
ANPTQILGKLKELNGTAPEEKLTEDDLILLEKILSLICNSSEKPTVQQLQ
ILWKAINCPEDIVFPALDILRLSIKHPSYNBNFCNEKEGAQFSSHLINLL
NPKGKPANQLLALRTFCNCFVGQAGQKLMMSQRESLMSHAELKSGSNI (SEQ ID NO:818),
HIALATLALNYSMCFHKD (SEQ ID NO:819),
KNIEGKAQCLSLISTILEVVQDLEATFRLLVALGTLISDDSNAVQLAKS (SEQ ID NO: 820),
LGVDSQIKIKYSSVSEPAKVSECCRFILNLL (SEQ ID NO:821),
YEGKEFDYVESIDVNEGGPSYKLPYNTSDDPWLTAYNFLQKNDLNPME- LD
QVAKEIIDNTKGQMLGLGNPSFSDPFTGGGRYPGSSGSSNTLPTADPFTG
AGRYVPGSASMGTTMAGVDPFTGNSAYRSAASKTMNIYFPRKEAVTFDQA
NPTQILGKLKBLNGTAPEEKKLTEDDLThLESLICNSSSEKPTVQQLQIL
WKAINCPEDIVFPALDILRLSIKHPSVNENFCNEKEGAQFSSHLINLLNP
KGKPANQLLALRTFCNCFVGQAGQKLMIMSQRESLMSHAIELKSGSNKNI
HIALATLALNYSVCFHKDHNIEGKAQCLSLISTILEVVQDLEATFRLLVA
LGTLISDDSNAVQLAKSLGVDSQIKKYSSVSEPAKVSECCRFILNLL (SEQ ID NO:822),
LNLLLITQKVKCWDLGIP AFQIHLQVVVG (SEQ ID NO:823),
IKHPSVNENFCNEKEGAQFSSHLINLLNP (SEQ ID NO:824),
AIELKSGSNKNIHIALATLALN (SEQ ID NO:825), VQLAKSLGVDSQIKKYSSVSEPA
(SEQ ID NO:826), YEGKEFDYVFSIDVNEGGPSYKLPYN (SEQ ID NO:827),
AYNFLQKNDLNPMF LDQVAKFIIDNT (SEQ ID NO:828), SFSDPFTGGGRYVPG (SEQ
ID NO:829), TADPFTGAGRY (SEQ ID NO:830), TTMAGVDPFTGNSAYRSAA (SEQ
ID NO:831), NIYFPKKEA (SEQ ID NO:832), TFDQANPTQILGKLKELNG (SEQ ID
NO:833), PEDIVFPALDILRLSIKHPSVNENFCNEKE (SEQ ID NO:834),
QFSSHLINLLNPKGKPANQLLALRTFCNCFV (SEQ ID NO:835), and/or
QAGQKLMMSQRESLMSHAIELKSGSN (SEQ ID NO:836).
[0602] Polnynucleotides encoding these polypeptides are also
encompassed by the invention. These polypeptides share significant
homology with phospholipase A2 activating protein, which is thought
to be important in signal transduction (see, e.g., Wang et al.,
Gene 161(2):237-241 (1995)). The gene encoding the disclosed cDNA
is believed to reside on chromosome 9. Accordingly, polynucleotides
related to this invention are useful as a marker in linkage
analysis for chromosome 9.
[0603] This gene is expressed primarily in endothelial cells, to a
less extent in placenta, endometrial stromal cells, osteosarcoma,
testis tumor, muscle, and infant brain that are likely to be rich
in blood vessles.
[0604] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, disorders of the vascular system, aberrent
angiogenesis, tumor angiogenesis or related disorders of
endothelial tissues. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the vascular system or tumors,
expression of this gene at significantly higher or lower levels may
be routinely detected in certain tissues or cell types (e.g.,
endothelial, placenta, skeletal, neural, and cancerous and wounded
tissues) or bodily fluids (e.g., lymph, amniotic fluid, serum,
plasma, urine, synovial fluid and spinal fluid) or another tissue
or cell sample taken from an individual having such a disorder,
relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0605] The tissue distribution of this gene in endothelial cells
and several potential highly vascularized tissues, combined with
the homology to the highly conserved phospholipase A2 activating
protein suggest that this gene may be involved in transducing
signals for endothelial cells in angiogenesis or vasculogenesis.
Furthermore, the protein may show utility for the treatment, and/or
prevention of embolism, thrombosis, aneurysm, atherosclerosis,
microvascular disease, or stroke. Protein, as well as, antibodies
directed against the protein may show utility as a tumor marker
and/or immunotherapy targets for the above listed tissues.
[0606] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:98 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1402 of SEQ ID NO:98, b is an integer
of 15 to 1416, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:98, and where b is greater
than or equal to a+14.
[0607] Features of Protein Encoded by Gene No: 89
[0608] In specific embodiments, polypeptides of the invention
comprise the sequence:
26 YPNQDGDILRDQVLHEHIQRLSKVVTANHRALQIPEVYLREAPWPSAQSE
IRTISAYKTPRDKVQCILRMCSTIMNLLSLANEDSVPGADDFVPVLVFVL
IKANPPCLLSTVQYISSFYASCLSGEESYWWMQFTAAVE (SEQ ID NO:837),
YPNQDGDILRDQVLHEHIQRLSKVVTANHRALQIPEVYLRENPWPSAQSE
IRTISAYKTPRDKVQCILRMCSTIMNLLSLANEDSVPGADDFVPVLVFVL
IKANPPCLLSTVQYISSFYASCLSGEESYWWMQFTAAVEFIKTI (SEQ ID NO:838),
YPNQDGDILRDQVL (SEQ ID NO:839), EAPWPSAQSEI (SEQ ID NO:840),
PVLVFVLIKANP (SEQ ID NO:845), SGEESYWWMQFTAAVEFIKTI (SEQ ID
NO:841), ADDFVPVLVFVLIKANPP (SEQ ID NO:842), YKTPRDKVQCIL (SEQ ID
NO:843), and/or GADDFVPVLVFVLIK (SEQ ID NO:844).
[0609] The translation product of this gene shares sequence
homology with human ras inhibitor and yeast VPS9p which is thought
to be important in golgi vacuole transport. The gene encoding the
disclosed cDNA is believed to reside on chromosome 9. Accordingly,
polynucleotides related to this invention are useful as a marker in
linkage analysis for chromosome 9.
[0610] This gene is expressed primarily in T cells and
melanocytes.
[0611] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune, hematopoietic, or integumentary disorders, such
as dysfunctions and disorders involving T cells and melanocytes.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune system, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g., cancerous and wounded tissues) or bodily fluids
(e.g., lymph, serum, plasma, urine, synovial fluid and spinal
fluid) or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[0612] The tissue distribution in T-cells and melanocytes, combined
with the homology to a ras inhibitor, indicates that the protein
product of this gene is useful for regulating signal transduction;
the diagnosis and treatment of disorders involving T cells and
melanocytes, and potentially in the prevention or study of immune
responses to aberrant integumentary cells and tissues, particularly
in tumors and cancers, such as skin cancers. Moreover, the protein
product of this gene is useful for the treatment, diagnosis, and/or
prevention of various skin disorders including congenital disorders
(i.e. nevi, moles, freckles, Mongolian spots, hemangiomas,
port-wine syndrome), integumentary tumors (i.e. keratoses, Bowen's
disease, basal cell carcinoma, squamous cell carcinoma, malignant
melanoma, Paget's disease, mycosis fungoides, and Kaposi's
sarcoma), injuries and inflammation of the skin (i.e.wounds,
rashes, prickly heat disorder, psoriasis, dermatitis),
atherosclerosis, uticaria, eczema, photosensitivity, autoimmune
disorders (i.e. lupus erythematosus, vitiligo, dermatomyositis,
morphea, scleroderma, pemphigoid, and pemphigus), keloids, striae,
erythema, petechiae, purpura, and xanthelasma. In addition, such
disorders may predispose increased susceptibility to viral and
bacterial infections of the skin (i.e. cold sores, warts,
chickenpox, molluscum contagiosum, herpes zoster, boils,
cellulitis, erysipelas, impetigo, tinea, althletes foot, and
ringworm). Moreover, the protein product of this gene may also be
useful for the treatment or diagnosis of various connective tissue
disorders such as arthritis, trauma, tendonitis, chrondomalacia and
inflammation, autoimmune disorders such as rheumatoid arthritis,
lupus, scleroderma, and dermatomyositis as well as dwarfism, spinal
deformation, and specific joint abnormalities as well as
chondrodysplasias (ie. spondyloepiphyseal dysplasia congenita,
familial osteoarthritis, Atelosteogenesis type II, metaphyseal
chondrodysplasia type Schmid). Protein, as well as, antibodies
directed against the protein may show utility as a tumor marker
and/or immunotherapy targets for the above listed tissues.
[0613] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:99 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1746 of SEQ ID NO:99, b is an integer
of 15 to 1760, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:99, and where b is greater
than or equal to a+14.
[0614] Features of Protein Encoded by Gene No: 90
[0615] The translation product of this gene shares sequence
homology with neuronal olfactomedin-related ER localized protein
which is thought to be important in the maintenance, growth, or
differentiation of chemosensory cilia on the apical dendrites of
olfactory neurons. Moreover, the protein also shares homology with
the conserved human AMY protein which is thought to be a glial
cell-specific transforming protein. In specific embodiments,
polypeptides of the invention comprise the sequence:
27 SARASTQPPAGQHPGPC (SEQ ID NO:846),
MPGRWRWQRDMHPARKLLSLLFLILMGTELTQD (SEQ ID NO:847),
SAAPDSLLRSSKGSTRGSL (SEQ ID NO:845), AAIVIWRGKSESRIAKTPGI (SEQ ID
NO:349), FRGGGTLVLPPTHTPEWLIL (SEQ ID NO:852), PLGITLPLGAPETGGGD
(SEQ ID NO:850), NSARASTQPPAGQHPGPCMPGRWRWQRD (SEQ ID NO:853),
YIVQGTTSPFEMPTIPTPARHRAPHSPPAGHVATAPQALHIKPAMHTAGR
HGCPSRSQRHNPHRLFLEPPRAALCPKGG (SEQ ID NO: 854), ASNAHSWPARWLPFQVSA
AQSPPPVSGAPKGSVMPKGRMSHS GVCVGG
RTKVPPPLKMPGVLAIRLSLFPLQMTIAAKDPLVLPFELL SRESGAAES (SEQ ID NO:855),
GRMSHSGVCVGGRTKVPPPLKMPGVLA (SEQ ID NO:856), and/or
CAAETWKGSQRAGQLCALLA (SEQ ID NO:851).
[0616] The gene encoding the disclosed cDNA is believed to reside
on chromosome 9. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
9.
[0617] This gene is expressed in pineal gland.
[0618] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neurological and endocrinological disorders. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
neurological or endocrine systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., neural, endocrine, and
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0619] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 338 as residues: Leu-20 to Ala-26, Arg-32 to Arg-39,
Thr-104 to Gly-112.
[0620] The tissue distribution in pineal gland, combined with the
homology to both the olfactomedin-related, and AMY proteins,
indicates that the protein product of this gene is useful for
maintenance, growth, or differentiation of neuron cells in pineal
gland. Therefore, the protein product of this gene may be useful
for the diagnosis and treament of neurological disorders in pineal
gland. Moreover, the protein product of this gene is useful for the
detection/treatment of neurodegenerative disease states,
behavioural disorders, or inflamatory conditions such as Alzheimers
Disease, Parkinsons Disease, Huntingtons Disease, Tourette
Syndrome, meningitis, encephalitis, demyelinating diseases,
peripheral neuropathies, neoplasia, trauma, congenital
malformations, spinal cord injuries, ischemia and infarction,
aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia,
obsessive compulsive disorder, panic disorder, learning
disabilities, ALS, psychoses, autism, and altered behaviors,
including disorders in feeding, sleep patterns, balance, and
perception. In addition, elevated expression of this gene product
in regions of the brain indicates that it plays a role in normal
neural function. Potentially, this gene product is involved in
synapse formation, neurotransmission, learning, cognition,
homeostasis, or neuronal differentiation or survival. Moreover, the
gene or gene product may also play a role in the treatment and/or
detection of developmental disorders associated with the developing
embryo, sexually-linked disorders, or disorders of the
cardiovascular system. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0621] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:100 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 585 of SEQ ID NO:100, b is an integer
of 15 to 599, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:100, and where b is greater
than or equal to a+14.
[0622] Features of Protein Encoded by Gene No: 91
[0623] This gene is expressed primarily in prostate and apoptotic T
cells.
[0624] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, reproductive, immune, or hematopoietic disorders,
particularly prostate disease and T cell dysfunction. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
prostate cancer, expression of this gene at significantly higher or
lower levels may be routinely detected in certain tissues or cell
types (e.g. prostate, immune, cancerous and wounded tissues) or
bodily fluids (e.g., lymph, seminal fluid, serum, plasma, urine,
synovial fluid and spinal fluid) or another tissue or cell sample
taken from an individual having such a disorder, relative to the
standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0625] The tissue distribution in prostate and T-cells indicates
that the protein product of this gene is useful for the detection
of abnormal activity in prostate and T cells, such as proliferative
conditions of the prostate, or possibly treatment of this
abnormality. This gene product may be involved in the regulation of
cytokine production, antigen presentation, or other processes that
may also suggest a usefulness in the treatment of cancer (e.g. by
boosting immune responses). Since the gene is expressed in cells of
lymphoid origin, the natural gene product may be involved in immune
functions. Therefore it may be also used as an agent for
immunological disorders including arthritis, asthma,
immunodeficiency diseases such as AIDS, leukemia, rheumatoid
arthritis, granulomatous disease, inflammatory bowel disease,
sepsis, acne, neutropenia, neutrophilia, psoriasis,
hypersensitivities, such as T-cell mediated cytotoxicity; immune
reactions to transplanted organs and tissues, such as
host-versus-graft and graft-versus-host diseases, or autoimmunity
disorders, such as autoimmune infertility, lense tissue injury,
demyelination, systemic lupus erythematosis, drug induced hemolytic
anemia, rheumatoid arthritis, Sjogren's disease, scleroderma and
tissues. In addition, this gene product may have commercial utility
in the expansion of stem cells and committed progenitors of various
blood lineages, and in the differentiation and/or proliferation of
various cell types. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0626] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:101 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 770 of SEQ ID NO:101, b is an integer
of 15 to 784, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:101, and where b is greater
than or equal to a+14.
[0627] Features of Protein Encoded by Gene No: 92
[0628] The gene encoding the disclosed cDNA is believed to reside
on chromosome 19. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
19.
[0629] This gene is expressed primarily in prostate, and to a
lesser extent, in smooth muscle cells, fibroblasts, and
placenta.
[0630] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, disorders in prostate or vascular tissues. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
prosate or vascular system, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. prostate, musculo-skeletal,
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
seminal fluid, serum, plasma, urine, synovial fluid and spinal
fluid) or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[0631] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 340 as residues: Ser-38 to Lys-46.
[0632] The tissue distribution in prostate and smooth muscle
indicates that the protein product of this gene is useful for
regulating the function of prostate or highly vascularized tissues,
such as the placenta. Similarly, the protein product of this gene
may be useful in the treatment and/or detection of vascular
disorders which include, but are not limited to, stroke, embolism,
thrombosis, aneurysm, microvascular disease, or atherosclerosis.
The protein may also show utility in the treatment or detection of
proliferative disorders of the prostate or male reproductive
system. Protein, as well as, antibodies directed against the
protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[0633] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:102 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 390 of SEQ ID NO:102, b is an integer
of 15 to 404, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:102, and where b is greater
than or equal to a+14.
[0634] Features of Protein Encoded by Gene No: 93
[0635] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence: GHQTAPETPSRSD (SEQ ID
NO:857). Polynucleotides encoding these polypeptides are also
encompassed by the invention.
[0636] This gene is expressed primarily in embryos and fetal
tissues, and to a lesser extent, in proliferative tissues.
[0637] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, disorders in embryonic development and cell
proliferation. Similarly, polypeptides and antibodies directed to
these polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the embryonic tissues and proliferative cells, expression of this
gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g., developmental,
differentiating, and cancerous and wounded tissues) or bodily
fluids (e.g., lymph, amniotic fluid, serum, plasma, urine, synovial
fluid and spinal fluid) or another tissue or cell sample taken from
an individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0638] The tissue distribution in embryonic and fetal tissues
indicates that the protein product of this gene is useful for the
diagnosis or treatment of abnormalities in developing and
proliferative cells and organs. Similarly, expression within
embryonic tissue and other cellular sources marked by proliferating
cells indicates that this protein may play a role in the regulation
of cellular division, and may show utility in the diagnosis and
treatment of cancer and other proliferative disorders. Similarly,
developmental tissues rely on decisions involving cell
differentiation and/or apoptosis in pattern formation. Thus, this
protein may also be involved in apoptosis or tissue differentiation
and could again be useful in cancer therapy. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[0639] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:103 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 2204 of SEQ ID NO:103, b is an
integer of 15 to 2218, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:103, and where
b is greater than or equal to a+14.
[0640] Features of Protein Encoded by Gene No: 94
[0641] The translation product of this gene shares sequence
homology with a transformation related protein which is thought to
be important in transformation. In specific embodiments,
polypeptides of the invention comprise the following amino acid
sequence: SQTDR (SEQ ID NO:858). Polynucleotides encoding these
polypeptides are also encompassed by the invention.The gene
encoding the disclosed cDNA is believed to reside on chromosome 2.
Accordingly, polynucleotides related to this invention are useful
as a marker in linkage analysis for chromosome 2.
[0642] This gene is expressed primarily in female reproductive
tissues, i.e., breast cancer cells, placenta, and ovary, and to a
lesser extent, in fetal lung.
[0643] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, cancer or dysfunction of reproductive tissues, in
addition to pulmonary or developmental disorders. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
reproduction system, expression of this gene at significantly
higher or lower levels may be routinely detected in certain tissues
or cell types (e.g., pulmonary, reproductive, ovarian, breast,
placental, develpomental, and cancerous and wounded tissues) or
bodily fluids (e.g., lymph, pulmonary surfactant or sputum,
amniotic fluid, serum, plasma, urine, synovial fluid and spinal
fluid) or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[0644] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 342 as residues: Ser-50 to Pro-61.
[0645] The tissue distribution in female reproductive tissues,
combined with the homology to the transformation related protein,
indicates that the protein product of this gene is useful for the
diagnosis and treatment of conditions caused by transformation,
i.e. tumorigenesis in reproductive organs, (e.g. breast, placenta,
and ovary). Similarly, expression within fetal tissue and other
cellular sources marked by proliferating cells indicates that this
protein may play a role in the regulation of cellular division, and
may show utility in the diagnosis and treatment of cancer and other
proliferative disorders. Similarly, developmental tissues rely on
decisions involving cell differentiation and/or apoptosis in
pattern formation. Thus this protein may also be involved in
apoptosis or tissue differentiation and could again be useful in
cancer therapy. Protein may also be useful in the treatment or
detection of a variety of pulmonary conditions, including, but not
limited to emphysema, ARDS, cystic fibrosis, asthma, etc. Protein,
as well as, antibodies directed against the protein may show
utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[0646] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:104 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1337 of SEQ ID NO:104, b is an
integer of 15 to 1351, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:104, and where
b is greater than or equal to a+14.
[0647] Features of Protein Encoded by Gene No: 95
[0648] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
28 NIYFKEKRKRGGAKMAGAIIEN (SEQ ID NO:859),
VYLCAYTSTINVTVTTANAKLINMCCLVDSNTRSCVVI DEGIFRSAEQF LIKFRN
KQSTIFPRFTWELHSIGLVFSIVFMGWCIQEHQSKDIQIPHPI DACEKGTVHL
DCDAAPFPMAFRYLTNDEEDDSHGSAGQGDKHEELEPKN (SEQ ID NO:860),
KMPCRMSPNSSIQVQSNPMENHSTGILIKVMEIPRAKMTFSRSTGGRDIM
VILLQYHTIMMKMLGVRKVFMANHTLVKPPFWWIPTNRISFISPIPTLIF FFSFTGSRMFKR
(SEQ ID NO:861), TTKSEK MQKSPWTFPWLTVMTHLLSGLKWPMKEYHGNSNAPSHLPRLQS
MRAVTMNVMSFLSWKLGLWPISFTF (SEQ ID NO:862),
IKFRNKQSTIFPRFTWELHSIGLVFSIVFMG (SEQ ID NO:863),
SSIQVQSNPMENHSTGILIKVMEIPRAKM (SEQ ID NO:864), and/or
LGVRKVFMANHTLVKPPFWWIPTNRISFISPIP (SEQ ID NO:865).
[0649] Polynucleotides encoding these polypeptides are also
encompassed by the invention. The gene encoding the disclosed cDNA
is believed to reside on chromosome 1. Accordingly, polynucleotides
related to this invention are useful as a marker in linkage
analysis for chromosome 1.
[0650] This gene is expressed primarily in testes,
rhabdomyosarcoma, infant brain and to a lesser extent in some
tumors and highly vascularized tissues.
[0651] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, tumorigenesis, abnormal angiogenesis, reproductive,
vascular, and/or neurological disorders., Similarly, polypeptides
and antibodies directed to these polypeptides are useful in
providing immunological probes for differential identification of
the tissue(s) or cell type(s). For a number of disorders of the
above tissues or cells, particularly of the tumor tissues or
vascular tissues, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g., muscle, neural, developmental, vascular,
reproductive, testicular, and cancerous and wounded tissues) or
bodily fluids (e.g., lymph, serum, seminal fluid, amniotic fluid,
plasma, urine, synovial fluid and spinal fluid) or another tissue
or cell sample taken from an individual having such a disorder,
relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0652] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 343 as residues: Arg-46 to Trp-54, Pro-60 to Ile-69,
Asn-116 to Ala-122, Arg,-147 to Lys-153, Ser-158 to Glu-170,
Ile-399 to Ser-405, Pro-486 to Met-499, Pro-502 to Asp-508.
[0653] The tissue distribution in infant brain indicates that the
protein product of this gene is useful for a range of disease
states including treatment of tumor or vascular disorders and the
treatment of neurological disorders such as Alzheimers Disease,
Parkinsons Disease, Huntingtons Disease, schizophrenia, mania,
dementia,paranoia, obsessive compulsive disorder and panic
disorder. Moreover, expression within vascular tissues indicates
that the protein product of this gene is useful in the treatment
and/or detection of a variety of vascular conditions, which include
but are not limited to emphysema, atherosclerosis, thrombosis,
miscrovascular disease, stroke or aneurysm. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[0654] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:105 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 2052 of SEQ ID NO:105, b is an
integer of 15 to 2066, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:105, and where
b is greater than or equal to a+14.
[0655] Features of Protein Encoded by Gene No: 96
[0656] The translation product of this gene is homologous to the
Clostridium perfringens enterotoxin (CPE)receptor gene product and
shares sequence homology with a human ORF specific to prostate and
a glycoprotein specific to oligodendrocytes, both of which are
tissue specific proteins. See e.g., Katahira et al. J Cell Biol.
136(6):1239-1247 (1997). PMID: 9087440; UI: 97242441. In specific
embodiments, polypeptides of the invention comprise the following
amino acid sequence:
29 TM ASMGLQV (SEQ TD NO:866),
KSWMMLWAVQDTGTITIRPANRNTTPATIMVLALALSSSRQLVHLPPTTD
SSTPRAATMMLMMTRARA ACRSCGSASSESYTLHCIWPVLCTTQFIHRP
SQMVCEVTMLLPMKAVTRHMGSAQHSMTASQPRTASAMP ITCSPMEAIV
QRPRELRTWKAEGIRLWGP (SEQ ID NO:867), LQVMGIALAVLGWLAVMLCCALPMWRVT
(SEQ ID NO:868), SNIVTSQTIWEGLWMNCVVQST (SEQ ID NO:869),
QMQCKVYDSLLALPQDLQ (SEQ ID NO:870), KCTNCLEDESAKAKTMIV (SEQ ID
NO:871), GVVFLLAGLMVIVPVSWTAHNIIQDFYNPLVA (SEQ ID NO:872), and/or
CCNCPPRTDKPY (SEQ ID NO:873).
[0657] Polynucleotides encoding these polypeptides are also
encompassed by the invention. The gene encoding the disclosed cDNA
is believed to reside on chromosome 7. Accordingly, polynucleotides
related to this invention are useful as a marker in linkage
analysis for chromosome 7.
[0658] This gene is expressed primarily in pancreas tumor and
ulcerative colitis, and to a lesser extent in several tumors and
normal tissues.
[0659] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, metabolic, gastrointestinal. or proliferative
disorders, such as pancreatic disorders, ulcerative colitis, tumors
and food poisoning. Similarly, polypeptides and antibodies directed
to these polypeptides are useful in providing immunological probes
for differential identification of the tissue(s) or cell type(s).
For a number of disorders of the above tissues or cells,
particularly of the digestive system or tumorigenic system,
expression of this gene at significantly higher or lower levels may
be routinely detected in certain tissues or cell types (e.g.,
metabolic, gastrointestinal, pancreatic, and cancerous and wounded
tissues) or bodily fluids (e.g., lymph, bile, serum, plasma, urine,
synovial fluid and spinal fluid) or another tissue or cell sample
taken from an individual having such a disorder, relative to the
standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0660] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 344 as residues: Gly-147 to Met-152, Cys-177 to
Lys-188.
[0661] The tissue distribution in pancrease, combined with the
homology to a prostate and oligodendrocyte-specific protein,
indicates that the protein product of this gene is useful as a
marker for the diagnosis or treatment of disorders in pancrease,
ulcerative colitis, and tumors. Furthermore, identity to the human
receptor for Clostridium perfringenes enterotoxin indicates that
the soluble portion of this receptor could be used in the treatment
of food poisoning associated with Clostridia perfringens by
blocking the activity of the perfringens enterotoxin. Protein, as
well as, antibodies directed against the protein may show utility
as a tumor marker and/or immunotherapy targets for the above listed
tissues.
[0662] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:106 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1691 of SEQ ID NO:106, b is an
integer of 15 to 1705, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:106, and where
b is greater than or equal to a+14.
[0663] Features of Protein Encoded by Gene No: 97
[0664] The translation product of this gene shares sequence
homology with an ATPase from Saccharomyces cerevisiae which is
thought to be important in metabolism (See Genbank Accession
No.g1181253). In specific embodiments, polypeptides of the
invention comprise the following amino acid sequence:
30 PFTAIAGSEIFSLE (SEQ ID NO:874), SKTEALTQAFR (SEQ ID NO:875),
VVHTVSLHEIDVINSRTQGFLALF (SEQ ID NO:876), PGVLFIDEVHMLDIE (SEQ ID
NO:877), AGIRQRFSARLWQLVSIMATVTATTKVPEIRDVTRIERIGAHSHIRGLGL
DDALEPRQASQGMVGQLAARRAAGVVLEMIREGKIAGRAVLIAGQPGTGK
TAIAMGMAQALGPDTPFTAIAGSEIFSLEMSKTEALTQAF RRSIGVRIK
EETEIIEGEVVEIQIDRPATGTGSKVGKLTLKTTEMETIYDLGTKMIXSL TKDKVQAGDVI
TIDKATGKISKLGRSFTRARELRRYGLPDQVRAVPRWG
APETQGGGAHRVPARDRRHQLSHPGLPGALLR (SEQ ID NO:878),
SPSTRRRARSPSWAAPSHAPANYDAMGSQTKFVQCPDGEL QKRKEVVHT
VSLHEIDVINSRTQGFLALFSG DTGEIKSEVREQINAKVAEWREEGKAE
IIPGVLFIDEVHMLDIESFSFLNRALESDMAPVQQVYGDAVRALVAGAPD
SRDATVGGLVPNSCSPGDPLVLERPPPRWXS (SEQ ID NO:879), WIPRAAGIRH
EATNRGITRIRGTSYQSPHGIPIDLLDRRHVTLQGPVEE GEALDVQHV
DLVDEQHSRDDLRLALLAPLSHLGIDLLTDF (SEQ ID NO:880),
YDAMGSQTKFVQCPDGELQKRKEVVHTVSL (SEQ ID NO:881),
KAEIIPGVLFIDEVHMLDIESFSFLNRALES (SEQ ID NO:882), and/or
EATNRGITRIRGTSYQSPHGIPIDLLDR (SEQ ID NO:883).
[0665] Polynucleotides encoding these polypeptides are also
encompassed by the invention.
[0666] This gene is expressed primarily in testes and several
hematopoietic cells.
[0667] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, reproductive, immune, or hematopoietic disorders,
particularly male infertility and leukemia. Similarly, polypeptides
and antibodies directed to these polypeptides are useful in
providing immunological probes for differential identification of
the tissue(s) or cell type(s). For a number of disorders of the
above tissues or cells, particularly of the hematopoietic system,
expression of this gene at significantly higher or lower levels may
be routinely detected in certain tissues or cell types (e.g.,
reproductive, immune, hematopoietic, testicular, and cancerous and
wounded tissues) or bodily fluids (e.g., lymph, seminal fluid,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0668] The tissue distribution in testes and hematopoietic cells,
combined with the homology to ATPases, indicates that the protein
product of this gene is useful as a marker for the diagnosis and
treatment of leukemia and other hematopoietic disorders. The
protein may also show utility as a contraceptive, or for the
treatment and/or detection of aberrant testicular function. The
secreted protein can also be used to determine biological activity,
to raise antibodies, as tissue markers, to isolate cognate-ligands
or receptors, to identify agents that modulate their interactions
and as nutritional supplements. It may also have a very wide range
of biological acitivities. Typical of these are cytokine, cell
proliferation/differentiation modulating activity or induction of
other cytokines; immunostimulating/immunosuppressant activities
(e.g. for treating human immunodeficiency virus infection, cancer,
autoimmune diseases and allergy); regulation of hematopoiesis (e.g.
for treating anaemia or as adjunct to chemotherapy); stimulation or
growth of bone, cartilage, tendons, ligaments and/or nerves (e.g.
for treating wounds); stimulation of follicle stimulating hormone
(for control of fertility); chemotactic and chemokinetic activities
(e.g. for treating infections, tumors); Hemostatic or thrombolytic
activity (e.g. for treating haemophilia, cardiac infarction etc.);
anti-inflammatory activity (e.g. for treating septic shock, Crohn's
disease); as antimicrobials; for treating psoriasis or other
hyperproliferative diseases; for regulation of metabolism, and
behaviour. Also contemplated is the use of the corresponding
nucleic acid in gene therapy procedures. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[0669] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:107 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1153 of SEQ ID NO:107, b is an
integer of 15 to 1167, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:107, and where
b is greater than or equal to a+14.
[0670] Features of Protein Encoded by Gene No: 98
[0671] In specific embodiments, polypeptides of the invention
comprise the sequence:
31 MRSARPSLGCLPSWAFSQALNI (SEQ ID NO:884), LLGLKGLAPAEISAVCEGNFN
(SEQ ID NO:885), VAHGLAWSYYIGYLRLIHPELQARIR (SEQ ID NO:886),
TYNQHYNNLLRGAVSQRC (SEQ ID NO:887), ILLPLDCGVPDNLS
MADPNIRFLDKLPQQTGDRAGIKDRVYSN (SEQ ID NO:888),
SIYELLENGQRAGTCVLEYATPLQTLFAMSQYSQAGFSGEDRLEQ (SEQ ID NO:889).
AKLFCRTLEDILADAPESQNNCRLIAYQEPADDSSFSLSQEVLRH- LRQEE
KEEVTVGSLKTSAVPSTSTMSQEPELLISGMEKPLPLRTDFS (SEQ ID NO:890),
LRLHSEKLPLA ARSAGPSLLVIIQSSQCP GGRRYRGSYWRTVRACLGC
PLRRGALLLLSIYFYYSLPNAVGPPFTW (SEQ ID NO:892),
VWLTPTFASWINCPSRPVTVLASRIGFTATASMSFWRTGSGRAPVSWS- TP
PPCRLCLPCHNTVKLALAGR IGLSRPNSSAGHLRTSWQMPLSLRTTAAS
LPTRNLQMTAASRCPRRFSGTCGRRKRKRLLWAA (SEQ ID NO:893),
GVCQVSFMGPSRPTPHPSPLPLPGDAELSQWYQQ APSPSGSWSCSIIGE
PQQKNGEEEEAEFGVLNPPAPTLQHQGCYGLSCRATLA (SEQ ID NO:894), and/or
LLGLKGLAPAEISAVCEKGNFNVAHGLAWSYYIGYLRLILPEL (SEQ ID NO:891).
[0672] Polynucleotides encoding these polypeptides are also
encompassed by the invention.
[0673] This gene is expressed primarily in prostate BPH, and to a
lesser extent, in bone marrow.
[0674] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, reproductive, hematopoietic, or immune disorders,
particularly benign prostatic hypertrophy, prostate cancer, or
leukemia. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the male urinary system, expression of this gene at significantly
higher or lower levels may be routinely detected in certain tissues
or cell types (e.g., reproductive, hematopoietic, immune,
prostatic, and cancerous and wounded tissues) or bodily fluids
(e.g., lymph, seminal fluid, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0675] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 346 as residues: Ile-60 to Asn-69, Leu-106 to
Asp-112, Glu-130 to Gly-136, Phe-160 to Glu-167, Pro-184 to
Cys-190, Glu-197 to Ser-202, Arg-215 to Glu-221, Thr-237 to
Pro-242.
[0676] The tissue distribution in prostate tissue indicates that
the protein product of this gene is useful for the diagnosis or
treatment of reproductive disorders, such as benign prostatic
hypertrophy or prostate cancer. Moreover, the protein product of
this gene is useful for the treatment and diagnosis of hematopoetic
related disorders such as anemia, pancytopenia, leukopenia,
thrombocytopenia or leukemia since stromal cells are important in
the production of cells of hematopoietic lineages. The uses include
bone marrow cell ex vivo culture, bone marrow transplantation, bone
marrow reconstitution, radiotherapy or chemotherapy of neoplasia.
The gene product may also be involved in lymphopoiesis, therefore,
it can be used in immune disorders such as infection, inflammation,
allergy, immunodeficiency etc. In addition, this gene product may
have commercial utility in the expansion of stem cells and
committed progenitors of various blood lineages, and in the
differentiation and/or proliferation of various cell types.
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[0677] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:108 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1893 of SEQ ID NO:108, b is an
integer of 15 to 1907, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:108, and where
b is greater than or equal to a+14.
[0678] Features of Protein Encoded by Gene No: 99
[0679] The gene encoding, the disclosed cDNA is believed to reside
on chromosome 15. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
15.
[0680] This gene is expressed primarily in salivary gland.
[0681] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, metabolic disorders, particularly of the salivary
gland. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
glandular tissues, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g. salivary gland, cancerous and wounded tissues) or
bodily fluids (e.g., lymph, serum, chyme, plasma, urine, synovial
fluid and spinal fluid) or another tissue or cell sample taken from
an individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0682] The tissue distribution in salivary glands indicates that
the protein product of this gene is useful for the treatment and/or
detection of disorders of or injuries to the salivary gland or
other glandular tissue. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0683] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:109 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 597 of SEQ ID NO:109, b is an integer
of 15 to 611, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:109, and where b is greater
than or equal to a+14.
[0684] Features of Protein Encoded by Gene No: 100
[0685] The translation product of this gene shares sequence
homology with a C. elegans gene. Based upon its degree of
conservation, an important cellular function can be attributed to
this protein. When tested against Jurkat cell lines, supernatants
removed from cells containing this gene activated the GAS (gamma
activating sequence) promoter element. Thus, it is likely that this
gene activates T-cells through the JAK-STAT signal transduction
pathway. GAS is a promoter element found upstream of many genes
which are involved in the Jak-STAT pathway. The Jak-STAT pathway is
a large, signal transduction pathway involved in the
differentiation and proliferation of cells. Therefore, activation
of the Jak-STAT pathway, reflected by the binding of the GAS
element, can be used to indicate proteins involved in the
proliferation and differentiation of cells. In specific
embodiments, polypeptides of the invention comprise the sequence:
DPRVRLNSLTCKHIFISLTQ (SEQ ID NO:902), TMKLLKLRRNIVK LSLYRHFTN (SEQ
ID NO:895), TLILAVAASIVFIIWTTMKFRI (SEQ ID NO:896),
VTCQSDWRELWVDDAIWRLLFSMILFVI (SEQ ID NO:897), MVLWRPSANNQ
RFAFSPLSEEEEEDEQ (SEQ ID NO:898), MVLWRPSANNQRFAFSPLSEEEEE DEQ (SEQ
ID NO:899), KEPMLKESFEGMKMRSTKQEPNGNSKVNKAQEDDL (SEQ ID NO:900),
NAFGRHSTAVK (SEQ ID NO:903), ESCLLCGISEYPIQRXIC
PGCFDPCRXAFSSETLTGSNPGHHSQSGIWHRQATPG- VTLHKVVVAXALYL
LFSGMEGVLRVTGAQTDLASLAFIPLAFLDTALCWWIFISLTQTMKLLKLRRN
IVKLSLYRHFTNTLILAVAASIVFIIWTTMKFRIVTCQSDWRELWVDDAIWRLLF
EPNGNSKVNKAQEDDLKWVEENVPSSVTDVALPALLDSDEERMITHFERSKM E (SEQ ID
NO:904), and/or DWVEENVPSSVTDVALPALLDSDEERMITHFERSK ME (SEQ ID
NO:901). Polynucleotides encoding these polypeptides are also
encompassed by the invention. The gene encoding the disclosed cDNA
is believed to reside on chromosome 15. Accordingly,
polynucleotides related to this invention are useful as a marker in
linkage analysis for chromosome 15.
[0686] This gene is expressed primarily in thyroid, and to a lesser
extent, in osteoclastoma, kidney medulla, and lung.
[0687] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, endocrine disorders, particularly thyroid dysfunction
or cancer. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the endocrine system, expression of this gene at significantly
higher or lower levels may be routinely detected in certain tissues
or cell types (e.g., endocrine, skeletal, urogenital, renal,
pulmonary, and cancerous and wounded tissues) or bodily fluids
(e.g., lymph, pulmonary surfactant or sputum, serum, plasma, urine,
synovial fluid and spinal fluid) or another tissue or cell sample
taken from an individual having such a disorder, relative to the
standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0688] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 348 as residues: Lys-107 to Leu-124, Glu-150 to
Thr-159, Pro-173 to Asp-179, Ser-192 to Ser-201.
[0689] The tissue distribution in thyroid, combined with the
detected GAS biological activity, indicates that the protein
product of this gene is useful for the diagnosis and treatment of
thyroid dysfunction or cancer. Protein, as well as, antibodies
directed against the protein may show utility as a tumor marker
and/or immunotherapy targets for the above listed tissues.
[0690] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:110 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 2618 of SEQ ID NO:110, b is an
integer of 15 to 2632, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:110, and where
b is greater than or equal to a+14.
[0691] Features of Protein Encoded by Gene No: 101
[0692] The gene encoding the disclosed cDNA is thought to reside on
chromosome 16. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
16. In specific embodiments, polypeptides of the invention comprise
the sequence: YEPMDFXMALIYD (SEQ ID NO:905), IRHELTVLRDT RPACA (SEQ
ID NO:906), and/or MDFXMALIYD (SEQ ID NO:907). Polynucleotides
encoding these polypeptides are also encompassed by the
invention.
[0693] This gene is expressed primarily in kidney cortex, and to a
lesser extent, in adult brain, corpus colosum, hippocampus, and
frontal cortex.
[0694] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neurological disorders, kidney disorders. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
central nervous system and renal system, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. kidney, brain, cancerous and
wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0695] The tissue distribution in adult brain, corpus colosum,
hippocampus, and frontal cortex indicates that the protein product
of this gene is useful for treatment or diagnosis of neurological
disorders, such as Alzheimers Disease, Parkinsons Disease,
Huntingtons Disease, Tourette Syndrome, schizophrenia, mania,
dementia, paranoia, obsessive compulsive disorder, panic disorder,
learning disabilities, ALS, psychoses, autism, and altered
bahaviors, including disorders in feeding, sleep patterns, balance,
and perception. In addition, the gene or gene product may also play
a role in the treatment and/or detection of developmental disorders
associated with the developing embryo, or sexually-linked
disorders. Furthermore, The tissue distribution in kidney indicates
that this gene or gene product could be used in the treatment
and/or detection of kidney diseases including renal failure,
nephritus, renal tubular acidosis, proteinuria, pyuria, edema,
pyelonephritis, hydronephritis, nephrotic syndrome, crush syndrome,
glomerulonephritis, hematuria, renal colic and kidney stones, in
addition to Wilms Tumor Disease, and congenital kidney
abnormalities such as horseshoe kidney, polycystic kidney, and
Falconi's syndrome. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0696] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:111 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 2235 of SEQ ID NO:111, b is an
integer of 15 to 2249, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:111, and where
b is greater than or equal to a+14.
[0697] Features of Protein Encoded by Gene No: 102
[0698] The translation product of this gene shares sequence
homology with F15C11.2 of C. elegans which is of unknown function.
In specific embodiments, polypeptides of the invention comprise the
sequence: MQEMMRNQDRALSNLESIPGGYNA (SEQ ID NO:908),
LRRMYTDIQEPMLSAAQEQFGGNPF (SEQ ID NO:909), ASLVSNTSS
GEGSQPSRTENRDPLPNPWAPQT (SEQ ID NO:910), SQSSSASSGTASTVGG
TTGSTASGTSGQSTTAPNLVPGVGASMFNTPGMQSLLQQITENPQLMQNMLSA PY (SEQ ID
NO:911), MRSMMQSLSQNPDLAAQMMLNNPLFAGNPQLQEQMR QQLPTFLQQ (SEQ ID
NO:912), MQNPDTLSAMSNPRAMQALLQIQQGLQTLAT
EAPGLIPGFTPGLGALGSTGGSSGTNGSNATP- SENTSPTAGT (SEQ ID NO:913),
TEPGHQQFIQQMLQALAGVNPQLQNPEVRFQQQLEQLSAMGFLNRE- ANLQALI
ATGGDINAAIERLLGSQPS (SEQ ID NO:914), RNPAMMQEMMRNQDRALS
NLESIPGGYNALRRMYTDIQEPMLSAA (SEQ ID NO:915), GNPFASLVSNTSS (SEQ ID
NO:918), GLTVHLVIKTQNRP (SEQ ID NO:919), SELQSQMQRQLLSNP EMM (SEQ
ID NO:920), PEISHMLNNPDIMR (SEQ ID NO:921), and/or
RQLIMANPQMQQLIQRNP (SEQ ID NO:922). Polynucleotides encoding these
polypeptides are also encompassed by the invention.
[0699] This gene is expressed primarily in breast.
[0700] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, breast cancer. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of tumor systems, expression of this
gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g. breast, cancerous
and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0701] The tissue distribution in breast indicates that the protein
product of this gene is useful for treatment and diagnosis of some
types of breast cancer. Protein, as well as, antibodies directed
against the protein may show utility as a tissue-specific marker
and/or immunotherapy target for the above listed tissues.
[0702] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:112 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 2184 of SEQ ID NO:1 12, b is an
integer of 15 to 2198, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:112, and where
b is greater than or equal to a+14.
[0703] Features of Protein Encoded by Gene No: 103
[0704] The translation product of this gene shares sequence
homology with secreted serine proteases and lysozyme C precursor,
which is thought to be important in bacteriolytic function. In
specific embodiments, polypeptides of the invention comprise the
sequene: NLCHVDCQDLLNPNLLAGIHCAKRIVS (SEQ ID NO:923), LDGFE
GYSLSDWLCLAFVESKFN (SEQ ID NO:924), NENADGSFDYGLFQINSHYWCN (SEQ ID
NO:925), NLCHVDCQDLLNPNLLAGIHCAKRIVS (SEQ ID NO:926), and/or
EPSALSCTSSPPR (SEQ ID NO:927). Polynucleotides encoding these
polypeptides are also encompassed by the invention.
[0705] This gene is expressed primarily in testes.
[0706] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, infection, immune system disorders, reproductive
disorders. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune system and reproductive system, expression of this gene
at significantly higher or lower levels may be routinely detected
in certain tissues or cell types (e.g. testes, cancerous and
wounded tissues) or bodily fluids (e.g., lymph, serum, seminal
fluid, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0707] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 351 as residues: Ile-62 to Phe-70, Asn-78 to
Asn-84.
[0708] The tissue distribution in testes, combined with the
homology to lysozyme C precursor indicates that the protein product
of this gene is useful for boosting the monocyte-macrophage system,
and for enhancing the activity of immunoagents. Alternatively, the
tissue distribution indicates that the protein product of this gene
is useful for the treatment and diagnosis of conditions concerning
proper testicular function (e.g. endocrine function, sperm
maturation), as well as cancer. Therefore, this gene product is
useful in the treatment of male infertility and/or impotence. This
gene product is also useful in assays designed to identify binding
agents, as such agents (antagonists) are useful as male
contraceptive agents. Similarly, the protein is believed to be
useful in the treatment and/or diagnosis of testicular cancer. The
testes are also a site of active gene expression of transcripts
that may be expressed, particularly at low levels, in other tissues
of the body. Therefore, this gene product may be expressed in other
specific tissues or organs where it may play related functional
roles in other processes, such as hematopoiesis, inflammation, bone
formation, and kidney function, to name a few possible target
indications.
[0709] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:113 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1029 of SEQ ID NO:113, b is an
integer of 15 to 1043, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:113, and where
b is greater than or equal to a+14.
[0710] Features of Protein Encoded by Gene No: 104
[0711] This gene is expressed primarily in apoptotic T-cell, and to
a lesser extent in CD34(+) cells.
[0712] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune disorders. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the immune system, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g. immune, cancerous
and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0713] The tissue distribution in T-cells indicates that the
protein product of this gene is useful for treatment and diagnosis
of some immune disorders. Furthermore, this gene product may be
involved in the regulation of cytokine production, antigen
presentation, or other processes that may also suggest a usefulness
in the treatment of cancer (e.g. by boosting immune responses).
Since the gene is expressed in cells of lymphoid origin, the gene
or protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues. Therefore it may be also used as an agent for
immunological disorders including arthritis, asthma, immune
deficiency diseases such as AIDS, leukemia, rheumatoid arthritis,
inflammatory bowel disease, sepsis, acne, and psoriasis. In
addition, this gene product may have commercial utility in the
expansion of stem cells and committed progenitors of various blood
lineages, and in the differentiation and/or proliferation of
various cell types. Expression of this gene product in T cells also
strongly indicates a role for this protein in immune function and
immune surveillance. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0714] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:114 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 689 of SEQ ID NO:114, b is an integer
of 15 to 703, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:1 14, and where b is greater
than or equal to a+14.
[0715] Features of Protein Encoded by Gene No: 105
[0716] The translation product of this gene shares sequence
homology with ARI protein of Drosophila (See Genbank Accession
2058299; EMBL: locus DMARIADNE, accession X98309), which is thought
to be important in axonal path-finding in the central nervous
system. In specific embodiments, polypeptides of the invention
comprise the sequence IREVNEVIQNPAT (SEQ ID NO:928), ITRILLSHFNWDKE
KLMERYFDGNLEKLFA (SEQ ID NO:929), NTRSSAQDMPCQICYLNYPNSYF (SEQ ID
NO:930), TGLECGHKFCMQCWSEYLTTKIMEEGMGQTIS- CPAHG (SEQ ID NO:936),
CDILVDDNTVMRLITDSKVKLKYQHLITNSFVECNRLLKW CPAPDCHHVVKVQYPDAKPV (SEQ
ID NO:931), CDILVDDNTVMRLITDSKVK LKYQHLITNSFVECNRLLKWCPAPDCHHVVKV
(SEQ ID NO:932), GCNHMV
CRNQNCKAEFCWVCLGPWEPHGSAWYNCNRYNEDDAKAARDAQERSRAA LQRYL (SEQ ID
NO:933), FYCNRYMNHMQSLRFEHKLYAQVKQKMEEMQQHN
MSWIEVQFLKKAVDVLCQCRATLMYT (SEQ ID NO:934), and/or YVFAFYLKKN
NQSITFENNQADLENATEVLSGYLERDISQDSLQDIKQKVQDKYRY- CESR (SEQ ID
NO:935) Polynucleotides encoding these polypeptides are also
encompassed by the invention.
[0717] This gene is expressed primarily in adult brain, and to a
lesser extent in testes, endometrial tumor, melanocytes, and infant
brain.
[0718] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, diseases or injuries involving axonal path development.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the central nervous system, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. brain, testes, cancerous and
wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0719] The tissue distribution in adult brain, combined with the
homology to ARI protein indicates that the protein product of this
gene is useful for the treatment of disease states or injuries
involving axonal path development, including neurodegenerative
diseases and nerve injury, such as Alzheimers Disease, Parkinsons
Disease, Huntingtons Disease, Tourette Syndrome, schizophrenia,
mania, dementia, paranoia, obsessive compulsive disorder, panic
disorder, learning disabilities, ALS, psychoses, autism, and
altered bahaviors, including disorders in feeding, sleep patterns,
balance, and perception. In addition, the gene or gene product may
also play a role in the treatment and/or detection of developmental
disorders associated with the developing embryo, or sexually-linked
disorders. Protein, as well as, antibodies directed against the
protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[0720] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:115 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 3670 of SEQ ID NO:115, b is an
integer of 15 to 3684, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:115, and where
b is greater than or equal to a+14.
[0721] Features of Protein Encoded by Gene No: 106
[0722] The translation product of this gene shares sequence
homology with cytochrome b561 [Sus scrofa] which is thought to be
an integral membrane protein of neuroendocrine storage vesicles of
neurotransmitters and peptide hormones. The gene encoding the
disclosed cDNA is thought to reside on chromosome 11. Accordingly,
polynucleotides related to this invention are useful as a marker in
linkage analysis for chromosome 11.
[0723] This gene is expressed primarily in frontal cortex, and to a
lesser extent in rhabdomyosarcoma.
[0724] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neurological disorders. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the central nervous system,
expression of this gene at significantly higher or lower levels may
be routinely detected in certain tissues or cell types (e.g. brain,
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0725] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 354 as residues: Ser-18 to Pro-24.
[0726] The tissue distribution in frontal cortex, combined with the
homology to cytochrome b561 [Sus scrofa] indicates that the protein
product of this gene is useful for the treatment and diagnosis of
neurological disorders. This gene may also be important in the
regulation of some types of cancers. Furthermore, the tissue
distribution indicates that the protein product of this gene is
useful for the diagnosis and/or treatment of disorders of the brain
and nervous system. Elevated expression of this gene product within
the frontal cortex of the brain indicates that it may be involved
in neuronal survival; synapse formation; conductance; neural
differentiation, etc. Such involvement may impact many processes,
such as learning and cognition. It may also be useful in the
treatment of such neurodegenerative disorders as schizophrenia;
ALS; or Alzheimer's.
[0727] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:116 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1951 of SEQ ID NO:116, b is an
integer of 15 to 1965, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:116, and where
b is greater than or equal to a+14.
[0728] Features of Protein Encoded by Gene No: 107
[0729] In specific embodiments, polypeptides of the invention
comprise the sequence: MWGYLFVDAAWNFLGCLICGW (SEQ ID NO:937),
MGFISSGNVSAIRSSILLLR XSLSYLGNCLRVSAIFVYFLLFLLLS (SEQ ID NO:938),
and/or MDQALRGSPSE
GFSTDPSPPQVGRQIPSFPPWRRLVLPKASGCFLEREWWLCVFKLRTRPGAEA
HAYNSSILGGRGKGIT (SEQ ID NO:939). Polynucleotides encoding these
polypeptides are also encompassed by the invention.
[0730] This gene is expressed primarily in pancreas tumor, and to a
lesser extent in cerebellum.
[0731] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, pancreatic tumors. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the endocrine system, expression
of this gene at significantly higher or lower levels may be
routinely detected in certain tissues or cell types (e.g. pancreas,
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0732] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 355 as residues: Pro-22 to Phe-33.
[0733] The tissue distribution in pancreas tumors indicates that
the protein product of this gene is useful for diagnosis and
treatment of pancreatic tumors, and/or tumors of metabolic tissues
and cell types. Protein, as well as, antibodies directed against
the protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[0734] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:117 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 489 of SEQ ID NO:117, b is an integer
of 15 to 503, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:117, and where b is greater
than or equal to a+14.
[0735] Features of Protein Encoded by Gene No: 108
[0736] The gene encoding the disclosed cDNA is thought to reside on
chromosome 17. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
17. In specific emobodiments, polypeptides of the invention
comprise the sequence:
MLPALASCCHFSPPEQAARLKKLQEQEKQQKVEFRKRMEKEVSDFIQDSGQIK
KKFQPMNKIERSILHDVVEVAGLTSFSFGEDDDCRYVMIFKKEFAPSDEELDSY
RRGEEWDPQKAEEKRNXKELAQRQ (SEQ ID NO:940), EEEAAQQGPVVV
SPASDYKDKYSHLIGKGAAKDAAHMLQANKTYGCXPVANKRDTRSIEEAMNE IRAKKRLRQSGE
(SEQ ID NO:941), PPRRPAQLPLTPGAGQGAGRDKAAAIRA HPGAPPLNHLLP (SEQ ID
NO:942), AVPQAGGKQVFDLSPLELGYVRGMCVCV (SEQ ID NO:943) and/or
MLPALASCCHFSPPEQAARLKKLQEQEKQQKVEFRK
RMEKEVSDFIQDSGQIKKKFQPMNKIERSILHDVVE- VAGLTSFSFGEDDDCRYV
MIFKKEFAPSDEELDSYRRGEEWDPQKAEEKRNXKELAQRQEEEAAQQGPVVV
SPASDYKDKYSHLIGKGAAKDAAHMLQANKTYGCXPVANKRDTRSIEEAMNE IRAKKRLRQSGE
(SEQ ID NO:944). Polynucleotides encoding these polypeptides are
also encompassed by the invention. The translation product of this
gene shares sequence homology with FSA-1, which may play a role as
a structural protein component of the acrosome. The mammalian
spermatozoon undergoes continuous modifications during
spermatogenesis, maturation in the epididymis, and capacitation in
the female reproductive tract. Only the capacitated spermatozoa are
capable of binding the zona-intact egg and undergoing the acrosome
reaction. The fertilization process is a net result of multiple
molecular events which enable ejaculated spermatozoa to recognize
and bind to the egg's extracellular coat, the zona pellucida (ZP).
Sperm-egg interaction is a species-specific event which is
initiated by the recognition and binding of complementary
molecule(s) present on sperm plasma membrane (receptor) and the
surface of the ZP (ligand). This is a carbohydrate-mediated event
which initiates a signal transduction cascade resulting in the
exocytosis of acrosomal contents. This step is believed to be a
prerequisite which enables the acrosome reacted spermatozoa to
penetrate the ZP and fertilize the egg. Recently, another group
published this gene, calling it sperm acrosomal protein [Homo
sapiens] (Proc. Natl. Acad. Sci. U.S.A. 95 (14), 8175-8180
(1998)).
[0737] This gene is expressed primarily in fetal kidney and
sperm.
[0738] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, male reproductive disorders, especially involving
acrosomal disfunction. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the male reproductive system,
expression of this gene at significantly higher or lower levels may
be routinely detected in certain tissues or cell types (e.g. sperm,
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0739] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 356 as residues: Met-12 to Gln-30, Lys-35 to Val-46,
Arg-49 to Val-56, Gln-61 to Glu-77, Gly-96 to Cys-101, Glu-110 to
Lys-139, Leu-141 to Gln-151, Ser-161 to Tyr-167, Asn-196 to
Ile-203, Arg-211 to Ser-227.
[0740] The tissue distribution in sperm, combined with the homology
to FSA-1 and the Homo sapiens sperm acrosomal protein indicates
that the protein product of this gene is useful for the treatment
of infertility due to acrosomal disfunction of sperm. Protein may
also be useful as a contraceptive either alone, or in combination
with other therapies. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0741] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:118 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1057 of SEQ ID NO:118, b is an
integer of 15 to 1071, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:118, and where
b is greater than or equal to a+14.
[0742] Features of Protein Encoded by Gene No: 109
[0743] This gene is expressed primarily in pituitary tissue, and to
a lesser extent in epididymus.
[0744] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, male reproductive disorders. Similarly, polypeptides
and antibodies directed to these polypeptides are useful in
providing immunological probes for differential identification of
the tissue(s) or cell type(s). For a number of disorders of the
above tissues or cells, particularly of the male reproductive
system, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g. epididymus, cancerous and wounded tissues) or bodily fluids
(e.g., lymph, serum, plasma, urine, synovial fluid and spinal
fluid) or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[0745] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 357 as residues: Met-1 to Trp-6.
[0746] Because the gene is found in both pituitary and epididymus,
this indicates that the protein product of this gene is useful for
the treatment and diagnosis of male reproductive disorders. This
may involve a secreted peptide produced in the pituitary targeting
the epididymus. Protein, as well as, antibodies directed against
the protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[0747] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:119 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1087 of SEQ ID NO: 119, b is an
integer of 15 to 1101, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:119, and where
b is greater than or equal to a+14.
[0748] Features of Protein Encoded by Gene No: 110
[0749] In specific embodiments, polpeptides of the invention
comprise the sequence: LLCPVLNSGXSENFPHPSQPEYSFHGFHSTRLWI (SEQ ID
NO:945), and/or PSTPWFLFLLGLTCPFSTSHPRWDSIPP (SEQ ID NO:946).
Polynucleotides encoding these polypeptides are also encompassed by
the invention.
[0750] This gene is expressed primarily in resting T-cells.
[0751] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, T-cell disorders. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the immune system, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g. immune, cancerous
and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0752] The tissue distribution in T-cells indicates that the
protein product of this gene is useful for the treatment and
diagnosis of certain immune disorders, especially those involving
T-cells. Furthermore, this gene product may be involved in the
regulation of cytokine production, antigen presentation, or other
processes that may also suggest a usefulness in the treatment of
cancer (e.g. by boosting immune responses). Since the gene is
expressed in cells of lymphoid origin, the gene or protein, as well
as, antibodies directed against the protein may show utility as a
tumor marker and/or immunotherapy targets for the above listed
tissues. Therefore it may be also used as an agent for
immunological disorders including arthritis, asthma, immune
deficiency diseases such as AIDS, leukemia, rheumatoid arthritis,
inflammatory bowel disease, sepsis, acne, and psoriasis. In
addition, this gene product may have commercial utility in the
expansion of stem cells and committed progenitors of various blood
lineages, and in the differentiation and/or proliferation of
various cell types. Expression of this gene product in T cells also
strongly indicates a role for this protein in immune function and
immune surveillance. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0753] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:120 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 268 of SEQ ID NO:120, b is an integer
of 15 to 282, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:120, and where b is greater
than or equal to a+14.
[0754] Features of Protein Encoded by Gene No: 111
[0755] The gene encoding the disclosed cDNA is thought to reside on
chromosome 10. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
10.
[0756] This gene is expressed primarily in cerebellum and whole
brain, and to a lesser extent in infant brain and fetal kidney.
[0757] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neurological disorders. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the central nervous system,
expression of this gene at significantly higher or lower levels may
be routinely detected in certain tissues or cell types (e.g. brain,
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0758] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 359 as residues: Asp-48 to Gly-55.
[0759] The tissue distribution in cerebellum and whole brain
indicates that the protein product of this gene is useful for
diagnosis and treatment of neurological disorders, such as
Alzheimers Disease, Parkinsons Disease, Huntingtons Disease,
Tourette Syndrome, schizophrenia, mania, dementia, paranoia,
obsessive compulsive disorder, panic disorder, learning
disabilities, ALS, psychoses, autism, and altered bahaviors,
including disorders in feeding, sleep patterns, balance, and
perception. In addition, the gene or gene product may also play a
role in the treatment and/or detection of developmental disorders
associated with the developing embryo, or sexually-linked
disorders. Protein, as well as, antibodies directed against the
protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[0760] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:121 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 2621 of SEQ ID NO:121, b is an
integer of 15 to 2635, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:121, and where
b is greater than or equal to a+14.
[0761] Features of Protein Encoded by Gene No: 112
[0762] The translation product of this gene shares sequence
homology with yeast mitochondrial ribosomal protein, which is
homologous to ribosomal protein s15 of E. coli, which is thought to
be important in the early assembly of ribosomes (See Genbank
Accession No. M38016). The gene encoding the disclosed CDNA is
thought to reside on chromosome 1. Accordingly, polynucleotides
related to this invention are useful as a marker in linkage
analysis for chromosome 1.
[0763] This gene is expressed primarily in developmental
tissues.
[0764] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, development of cancers and tumors in addition to
healing wounds. Similarly, polypeptides and antibodies directed to
these polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune and developmental systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. developmental, cancerous and
wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0765] The tissue distribution in developmental tissues, combined
with the homology to ribosomal protein s15 of E. coli indicates
that the protein product of this gene is useful for the diagnosis
and/or treatment of diseases related to the assembly of ribosomes
in the mitochondria, which is important in the translation of RNA
into protein. Therefore, this indicates that the protein product of
this gene is also useful for the diagnosis and intervention of
multiple tumors, as well as in healing wounds, which are thought to
be under similar regulation as developmental tissues. Protein, as
well as, antibodies directed against the protein have utility as
tumor markers, in addition to immunotherapy targets, for the above
listed tumors and tissues.
[0766] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:122 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 980 of SEQ ID NO:122, b is an integer
of 15 to 994, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:122, and where b is greater
than or equal to a+14.
[0767] Features of Protein Encoded by Gene No: 113
[0768] The translation product of this gene shares sequence
homology with human poliovirus receptor precursors which are
thought to be important in viral binding and uptake. The
translation product of this gene also shares homology with a mouse
member of the immunosuperfamily, which is thought to be important
in proper immune function (GENBANK: accession AF061260). Preferred
polypeptide fragments comprise the following amino acid sequence:
ELSISISNVALADEGEYTCSIFTMPVRTAKSLVTVLGIPQKPIITGYKSSLREKDT
ATLNCQSSGSKPAARLTWRKGDQELHGEPTRIQEDPNGKTFTVSSSVTF
QVTREDDGASIVCSVNHESLKGA- DRSTSQRIEVLYTPTAMIRPDPPHPREGQ
KLLLHCEGRGNPVPQQYLWEKEGSVPPLKMTQESALIFPFLNKS- DSGT
YGCTATSNMGSYKAYYTLNVND (SEQ ID NO:947), ELSISISNVALADEGEY
TCSIFTMPVRTAKSLVTVLGIPQKPIITGYKSSLREKDTATLNCQSS (SEQ ID NO:948),
CQSSGSKPAARLTWRKGDQELHGEPTRIQEDPNGKTFTVSSSV TFQVTREDDGASIVCSVNHESL
(SEQ ID NO:949), HESLKGADRSTSQRIEV
LYTPTAMIRPDPPHPREGQKLLLHCEGRGNPVPQQYLWEKE (SEQ ID NO:950),
WEKEGSVPPLKMTQESALIFPFLNKSDSGTYGCTATSNMGSYKAYYTLNVND (SEQ ID
NO:951), PSPVPSSSSTYHAIIGGIVAFIVFLLLIMLIFLGHY (SEQ ID NO:952),
and/or LIRHKGTYLTHEAKGSDDAPDADTAIINAEGGQSGGDDKK EYFI (SEQ ID
NO:953). Also preferred are polynucleotide fragments encoding these
polypeptide fragments. The gene encoding the disclosed cDNA is
thought to reside on chromosome 1. Accordingly, polynucleotides
related to this invention are useful as a marker in linkage
analysis for chromosome 1.
[0769] This gene is expressed almost exclusively in human brain
tissue.
[0770] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, suceptibility to viral disease and diseases of the CNS,
especially cancers of that system. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the central nervous system,
expression of this gene at significantly higher or lower levels may
be routinely detected in certain tissues or cell types (e.g. brain,
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0771] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 361 as residues: Leu-26 to Asp-37, Lys-53 to
Ser-59.
[0772] The tissue distribution in brain, combined with the homology
to poliovirus receptor precursors indicates that the protein
product of this gene is useful for the treatment and prevention of
diseases that involve the binding and uptake of virus particles for
infection. It is also helpful in genetic therapy where the goal is
to insert foreign DNA into infected cells. With the help of this
protein, the binding and uptake of this foreign DNA might be aided.
In addition, it is expected that over expression of this gene will
indicate abnormalities involving the CNS, particularly cancers of
that system. Protein, as well as, antibodies directed against the
protein may show utility as a tissue-specific marker and/or
immunotherapy target for the above listed tissues.
[0773] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:123 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1528 of SEQ ID NO:123, b is an
integer of 15 to 1542, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:123, and where
b is greater than or equal to a+14.
[0774] Features of Protein Encoded by Gene No: 114
[0775] The translation product of this gene shares sequence
homology with YO87_CAEEL hypothetical 28.5 KD protein ZK1236.7 in
chromosome III of Caenorhabditis elegans in addition to alpha-1
collagen type III (See Genbank Accession No. gi.vertline.537432).
One embodiment for this gene is the polypeptide fragment(s)
comprising the following amino acid sequence:
VPELPDRVHQLHQAVQGCALGRPGFPGGPTHSGHHKSHPGPAGGDYNRCDR
PGQVHLHNPRGTGRRGQLHPTAGPGVHRRACPSQQLPHRLGPGVPCPSPS
LTPVLPSWTQSWCGLPGYTSSS (SEQ ID NO:954), VHQLHQAVQGCALGRPGF PGGP
(SEQ ID NO:955), PTHSGHHKSHPGPAGGDYNRCDRPGQVHLHN PRGTGRRGQLH (SEQ
ID NO:956), and/or LHPTAGPGVHRRACPSQQLPHRLG
PGVPCPSPSLTPVLPSWTQSWCGLPGYTSSS (SEQ ID NO:957). An additional
embodiment is the polynucleotide fragment(s) encoding these
polypeptide fragments.
[0776] This gene is expressed primarily in brain cells, and to a
lesser extent in activated B and T cells.
[0777] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neurodegeneration and immunological disorders.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the neural and immune systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. brain, immune, cancerous and
wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0778] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 362 as residues: Glu-34 to Glu-39, Gly-51 to Ser-72,
Ala-88 to Glu-93, Gln-100 to Val-105.
[0779] The tissue distribution in brain cells, combined with the
homology to YO87_CAEEL hypothetical 28.5 KD protein ZK1236.7 in
chromosome III of Caenorhabditis elegans as well as to a conserved
alpha-1 collagen type III protein indicates that the protein
product of this gene is useful for the detection and treatment of
neurodegenerative disease states and behavioral disorders such as
Alzheimer's Disease, Parkinson's Disease, Huntington's Disease,
schizophrenia, mania, dementia, paranoia, obsessive compulsive
disorder and panic disorders. Because the gene is expressed in
cells of lymphoid origin, the natural gene product may be involved
in immune functions. Therefore it may be also used as an agent for
immunological disorders including arthritis, asthma, immune
deficiency diseases such as AIDS, and leukemia. Protein, as well
as, antibodies directed against the protein may show utility as a
tissue-specific marker and/or immunotherapy target for the above
listed tissues.
[0780] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:124 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1376 of SEQ ID NO:124, b is an
integer of 15 to 1390, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:124, and where
b is greater than or equal to a+14.
[0781] Features of Protein Encoded by Gene No: 115
[0782] The translation product of this gene shares sequence
homology with alpha 3 type IX collagen which is thought to be
important in hyaline cartilage formation via its ability to uptake
inorganic sulfate by cells (See Genbank Accession No.
gi.vertline.975657). One embodiment of this gene is the polypeptide
fragment comprising the following amino acid sequence:
32 SLRRPRSAAXQTLTTFLSSVSSASSSALPGSREPCDPRAPPPPRSGSAASCCSCC (SEQ ID
NO:958), CSCPRRRAPLRSPRGSKRRIRQREVVDLYNGMCLQGPAGVPGRDGSPGAN
GIPGTPGIPGRDGFKGEKGECLRESFEESWTPNYKQCSWSSLNYGIDLGKIA
ECTFTKMRSNSALRVLFSGSLRLKCRNACCQRWYETFNGAECSGPLPIEAIIYL
DQGSPEMNSTINIHRTSSVEGLCEGIGAGLVDVAIWVGTCSDYPKGDASTGWN
SVSRTIIIEELPK, SLRRPRSAAXQTLTTFLSSVSSASSSALPGSREPCDPRAPPP-
PRSGSAASCCSCCCSCPRR, (SEQ ID NO:959),
RAPLRSPRGSKRRIRQREVVDLYNGMCLQGPAGVPGRDGSPGANGIPGTPGI (SEQ ID
NO:960), TPGIPGRDGFKGEKGECLRESFEESWTPNYKQCSWSSLNYGIDLGKIAECTF (SEQ
ID NO:961), FTKMRSNSALRVLFSGSLRLKCRNACCQRWYFTFNGAECSGPLPIEAI-
ILDQGSPEMNSTINIHR (SEQ ID NO:962), and/or
RTSSVEGLCEGIGAGLVDVAIWVGTCSDYPKGDASTGWNSVSRIIIEELPK (SEQ ID
NO:963).
[0783] An additional embodiment are the polynucleotide fragments
encoding these polypeptide fragments.
[0784] This gene is expressed primarily in smooth muscle, and to a
lesser extent in synovial tissue.
[0785] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, dwarfism, spinal deformation, and specific joint
abnormalities as well as chondrodysplasias ie. spondyloepiphyseal
dysplasia congenita familial osteoarthritis, Atelosteogenesis type
II, metaphyseal chondrodysplasia type Schmid and autoimmune
disorders . Similarly, polypeptides and antibodies directed to
these polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the skeletal system, expression of this gene at significantly
higher or lower levels may be routinely detected in certain tissues
or cell types (e.g. muscle, synovial tissues, cancerous and wounded
tissues) or bodily fluids (e.g., lymph, serum, plasma, urine,
synovial fluid and spinal fluid) or another tissue or cell sample
taken from an individual having such a disorder, relative to the
standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0786] The tissue distribution in smooth muscle, and homology to
alpha 3 type IX collagen indicates that the protein product of this
gene is useful for the treatment and diagnosis of diseases
associated with the mutation in this gene which leads to the many
different types of chondrodysplasias. By the use of this product,
the abnormal growth and development of bones of the limbs and spine
could be detected or treated in utero, since the protein or muteins
thereof could affect epithelial cells early in development, and
later the chondrocytes of the developing craniofacial structure. In
addition, the expression of this gene product in synovium would
suggest a role in the detection and treatment of disorders and
conditions affecting the skeletal system, in particular
osteoporosis as well as disorders afflicting connective tissues
(e.g. arthritis, trauma, tendonitis, chrondomalacia and
inflammation), such as in the diagnosis or treatment of various
autoimmune disorders such as rheumatoid arthritis, lupus,
scleroderma, and dermatomyositis as well as dwarfism, spinal
deformation, and specific joint abnormalities as well as
chondrodysplasias (ie. spondyloepiphyseal dysplasia congenita,
familial osteoarthritis, Atelosteogenesis type II, metaphyseal
chondrodysplasia type Schmid). Moreover, the expression within
smooth muscle indicates t that polynucleotides and polypeptides
corresponding to this gene are useful for the treatment, detection,
and/or prevention of a variety of vascular disorders, which
include, but are not limited to, atherosclerosis, embolism, stroke,
aneurysm, or niscrovascular disease. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[0787] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:125 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1274 of SEQ ID NO:125, b is an
integer of 15 to 1288, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:125, and where
b is greater than or equal to a+14.
[0788] Features of Protein Encoded by Gene No: 116
[0789] The translation product of this gene shares sequence
homology with retrovirus-related reverse transcriptase, which is
thought to be important in viral replication. Preferred polypeptide
fragments comprising the following amino acid sequence:
TKKENCRPASLMNIDTKILNKILMNQ (SEQ ID NO:964). An additional
embodiment is the polynucleotide fragments encoding this
polypeptide fragment (See Genbank Accession No.
pir.vertline.A25313.vertline.GNHUL1).
[0790] This gene is expressed primarily in human meningima.
[0791] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, retroviral diseases such as AIDS, and possibly certain
cancers due to transactivation of latent cell division genes.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune system, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g. meningima, cancerous and wounded tissues) or
bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0792] The tissue distribution in human meningima, combined with
the homology to a retrovirus-related reverse transcriptase
indicates that the protein product of this gene is useful for the
detection and treatment of diseases and conditions associated with
retroviral infection, since a functional reverse transcriptase (RT)
or RT-like molecule is an integral component of the retroviral life
cycle. Protein, as well as, antibodies directed against the protein
may show utility as a tumor marker and/or immunotherapy targets for
the above listed tissues.
[0793] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:126 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1503 of SEQ ID NO:126, b is an
integer of 15 to 1517, where both a and b correspond to the
positions of nucleotide residues shown 35 in SEQ ID NO:126, and
where b is greater than or equal to a+14.
[0794] Features of Protein Encoded by Gene No: 117
[0795] The translation product of this gene shares sequence
homology with an unknown gene from C. elegans, as well as weak
homolog with mammalian metaxin, a gene contiguous to both
thrombospondin 3 and glucocerebrosidase, and is known to be
required for embryonic development. Recently another group gened
and sequenced this gene from humans, naming it metaxin 2. It is
thought that metaxin 1 and metaxin 2 interact, and are associated
with the mammalian mitochondrial outer membrane (See Genbank
Accession No. AF05355 1). Preferred polypeptide fragments comprise
the following amino acid sequence:
33 MCNLPIKVVCRANAEYMSPSGKVPXXHVGNQVVSELGPIVQFVKAKGHSLSD (SEQ ID
NO:965), GLEEVQKAEMKAYMELVNNMLLTAELYLQWCDEATVGXITHXRYGSPYPWP
LXHILAYQKQWEVKRKXKAIGWGKKTLDQVLEDVDQCCQALSQRLGTQPYFF
NKQPTELDALVFGHLYTILTTQLTNDELSEKVKNYSNLLAFCRRIEQHYFED RGKGRLS,
MCNLPIKVVCPANAEYMSPSGKVPXXHVGNQVVSELGPIVQFVK (SEQ ID NO:966),
FVKAKGHSLSDGLEEVQKAEMKAYMELMNNMLLTAELYLQWCDE (SEQ ID NO:967),
LQWCDEATVGXITHXRYGSPYPWPLXHILAYQKQWEVKRKXKAIGWGK- KTL (SEQ ID
NO:963), DQVLEDVDQCCQALSQRLGTQPYFFNKQPTELDALVI- FGHLYTI (SEQ D
NO:969), and/or LTTQLTNDELSEKVKNYSNLLAFCRRI- EQHYFEDRGKGRLS (SEQ ID
NO:970).
[0796] Also preferred are the polynucleotide fragments encoding
these polypeptide fragments (See Genbank Accession No.
gi.vertline.1326108). The gene encoding the disclosed cDNA is
thought to reside on chromosome 2. Accordingly, polynucleotides
related to this invention are useful as a marker in linkage
analysis for chromosome 2.
[0797] This gene is expressed primarily in fetal tissues, and to a
lesser extent in hematopoietic cells and tissues, including spleen,
monocytes, and T cells.
[0798] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, cancer; lymphoproliferative disorders; inflammation;
chondrosarcoma, and Gaucher disease. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the hematopoietic and embryonic
systems, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g. immune, fetal, cancerous and wounded tissues) or bodily
fluids (e.g., lymph, serum, plasma, urine, synovial fluid and
spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0799] The tissue distribution in fetal tissues indicates that the
protein product of this gene is useful for the diagnosis and
treatment of cancer and other proliferative disorders. Moreover,
this protein may play a role in the regulation of cellular
division. Additionally, the expression in hematopoietic cells and
tissues indicates that this protein may play a role in the
proliferation, differentiation, and survival of hematopoietic cell
lineages. Thus, this gene may be useful in the treatment of
lymphoproliferative disorders, and in the maintenance and
differentiation of various hematopoietic lineages from early
hematopoietic stem and committed progenitor cells. Protein, as well
as, antibodies directed against the protein may show utility as a
tumor marker and/or immunotherapy targets for the above listed
tissues.
[0800] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:127 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1059 of SEQ ID NO:127, b is an
integer of 15 to 1073, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:127, and where
b is greater than or equal to a+14.
[0801] Features of Protein Encoded by Gene No: 118
[0802] The translation product of this gene shares sequence
homology with reverse transcriptase, which is important in the
synthesis of a cDNA chain from an RNA molecule, and is a method
whereby the infecting RNA chains of retroviruses are transcribed
into their DNA complements. Specific embodiments for this gene are
the polypeptide fragments comprising the following amino acid
sequences:
34 MXXXNSHITIFTLNVNGLNAPNERHRLANWIQSQDQVCCIQETHLTGRDTHRL (SEQ ID
NO:971), KIKGWRKIYQANGKQKK, FTLNVNGLNAPNERHRLANWIQSQDQVC (SEQ ID
NO:972), THLTGRDTHRLKIKGWR (SEQ ID NO:973), and/or GWRKIYQANGKQKK
(SEQ ID NO:974).
[0803] Additional embodiments are the polynucleotide fragments
comprising polynucleotides encoding these polypeptide fragments
(See Genbank Accession No. gi.vertline.2072964).
[0804] This gene is expressed primarily in skin, and to a lesser
extent in neutrophils.
[0805] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, cancers; hematopoietic disorders; inflammation;
disorders of immune surveillance. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the epidermis and/or
hematopoietic system, expression of this gene at significantly
higher or lower levels may be routinely detected in certain tissues
or cell types (e.g. skin, immune, cancerous and wounded tissues) or
bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0806] The tissue distribution in skin, combined with the homology
to a reverse transcriptase indicates that the protein product of
this gene is useful for cancer therapy, particularly of the
integumentary system. Expression in the skin also indicates that
this gene is useful in wound healing and fibrosis. Expression by
neutrophils also indicates that this gene product plays a role in
inflammation and the control of immune surveillance (i.e.,
recognition of viral pathogens). Reverse transcriptase family
members are also useful in the detection and treatment of AIDS.
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[0807] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:128 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 286 of SEQ ID NO:128, b is an integer
of 15 to 300, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:128, and where b is greater
than or equal to a+14.
[0808] Features of Protein Encoded by Gene No: 119
[0809] The translation product of this gene shares sequence
homology with reverse transcriptase, which is important in the
synthesis of a cDNA copy of an RNA molecule, and is a method
whereby a retrovirus reverse-transcribes its genome into an
inheritable DNA copy.
[0810] This gene is expressed primarily in the frontal cortex of
brain.
[0811] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, cancer and neurodegenerative disorders. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the CNS
and peripheral nervous system, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. brain, cancerous and wounded
tissues) or bodily fluids (e.g., lymph, serum, plasma, urine,
synovial fluid and spinal fluid) or another tissue or cell sample
taken from an individual having such a disorder, relative to the
standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0812] The tissue distribution in the frontal cortex, combined with
the homology to a reverse transcriptase suggest that this gene is
useful in the treatment of cancer and AIDS, particularly of the
neural system. The expression in brain indicates that it plays a
role in neurodegenerative disorders and in neural degeneration.
Furthermore, elevated expression of this gene product within the
frontal cortex of the brain indicates that it may be involved in
neuronal survival; synapse formation; conductance; neural
differentiation, etc. Such involvement may impact many processes,
such as learning and cognition. It may also be useful in the
treatment of such neurodegenerative disorders as schizophrenia;
ALS; or Alzheimer's. Protein, as well as, antibodies directed
against the protein may show utility as a tissue-specific marker
and/or immunotherapy target for the above listed tissues.
[0813] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:129 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1261 of SEQ ID NO:129, b is an
integer of 15 to 1275, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:129, and where
b is greater than or equal to a+14.
[0814] Features of Protein Encoded by Gene No: 120
[0815] The translation product of this gene shares homology to a
hypothetical protein in Schizosaccharomyces pombe (See Genbank
Accession No. 2281980). One embodiment of this gene is the
polypeptide fragments comprising the following amino acid
sequence:
35 IYHLHSWIFFHFKRAFCMCFITMKVIHAHCSKLRKCXNAQIS (SEQ ID NO:975),
VFCTTLTASYPT, IYHLHSWIFFHFKRAFCMCFITM (SEQ ID NO:976), and/or
KVIHAHCSKLRKCXNAQISVFCTTLTASYPT (SEQ ID NO:977).
[0816] An additional embodiment is the polynucleotide fragments
encoding these polypeptide fragments. The gene encoding the
disclosed cDNA is thought to reside on chromosome 18. Accordingly,
polynucleotides related to this invention are useful as a marker in
linkage analysis for chromosome 18.
[0817] This gene is expressed primarily in adult hypothalamus and
to a lesser extent in infant brain.
[0818] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neurodegenerative disorders; endocrine function; and
vertigo. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the brain, CNS and peripheral nervous system, expression of this
gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g. brain, cancerous
and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0819] The tissue distribution in adult hypothalamus and infant
brain indicates that the protein product of this gene is useful for
the treatment and diagnosis of neurodegenerative disorders;
diagnosis of tumors of a brain or neuronal origin; treatments
involving hormonal control of the entire body and of homeostasis,
behavioral disorders, such as Alzheimer's Disease, Parkinson's
Disease, Huntington's Disease, schizophrenia, mania, dementia,
paranoia, obsessive compulsive disorder and panic disorder. In
addition, the gene or gene product may also play a role in the
treatment and/or detection of developmental disorders associated
with the developing embryo. Protein, as well as, antibodies
directed against the protein may show utility as a tissue-specific
marker and/or immunotherapy target for the above listed
tissues.
[0820] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:130 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 458 of SEQ ID NO:130, b is an integer
of 15 to 472, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:130, and where b is greater
than or equal to a+14.
[0821] Features of Protein Encoded by Gene No: 121
[0822] The translation product of this gene shares sequence
homology with the human IRLB protein which is thought to be
important in binding to a c-myc promoter element and thus
regulating its transcription (See Genbank Accession No.
gi.vertline.33969). The gene encoding the disclosed cDNA is thought
to reside on chromosome 1. Accordingly, polynucleotides related to
this invention are useful as a marker in linkage analysis for
chromosome 1. One embodiment of this gene is the polypeptide
fragments comprising the following amino acid sequence:
36 WNLLWYFQRLRLPSILPGLVLASCDGPSXSQAPSPWLTPDPASVQVRLLWDVL (SEQ ID
NO:978), TPDPN, QRGIYREILFLTMAALGKDHVDIVAFDKKYKSA-
FNKLASSMGKEELRHRRAQMP (SEQ ID NO:979), and/or
WNLLWYFQRLRLPSILPGLVLAS (SEQ ID NO:980).
[0823] An additional embodiment is the polynucleotide fragments
encoding these polypeptide fragments.
[0824] This gene is expressed primarily in brain and breast, and to
a lesser extent in a variety of hematopoietic tissues and
cells.
[0825] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, cancer of the brain and breast; lympho-proliferative
disorders; neurodegenerative diseases. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the CNS, breast, and immune
system, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g. brain, breast, immune, cancerous and wounded tissues) or
bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0826] The tissue distribution in brain indicates that the protein
product of this gene is useful for the treatment and diagnosis of
cancer of the brain, breast, and hematopoietic system. In addition,
it is useful for the treatment of neurodegenerative disorders, as
well as disorders of the hematopoietic system, including defects in
immune competency and inflammation. Protein, as well as, antibodies
directed against the protein may show utility as a tumor marker and
immunotherapy targets for the above listed tumors and tissues.
[0827] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:131 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1936 of SEQ ID NO:131, b is an
integer of 15 to 1950, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:131, and where
b is greater than or equal to a+14.
[0828] Features of Protein Encoded by Gene No: 122
[0829] The translation product of this gene shares sequence
homology with an ATP synthase, a key component of the proton
channel that is thought to be important in the translocation of
protons across the membrane.
[0830] This gene is expressed primarily in T-cell lymphoma.
[0831] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, T cell lymphoma. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the immune system, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g. immune, cancerous
and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0832] The tissue distribution in T-cell lymphoma, combined with
the homology to an ATP synthase indicates that the protein product
of this gene is useful for the treatment of defects in proton
transport, homeostasis, and metabolism, as well as the diagnosis
and treatment of lymphoma. Because the gene is expressed in cells
of lymphoid origin, the natural gene product may be involved in
immune functions. Therefore it may be also used as an agent for
immunological disorders including arthritis, asthma, immune
deficiency diseases such as AIDS, and leukemia. Protein, as well
as, antibodies directed against the protein may show utility as a
tumor marker and/or immunotherapy targets for the above listed
tissues.
[0833] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:132 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 976 of SEQ ID NO:132, b is an integer
of 15 to 990, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:132, and where b is greater
than or equal to a+14.
[0834] Features of Protein Encoded by Gene No: 123
[0835] The gene encoding the disclosed cDNA is thought to reside on
chromosome 15. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
15.
[0836] This gene is expressed primarily in a variety of fetal
tissues, including fetal liver, lung, and spleen, and to a lesser
extent in a variety of blood cells, including eosinophils and T
cells.
[0837] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, cancer (abnormal cell proliferation); T cell lymphomas;
and hematopoietic disorders. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the fetus and immune system,
expression of this gene at significantly higher or lower levels may
be routinely detected in certain tissues or cell types (e.g. fetal,
immune, cancerous and wounded tissues) or bodily fluids (e.g.,
lymph, serum, plasma, urine, synovial fluid and spinal fluid) or
another tissue or cell sample taken from an individual having such
a disorder, relative to the standard gene expression level, i.e.,
the expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0838] The tissue distribution in fetal tissues indicates that the
protein product of this gene is useful for the treatment and
diagnosis of conditions involving cell proliferation. Similarly,
the fetal tissue expression, as well as the expression in a variety
of blood cell lineages, indicates that it may play a role in either
cellular proliferation, apoptosis, or cell survival. Thus it may be
useful in the management and treatment of a variety of cancers and
malignancies. In addition, its expression in blood cells indicates
that it may play additional roles in hematopoietic disorders and
conditions, and could be useful in treating diseases involving
autoimmunity, immune modulation, immune surveillance, and
inflammation. Protein, as well as, antibodies directed against the
protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[0839] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:133 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1706 of SEQ ID NO:133, b is an
integer of 15 to 1720, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:133, and where
b is greater than or equal to a+14.
[0840] Features of Protein Encoded by Gene No: 124
[0841] This gene is expressed primarily in placenta, and to a
lesser extent in pineal gland and rhabdomyosarcoma.
[0842] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, developmental, endocrine, and female reproductive
disorders. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the placenta and endocrine system, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. placental, endocrine, cancerous
and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0843] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 372 as residues: Leu-69 to Val-76.
[0844] The tissue distribution in placenta indicates that the
protein product of this gene is useful for the diagnosis and
treatment of developmental disorders. Furthermore, the tissue
distribution indicates that the protein product of this gene is
useful for the diagnosis and/or treatment of disorders of the
placenta. Specific expression within the placenta indicates that
this gene product may play a role in the proper establishment and
maintenance of placental function. Alternately, this gene product
may be produced by the placenta and then transported to the embryo,
where it may play a crucial role in the development and/or survival
of the developing embryo or fetus. Expression of this gene product
in a vascular-rich tissue such as the placenta also indicates that
this gene product may be produced more generally in endothelial
cells or within the circulation. In such instances, it may play
more generalized roles in vascular function, such as in
angiogenesis. It may also be produced in the vasculature and have
effects on other cells within the circulation, such as
hematopoietic cells. It may serve to promote the proliferation,
survival, activation, and/or differentiation of hematopoietic
cells, as well as other cells throughout the body. Protein, as well
as, antibodies directed against the protein may show utility as a
tissue-specific marker and/or immunotherapy target for the above
listed tissues.
[0845] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:134 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 691 of SEQ ID NO:134, b is an integer
of 15 to 705, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:134, and where b is greater
than or equal to a+14.
[0846] Features of Protein Encoded by Gene No: 125
[0847] Contact of cells with supernatant expressing the product of
this gene increases the permeability of THP-1 Monocyte cells to
calcium. Thus, it is likely that the product of this gene is
involved in a signal transduction pathway that is initiated when
the product of this gene binds a receptor on the surface of the
Monocyte cell. Thus, polynucleotides and polypeptides have uses
which include, but are not limited to, activating monocyte
cells.
[0848] This gene is expressed primarily in benign prostatic
hyperplasia.
[0849] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of benign prostatic hyperplasia. Similarly, polypeptides
and antibodies directed to these polypeptides are useful in
providing immunological probes for differential identification of
the tissue(s) or cell type(s). For a number of disorders of the
above tissues or cells, particularly of the reproductive system,
expression of this gene at significantly higher or lower levels may
be routinely detected in certain tissues or cell types (e.g.
reproductive, cancerous and wounded tissues) or bodily fluids
(e.g., lymph, serum, plasma, urine, synovial fluid and spinal
fluid) or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[0850] The tissue distribution in benign prostatic hyperplasia
tissue indicates that the protein product of this gene is useful
for the treatment and diagnosis of proliferative disorders of the
prostate. Furthermore, the biological activity data indicates that
the translation product of this gene is useful for the stimulation
of certain immune system cells, such as monocytes, which may be
useful for helping the body to defend against infection. Protein,
as well as, antibodies directed against the protein may show
utility as a tumor marker and immunotherapy targets for the above
listed tumors and tissues.
[0851] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:135 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 309 of SEQ ID NO:135, b is an integer
of 15 to 323, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:135, and where b is greater
than or equal to a+14.
[0852] Features of Protein Encoded by Gene No: 126
[0853] This gene is expressed primarily in Raji cells.
[0854] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, inflammation and T cell autoimmune disorders.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune system, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g., cancerous and wounded tissues) or bodily fluids
(e.g., lymph, serum, plasma, urine, synovial fluid and spinal
fluid) or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[0855] The tissue distribution in Raji cells indicates that the
protein product of this gene is useful for treatment and diagnosis
of inflammation and T cell autoimmune disorders. Because the gene
is expressed in cells of lymphoid origin, the natural gene product
may be involved in immune functions. Therefore it may be also used
as an agent for immunological disorders including arthritis,
asthma, immune deficiency diseases (such as AIDS), and leukemia.
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[0856] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:136 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 568 of SEQ ID NO:136, b is an integer
of 15 to 582, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:136, and where b is greater
than or equal to a+14.
[0857] Features of Protein Encoded by Gene No: 127
[0858] This gene is expressed primarily in apoptotic T-cells, and
to a lesser extent in suppressor T cells and ulcerative
colitis.
[0859] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, diseases involving premature apoptosis, and
immunological and gastrointestinal disorders. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the immune
system, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g. immune, gastrointestinal, cancerous and wounded tissues) or
bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0860] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 375 as residues: Asp-23 to Gly-29.
[0861] The tissue distribution in apoptotic T-cells indicates that
the protein product of this gene is useful for the treatment and
diagnosis of disorders involving inappropriate levels of apoptosis,
especially in immune cell lineages. Because the gene is expressed
in cells of lymphoid origin, the natural gene product may be
involved in immune functions. Therefore it may be also used as an
agent for immunological disorders including arthritis, asthma,
immune deficiency diseases (such as AIDS), and leukemia.
Furthermore, expression of this gene product in T cells also
strongly indicates a role for this protein in immune function and
immune surveillance. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0862] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:137 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1007 of SEQ ID NO:137, b is an
integer of 15 to 1021, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:137, and where
b is greater than or equal to a+14.
[0863] Features of Protein Encoded by Gene No: 128
[0864] The translation product of this gene shares sequence
homology with an C. elegans coding region C47D12.2 of unknown
function (See Genbank Accession No.
gnl.vertline.PID.vertline.e348986). One embodiment for this gene is
the polypeptide fragments comprising the following amino acid
sequence:
37 EDDGFNRSIHEVILKNITWYSERVL (SEQ ID NO:981),
TEISLGSLLILVVIRTIQYNMTRTRDKYLHTNCLAALANMSAQFRSLHQYAAQRI
ISLFSLLSKKHNKVLEQATQSLRGSLSSNDVPLPDYAQDLNVIEEVIRMMLE
IINSCLTNSLHHNPNLVYALLYKRDLFEQPRTHPSFQDIMQNIDLVISFFSSRL LQAGS
EDDGFNRSIHEVILKNITWYSERVLTEISLGSLLILVV (SEQ ID NO:982),
RTIQYNMTRTRDKYLHTNCLAALANMSAQFRSLHQYAAQRIISLFSLLSKKHN (SEQ ID
NO:983), SCLTNSLHHNPNLVYALLYKRDLFEQFRTHPSFQDIMQNIDLVISFFS- SRLLQAGS
(SEQ ID NO:984), KKHNKVLEQATQSLRGSLSSNDVPLPDYAQD (SEQ ID NO:985),
TISNSSFISGYNAKY (SEQ ID NO:986), and/or
LKVAASWELSCQWNGSWKSLSKASLRCPKTD (SEQ ID NO:987).
[0865] An additional embodiment is the polynucleotide fragments
encoding these polypeptide fragments. The gene encoding the
disclosed cDNA is thought to reside on chromosome 18. Accordingly,
polynucleotides related to this invention are useful as a marker in
linkage analysis for chromosome 18.
[0866] This gene is expressed primarily in smooth muscle, and to a
lesser extent in fetal liver/spleen.
[0867] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, atherosclerosis and other cardiovascular and hepatic
disorders. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the circulatory system, expression of this gene at significantly
higher or lower levels may be routinely detected in certain tissues
or cell types (e.g. muscle, fetal liver/spleen, cancerous and
wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0868] The tissue distribution in smooth muscle indicates that the
protein product of this gene is useful for the diagnosis and
treatment of circulatory system disorders such as atherosclerosis,
hypertension, stroke, aneurysms, embolisms, and thrombosis. In
addition, the tissue distribution indicates that the protein
product of this gene is useful for the detection and treatment of
liver disorders and cancers (e.g. hepatoblastoma, jaundice,
hepatitis, liver metabolic diseases and conditions that are
attributable to the differentiation of hepatocyte progenitor
cells). In addition the expression in fetus indicates a useful role
for the protein product in developmental abnormalities, fetal
deficiencies, pre-natal disorders and various would-healing models
and/or tissue trauma. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0869] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:138 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1763 of SEQ ID NO:138, b is an
integer of 15 to 1777, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:138, and where
b is greater than or equal to a+14.
[0870] Features of Protein Encoded by Gene No: 129
[0871] The translation product of this gene shares sequence
homology with a ribosomal protein which is thought to be important
in cellular metabolism, in addition to the C.elegans protein
F40F11.1 which does not have a known function at the current time
(See Genbank Accession No. gnl.vertline.PID.vertline.e244552).
Preferred polypeptide fragments comprise the following amino acid
sequence:
38 MADIQTERAYQKQPTIFQNKKRVLLGETGKEKLPRVTNKNIGLGFKDTPRRLL (SEQ ID
NO:988), RGTYIDKKCPFTGNVSIRGRILSGVVTQDEDAEDHCHPPRLSALHPQVQPLREA
PQEHVCTPVPLLQGRPDR, MKMQRTIVIRRDYLHYIRKYN (SEQ ID NO:989),
RFEKRHKNMSVHLSPCFRDVQIGDIVTVGECRPLSKTVRFNVLKVTAGTKKQFQKF,
MADIQTERAYQKQPTIFQNKKRVLLGETGK (SEQ ID NO :990),
KLPRVTNKNIGLGFKDTPRRLLRGTYIDKKCPFTGNVSIRGRILSGVVTQDEDAEDHC (SEQ ID
NO:991), HCHPPRLSALHPQVQPLREAPQEHVCTPVPLLQGRPDR (SEQ ID NO:992),
MKMQRTIVIRRDYLHYIRKYNRFEKRHKNMSVHLSP (SEQ ID NO:993),
CFRDVQIGDIVTVGECRPLSKTVRFNVLKVTKAAGTKKQFQKF (SEQ ID NO:994),
PRRLLRGTYIDKKCPFTGNVSIRGRILSGVVTQ (SEQ ID NO:995),
SRGTGVQTCSCGASRSGCTCGCSADSLGG (SEQ ID NO:996), and/or
QWSSASSSWVTTPERIRPRMDTLPVKGHELSM (SEQ ID NO:997).
[0872] Also preferred are the polynucleotide fragments encoding
these polypeptide fragments. The gene encoding the disclosed cDNA
is thought to reside on chromosome 19. Accordingly, polynucleotides
related to this invention are useful as a marker in linkage
analysis for chromosome 19.
[0873] This gene is expressed primarily in Wilm's tumor, and to a
lesser extent in thymus and stromal cells.
[0874] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, Kidney disorders and cancer, diseases affecting RNA
translation. Similarly, polypeptides and antibodies directed to
these polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the Wilm's tumors, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g. kidney, thymus, cancerous and wounded tissues) or
bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0875] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 377 as residues: Arg-15 to Gly-22.
[0876] The tissue distribution in Wilm's tumor, combined with the
homology to a ribosomal protein indicates that the protein product
of this gene is useful for diseases affecting RNA translation, in
addition to proliferative disorders. Furthermore, given the tissue
distribution, the translation product of this gene may be useful in
treating and/or detecting Wilm's tumor or tumors of other tissues
mentioned previously. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0877] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:139 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 629 of SEQ ID NO:139, b is an integer
of 15 to 643, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:139, and where b is greater
than or equal to a+14.
[0878] Features of Protein Encoded by Gene No: 130
[0879] The translation product of this gene shares sequence
homology with a yeast DNA helicase, which is thought to be
important in global transcriptional regulation (See Genbank
Accession No. gnl.vertline.PID.vertline.e243594). Preferred are the
polypeptide fragments comprising the following amino acid
sequence:
39 TFYDSDWNPTVDQQAMDRAHRLGQTKQVTVYRLICKGTIEERILQRAKEKSEIQRMVISG
(SEQ ID NO:998), TRMIDLLEEYMVYRKHTYXRLDGSSKISERRDMV (SEQ ID
NO:999), ADFQNRNDTFVFLLSTRAGGLGINLTAXDTVHF
IFYDSDWNPTVDQQAMDRAHRLGQTKQVTVYR, (SEQ ID NO:1000),
VYRLICKGTIEERILQRAKEKSEIQRMVISG (SEQ ID NO:1001),
TRMIDLLEEYMVYRKHTYXRLDGSSKISERRDM (SEQ ID NO:1002),
RRDMVADFQNRNDIFVFLLSTRAGGLGINLTAXDTVHF (SEQ ID NO:1003),
IFYDSDWNPTVDQQAMDRAHRLGQTKQVTVYRLICKG (SEQ ID NO:1004),
IFYDSDWNPTVDQQAMDRAHRLGQTKQVTVYRLICKG (SEQ ID NO:1005),
RLICKGTIEERILQRAKEKSEIQRMVISG (SEQ ID NO:1006), and/or
GTRMIDLLEEYMVYRKHTYXRLDGSSKISERRDM (SEQ ID NO:1007),
VADFQNRNDIFVFLLSTRAGGLGINLTAXDTVHFL.
[0880] An additional embodiment is the polynucleotide fragments
encoding these polypeptide fragments.
[0881] This gene is expressed primarily in amygdala.
[0882] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, diseases and disorders of the brain and the endocrine
system. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the central nervous system, endocrine system, expression of this
gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g. brain, endocrine,
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0883] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 378 as residues: Lys-24 to Tyr-34.
[0884] The tissue distribution in amygdala, combined with the
homology to a DNA helicase indicates that the protein product of
this gene is useful for diseases affecting RNA transcription,
particularly developmental disorders and healing wounds, since the
later are thought to approximate developmental transcriptional
regulation. The amygdala processes sensory information and relays
this to other areas of the brain including the endocrine and
autonomic domains of the hypothalamus and the brain stem.
Therefore, the translation product of this gene is also useful for
the detection and/or treatment of disorders of the endocrine and/or
neural systems. Protein, as well as, antibodies directed against
the protein may show utility as a tissue-specific marker and/or
immunotherapy target for the above listed tissues.
[0885] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:140 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1206 of SEQ ID NO:140, b is an
integer of 15 to 1220, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:140, and where
b is greater than or equal to a+14.
[0886] Features of Protein Encoded by Gene No: 131
[0887] This gene is expressed primarily in prostate, and to a
lesser extent in amygdala and pancreatic tumors.
[0888] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, prostate enlargement and gastrointestinal disorders,
particularly of the pancrease and gall bladder. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
reproductive system, expression of this gene at significantly
higher or lower levels may be routinely detected in certain tissues
or cell types (e.g. reproductive, cancerous and wounded tissues) or
bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0889] The tissue distribution in prostate indicates that the
protein product of this gene is useful for the treatment and
diagnosis of prostate or reproductive diseases, including benign
prostatic hyperplasia and prostate cancer. In addition, the tissue
distribution in tumors of the pancreas indicates that the protein
product of this gene is useful for the diagnosis and intervention
of these tumors, in addition to other tissues where expression has
been indicated. Protein, as well as, antibodies directed against
the protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tumors and tissues.
[0890] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:141 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 707 of SEQ ID NO:141, b is an integer
of 15 to 721, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:141, and where b is greater
than or equal to a+14.
[0891] Features of Protein Encoded by Gene No: 132
[0892] The gene encoding the disclosed cDNA is thought to reside on
chromosome 3. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
3.
[0893] This gene is expressed primarily in adult lung, and to a
lesser extent in the hypothalamus.
[0894] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, pulmonary diseases and neurological disorders.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the pulmonary and respiratory systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. lung, brain, cancerous and
wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0895] The tissue distribution in adult lung indicates that the
protein product of this gene is useful for the diagnosis and
treatment of pulmonary and respiratory disorders such as emphysema,
pneumonia, and pulmonary edema and emboli. In addition, the tissue
distribution indicates that the protein product of this gene is
useful for the detection/treatment of neurodegenerative disease
states and behavioural disorders such as Alzheimer's Disease,
Parkinson's Disease, Huntington's Disease, schizophrenia, mania,
dementia, paranoia, obsessive compulsive disorder and panic
disorder. In addition, the gene or gene product may also play a
role in the treatment and/or detection of developmental disorders
associated with the developing embryo, sexually-linked disorders,
or disorders of the cardiovascular system. Protein, as well as,
antibodies directed against the protein may show utility as a
tissue-specific marker and/or immunotherapy target for the above
listed tissues.
[0896] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:142 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1454 of SEQ ID NO:142, b is an
integer of 15 to 1468, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:142, and where
b is greater than or equal to a+14.
[0897] Features of Protein Encoded by Gene No: 133
[0898] This gene is expressed primarily in human liver.
[0899] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, cirrhosis of the liver and other hepatic disorders.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the digestive system, expression of this gene at significantly
higher or lower levels may be routinely detected in certain tissues
or cell types (e.g. liver, cancerous and wounded tissues) or bodily
fluids (e.g., lymph, serum, plasma, urine, synovial fluid and
spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0900] The tissue distribution in human liver indicates that the
protein product of this gene is useful for the detection and
treatment of liver disorders and cancers (e.g. hepatoblastoma,
jaundice, hepatitis, liver metabolic diseases and conditions that
are attributable to the differentiation of hepatocyte progenitor
cells). Protein, as well as, antibodies directed against the
protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[0901] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:143 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 286 of SEQ ID NO:143, b is an integer
of 15 to 300, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:143, and where b is greater
than or equal to a+14.
[0902] Features of Protein Encoded by Gene No: 134
[0903] The gene encoding the disclosed cDNA is thought to reside on
chromosome 5. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
5.
[0904] This gene is expressed primarily in fetal kidney, and to a
lesser extent in fetal liver and spleen.
[0905] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, development and regeneration of liver and kidney and
immunological disorders. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the digestive and excretory
systems, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g. kidney, liver, spleen, cancerous and wounded tissues) or
bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0906] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 382 as residues: Pro-70 to Arg-77, Tyr-102 to
Thr-107.
[0907] The tissue distribution in fetal kidney indicates that the
protein product of this gene is useful for the diagnosis and
treatment of diseases of the kidney and liver, such as cirrhosis,
kidney failure, kidney stones, and liver failure, hepatoblastoma,
jaundice, hepatitis, liver metabolic diseases and conditions that
are attributable to the differentiation of hepatocyte progenitor
cells. In addition the expression in fetus would suggest a useful
role for the protein product in developmental abnormalities, fetal
deficiencies, pre-natal disorders and various would-healing models
and/or tissue trauma. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0908] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:144 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 2229 of SEQ ID NO:144, b is an
integer of 15 to 2243, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:144, and where
b is greater than or equal to a+14.
[0909] Features of Protein Encoded by Gene: 135
[0910] This gene is expressed primarily in brain, bone marrow, and
to a lesser extent in placenta, T cell, testis and neutrophils.
[0911] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neurodegenerative and immunological diseases and
cancer. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the nervous and immune systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., CNS, immune, cancerous and
wounded tissues) or bodily fluids (e.g., lymph, serum, seminal
fluid, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0912] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 383 as residues: Met-1 to His-6.
[0913] The tissue distribution in brain indicates that the protein
product of this gene is useful for the detection/treatment of
neurodegenerative disease states and behavioural disorders such as
Alzheimers Disease, Parkinsons Disease, Huntingtons Disease,
schizophrenia, mania, dementia, paranoia, obsessive compulsive
disorder and panic disorder. In addition, the gene or gene product
may also play a role in the treatment and/or detection of
developmental disorders associated with the developing embryo, or
sexually-linked disorders. Furthermore, the tissue distribution
indicates that the protein product of this gene is useful for the
diagnosis and/or treatment of hematopoietic disorders. This gene
product is expressed in hematopoietic cells and tissues, suggesting
that it plays a role in the survival, proliferation, and/or
differentiation of hematopoieitic lineages. Expression of this gene
product in T cells and neutrophils also strongly indicates a role
for this protein in immune function and immune surveillance.
[0914] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:145 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1068 of SEQ ID NO:145, b is an
integer of 15 to 1082, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:145, and where
b is greater than or equal to a+14.
[0915] Features of Protein Encoded by Gene No: 136
[0916] The translation product of this gene is homologous to the
human WD repeat protein HAN11, which is thought to function in
signal transduction pathways. Preferred polypeptide fragments
comprise the following amino acid sequence:
40 MSLHGKRKEIYKYEAPWTVYAMNWSVRPDKRFRLALGSFVEEYNNKVQLVG (SEQ ID
NO:1008), LDEESSEFICRNTFDHPYPTTKLMWIPDTKGVYPDLLATSGDYLRVWRVGETE
TRLECLLNNNKNSDFCAPLTSFDWNEVDPYLLGTSSIDTTCTIWGLETGQVLG
RVNLVSGHVKTQLIAHDKEVYDIAFSRAGGGRDMFASVGADGSRMFDLRHL
EHSTIIYEDPQHPLLRLCWNKQDPNYLATMAMDGMEVVILDVRVPAHLXP
GTTIEHVSMALLGPHIHPATSALQRMTTRLSSGTSSKCPEPLRTLSWPTQLXG
EINNVQWASTQPELSPSATTTAWRYSECSVGGAVPTRQGLLYFLPLPHPQS
MSLHGKRKEIYKYEAPWTVYAMNWSVRPDKRIPLALGS (SEQ ID NO:1009),
FVEEYNNKVQLVGLDEESSEFICRNTFDHPYPTTKLMWIPDTKGVYPDLLAT
SGDYLRVWRVGETETRLECLLNNNKNSDFCAPLTSFDWNEVDPYLL,
SFDWNEVDPYLLGTSSIDTTCTIWGLETGQVLGRVNLVSGHVKT (SEQ ID NO:1010),
and/or QLIAHDKEVYDIAFSRAGGGRDMFASVGADGSVRMFDLRHLEHSTIIYEDPQH
HPLLRLCWNKQDPNYLATMAMDGMEVVILDVRVPAHLXPGTTI,
VGADGSVRMFDLRHLEHSTIIYEDPQHHPLLRLCWNKQD (SEQ ID NO:1011),
PNYLATMAMDGEVVILDVRVPAHLXPGTTIEHVSMALLGPHIHPATSALQRM
TTRLSSGTSSKCPEPLRTLSWPTQLXGEINNVQWASTQPELSPSATTTAWRYSE
CSVGGAVPTRQGLLYFLPLPHPQS.
[0917] Also preferred are polynucleotide fragments encoding these
polypeptide fragments. The gene encoding the disclosed cDNA is
thought to reside on chromosome 17. Accordingly, polynucleotides
related to this invention are useful as a marker in linkage
analysis for chromosome 17.
[0918] This gene is expressed primarily in placenta, embryo, T cell
and fetal lung, and to a lesser extent in endothelial, tonsil and
bone marrow.
[0919] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immunological and developmental diseases in addition to
cancers. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune system, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g. immune, cancerous and wounded tissues) or bodily
fluids (e.g., lymph, serum, plasma, urine, synovial fluid and
spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0920] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 384 as residues: Gly-19 to Gln-28, Pro-36 to
Phe-42.
[0921] The tissue distribution in tumors of colon, ovary, and
breast origins indicates that the protein product of this gene is
useful for the diagnosis and intervention of these tumors, in
addition to other tumors where expression has been indicated.
Because the gene is expressed in cells of lymphoid origin, the
natural gene product may be involved in immune functions. Therefore
it may also be used as an agent for immunological disorders
including arthritis, asthma, immune deficiency diseases such as
AIDS, and leukemia. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tumors and tissues.
[0922] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:146 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 4299 of SEQ ID NO:146, b is an
integer of 15 to 4313, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:146, and where
b is greater than or equal to a+14.
[0923] Features of Protein Encoded by Gene No: 137
[0924] This gene is expressed primarily in TNF and INF induced
epithelial cells, T cells and kidney.
[0925] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, inflammatory conditions particularly inflammatory
reactions in the kidney. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of renal system, expression of this
gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g. kidney, immune,
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0926] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 385 as residues: Thr-67 to Gly-72, Gln-132 to
Ala-145, Arg-150 to Pro-157.
[0927] The tissue distribution in TNF and INF induced epithelial
cells indicates that the protein products of this gene are useful
for treating the damage caused by inflammation of the kidney.
Furthermore, the tissue distribution in kidney indicates that this
gene or gene product is useful in the treatment and/or detection of
kidney diseases including renal failure, nephritus, renal tubular
acidosis, proteinuria, pyuria, edema, pyelonephritis,
hydronephritis, nephrotic syndrome, crush syndrome,
glomerulonephritis, hematuria, renal colic and kidney stones, in
addition to Wilms Tumor Disease, and congenital kidney
abnormalities such as horseshoe kidney, polycystic kidney, and
Falconi's syndrome. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[0928] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:147 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1169 of SEQ ID NO:147, b is an
integer of 15 to 1183, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:147, and where
b is greater than or equal to a+14.
[0929] Features of Protein Encoded by Gene No: 138
[0930] The gene encoding the disclosed cDNA is thought to reside on
chromosome 1. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
1. (See Genbank Accession No. D63485).
[0931] This gene is expressed primarily in breast cancer and colon
cancer, and to a lesser extent in thymus and fetal spleen.
[0932] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, cancers, especially of the breast and colon tissues.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune system, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g. breast, colon, cancerous and wounded tissues) or
bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0933] The tissue distribution in tumors of colon and breast
origins indicates that the protein product of this gene is useful
for the diagnosis and intervention of these tumors, in addition to
other tumors where expression has been indicated. Protein, as well
as, antibodies directed against the protein may show utility as a
tumor marker and/or immunotherapy targets for the above listed
tumors and tissues.
[0934] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:148 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 720 of SEQ ID NO:148, b is an integer
of 15 to 734, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:148, and where b is greater
than or equal to a+14.
[0935] Features of Protein Encoded by Gene No: 139
[0936] The gene encoding the disclosed cDNA is thought to reside on
chromosome 17. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
17.
[0937] This gene is expressed primarily in CD34 positive cells, and
to lesser extent in activated T-cells and neutrophils.
[0938] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immunologically related diseases and hematopoietic
disorders. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune system and hematopoietic system, expression of this gene
at significantly higher or lower levels may be routinely detected
in certain tissues or cell types (e.g. immune, cancerous and
wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0939] The tissue distribution in CD34 positive cells, T-cells and
neutrophils indicates that the protein product of this gene is
useful for the treatment and diagnosis of hematopoietic disorders
and immunologically related diseases, such as anemia, leukemia,
inflammation, infection, allergy, immunodeficiency disorders,
arthritis, asthma, immune deficiency diseases such as AIDS.
Furthermore, this gene product may be involved in the regulation of
cytokine production, antigen presentation, or other processes that
may also suggest a usefulness in the treatment of cancer (e.g. by
boosting immune responses). Since the gene is expressed in cells of
lymphoid origin, the gene or protein, as well as, antibodies
directed against the protein may show utility as a tumor marker
and/or immunotherapy targets for the above listed tissues. In
addition, this gene product may have commercial utility in the
expansion of stem cells and committed progenitors of various blood
lineages, and in the differentiation and/or proliferation of
various cell types. Expression of this gene product in T cells and
neutrophils also strongly indicates a role for this protein in
immune function and immune surveillance. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[0940] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:149 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1391 of SEQ ID NO:149, b is an
integer of 15 to 1405, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:149, and where
b is greater than or equal to a+14.
[0941] Features of Protein Encoded by Gene No: 140
[0942] This gene was recently published by another group, who
called the gene KIAA0313 gene. (See Genbank Accession No.
d1021609.) Preferred polypeptide fragments comprise the amino acid
sequence:
41 LYATATVISSPSTEXLSQDQGDRASLDAADSGRGSWTSCSSGSHDNIQTIQHQR (SEQ ID
NO:1012), SWETLPFGHTHFDYSGDPAGLWASSSHMDQIMESDHSTKYNRQNQSRESL
EQAQSRASWASSTGYWGEDSEGDTGTIKRRGGKDVSIEAESSSLTSVTTE
ETKPVPMPAHIAVASSTTKGLIARKEGRYREPPPTPPGYIGIPITDFPEGHSHPA
RKPPDYNVALQRSRMVARSSDTAGPSSVQQPHGHPTSSRPVNKPQWHKXN
ESDPRLAPYQSQGFSTEEDEDEQVSAV HMDQIMFSDHSTKYNRQNQSRESLEQAQS-
RASWASSTGYWGE (SEQ ID NO:1013), SVTTEETKPVPMPAHIAVASSTTKGL-
IARKEGRYREPPPTPPGYIGIPITD (SEQ ID NO:1014), and/or
VALQRSRMVARSSDTAGPSSVQQPHGHPTSSRPVNKPQWHKXNESDPRLAPYQSQGF (SEQ ID
NO:1015).
[0943] Also preferred are the polynucleotide fragments encoding
these polypeptide fragments. The gene encoding the disclosed cDNA
is thought to reside on chromosome 4. Accordingly, polynucleotides
related to this invention are useful as a marker in linkage
analysis for chromosome 4. (See Genbank Accession No.
AB002311).
[0944] This gene is expressed primarily in ovarian cancer, tumors
of the Testis, brain, and colon.
[0945] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, ovarian, testical, brain and colon cancers. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the male
and female reproductive systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. brain, testis, colon, ovary,
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0946] The tissue distribution in tumors of colon, ovary, testis,
and brain origins indicates that the protein product of this gene
is useful for the diagnosis and intervention of these tumors, in
addition to other tumors where expression has been indicated.
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tumors and tissues.
[0947] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:150 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 2876 of SEQ ID NO:150, b is an
integer of 15 to 2890, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:150, and where
b is greater than or equal to a+14.
[0948] Features of Protein Encoded by Gene No: 141
[0949] The gene encoding, the disclosed cDNA is thought to reside
on chromosome 18. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
18.
[0950] This gene is expressed primarily in spleen and colon
cancer.
[0951] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, colon cancer and immunological disorders. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
gastrointestinal tract and immune systems, expression of this gene
at significantly higher or lower levels may be routinely detected
in certain tissues or cell types (e.g. spleen, colon, cancerous and
wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0952] The tissue distribution in colon tumors indicates that the
protein product of this gene is useful for the diagnosis and
intervention of such tumors, in addition to other tissues and cell
types where expression has been indicated. This gene product may be
involved in the regulation of cytokine production, antigen
presentation, or other processes that may also suggest a usefulness
in the treatment of cancer (e.g. by boosting immune responses).
Since the gene is expressed in cells of lymphoid origin, the
natural gene product may be involved in immune functions. Therefore
it may be also used as an agent for immunological disorders
including arthritis, asthma, immunodeficiency diseases such as
AIDS, leukemia, rheumatoid arthritis, granulomatous disease,
inflammatory bowel disease, sepsis, acne, neutropenia,
neutrophilia, psoriasis, hypersensitivities, such as T-cell
mediated cytotoxicity; immune reactions to transplanted organs and
tissues, such as host-versus-graft and graft-versus-host diseases,
or autoimmunity disorders, such as autoimmune infertility, lense
tissue injury, demyelination, systemic lupus erythematosis, drug
induced hemolytic anemia, rheumatoid arthritis, Sjogren's disease,
scleroderma and tissues. In addition, this gene product may have
commercial utility in the expansion of stem cells and committed
progenitors of various blood lineages, and in the differentiation
and/or proliferation of various cell types. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed tissues.
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tumors and tissues.
[0953] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:151 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 2385 of SEQ ID NO:151, b is an
integer of 15 to 2399, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:151, and where
b is greater than or equal to a+14.
[0954] Features of Protein Encoded by Gene No: 142
[0955] The translation product of this gene is homologous to a T
cell translocation protein, a putative zinc finger factor (See
Genbank Accession No. 340454), as well as to the G-protein coupled
receptor TM5 consensus polypeptide (See Genbank Accession No.
R50734). Preferred polypeptide fragments comprise the following
amino acid sequence: CLLFVFVSLGMRCLFWTIVYNVLYLKHKCNTVLLCYHLCSI (SEQ
ID NO:1016), and/or ACSKLIPAFEMVMRAKDNVYHLDCFACQLCNQRXCVGDKF
FLKNNXXLCQTDYEEGLMKEGYAPXVR (SEQ ID NO:1017). Also preferred are
the polynucleotide fragments encoding these polypeptide
fragments.
[0956] This gene is expressed primarily in fetal brain, and to a
lesser extent in frontal cortex.
[0957] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neurological disorders, including brain cancer.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the Central Nervous System, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. brain, cancerous and wounded
tissues) or bodily fluids (e.g., lymph, serum, plasma, urine,
synovial fluid and spinal fluid) or another tissue or cell sample
taken from an individual having such a disorder, relative to the
standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0958] The tissue distribution in fetal brain indicates that the
protein product of this gene is useful for the detection/treatment
of neurodegenerative disease states and behavioural disorders such
as Alzheimers Disease, Parkinsons Disease, Huntingtons Disease,
schizophrenia, mania, dementia, paranoia, obsessive compulsive
disorder and panic disorder. In addition, the gene or gene product
may also play a role in the treatment and/or detection of
developmental disorders associated with the developing embryo.
Furthermore, elevated expression of this gene product within the
frontal cortex of the brain indicates that it may be involved in
neuronal survival; synapse formation; conductance; neural
differentiation, etc. Such involvement may impact many processes,
such as learning and cognition. It may also be useful in the
treatment of such neurodegenerative disorders as schizophrenia;
ALS; or Alzheimer's. Protein, as well as, antibodies directed
against the protein may show utility as a tissue-specific marker
and/or immunotherapy target for the above listed tissues.
[0959] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:152 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 788 of SEQ ID NO:152, b is an integer
of 15 to 802, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:152, and where b is greater
than or equal to a+14.
[0960] Features of Protein Encoded by Gene No: 143
[0961] The translation product of this gene has significant
homology to the Fas ligand, which is a cysteine-rich type II
transmembrane protein/tumor necrosis factor receptor homolog.
Mutations within this protein have been shown to result in
generalized lymphoproliferative diseases leading to the development
of lymphadenopathy and autoimmune disease (See Medline Article No.
94185175). Preferred polypeptide fragments comprise the following
amino acid sequence: SALSEPGAPDRRRPCPESVPRRPDDEQWPPPTALCLDVAPLPPSS
(SEQ ID NO:1018). Also preferred are polynucleotide fragments
encoding these polypeptide fragments (See Genbank Accession No.
473565).
[0962] This gene is expressed primarily in osteoblasts, lung, and
brain.
[0963] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, osteoblast-related, pulmonary, neurological, and
immunological diseases. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the skeletal and nervous systems,
expression of this gene at significantly higher or lower levels may
be routinely detected in certain tissues or cell types (e.g. lung,
brain, skeletal, cancerous and wounded tissues) or bodily fluids
(e.g., lymph, serum, plasma, urine, synovial fluid and spinal
fluid) or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[0964] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 391 as residues: Trp-33 to Thr-40, Lys-45 to
Ile-63.
[0965] The tissue distribution in osteoblasts, lung, and brain,
combined with its homology to the Fas ligand, indicates that the
protein product of this gene is useful for the diagnosis and
intervention of these tumors, in addition to other tumors where
expression has been indicated. Protein, as well as, antibodies
directed against the protein may show utility as a tumor marker
and/or immunotherapy targets for the above listed tumors and
tissues. Because the Fas ligand gene is known to be expressed in
cells of lymphoid origin, the natural gene product may be involved
in immune functions. Therefore it may be also used as an agent for
immunological disorders including asthma, immune deficiency
diseases such as AIDS and leukemia, and various autoimmune
disorders including lupus and arthritis. Protein, as well as,
antibodies directed against the protein may show utility as a
tissue-specific marker and/or immunotherapy target for the above
listed tissues.
[0966] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:153 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 447 of SEQ ID NO:153, b is an integer
of 15 to 461, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:153, and where b is greater
than or equal to a+14.
[0967] Features of Protein Encoded by Gene No: 144
[0968] This gene shares sequence homology with a 21.5 KD
transmembrane protein in the SEC15-SAP4 intergenic region of yeast.
(See Genbank Accession No. 1723971.) Preferred polypeptide
fragments comprise the amino acid sequence:
PVGYLDKQVPDTSVQETDRILVEKRCWDIALGPLKQIPMNLFI (SEQ ID NO:1019),
AHASESGERWWACCGVRFGLRSIFAIGRSCCHDGPGGLVANRGR
RFKWAIELSGPGGGSRGRSDRGSGQGDALYPVGYLDKQVPDTSVQETDRILV
EKRCWDIALGPLKQIPMNLFIMYMAGNTISIFPTMMVCMMAWRPIQALMAISA
TFKMLESSSQKFLQGLVYLIGMLMGLALAVYKCQSMGLLFTHASDWLAFIEPP ERMEFSGGGLLL
(SEQ ID NO:1020), PVGYLDKQVPDTSVQETDRILVEKRCW DIALGPLKQIPMNLFI (SEQ
ID NO:1022), and/or ATFKMLESSSQKFLQGLVYL IGNLMGLALAVYKCQSMGLLPTHASD
(SEQ ID NO:1021). Also preferred are polynucleotide fragments
encoding these polypeptide fragments.
[0969] This gene is expressed primarily in osteoclastoma,
hemangiopericytoma, liver, lung.
[0970] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, osteoclastoma, hemangiopericytoma, liver and lung
tumors. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the above tissue(s) or cell type(s).
For a number of disorders of the above tissues or cells,
particularly of the lung and liver systems, expression of this gene
at significantly higher or lower levels may be routinely detected
in certain tissues or cell types (e.g. lung, liver, cancerous and
wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0971] The tissue distribution indicates that the protein product
of this gene is useful for the diagnosis and/or treatment of tumors
of the osteoclastoma, hemangiopericytoma, liver and lung, in
addition to other tumors where expression has been indicated.
Protein, as well as, antibodies directed against the protein may
show utility as a tissue-specific marker and/or immunotherapy
target for the above listed tissues.
[0972] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:154 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 2374 of SEQ ID NO:154, b is an
integer of 15 to 2388, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:154, and where
b is greater than or equal to a+14.
[0973] Features of Protein Encoded by Gene No: 145
[0974] The translation product of this gene shares homology with
the glucagon-69 gene which may indicate this gene plays a role in
regulating metabolism. (See Genbank Accession No. A60318) Preferred
are the polypeptide fragments comprising the following amino acid
sequence: PTTKLDIMEKKKHIQIRFPSFYHKLVDSGRMRSKRETRREDSDTKHNL (SEQ ID
NO:1023), FLWKSLLLRYFKMRQH (SEQ ID NO:1024), and/or YHYLLSSFLSY
SSSSQNLPVYGRKMGTLFECVFFFP (SEQ ID NO:1025). An additional
embodiment is the polynucleotide fragments encoding this
polypeptide fragment.
[0975] This gene is expressed primarily in brain, kidney, colon,
and testis.
[0976] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, brain, kidney, colon, and testicular cancer. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the male
reproductive system, neurological, circulatory, and
gastrointestinal sysyems, expression of this gene at significantly
higher or lower levels may be routinely detected in certain tissues
or cell types (e.g. brain, kidney, colon, testis, cancerous and
wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[0977] The tissue distribution in brain, kidney, colon, and testis
origins, indicates that the protein product of this gene is useful
for the diagnosis and intervention of tumors of these tissues. The
protein product of this gene is useful for the detection/treatment
of neurodegenerative disease states, behavioural disorders, or
inflamatory conditions such as Alzheimers Disease, Parkinsons
Disease, Huntingtons Disease, Tourette Syndrome, meningitis,
encephalitis, demyelinating diseases, peripheral neuropathies,
neoplasia, trauma, congenital malformations, spinal cord injuries,
ischemia and infarction, aneurysms, hemorrhages, schizophrenia,
mania, dementia, paranoia, obsessive compulsive disorder, panic
disorder, learning disabilities, ALS, psychoses, autism, and
altered bahaviors, including disorders in feeding, sleep patterns,
balance, and perception. In addition, elevated expression of this
gene product in regions of the brain indicates that it plays a role
in normal neural function. Potentially, this gene product is
involved in synapse formation, neurotransmission, learning,
cognition, homeostasis, or neuronal differentiation or survival.
Moreover, the gene or gene product may also play a role in the
treatment and/or detection of developmental disorders associated
with the developing embryo, sexually-linked disorders, or disorders
of the cardiovascular system. Protein, as well as, antibodies
directed against the protein may show utility as a tumor marker
and/or immunotherapy targets for the above listed tissues. Protein,
as well as, antibodies directed against the protein may show
utility as a tumor marker and/or immunotherapy targets for the
above listed tumors and tissues. The tissue distribution indicates
that the protein product of this gene is useful for the
detection/treatment of neurodegenerative disease states and
behavioural disorders such as Alzheimers Disease, Parkinsons
Disease, Huntingtons Disease, schizophrenia, mania, dementia,
paranoia, obsessive compulsive disorder and panic disorder. In
addition, the gene or gene product may also play a role in the
treatment and/or detection of developmental disorders associated
with the developing embryo, sexually-linked disorders, or disorders
of the cardiovascular system.
[0978] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:155 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 628 of SEQ ID NO:155, b is an integer
of 15 to 642, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:155, and where b is greater
than or equal to a+14.
[0979] Features of Protein Encoded by Gene No: 146
[0980] The translation product of this gene shares sequence
homology with goliath protein, which is a Drosophila protein
thought to be important in the regulation of gene expression during
development. Protein may serve as a transcription factor. Preferred
are the polypeptide fragments comprising the following amino acid
sequence: TEHIIAVMITELRGKDILSYLEKNISV-
QMTIAVGTRMPPKNFSRGSLVFVSISFIV
LMIISSAWLIFYFIQKIRYTNARDRNQRRLGDAAKKAISKLTTR- TVKKGDK
ETDPDFDHCAVCIESYKQNDVVRILPCKHVFHKSCVDPWLSEHCTCPM CKLNILKALGIV (SEQ
ID NO:1026), MTHPGTEHILAVMITELRGKDILSYLEKNI
SVQMTIAVGTRMPPKNFSRGSLVFVSISF- IVLMIISSAWLIFYFIQKIRYTNARDR
NQRRLGDAAKKAISKLTTRTVKKGDKETDPDFDHCAVCIESYKQND- VVRI
LPCKHVFHKSCVDPWLSEHCTCPMCKLNILKALGIVPNLPCTDNVAFDMERLT
RTQAVNRRSALGDLAGDNSLGLEPLRTSGISPLPQDGELTPRTGEINIAVTKEW
FILASFGLLSALTLCYMIIRATASLNANEVEWF (SEQ ID NO:1027), TEHIIAV
MITELRGKDILSYLEKNISVQMTIAVGTRMPPKNFSRGSLVFVSISFIVLMIISSA WLIFYF
(SEQ ID NO:1028), SISFIVLMIISSAWLIFYFIQKIRYTNARDRNQRR
LGDAAKKAISKLTTRTVKKGDKE (SEQ ID NO:1029), VKKGDKETDPDFDH
CAVCIESYKQNDVVRILPCKHVFHKSCVDPWLSEHCTCPM- CKLNILKALGIV (SEQ ID
NO:1030), MTHPGTEHIIAVMITELRGKDILSYLEKNISVQMTLAVGTR
MPPKNFSRGSLVFVSISFIVLMIISSAWLIFYFIQKIRYTNARDRNQRRLGDAAK KAISKLTTRT
(SEQ ID NO:1031), AAKKAISKLTTRTVKKGDKETDPDFDHCAV
CIESYKQNDVVRILPCKHVFHKSCVDPWL- SEHCTCPMCKLNILKALGIVPNLPC (SEQ ID
NO:1032), TQAVNRRSALGDLAGDNSLGLEPLRTSGIS- PLPQDGE
LTPRTGEINIAVTKEWFILASFGLLSALTLCYMIIRATASLNANEVEWF (SEQ ID NO:1033),
PLHGVADHLGCDPQTRFFVPPNIKQWIALLQRGNCTFKEKISRA
AFHNAVAVVIYNNKSKEEPVTMTHPGTEHIIAVMITELRGKDILSYLEKNISVQ
MTIAVGTRMPPKNFSRGSLVFVSISFIVLMIISSAWLIFYFIQKIRYTNARDRNQR
RLGDAAKKAISKLTTRTVKKGDKETDPDFDHCAVCIESYKQNDVVRILPCKHV
FHKSCVDPWLSEHCTCPMCKLNILKALGIVPNLPCTDNVAFDMERLTRTQAVN
RRSALGDLAGDNSLGLEPLRTSGISPLPQDGELTPRTGEINIAVTKEWFIIASFGL
LSALTLCYMIIRATASLNANEVEWF (SEQ ID NO:1034), and/or HGVADHLGCD
PQTRFFVPPNIKQWIALLQRGNCTFKEKISRAAFHNAVAVVTYNNKSKEE (SEQ ID
NO:1035). An additional embodiment is the polynucleotide fragments
encoding these polypeptide fragments (See Genbank Accession No.
157535). When tested against Jurkat cell lines, supernatants
removed from cells containing this gene activated the GAS assay.
Thus, it is likely that this gene activates T-cells through the
Jak-STAT signal transduction pathway. The gamma activating sequence
(GAS) is a promoter element found upstream of many genes which are
involved in the Jak-STAT pathway. The Jak-STAT pathway is a large,
signal transduction pathway involved in the differentiation and
proliferation of cells. Therefore, activation of the Jak-STAT
pathway, reflected by the binding of the GAS element, can be used
to indicate proteins involved in the proliferation and
differentiation of cells.
[0981] This gene is expressed primarily in macrophage, breast,
kidney and to a lesser extent in synovium, hypothalamus and
rhabdomyosarcoma.
[0982] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, schizophrenia and cancer. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the immune and neural system,
expression of this gene at significantly higher or lower levels may
be routinely detected in certain tissues or cell types (e.g. brain,
kidney, immune, cancerous and wounded tissues) or bodily fluids
(e.g., lymph, serum, plasma, urine, synovial fluid and spinal
fluid) or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[0983] The tissue distribution in macrophage, hypothalamus, and
kidney, combined witht the homology to a zinc finger protein
indicates that the protein product of this gene is useful for the
treatment of schizophrenia, kindey disease and other cancers.
Furthermore, the tissue distribution in macrophage, breast, and
kidney origins indicates that the protein product of this gene is
useful for the diagnosis and intervention of tumors within these
tissues, in addition to other tumors where expression has been
indicated. Protein, as well as, antibodies directed against the
protein may show utility as a tumor marker and/or immunotherapy
targets for-the above listed tumors and tissues. Because the gene
is expressed in cells of lymphoid origin, the natural gene product
may be involved in immune functions. Therefore it may be also used
as an agent for immunological disorders including arthritis,
asthma, immune deficiency diseases such as AIDS, and leukemia.
[0984] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:156 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1237 of SEQ ID NO:156, b is an
integer of 15 to 1251, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:156, and where
b is greater than or equal to a+14.
[0985] Features of Protein Encoded by Gene No: 147
[0986] The translation product of this gene shares sequence
homology with HNP36 protein, an equilibrative nucleoside
transporter, which is thought to be important in gene transcription
as well as serving as an important component of the nucleoside
transport apparatus (See Genbank Accession No. 1845345). Preferred
are the polypeptide fragments comprising the following amino acid
sequence: MSGQGLAGFFASVAMICAIASGSELSESAFGYFITACAVIIL-
TIICYLGLPRLEFYR YYQQLKLEGPGEQETKLDLISKGEEPRAGKEESGVSVSNSQPTNESHS
IKAILKNISVLAFSVCFIFTITIGMFPAVTVEVKSSIAGSSTWERYFIPVSCFLTFN
IFDWLGRSLTAVFMWPGKDSRWLPSWXLARLVFVPLLLLCNIKPRRYLTVV
FEHDAWFIFFMAAFAFSNGYLASLCMCFGPKKVKPAEAETAEPSWPSSCVWV
WIIWGLFSPSCSGQLCDKGWTEGLPASLPVCLLPLPSARGDPEWSGGFFF (SEQ ID
NO:1036), MSGQGLAGFFASVAMICAIASGSELSESAFGYFITACAVI
ILTIICYLGLPRLEFYRYYQQLKLEGPGEQET- KLSLISKGEEPRAGKEESGVSVS
NSQPTNESHSI (SEQ ID NO:1037), SGVSVSNSQPTNESHSIKAILKNISVLAFSV
CFIFTITIGMFPAVTVEVKSSIAGSSTWERYFIPVSCFLTF- NIFDWLGRS (SEQ ID
NO:1038), TIGMFPAVTVEVKSSIAGSSTWERYFIPVSCFLTFNIFDWLGRSLT- A
VFMWPGKDSRWLPSWXLARLVFVPLLLLCNIKPRRYLTVVFEHDA (SEQ ID NO:1039),
and/or FGPKKVKPAEAETAEPSWPSSCVWVWHWGLFSPSCSGQL
CDKGWTEGLPASLPVCLLPLPSARGDPEWSGGF- FF (SEQ ID NO:1040). An
additional embodiment is the polynucleotide fragments encoding
these polypeptide fragments. The gene encoding the disclosed cDNA
is thought to reside on chromosome 6. Accordingly, polynucleotides
related to this invention are useful as a marker in linkage
analysis for chromosome 6.
[0987] This gene is expressed primarily in eosinophils and aortic
endothelium, and to a lesser extent in umbilical vein endothelial
cell and thymus.
[0988] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, haemopoietic disease. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the circulatory system,
expression of this gene at significantly higher or lower levels may
be routinely detected in certain tissues or cell types (e.g.
circulatory, immune, cancerous and wounded tissues) or bodily
fluids (e.g., lymph, serum, plasma, urine, synovial fluid and
spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[0989] The tissue distribution eosinophils and aortic endothelium,
combined with the homology to the HNP36 protein indicates that the
protein product of this gene is useful for the treatment of blood
neoplasias and other haemopoietic disease. Furthermore, elevated
expression of this gene product by endothelial cells indicates that
it may play vital roles in the regulation of endothelial cell
function; secretion; proliferation; or angiogenesis. Protein, as
well as, antibodies directed against the protein may show utility
as a tumor marker and/or immunotherapy targets for the above listed
tissues.
[0990] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:157 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 2113 of SEQ ID NO:157, b is an
integer of 15 to 2127, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:157, and where
b is greater than or equal to a+14.
[0991] Features of Protein Encoded by Gene No: 148
[0992] The gene encoding the disclosed cDNA is thought to reside on
chromosome 5. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
5.
[0993] This gene is expressed primarily in breast cancer cell
lines, thymus stromal cells, and ovary.
[0994] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, endocrine and female reproductive system diseases
including breast cancer. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the endocrine system, expression
of this gene at significantly higher or lower levels may be
routinely detected in certain tissues or cell types (e.g. thymus,
ovary, cancerous and wounded tissues) or bodily fluids (e.g.,
lymph, serum, plasma, urine, synovial fluid and spinal fluid) or
another tissue or cell sample taken from an individual having such
a disorder, relative to the standard gene expression level, i.e.,
the expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[0995] The tissue distribution in breast cancer cells and ovary
indicates that the protein product of this gene is useful for the
diagnosis and treatment of endocrine disorders. In addition, the
tissue distribution in tumors of thymus, ovary, and breast origins
indicates that the protein product of this gene is useful for
diagnosis and intervention of these tumors, in addition to other
tumors where expression has been indicated. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed tumors and
tissues.
[0996] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:158 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1611 of SEQ ID NO:158, b is an
integer of 15 to 1625, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:158, and where
b is greater than or equal to a+14.
[0997] Features of Protein Encoded by Gene No: 149
[0998] The translation product of this gene has homology to pmt1
and pmt 2, two conserved Schizosaccharomyces pombe genes. Preferred
are the polypeptide fragments comprising the following amino acid
sequence: DDDGFEIVPIEDPAKHRILDPEGLALGAVIASSKKAKRDLIDNSFNRYTFNEDEG
ELPEWFVQEEKQHRIRQLPVGKKEVEHYRKRWREINARPIXXXXXXXXX
XXXXXXXXLEQTRKKAEAVVNTV- DIXRTRES (SEQ ID NO:1041), DDDG
PEIVPIEDPAKHRILDPEGLALGAVIASSKKAKRDLIDNSFN- RYTF (SEQ ID NO:1042),
and/or KRWREINARPIXXXXXXXXXXXXXXXXXLEQTRKKAE AVVNTVDIXRTRES (SEQ ID
NO:1043). An additional embodiment is the polynucleotide fragments
encoding these polypeptide fragments (See Genbank Accession No.
e1216734).
[0999] This gene is expressed primarily in retina and ovary, and to
a lesser extent in breast cancer cells, epididymu s and
osteosarcoma.
[1000] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neuronal growth disorders, cancer and reproductive
system disorders. Similarly, polypeptides and antibodies directed
to these polypeptides are useful in providing immunological probes
for differential identification of the tissue(s) or cell type(s).
For a number of disorders of the above tissues or cells,
particularly of the neural and reproductive system, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g. retina, ovary,
reproductive, cancerous and wounded tissues) or bodily fluids
(e.g., lymph, serum, plasma, urine, synovial fluid and spinal
fluid) or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[1001] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 397 as residues: Met-1 to Gly-7.
[1002] The tissue distribution in ovary, breast cancer cells, and
epididymus indicates that the protein product of this gene is
useful for the diagnosis or treatment of reproductive system
diseases and cancers, in addition to other tumors where expression
has been indicated. Protein, as well as, antibodies directed
against the protein may show utility as a tissue-specific marker
and/or immunotherapy target for the above listed tissues.
[1003] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:159 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1673 of SEQ ID NO:159, b is an
integer of 15 to 1687, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:159, and where
b is greater than or equal to a+14.
[1004] Features of Protein Encoded by Gene No: 150
[1005] Preferred are the polypeptide fragments comprising the
following amino acid sequence: MIKDKGRARTALTSSQPAHLCPENPLLHL
KAAVKEKKRNKKKKTIGSPKRIQSPLNNKLLNSPAKTLPGACGSPQKLIDGFL
KHEGPPAEKPLEELSASTSGVPGLSSLQSDPAGCVRPPAPNLAGAVEFNDV
KTLLREWITTISDPMEEDILQVVKYCTDLIEEKDLEKLDLVIKYMKRLMQQSVES
VWNMAFDFILDNVQVVLQQTYGSTLKVT (SEQ ID NO:1044), MIKDKGRART
ALTSSQPAHLCPENPLLHLKAAVKEKKRNKKKKTIGSPKRIQ (SEQ ID NO:1045),
KRIQSPLNNKLLNSPAKTLPGACGSPQKLIDGFLKHEGPPAE
KPLEELSASTSGVPGLSSLQSDPAGCVRPP- APNLAGAVEFNDVKTLLREWITTI SDPM (SEQ
ID NO:1046), TISDPMEEDILQVVKYCTDLIEEKDL- EKLDLVIKYMK
RLMQQSVESVWNMAFDFILDNVQVVLQQTYGSTLKVT (SEQ ID NO:1047),
VCCKTTWTLSRIKSNAIFQTDSTDCCISLFMYFITRSSFSKSFSSIRSVQYFT
TWRMSSSIGSEIVVIHSLSKVFTSLNSTAPARLGAGGLTQPAGSDCKLERPGTP
EVEAESSSRGFSAGGPSCFRNPSINFWGLPQAPGRVFAGLLSSLLFKGL (SEQ ID NO:1048),
WTLSRIKSNAIFQTDSTDCCISLFM (SEQ ID NO:1049), FTTWR
MSSSIGSEIVVIHSLSKVFTSLN- STAPARLGA (SEQ ID NO:1050), and/or GGPS
CFRNPSINFWGLPQAPGRVFAGLL (SEQ ID NO:1051). An additional embodiment
is the polynucleotide fragments encoding these polypeptide
fragments. The gene encoding the disclosed cDNA is believed to
reside on chromosome 2. Accordingly, polynucleotides related to
this invention are useful as a marker in linkage analysis for
chromosome 2.
[1006] This gene is expressed primarily in 12 week embryo, and to a
lesser extent, in hemangiopericytoma and frontal cortex.
[1007] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, developmental or neural disorders, particularly
hemangiopericytoma, and other proliferative conditions, including
cancers. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the neural system and developing systems, expression of this gene
at significantly higher or lower levels may be routinely detected
in certain tissues or cell types (e.g., developmental, neural, and
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
amniotic fluid, serum, plasma, urine, synovial fluid and spinal
fluid) or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[1008] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 398 as residues: Leu-4 to Lys-11.
[1009] The tissue distribution in embryonic and neural tissues
indicates that the protein product of this gene is useful for the
treatment of growth disorders, hemangiopericytoma and other soft
tissue tumors. Moreover, the protein product of this gene is useful
for the detection/treatment of neurodegenerative disease states,
behavioural disorders, or inflamatory conditions such as Alzheimers
Disease, Parkinsons Disease, Huntingtons Disease, Tourette
Syndrome, meningitis, encephalitis, demyelinating diseases,
peripheral neuropathies, neoplasia, trauma, congenital
malformations, spinal cord injuries, ischemia and infarction,
aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia,
obsessive compulsive disorder, panic disorder, learning
disabilities, ALS, psychoses, autism, and altered behaviors,
including disorders in feeding, sleep patterns, balance, and
perception. In addition, elevated expression of this gene product
in regions of the brain indicates that it plays a role in normal
neural function. Potentially, this gene product is involved in
synapse formation, neurotransmission, learning, cognition,
homeostasis, or neuronal differentiation or survival. Moreover, the
gene or gene product may also play a role in the treatment and/or
detection of developmental disorders associated with the developing
embryo, sexually-linked disorders, or disorders of the
cardiovascular system. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[1010] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:160and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1828 of SEQ ID NO:160, b is an
integer of 15 to 1842, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:160, and where
b is greater than or equal to a+14.
[1011] Features of Protein Encoded by Gene No: 151
[1012] The translation product of this gene has been found to have
homology to a human DNA mismatch repair protein PMS3 (See Genbank
Accession No. R95250). Preferred polypeptide fragments comprise the
following amino acid sequence: FCHDCKFPEASPAMNCEP (SEQ ID NO:1052),
FCHDCKFPEASPAMNCEP (SEQ ID NO:1053), and/or HEPYAVLVI (SEQ ID
NO:1054). Also preferred are polynucleotide fragments encoding
these polypeptide fragments.
[1013] This gene is expressed primarily in neutrophils.
[1014] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune or hematopoietic disorders, such as lymphoma,
immunodeficiency diseases, and cancers resulting from genetic
instability. Similarly, polypeptides and antibodies directed to
these polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune system, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g., immune, hematopoietic, and cancerous and wounded
tissues) or bodily fluids (e.g., lymph, serum, plasma, urine,
synovial fluid and spinal fluid) or another tissue or cell sample
taken from an individual having such a disorder, relative to the
standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[1015] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 399 as residues: Met-1 to Lys-6.
[1016] The tissue distribution in neutrophils, combined with the
sequence homology to a human mismatch DNA repair enzyme indicates
that the protein product of this gene is useful for diagnosis of
Hodgkin's lymphoma, since the elevated expression and secretion by
the tumor mass may be indicative of tumors of this type.
Additionally the gene product may be used as a target in the
immunotherapy of the cancer. Because the gene is expressed in cells
of lymphoid origin, the natural gene product may be involved in
immune functions. Therefore it may be also used as an agent for
immunological disorders including arthritis, asthma, immune
deficiency diseases such as AIDS, and leukemia. Furthermore, its
homology to a known DNA repair protein would suggest the gene may
be useful in establishing cancer predisposition and prevention or
be of use in gene therapy applications. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[1017] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:161 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 756 of SEQ ID NO:161, b is an integer
of 15 to 770, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:161, and where b is greater
than or equal to a+14.
[1018] Features of Protein Encoded by Gene No: 152
[1019] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
PQPSNFPTTVRNLPYSGAGAQPPPSNC (SEQ ID NO:1055). Polynucleotides
encoding these polypeptides are also encompassed by the
invention.
[1020] This gene is expressed primarily in neutrophils.
[1021] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune or hematopoietic disorders, such as infectious
diseases and lymphoma. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the immune system, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g., immune,
hematopoietic, and cancerous and wounded tissues) or bodily fluids
(e.g., lymph, serum, plasma, urine, synovial fluid and spinal
fluid) or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[1022] The tissue distribution in neutrophils indicates that the
protein product of this gene is useful for the treatment of
inflammation and infectious diseases. Expression of this gene
product in neutrophils indicates a role in regulating the
proliferation; survival; differentiation; and/or activation
of-hematopoietic cell lineages, including blood stem cells. This
gene product may be involved in the regulation of cytokine
production, antigen presentation, or other processes that may also
suggest a usefulness in the treatment of cancer (e.g. by boosting
immune responses). Since the gene is expressed in cells of lymphoid
origin, the natural gene product may be involved in immune
functions. Therefore it may be also used as an agent for
immunological disorders including arthritis, asthma,
immunodeficiency diseases such as AIDS, leukemia, rheumatoid
arthritis, granulomatous disease, inflammatory bowel disease,
sepsis, acne, neutropenia, neutrophilia, psoriasis,
hypersensitivities, such as T-cell mediated cytotoxicity; immune
reactions to transplanted organs and tissues, such as
host-versus-graft and graft-versus-host diseases, or autoimmunity
disorders, such as autoimmune infertility, lense tissue injury,
demyelination, systemic lupus erythematosis, drug induced hemolytic
anemia, rheumatoid arthritis, Sjogren's disease, scleroderma and
tissues. In addition, this gene product may have commercial utility
in the expansion of stem cells and committed progenitors of various
blood lineages, and in the differentiation and/or proliferation of
various cell types. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[1023] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:162 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 505 of SEQ ID NO:162, b is an integer
of 15 to 519, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:162, and where b is greater
than or equal to a+14.
[1024] Features of Protein Encoded by Gene No: 153
[1025] Preferred polypeptide fragments encoded by this gene
comprise the following amino acid sequence:
MASSVPAGGHTRAGGIFLIGKLDLEASLFKSFQWLPFVLRKK- CNFFCWDSSAH
SLPLHPLSASCSAPACHASDTHLLYPSTRALCPSIFAWLVAPHSVFRTNAP
GPTPSSQSSPVFPVFPVSFMALIVCXLVCC (SEQ ID NO:1056), MASSVPAGG
HTRAGGIFLIGKLDLEASLFKSFQWLPFVLRKKCNFFCWDSSAHSLPLHPLSA SCSAPACHA
(SEQ ID NO:1057), FAWLVAPHSVFRTNAPGPTPSSQSSPVFPVFP VSFMALIVCXLVCC
(SEQ ID NO:1058), MASSVPAGGHTRAGGIFLIGKLDLE
ASLFKSFQWLPFVLRKKCNFFCWDSSAHSLPLHPLSA- SCSAPACHASDT
HLLYPSTRALCPSIFAWLVAPHSVFRTNAPGPTPSSQSSPVFPVFPVSFMALIV CXLVCC (SEQ
ID NO:1059), LVNWILKLHCLNLFSGFPLYLEKNATSSAGT
HPLTAFPSTLSLPHALPLPAMPP- ILTFCTPAPVPSAPRSLPGWLLLTQCSGQM
LLALPHLASLARSSLSSLFHSWLLLFVXLCAVDF (SEQ ID NO:1060), NLFSG
FPLYLEKNATSSAGTHPL (SEQ ID NO:1061), and/or PHLASLARSSLSSLFHS WLLL
(SEQ ID NO:1062). An additional embodiment is the polynucleotide
fragments encoding these polypeptide fragments.
[1026] This gene is expressed primarily in neutrophils.
[1027] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune or hematopoietic disorders, such as inflammation
and infectious diseases. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the immune system, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g., immune,
hematopoietic, and cancerous and wounded tissues) or bodily fluids
(e.g., lymph, serum, plasma, urine, synovial fluid and spinal
fluid) or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[1028] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 401 as residues: Ser-11 to Pro-17.
[1029] The tissue distribution in neutrophils indicates that the
protein product of this gene is useful for the treatment of
infectous diseases and inflammation. Moreover, the expression of
this gene product indicates a role in regulating the proliferation;
survival; differentiation; and/or activation of hematopoietic cell
lineages, including blood stem cells. This gene product may be
involved in the regulation of cytokine production, antigen
presentation, or other processes that may also suggest a usefulness
in the treatment of cancer (e.g. by boosting immune responses).
Since the gene is expressed in cells of lymphoid origin, the
natural gene product may be involved in immune functions. Therefore
it may be also used as an agent for immunological disorders
including arthritis, asthma, immunodeficiency diseases such as
AIDS, leukemia, rheumatoid arthritis, granulomatous disease,
inflammatory bowel disease, sepsis, acne, neutropenia,
neutrophilia, psoriasis, hypersensitivities, such as T-cell
mediated cytotoxicity; immune reactions to transplanted organs and
tissues, such as host-versus-graft and graft-versus-host diseases,
or autoimmunity disorders, such as autoimmune infertility, lense
tissue injury, demyelination, systemic lupus erythematosis, drug
induced hemolytic anemia, rheumatoid arthritis, Sjogren's disease,
scleroderma and tissues. In addition, this gene product may have
commercial utility in the expansion of stem cells and committed
progenitors of various blood lineages, and in the differentiation
and/or proliferation of various cell types. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[1030] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:163 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 739 of SEQ ID NO:163, b is an integer
of 15 to 753, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:163, and where b is greater
than or equal to a+14.
[1031] Features of Protein Encoded by Gene No: 154
[1032] This gene is primarily expressed in ovary, uterus, adipose
tissue, brain, and the liver.
[1033] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, reproductive, neural, hepatic, and metabolic disorders.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the female reproductive system, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., ovary, uterus, adipose tissue,
brain, liver, and cancerous and wounded tissues) or bodily fluids
(e.g., lymph, bile, amniotic fluid, serum, plasma, urine, synovial
fluid and spinal fluid) or another tissue or cell sample taken from
an individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[1034] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 402 as residues: Asn-56 to Gly-67.
[1035] The tissue distribution of this gene product in ovary and
uterus indicates that the protein product of this gene is useful
for diagnostic or therapeutic uses in the treatment of the female
reproductive system, obesity, and liver disorders, particularly
cancer in the above tissues. Protein, as well as, antibodies
directed against the protein may show utility as a tumor marker
and/or immunotherapy targets for the above listed tissues.
[1036] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:164 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1879 of SEQ ID NO:164, b is an
integer of 15 to 1893, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:164, and where
b is greater than or equal to a+14.
[1037] Features of Protein Encoded by Gene No: 155
[1038] The gene encoding the disclosed cDNA is believed to reside
on chromosome 3. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
3.
[1039] This gene is expressed in multiple tissues including brain,
aortic endothelial cells, smooth muscle, pituitary, testis,
melancytes, spleen, neutrophils, and placenta.
[1040] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immunological or vascular disorders, including
immunodeficiencies, cancers of the brain and the female
reproductive system, as well as cardiovascular disorders, such as
atherosclerosis and stroke. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the central nervous and immune
systems, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g., immune, vascular, endothelial, neural, hematopoietic,
reproductive, integumenatary, placental, endocrine, and cancerous
and wounded tissues) or bodily fluids (e.g., lymph, amniotic fluid,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[1041] The tissue distribution in neural tissue indicates that the
protein product of this gene is useful in the treatment/detection
of disorders in the nervous system, including schizophrenia,
neurodegeneration, neoplasia, brain cancer as well as vascular and
female reproductive disorders, including cancer within the above
tissues. Moreover, the protein product of this gene may also be
useful in the treatment and/or detection of other vascular
disorders which include, but are not limited to, aneurysms, emboli,
thromosis, atherosclerosis, microvascular disease, or stroke.
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[1042] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:165 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b. where
a is any integer between 1 to 2139 of SEQ ID NO:165, b is an
integer of 15 to 2153, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:165, and where
b is greater than or equal to a+14.
[1043] Features of Protein Encoded by Gene No: 156
[1044] The translation product of this gene shares sequence
homology with the human gene encoding cytochrome b561 (See Genbank
Accession No. P10897). Cytochrome b561 is a transmembrane electron
transport protein that is specific to a subset of secretory
vesicles containing catecholamines and amidated peptides. This
protein is thought to supply reducing equivalents to the
intravesicular enzymes dopamine-beta-hydroxylase and alpha-peptide
amidase. Preferred polypeptides of the invention comprise the amino
acid sequence: MAMEGYWRFLALLGSALLVGFLSVIFALVWVLHYREGLGWDGSALEFNWHP
VLMVTGFVFIQGIAIIVYRLPWTWKCSKLLMKSIHAGLNAVAAILAIISVV
AVFENHNVNNIANMYSLHSWVGLIAVICYLLQLLSGFSVFLLPWAPLSLRAF
LMPIHVYSGIVIFGTVIATALMGLTEKLIFSLRDPAYSTFPPEGVFVNTLG
LLILVFGALIFWIVTRPQWKRPKEPNSTILHPNGGTEQGARGSMPAYSGNNMD
KSDSELNSEVAARKRNLALDEAGQRSTM (SEQ ID NO:1063), AHASAHASG GAEYGAL
(SEQ ID NO:1064), QYSQYVQSAQLGWTDSCHMLFVTASFRFFSL
SASMGSAFSPSISHAHTCLFWNCHLWNSDCN- STYGIDRETDFFPERSCIQYIP
ARRCFRKYAWPSDPGVRGPHFLDSHQTAMETS (SEQ ID NO:1065), ASMGS
AFSPSISHAHTCLFWNCHLWNSDCNSTYG (SEQ ID NO:1066), FVHVVARVG
WHGTSCSLFSASIWMDNGRIWLLRTFPLRSGDYPKNEGPEHQDQKAKRIYEN
TFWRECTVCRISQGKNQFLCQSHKCCCNHCSKDDNSRINMYGHEKCSER KRSPWKQKD (SEQ ID
NO:1067), and/or ASIWMKNGRIWLLRTFPLRSGDY PKNEGPEHQ (SEQ ID
NO:1068), as well as antigenic fragments of at least 20 amino acids
of this gene and/or biologically active fragments. Also preferred
are polynucleotide fragments encoding these polypeptide fragments.
The gene encoding the disclosed cDNA is believed to reside on
chromosome 2. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
2.
[1045] This gene is expressed primarily in anergic T-cells.
[1046] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune or hematopoietic disorders, and metabolic
related diseases. Similarly, polypeptides and antibodies directed
to these polypeptides are useful in providing immunological probes
for differential identification of the tissue(s) or cell type(s).
For a number of disorders of the above tissues or cells,
particularly of the immune system, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., immune, hematopoietic,
metabolic, and cancerous and wounded tissues) or bodily fluids
(e.g., lymph, serum, plasma, urine, synovial fluid and spinal
fluid) or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[1047] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 404 as residues: Pro-222 to Asn-231, Asn-238 to
Gly-247, Ala-251 to Leu-264, Ala-280 to Thr-285.
[1048] The tissue distribution in anergic T-cells indicates that
the protein product or mRNA of this gene is useful for the
treatment or diagnosis of immune system and metabolic diseases or
conditions including Tay-Sachs disease, phenylketonuria,
galactosemnia, various porphyrias, and Hurler's syndrome. Protein,
as well as, antibodies directed against the protein may show
utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[1049] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:166 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1237 of SEQ ID NO:166, b is an
integer of 15 to 1251, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:166, and where
b is greater than or equal to a+14.
[1050] Features of Protein Encoded by Gene No: 157
[1051] The translation product of this gene shares sequence
homology with collagen which is important in mammalian development.
This gene also shows sequence homology with bcl-2 and the HNK-1
sulfotransferase of Rattus norvegicus which is thought be involved
in carbohydrate biosynthesis. (See Genbank Accession No. P80988 and
AF022729, respectively.) When tested against Jurket cell lines,
supernatants removed from cells containing this gene activated the
GAS (gamma activating sequence) promoter element. Thus, it is
likely that this gene activates T-cells cells through the JAK-STAT
signal transduction pathway. GAS is a promoter element found
upstream of many genes which are involved in the Jak-STAT pathway.
The Jak-STAT pathway is a large, signal transduction pathway
involved in the differentiation and proliferation of cells.
Therefore, activation of the Jak-STAT pathway, reflected by the
binding of the GAS element, can be used to indicate proteins
involved in the proliferation and differentiation of cells.
Preferred polypeptide fragments comprise the amino acid sequence:
PGRAGPSPGLSLQLPAEPGHPAGNLAPLT- SRPQPLCRIPAVPG (SEQ ID NO:1069).
Also preferred are polynucleotide sequences encoding this
polypeptide fragment.
[1052] This gene is expressed primarily in HL-60 tissue culture
cells, and to a lesser extent, in liver, breast, and uterus.
[1053] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immunological diseases, hereditary disorders involving
the MHC class of immune molecules, as well as developmental
disorders and reproductive disorders. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the immune and reproductive
system expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g., reproductive, hepatic, immune, hematopoietic, and cancerous
and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[1054] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 405 as residues: Ser-39 to Gly-46, Leu-49 to
Ala-62.
[1055] The tissue distribution in reproductive, and immune tissues
combined with the homology to collagen and the detected GAS
biological activity indicates that the protein product of this gene
is useful for diagnosis and treatment of hereditary MHC disorders
and particularly autoimmune disorders including rheumatoid
arthritis, lupus, scleroderma, and dermatomyositis, as well as many
reproductive disorders, including cancer of the uterus, and breast
tissues. Protein, as well as, antibodies directed against the
protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[1056] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:167 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 868 of SEQ ID NO:167, b is an integer
of 15 to 882, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:167, and where b is greater
than or equal to a+14.
[1057] Features of Protein Encoded by Gene No: 158
[1058] This gene is expressed primarily in the amygdala region of
the brain.
[1059] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, a variety of brain disorders, particularly those
effecting mood and personality, in addition to neurodegenerative
conditions. Similarly, polypeptides and antibodies directed to
these polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the brain and central nervous system, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., neural, and cancerous and
wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[1060] The tissue distribution in the amygdala indicates that the
protein product of this gene is useful for the treatment and/or
diagnosis of a variety of brain disorders, particulary bi-polar
disorder, uni-polar depression, and dementia. Moreover, The tissue
distribution indicates that the protein product of this gene is
useful for the detection/treatment of neurodegenerative disease
states, behavioural disorders, or inflammatory conditions which
include, but are not limited to Alzheimers Disease, Parkinsons
Disease, Huntingtons Disease, Tourette Syndrome, meningitis,
encephalitis, demyelinating diseases, peripheral neuropathies,
neoplasia, trauma, congenital malformations, spinal cord injuries,
ischemia and infarction, aneurysms, hemorrhages, schizophrenia,
mania, dementia, paranoia, obsessive compulsive disorder, panic
disorder, learning disabilities, ALS, psychoses, autism, and
altered behaviors, including disorders in feeding, sleep patterns,
balance, and perception. In addition, elevated expression of this
gene product in regions of the brain indicates that it plays a role
in normal neural function. Potentially. this gene product is
involved in synapse formation, neurotransmission, learning,
cognition, homeostasis, or neuronal differentiation or survival.
Moreover, the gene or gene product may also play a role in the
treatment and/or detection of developmental disorders associated
with the developing embryo, sexually-linked disorders, or disorders
of the cardiovascular system. Protein, as well as, antibodies
directed against the protein may show utility as a tumor marker
and/or immunotherapy targets for the above listed tissues.
[1061] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:168 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1 194 of SEQ ID NO:168, b is an
integer of 15 to 1208, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:168, and where
b is greater than or equal to a+14.
[1062] Features of Protein Encoded by Gene No: 159
[1063] This gene is expressed in a variety of tissues and cell
types including brain, smooth muscle, kidney, salivary gland, and
T-cells.
[1064] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neural, renal, vascular, metabolic, or immune
disorders, particularly cancers. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the central nervous, urinary,
salivary, digestive, and immune systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., neural, renal, vascular,
metabolic, immune cancerous and wounded tissues) or bodily fluids
(e.g., lymph, serum, plasma, urine, synovial fluid and spinal
fluid) or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[1065] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 407 as residues: Asp-43 to Asp-60.
[1066] The tissue distribution in brain, smooth muscle, and T-cells
indicates that the protein product of this gene is useful for
diagnosis of various neurological, and cardiovascular disorders,
but not limited to cancer within the above tissues. Additionally
the gene product may be used as a target in the immunotherapy of
the cancer. Because the gene is expressed in cells of lymphoid
origin, the natural gene product may be involved in immune
functions. Therefore it may be also used as an agent for
immunological disorders including arthritis, asthma, immune
deficiency diseases such as AIDS, and leukemia. Protein, as well
as, antibodies directed against the protein may show utility as a
tumor marker and/or immunotherapy targets for the above listed
tissues.
[1067] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:169 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1244 of SEQ ID NO:169, b is an
integer of 15 to 1258, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:169, and where
b is greater than or equal to a+14.
[1068] Features of Protein Encoded by Gene No: 160
[1069] The translation product of this gene shares sequence
homology with collagen, which is thought to be important in
cellular interactions, extracellular matrix formation, and has been
found to be an identifying determinant in autoimmune disorders.
Moreover, this gene shows sequence homology with the yeast protein,
Sls1p, an endoplasmic reticulum component involved in the protein
translocation process in the Yeast Yarrowia lipolytica. (See
Genbank Accession No. 1052828; see also J. Biol. Chem. 271,
11668-11675 (1996).) In Mus musculus, this same region shows
sequence homology with the heavy chain of kinesin. (See Genbank
Accession No. 2062607.) Recently, suppression of the heavy chain of
kinesin was shown to inhibit insulin secretion from primary
cultures of mouse beta-cells. (See Endocrinology 138 (5), 1979-1987
(1997).) Moreover, kinesin was found associated with drug
resistance and cell immortalization. (See Genbank Accession No.
468355.) Thus, it is likely that this gene also acts as a genetic
suppressor element. In specific embodiments, polypeptides of the
invention comprise the following amino acid sequence:
42 ARGRRRGRLELWELCLPLGCRRRRSLTMAPQSLPSSRMAPLG (SEQ ID NO:1070),
NGQASTAKMSSCLRSPPTLAPLSLTSGIPVQSWCGAS (SEQ ID NO:1071),
SQLLQQAVDRAQQLLEVALVLTILQLQAGQHLVLSLQAGQCPAELGVLTVAVPA
GGQEDAQCLQKLLTGIMLGQRQEVGRDLAPALFPQAWQEVYLAILLQLL
WGHLLGQLSLLLGEHLLRDQVVEQCDHAHGEHLRALLLHQGPQDLQPPELQEL
PLGIGEVAQQGAQCKQDLLLCSERLLRGQDDQQLLQGSPFDGLHLDLGVAG
KGSAQHKRSILLHEGLCAVQPIDHHLKTTKGKQVLRIVHLMDIIFKIKERS
NLLFQTGAGTIELVDQPYHDLHVSLNDNIQLIKVFLQFLNGAEEPLYLSLPCL VFL
QHLVLSLQAGQCPAELGVLTVAVPAGGQEDAQC (SEQ ID NO:1072),
QLSLLLGEHLLRDQVVEQCDHAHGEHGS (SEQ ID NO: 1073)
PFDGLHLDLGVAGKGSAQHKRSILLHEGLC (SEQ ID NO:1074), and/or
HLMDIIFKIKERSNLLFQTGAGTIELVDQP (SEQ ID NO:1075).
[1070] Polynucleotides encoding these polypeptides are also
encompassed by the invention. The gene encoding the disclosed cDNA
is believed to reside on chromosome 5. Accordingly, polynucleotides
related to this invention are useful as a marker in linkage
analysis for chromosome 5.
[1071] This gene is expressed primarily in the greater omentum, and
to a lesser extent in gall bladder, stromal bone marrow cells,
lymph node, liver, testes, pituitary, and thymus.
[1072] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, disorders of the endocrine, gastrointestinal, and
immunological systems, including autoimmune disorders and cancers.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune and gastrointestinal systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., gastrointestinal, metabolic,
immune, hematopoietic, hepatic, reproductive, endocrine, and
cancerous and wounded tissues) or bodily fluids (e.g., lymph, bile,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[1073] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 408 as residues: Asn-27 to Leu-47, Gln-81 to Lys-88,
Asp-93 to Lys-102, Asn-107 to Leu-116, Met-129 to Glu-141, Glu-150
to Asp-157, Lys-176 to Glu-185, Glu-333 to Tyr-349, Cys-393 to
Leu-403, Gln-423 to Gly-429.
[1074] The tissue distribution within gastrointestinal, endocrine
and immunological tissues, combined with the sequence homology to a
conserved collagen motif, indicates that the protein product of
this gene is useful for the diagnosis of various autoimmune
disorders including, but not limited to, rheumatoid arthritis,
lupus erthyematosus, scleroderma, and dermatomyositis. Because the
gene is expressed in cells of lymphoid origin, the natural gene
product may be involved in immune functions. Therefore it may be
also used as an agent for immunological disorders including
arthritis, asthma, immune deficiency diseases such as AIDS, and
leukemia. Protein, as well as, antibodies directed against the
protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[1075] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:170 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1610 of SEQ ID NO:170, b is an
integer of 15 to 1624, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:170, and where
b is greater than or equal to a+14.
[1076] Features of Protein Encoded by Gene No: 161
[1077] This gene has homology to the tissue inhibitor of
metalloproteinase 2. Such inhibitors are vital to the proper
regulation of metalloproteins such as collagenases, which has
implications for tissue regeneration and autoimmune disorders (See
Genbank Accession No. P16368). When tested against Jurkat cell
lines, supernatants removed from cells containing this gene
activated the GAS (gamma activating sequence) promoter element.
Thus, it is likely that this gene activates T-cells cells through
the JAK-STAT signal transduction pathway. GAS is a promoter element
found upstream of many genes which are involved in the Jak-STAT
pathway. The Jak-STAT pathway is a large, signal transduction
pathway involved in the differentiation and proliferation of cells.
Therefore, activation of the Jak-STAT pathway, reflected by the
binding of the GAS element, can be used to indicate proteins
involved in the proliferation and differentiation of cells. In
addition, this gene maps to chromosome 17, and therefore, may be
used as a marker in linkage analysis for chromosome 17 (See Genbank
Accession No. P16368).
[1078] This gene is expressed primarily in several types of cancers
including osteoclastoma, chondrosarcoma, and rhabdomyosarcoma, and
to a lesser extent, in non-malignant tissues including synovium,
amygdala, testes, and placenta.
[1079] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune or integumentary disorders, particularly cancers
of bone and cartilage, as well as various autoimmune disorders.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the musculoskeletal system, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., skeletal, integumentary,
synovium, muscle, fibroids, reproductive, neural, and cancerous and
wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[1080] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 409 as residues: Thr-24 to Thr-34.
[1081] The tissue distribution in various cancers, combined with
the sequence homology to a collagenase inhibitor and the detected
GAS biological activity, indicates that the protein product of this
gene is useful for the detection of various autoimmune disorders
such as rheumatoid arthritis, lupus, scleroderma, and
dermatomyositis. Therefore it may be also used as an agent for
immunological disorders including arthritis, asthma, immune
deficiency diseases such as AIDS, and leukemia. The expression of
this gene product would also suggest a role in the detection and
treatment of disorders and conditions afflicting the skeletal
system, in particular osteoporosis, bone cancer, as well as,
connective tissue disorders (e.g. arthritis, trauma, tendonitis,
chrondomalacia and inflammation), such as in the diagnosis or
treatment of various autoimmune disorders such as rheumatoid
arthritis, lupus, scleroderma, and dermatomyositis as well as
dwarfism. spinal deformation, and specific joint abnormalities as
well as chondrodysplasias (ie. spondyloepiphyseal dysplasia
congenita, familial osteoarthritis, Atelosteogenesis type II,
metaphyseal chondrodysplasia type Schmid). Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[1082] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:171 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1989 of SEQ ID NO:171, b is an
integer of 15 to 2003, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:171, and where
b is greater than or equal to a+14.
[1083] Features of Protein Encoded by Gene No: 162
[1084] This gene is homologous to the mitochondrial ATP6 gene, and
therefore is likely a homolog of this gene family (See Genbank
Accession No. X76197).
[1085] This gene is expressed primarily in brain tissue.
[1086] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neural disorders, including, but not limited to,
neurodegenerative conditions, Down's syndrome, depression,
Schizophrenia, and epilepsy. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the central nervous system,
expression of this gene at significantly higher or lower levels may
be routinely detected in certain tissues or cell types (e.g.,
neural, and cancerous and wounded tissues) or bodily fluids (e.g.,
lymph, serum, plasma, urine, synovial fluid and spinal fluid) or
another tissue or cell sample taken from an individual having such
a disorder, relative to the standard gene expression level, i.e.,
the expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[1087] The tissue distribution in brain tissue indicates this gene
is useful for diagnosis of various neurological disorders
including, but not limited to, brain cancer. Additionally the gene
product may be used as a target in the immunotherapy of cancer in
the brain as well as for the diagnosis of metabolic disorders such
as obesity, Tay-Sachs disease, phenylketonuria and Hurler's
Syndrome. Similarly, the protein product of this gene is useful for
the detection/treatment of neurodegenerative disease states,
behavioural disorders, or inflammatory conditions which include,
but are not limited to Alzheimers Disease, Parkinsons Disease,
Huntingtons Disease, Tourette Syndrome, meningitis, encephalitis,
demyelinating diseases, peripheral neuropathies, neoplasia, trauma,
congenital malformations, spinal cord injuries, ischemia and
infarction, aneurysms, hemorrhages, schizophrenia, mania, dementia,
paranoia, obsessive compulsive disorder, depression, panic
disorder, learning disabilities, ALS, psychoses, autism, and
altered behaviors, including disorders in feeding, sleep patterns,
balance, and perception. In addition, elevated expression of this
gene product in regions of the brain indicates that it plays a role
in normal neural function. Potentially, this gene product is
involved in synapse formation, neurotransmission, learning,
cognition, homeostasis, or neuronal differentiation or survival.
Moreover, the gene or gene product may also play a role in the
treatment and/or detection of developmental disorders associated
with the developing embryo, sexually-linked disorders, or disorders
of the cardiovascular system. Protein, as well as, antibodies
directed against the protein may show utility as a tumor marker
and/or immunotherapy targets for the above listed tissues.
[1088] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:172 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 772 of SEQ ID NO:172, b is an integer
of 15 to 786, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:172, and where b is greater
than or equal to a+14.
[1089] Features of Protein Encoded by Gene No: 163
[1090] The translation product of this gene was found to have
homology to the MRS3 and 4 protein of Saccharomyces cerevisiae (See
Genbank Accession No. gi.vertline.3996), which is known to suppress
a splice defect in mitochondrial by possibly serving to modulate
the cation-solute concentration in mitochondria. In specific
embodiments, polypeptides of the invention comprise the following
amino acid sequence:
43 DEPCPPPAASCAPPSWRMELRTGSVGSQAVARRMDGDSRDGGGGKDATGSED (SEQ ID
NO:1076), YENLPTSASVSTHMTAGAMAGILEHSVMYPVDSVKTRMQSLSPDPKAQYTSIY
GALKKIMRTEASGGPCEASTS RMELRTGSVGSQAVARRMDGDSRDGGGGKD- ATGS (SEQ ID
NO:1077), and/or PVDSVKTRMQSLSPDPKAQYTSIYGAL (SEQ ID NO:1078).
[1091] Polynucleotides encoding these polypeptides are also
encompassed by the invention. The gene encoding the disclosed cDNA
is believed to reside on chromosome 8. Accordingly, polynucleotides
related to this invention are useful as a marker in linkage
analysis for chromosome 8.
[1092] This gene is expressed primarily in placenta, neutrophils,
and microvascular endothelial cells, and to a lesser extent, brain,
prostate, spleen, thymus, and bone.
[1093] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune, vascular, or reproductive disorders. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the immune
system, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g., immune, hematopoietic, vascular, endothelial, reproductive,
neural, skeletal, and cancerous and wounded tissues) or bodily
fluids (e.g., lymph, amniotic fluid, serum, plasma, urine, synovial
fluid and spinal fluid) or another tissue or cell sample taken from
an individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[1094] Features of Protein Encoded by Gene No: 164
[1095] The gene encoding the disclosed cDNA is believed to reside
on chromosome 7. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
7.
[1096] This gene is expressed primarily in neutrophils, monocytes,
bone marrow, and fetal liver.
[1097] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune system or hematopoietic disorders including, but
not limited to, autoimmune disorders such as lupus, leukemia and
immunodeficiency disorders . Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the immune system, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g., immune,
hematopoietic, hepatic, developmental, and cancerous and wounded
tissues) or bodily fluids (e.g., lymph, serum, amniotic fluid,
plasma, urine, synovial fluid and spinal fluid) or another tissue
or cell sample taken from an individual having such a disorder,
relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[1098] The tissue distribution in various immune system tissues
indicates that the protein product of this gene is useful for the
diagnosis of various immunological disorders such as Hodgkin's
lymphoma, arthritis, asthma, immune deficiency diseases such as
AIDS, and leukemia. Moreover, the protein product of this gene is
useful for the treatment and diagnosis of hematopoetic related
disorders such as anemia, pancytopenia, leukopenia,
thrombocytopenia or leukemia since stromal cells are important in
the production of cells of hematopoietic lineages. The uses include
bone marrow cell ex vivo culture, bone marrow transplantation, bone
marrow reconstitution, radiotherapy or chemotherapy of neoplasia.
The gene product may also be involved in lymphopoiesis, therefore,
it can be used in immune disorders such as infection, inflammation,
allergy, immunodeficiency etc. In addition, this gene product may
have commercial utility in the expansion of stem cells and
committed progenitors of various blood lineages, and in the
differentiation and/or proliferation of various cell types.
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[1099] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:174 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1355 of SEQ ID NO:174, b is an
integer of 15 to 1369, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:174, and where
b is greater than or equal to a+14.
[1100] Features of Protein Encoded by Gene No: 165
[1101] The translation product of this gene shares sequence
homology with dystrophin which is thought to be defective in both
Duchene and Becker Muscular Dystrophy. Preferred polypeptide
fragments comprise the following amino acid sequence:
44 MKLLGECSSSIDSVKRLEHKLKEEEESLPGFVNLHSTETQTAGVIDRWELLQ (SEQ ID
NO:1079), AQALSKELRMKQNLQKWQQFNSDLNSIWAWLGDTEEELEQLQRLELSTDIQTIE
LQIKKLKELQKAVDHRKAIILSINLCSPEFTQADSKESRDLQDRLXQMN
GRWDRVCSLLEEWRGLLQDALMQCQGFHEMSHGLLLMLENIDRRKNEIVPID
SNLDAEILQDHHKQLMQIKHELLESQLRVASLQDMSCQLLVNAEGTDCLEAKE
KVHVIGNRLKLLLKEVSRHIKELEKLLDVSSSQQDLSSWSSADELDTSGSVSPX
SGRSTPNRQKTPRGKCSLSQPGPSVSSPHSRSTKGGSDSSLSEPXPGRSGRG
FLFRVLRAALPLQLLLLLLIGLACLVPMSEEDYSCALSNNFARSFHPMLRYTNG PPPL
MKLLGECSSSIDSVKRLEHKLKEEEESLPGFVNL (SEQ ID NO:1080),
HSTETQTAGVIDRWELLQAQALSKELRMKQNLQKWQQFNSDLNSIWAW
LGDTEEEEQLQRLELSTDIQTIELQIK KLKELQKAVDHR (SEQ ID NO:1081),
KAIILSINLCSPEFTQADSKESRDLQDRLXQMNGRWDRVCSLLEEWRGLLQDAL
MQCQGFHEMSHGLLLMLENIDRRKNEIVPIDSNLDAEILQDHHKQLMQIKM
ELLESQLRVASLQDMSCQL QDMSCQLLVNAEGTDCLEAK (SEQ ID NO:1082),
EKVHVIGNRLKLLLKEVSRHIKELEKLLDVSSSQQDLSSWSSADELDTSGSVSP
XSGRSTPNRQKTPRGKCSLSQPGPSVSSPHS DSSLSEP (SEQ ID NO:1083),
XPGRSGRGFLFRVLRAALPLQLLLLLLIGLACLVPMSEEDYSCALSNNFAR SFHPMLRYTNGPPPL
QRFLPPGSCXLIRGPQCPRVTDPTTG (SEQ ID NO:1084),
QSLDDSRFQIQQTENIIRSKTPTGPELDTSYKGY SISAS (SEQ ID NO:1085),
RLESIGTISFFLLSMFSSIRSKPWLISWKPWHCIRASCSRPRHSSSRE- HTRSQ
RPFICXKRSCRSRLSLLSAWVNSGLQRLMIERMMALRWSTAFWSSLSFLIWSS
MVWMSVLSSRRWSCSNSSSVSPSQAQMLFKSELNCCHFWRFCFILNSLLN
AWAWRSSHRSITPAVWVSVLCRLTKPGRLSSSSFSLCSSLFTESILLLHSPSSFM
TAFWSSLSFLIWSSMVWMSVLSSRRWSCSNSSSVS (SEQ ID NO:1086),
LLNAWAWRSSHRSITPAVWVSVLCRL (SEQ ID NO:1087),
LARHVLQRGYSELGFQQLMLYLHKLFVMVLKYLCIKVRINRDNFIIFPSVNY (SEQ ID
NO:1088), LQHKKQTMAHFMETLALHOGILQQAPPLLQQRAHSVPAPIHLXQAILQVPALLA
VSLGELRAAEIDGEDDGFAVVHSFLELLELFDLELDGLDVSAEFQTLELFQ LLLRVPQPGPDAVQV
YSELGFQQLMLYLHKLFVMVLKYLCIKV (SEQ ID NO:1089), AMVCFLCWRTLTEGK (SEQ
ID NO:1091), and/or VHSFLELLELFDLELDGLDVSAEFQTLEL (SEQ ID
NO:1090).
[1102] Also preferred are polynucleotide fragments encoding these
polypeptide fragments. Furthermore, this gene maps to chromosome 6,
and therefore, may be used as a marker in linkage analysis for
chromosome 6 (See Genbank Accession No. N62896).
[1103] This gene is expressed in numerous tissues including the
heart, kidney, and brain.
[1104] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, musculoskeletal disorders including Muscular Dystrophy
and cardiovascular diseases. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the muscle tissues, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g., muscle, heart, and
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[1105] The tissue distribution in heart, combined with the homology
to the human dystrophin gene indicates that the protein product of
this gene is useful for the diagnosis and treatment of Muscular
Dystrophy and other muscle disorders, particularly
musculodegenerative conditions. Protein, as well as, antibodies
directed against the protein may show utility as a tumor marker
and/or immunotherapy targets for the above listed tissues.
[1106] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:175 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 2365 of SEQ ID NO:175, b is an
integer of 15 to 2379, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:175, and where
b is greater than or equal to a+14.
[1107] Features of Protein Encoded by Gene No: 166
[1108] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
45 GAGVGTAMPRVPQSAGGAVTWWGVGLSQPSSVQGGARPGTVPGTPGPLPGL (SEQ ID
NO:1092), SPAPPPQHPPPLPKLFLLCLSXSLPQDFSLLLCLSLDPCPSSTSDL (SEQ ID
NO:1093), GTVPGTPGPLPGLSPAPPPQHPPPLPKLFL (SEQ ID NO:1094),
APSRCRRSVVQVPYSAFSSCSWTPTALRRGVLLYAGLSTSSASKAQGWHCLGL
EYPSGAIMEVRGRGGDRYAQGPSKCWRGCXLVGSGSVTAILCPGWGKAWD
SARHPRTPSRLVSCSTASTPPTPAQAVSPLPLXFPAPGLLSSPLPLLGPLPFLYL
TALRRGVLLYAGLSTSSASKAQGWHCLGLEYPSGAIM (SEQ ID NO:1095),
AILCPGWGKAWDSARHPRTPSRLVSCSTASTPP (SEQ ID NO:1096),
PPVFMASHRPXGMEPGEWRFVLVHIAFXCAWDLVCEHVSVC (SEQ ID NO:1097), and/or
SQVRGRGRAGVQGEAEEKREVLGQGXREAEEKQLGQGWGVLRRWSRRQAW
KGSWGAWHCPRPCPTLDRGWL HVSVCSQVRGRGRAGVQGEAEEKREVLGQ (SEQ ID
NO:1098).
[1109] Polynucleotides encoding these polypeptides are also
encompassed by the invention.
[1110] This gene is expressed primarily in human cerebellum.
[1111] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, diseases of the central nervous system, including
Alzheimer's Disease, Parkinson's Disease, ALS, and mental
illnesses. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the central nervous system, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., neural, and cancerous and
wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[1112] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 414 as residues: Pro-20 to Gly-26, Leu-37 to Pro-42,
His-57 to Gly-63.
[1113] The tissue distribution in human cerebellum indicates that
the protein products of this gene are useful for the
treatment/diagnosis of diseases of the central nervous system and
may protect or enhance survival of neuronal cells by slowing
progression of neurodegenerative diseases. Moreover, the protein
product of this gene is useful for the detection/treatment of
neurodegenerative disease states, behavioural disorders, or
inflammatory conditions which include, but are not limited to
Alzheimers Disease, Parkinsons Disease, Huntingtons Disease,
Tourette Syndrome, meningitis, encephalitis, demyelinating
diseases, peripheral neuropathies, neoplasia, trauma, congenital
malformations, spinal cord injuries, ischemia and infarction,
aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia,
obsessive compulsive disorder, depression, panic disorder, learning
disabilities, ALS, psychoses, autism, and altered behaviors,
including disorders in feeding, sleep patterns, balance, and
perception. In addition, elevated expression of this gene product
in regions of the brain indicates that it plays a role in normal
neural function. Potentially, this gene product is involved in
synapse formation, neurotransmission, learning, cognition,
homeostasis, or neuronal differentiation or survival. Moreover, the
gene or gene product may also play a role in the treatment and/or
detection of developmental disorders associated with the developing
embryo, sexually-linked disorders, or disorders of the
cardiovascular system. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[1114] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:176 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1334 of SEQ ID NO:176, b is an
integer of 15 to 1348, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:176, and where
b is greater than or equal to a+14.
[1115] Features of Protein Encoded by Gene No: 167
[1116] Preferred polypeptides encoded by this gene comprise the
following amino acid sequence:
MKLLICGNYLAPSHSESSRRCCLLCFYPLCLEINFGMKVFLSMPFLVLFQSL- IQED (SEQ ID
NO:1099). Polynucleotides encoding such polypeptides are also
provided. The gene encoding the disclosed cDNA is believed to
reside on chromosome 15. Accordingly, polynucleotides related to
this invention are useful as a marker in linkage analysis for
chromosome 15.
[1117] This gene is expressed primarily in human testes tumor, and
to a lesser extent, in normal human testes.
[1118] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, diseases of the testes, particularly cancer, and other
reproductive disorders. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the male reproductive tissues,
expression of this gene at significantly higher or lower levels may
be routinely detected in certain tissues or cell types (e.g.,
reproductive, testicular, and cancerous and wounded tissues) or
bodily fluids (e.g., lymph, serum, seminal fluid, plasma, urine,
synovial fluid and spinal fluid) or another tissue or cell sample
taken from an individual having such a disorder, relative to the
standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[1119] The tissue distribution in human testicular tissue indicates
that the protein products of this gene are useful for the
treatment/diagnosis of reproductive diseases including cancers.
Moreove, the protein may possibly have utility as a contraceptive
or may be used to ameliorate disorders related to aberrant male
secondary characteristics (e.g. hair, etc.). Protein, as well as,
antibodies directed against the protein may, show utility as a
tumor marker and/or immunotherapy targets for the above listed
tissues.
[1120] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:177 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1488 of SEQ ID NO:177, b is an
integer of 15 to 1502, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:177, and where
b is greater than or equal to a+14.
[1121] Features of Protein Encoded by Gene No: 168
[1122] The translation product of this gene was found to have
homology to the gar2 gene product of Schizosaccharomyces pombe,
which is thought to be involved in protein metabolism (See Genbank
Accession No. gi.vertline.663262). In specific embodiments,
polypeptides of the invention comprise the following amino acid
sequence:
46 FSSPQGLKFRSKSSLANYLHKNGETSLKPEDFDFTVLSKRGIKSRYKDCS (SEQ ID
NO:1100), ELLCYICWKNTGLFSFFLSVFRGMVSSVKSFLVGEQLLS (SEQ ID NO:1101),
and/or ISEPRFKMSVCKCSFLSTTSTFVPISSDSKKVSSYFSLCSESLAEQ- NLFMMP
EVECSEQKFDPELNDLSFFFTRLFSSLVTLRVSPHAPASEMQTVLS
TFVPISSDSKKVSSYESLCSESLAEQNLFMMPEVFC (SEQ ID NO:1102).
[1123] Polynucleotides encoding these polypeptides are also
encompassed by the invention. The gene encoding the disclosed cDNA
is believed to reside on chromosome 3. Accordingly, polynucleotides
related to this invention are useful as a marker in linkage
analysis for chromosome 3.
[1124] This gene is expressed primarily in fetal liver.
[1125] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, hepatic disorders, in addition to conditions affecting
hematopoietic development and metabolic diseases. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
hepatic system, and fetal hematopoietic system, expression of this
gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g., hepatic,
metabolic, hematopoietic, and cancerous and wounded tissues) or
bodily fluids (e.g., lymph, serum, bile, plasma, urine, synovial
fluid and spinal fluid) or another tissue or cell sample taken from
an individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[1126] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 416 as residues: His-7 to Trp-17, Leu-19 to Lys-27,
Pro-33 to Gly-44, Lys-68 to Gly-74, Lys-85 to Cys-95.
[1127] The tissue distribution in liver, combined with the homology
to the gar2 protein, indicates that the protein products of this
gene are useful for the treatment/diagnosis of diseases of the
developing liver and hematopoietic system, and act as a growth
differentation factor for hematopoietic stem cells. Moreover, the
protein product of this gene is useful for the detection and
treatment of liver disorders and cancers (e.g. hepatoblastoma,
jaundice, hepatitis, liver metabolic diseases and conditions that
are attributable to the differentiation of hepatocyte progenitor
cells). In addition, the expression in fetus would suggest a useful
role for the protein product in developmental abnormalities, fetal
deficiencies, pre-natal disorders, and various would-healing models
and/or tissue trauma. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[1128] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:178 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1623 of SEQ ID NO:178, b is an
integer of 15 to 1637, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:178, and where
b is greater than or equal to a+14.
[1129] Features of Protein Encoded by Gene No: 169
[1130] The polypeptide encoded by this gene is believed to be a
membrane bound receptor. Additionally, the extracellular domain of
this polypeptide is expected to consist of the following amino acid
sequence:
47 RILLVKYSANEENKYDYLPTTVNVCSELVKLVFCVLVSFCVIKKDHQSRNLKY (SEQ ID
NO:1103), ASWKEFSDFMKWSIPAFLYFLDNLIVFYVLSYLQPAMAVIFSNFSIITTALLFRI-
V LKXRLNWIQWASLLTLFLSIVALTAGTKTLQHNLAGRGFHHDAFESPSNSCLL
FRNECPRKDNCTAKEWTFPEAKWNTTARVFSHIRLGMGHVLIIVQCFISSMANI
YNEKILKEGNQLTEXIFIQNSKLYFFGILFNGLTLGLQRSNRDQIKNCGFFYGH
TVNVCSELVKLVFCVLVSFCVIKKDHQSRN (SEQ ID NO:1104),
LIVFYVLSYLQPAMAVIFSNFSIITTALLFR (SEQ ID NO:1105),
FFSPSNSCLLFRNECPRKDNCTAKEWT (SEQ ID NO:1106), and/or
YFFGILFNGLTLGLQRSNRDQIKNCGFF (SEQ ID NO:1107).
[1131] Thus, preferred polypeptides encoded by this gene comprise
the extracellular domain, as shown above. It will be recognized,
however, that deletions of either end of the extracellular domain
up to the first cysteine from the N-terminus and the first cysteine
of the C-terminus, is expected to retain the biological functions
of the full-length extracellular domain, because the cysteines are
thought to be responsible for providing secondary structure to the
molecule. Thus, deletions of one or more amino acids from either
end (or both ends) of the extracellular domain are contemplated. Of
course, further deletions including the cysteines are also
contemplated as useful, as such polypeptides is expected to have
immunological properties such as the ability to evoke an immune
response. Polynucleotides encoding all of the foregoing
polypeptides are provided.
[1132] This gene is expressed primarily in human osteoclastoma, and
to a lesser extent, in hippocampus and chondrosarcoma.
[1133] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, skeletal or connective tissue disorders, particularly
cancers. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the skeletal system, expression of this gene at significantly
higher or lower levels may be routinely detected in certain tissues
or cell types (e.g., skeletal, neural, immune, connective, and
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[1134] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 417 as residues: Met-1 to Cys-6, Ala-41 to Tyr-49,
Lys-76 to Lys-84.
[1135] The tissue distribution in osteoclastoma and chondrosarcoma
indicates that the protein products of this gene are useful for the
diagnosis of cancers of the bone and connective tissues, and may
act as growth factors for cells involved in bone or connective
tissue growth. Moreover, this gene product may show utility in the
detection and treatment of disorders and conditions affecting the
skeletal system, in particular osteoporosis, bone cancer, as well
as, disorders afflicting connective tissues (e.g. arthritis,
trauma, tendonitis, chrondomalacia and inflammation), such as in
the diagnosis or treatment of various autoimmune disorders such as
rheumatoid arthritis, lupus, scleroderma, and dermatomyositis, as
well as dwarfism, spinal deformation, and specific joint
abnormalities as well as chondrodysplasias (ie. spondyloepiphyseal
dysplasia congenita, familial osteoarthritis, Atelosteogenesis type
II, metaphyseal chondrodysplasia type Schmid). Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[1136] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:179 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 2897 of SEQ ID NO:179, b is an
integer of 15 to 2911, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:179, and where
b is greater than or equal to a+14.
[1137] Features of Protein Encoded by Gene No: 170
[1138] Preferred polypeptides encoded by this gene comprising the
following amino acid sequence:
48 NSVPNLQTLAVLTEAIGPEPAIPRXPREPPVATSTPATPSAGPQPLPTGTVLVPG (SEQ ID
NO:1108), GPAPPCLGEAWALLLPPCRPSLTSCFWSPRPSPWKETGV (SEQ ID NO:1109),
VTAGRVGGGGPMPPQGKVGQDPQGPARSRLGGAGARQRVWQVWTWQ QAAPGGXGGWRALGQWPQ
STPATPSAGPQPLPTGTVLVPGGPAP (SEQ ID NO:1110), and/or
QDPQGPARSRLGGAGARQR (SEQ ID NO:1111).
[1139] Polynucleotides encoding such polypeptides are also provided
herein.
[1140] This gene is expressed primarily in hematopoietic progenitor
cells.
[1141] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, hematopoietic or immune disorders, particularly cancer
and autoimmune disorders. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the blood/circulatory system,
expression of this gene at significantly higher or lower levels may
be routinely detected in certain tissues or cell types (e.g.,
hematopoietic, immune, and cancerous and wounded tissues) or bodily
fluids (e.g., lymph, serum, plasma, urine, synovial fluid and
spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[1142] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 418 as residues: Gln-4 to His-10, Pro-25 to
His-32.
[1143] The tissue distribution in hematopoietic progenitor cells
indicates that the protein products of this gene are useful for
diagnosis of diseases involving growth differentation of
hematopoietic cells. Moreover, the protein product of this gene is
useful for the treatment and diagnosis of hematopoetic related
disorders such as anemia, pancytopenia, leukopenia,
thrombocytopenia or leukemia since stromal cells are important in
the production of cells of hematopoietic lineages. The uses include
bone marrow cell ex vivo culture, bone marrow transplantation, bone
marrow reconstitution, radiotherapy or chemotherapy of neoplasia.
The gene product may also be involved in lymphopoiesis, therefore,
it can be used in immune disorders such as infection, inflammation,
allergy, immunodeficiency etc. In addition, this gene product may
have commercial utility in the expansion of stem cells and
committed progenitors of various blood lineages, and in the
differentiation and/or proliferation of various cell types.
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[1144] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:180 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 505 of SEQ ID NO:180, b is an integer
of 15 to 519, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:180, and where b is greater
than or equal to a+14.
[1145] Features of Protein Encoded by Gene No: 171
[1146] Preferred polypeptides encoded by this gene comprise the
following amino acid sequences:
49 ALQLAFYPDAVEEWLEENVHPSLQRLQXLLQDLSEVSAPP (SEQ ID NO:1112),
CHPPALAGTLLRTPEGRAHARGLLLEAGGA (SEQ ID NO:1113),
GSSSTRSWFSTSSPQRSASWHSGAPSCRSWRLPCSWLSTRMPWRSGWRKTCT (SEQ ID
NO:1114), PACSGCKASTLQPSLSPSSPPLXPPVETAVXSRALRREG (SEQ ID NO:1115),
AGSFPGSNILALVTQVSLHLRSSVDALLEGNRYVTGWFSPYHRQRKLTIHPV
PLGPEKAGLAXPLVXHAARPCPSTSLQSQCSPSLXXEP (SEQ ID NO:1116),
XXPPRSXVISGGFDEDVKAKVENLLGISSLEKTDPVRQAPCSPPCPLLPL
PFXRPWROLFSAGLSAGRGPAPSLAATSLPLSHKSASICAALWMRCWRATGM
SLAGSAPTTASGSSSTRSWFSTSSPORSASWHSGAPSCRSWRLPCSWLSTRMP
WRSGWRKTCTPACSGCKLCCRTSARCLPPRCHPPALAGTLLRTPEGRAHAR
GLLLEAGGALXXXXAWAIRPTWASCPLAQQCLAHTQFLRALGSPWGRD (SEQ ID NO:1116),
FQEDLMKMLKRKWRTFSGFPAWKKRTLLGKHPAALPVPFFP (SEQ ID NO:1117),
SPSPARGDSCXQQGSPQGGGRLLPWQQHPCPCHTSQPPSAQLCGCAAGGQQV
CHWLVQPLPPPAEAHPPGHGSAHPARSAQPPGTVEHPRAGAGGCPAAGFLPG
CRGGVAGGKRAPQPAAAAXSAAGPQRGVCPPAATHQPWQGRCSGPLRGE
LMPGGSCWRLGGLCXXXWPGQYGPRGRRALWPSSVLPTLSS
ALPSGVLSNVPARAGGWQRGGRHLAEVLQQSLQPLQAGVH (SEQ ID NO:1118),
VFLQPLLHGIRVESQLQGSLQLLHEGAPLCQEAERCGLDVLNHDRVDEL
PLAVVGAEPASDIPVALQQRIHRAAQMEADLCDKGKDVAAREGAGPLPA
ESPAENSCLHGRXKGRGRRGQGGLQGACLTGSVFSRLEIPRRFSTFALTSSSN
PPEITXXRGGXXGSXXREGLHWDCRLVLGHGRAAWXTNGQANPAFSGPKG
RQLFSAGLSAGRGPAPSLAATSLPLSHKS (SEQ ID NO:1119),
ELPLAVVGAEPASDIPVALQQRIHRAAQ (SEQ ID NO: 1120), and/or
QPPGTVEHPRAGAGGCPAAGFLPGCRG (SEQ ID NO:1121).
[1147] Polynucleotides encoding such polypeptides are also
provided. The protein product of this gene shares sequence homology
with metallothionines. Thus, polypeptides encoded by this gene are
expected to have metallothionine activity. Furthermore, such
activities are known in the art and described elsewhere herein.
[1148] This gene is expressed primarily in kidney cortex.
[1149] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, renal disorders, particularly diseases of the kidney
including cancer and renal dysfunction. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the renal system, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g., renal, urogenital,
and cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[1150] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 419 as residues: Ser-47 to Gln-52.
[1151] The tissue distribution in kidney cortex indicates that the
protein product of this gene is useful for the treatment/diagnosis
of diseases of the kidney, including kidney failure. Moreover, this
gene or gene product could be used in the treatment and/or
detection of kidney diseases including nephritus, renal tubular
acidosis, proteinuria, pyuria, edema, pyelonephritis,
hydronephritis, nephrotic syndrome, crush syndrome,
glomerulonephritis, hematuria, renal colic and kidney stones, in
addition to Wilms Tumor Disease, and congenital kidney
abnormalities such as horseshoe kidney, polycystic kidney, and
Falconi's syndrome. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[1152] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:181 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 954 of SEQ ID NO:181, b is an integer
of 15 to 968, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:181, and where b is greater
than or equal to a+14.
[1153] Features of Protein Encoded by Gene No: 172
[1154] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
50 SVFERTNEFRDVLWSSI (SEQ ID NO:1122), GVVQVTFMS (SEQ ID NO:1123),
SVSRVTWGCQPSICPGAPPAAALAGGLRLLFERELFGLPVSSPLICSF- LEHHP
RTSPPPSDCELLEGRSCVLLFIFLSPEPCTDPGMW SKQI (SEQ ID NO:1124),
HSFVHSFIHLFNTHLLSTYHIPGSVQGSGDRKMNRRTQLLPSR- SSQSDGGGDV
LGWCSKKEQIRGEETGRPNSSLSKRSLRPPARAAAGGAPGQMLG
VTWGCQPSICIPGAPPAAALAGGLRLLFE (SEQ ID NO:1125), and/or
EQIRGEETGRPNSSLSKRSLRPP (SEQ ID NO:1126).
[1155] Polynucleotides encoding these polypeptides are also
encompassed by the invention.
[1156] This gene is expressed primarily in 12 week old early stage
human.
[1157] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, developmental abnormalities. Similarly, polypeptides
and antibodies directed to these polypeptides are useful in
providing immunological probes for differential identification of
the tissue(s) or cell type(s). For a number of disorders of the
above tissues or cells, particularly of the developing embryo,
expression of this gene at significantly higher or lower levels may
be routinely detected in certain tissues or cell types (e.g.,
developmental, and cancerous and wounded tissues) or bodily fluids
(e.g., lymph, amniotic fluid, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[1158] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 420 as residues: Gln-31 to Thr-43, Gly-51 to Ser-58,
Pro-65 to Pro-72.
[1159] The tissue distribution in embryonic tissue indicates that
the protein product of this gene is useful for treatment/diagnosis
of developmental conditions. The gene may be involved in vital
organ development in the early stage, especially hematopoiesis, the
cardiovascular system, and neural development. Moreover, expression
within embryonic tissue indicates that this protein may play a role
in the regulation of cellular division, and may show utility in the
diagnosis and treatment of cancer and other proliferative
disorders. Similarly, developmental tissues rely on decisions
involving cell differentiation and/or apoptosis in pattern
formation. Thus this protein may also be involved in apoptosis or
tissue differentiation and could again be useful in cancer therapy.
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[1160] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:182 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1114 of SEQ ID NO:182, b is an
integer of 15 to 1128, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:182,and where b
is greater than or equal to a+14.
[1161] Features of Protein Encoded by Gene No: 173
[1162] The translation product of this gene shares sequence
homology with TGN38, an integral membrane protein previously shown
to be predominantly localized to the trans-Golgi network (TGN) of
cells. The gene encoding the disclosed cDNA is believed to reside
on chromosome 5. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
5.
[1163] This gene is expressed primarily in developing embryo, and
to a lesser extent, in cancer tissues including lymphoma,
endometrial, prostate and colon.
[1164] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, developmental abnormalities and cancer. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
developing fetus, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g., developmental, reproductive, immune,
gastrointestinal, and cancerous and wounded tissues) or bodily
fluids (e.g., lymph, amniotic fluid, seminal fluid, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[1165] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 421 as residues: His-65 to Ser-72, Pro-82 to Gly-91,
Pro-98 to Glu-118, Ser-126 to Gly-166, Pro-180 to Asp-188, Tyr-209
to Lys-214, Gln-220 to Leu-228.
[1166] The tissue distribution in the embryo, combined with the
homology to an integral membrane protein indicates that the protein
product of this gene is useful for the diagnosis of cancers and
developmental abnormalities where aberrant expression relates to an
abnormality. Expression within embryonic tissue and other cellular
sources marked by proliferating cells indicates that this protein
may play a role in the regulation of cellular division, and may
show utility in the diagnosis and treatment of cancer and other
proliferative disorders. Similarly, developmental tissues rely on
decisions involving cell differentiation and/or apoptosis in
pattern formation. Thus this protein may also be involved in
apoptosis or tissue differentiation and could again be useful in
cancer therapy. Protein, as well as, antibodies directed against
the protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[1167] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:183 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 2262 of SEQ ID NO:183, b is an
integer of 15 to 2276, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:183, and where
b is greater than or equal to a+14.
[1168] Features of Protein Encoded by Gene No: 174
[1169] The translation product of this gene shares sequence
homology with a dnaJ heat shock protein from E. coli which is
allelic to sec63, a gene that affects transit of nascent secretory
proteins across the endoplasmic reticulum in yeast. In specific
embodiments, polypeptides of the invention comprise the following
amino acid sequence:
51 QWEHLLLLPHLLRGAHRDPGDILPLAPRSECRANSIKEYQKSIWKVYVVRLR (SEQ ID
NO:1127), LLKPQPNIIPTVKKIVLLAGWALFLFLAYKVSKTDREYQEYNPYEVLNLDPGAT
VAEIKKQYRLLSLKYHPDKGGDEV EERGGGGGAMAG (SEQ ID NO:1128),
QQFQYDDSGNTFFYFLTSFVGLIVIPATYYLWPRDQNAEQIRLKNIRKVYGRC
RLYTGCVIFDLVSNRALSFRCMLCCNSCHSASSSLFC (SEQ ID NO:1129),
FSSCSLSESLSLPSSFSLWESLLVSSSSESLPLSETSSSSSFTAASFPTTPFACF
CFCCFDCGNSTGVGFFFKGFFFFDLAVFLGPLLFCCHPPFVLFLLVSPCPSSA
GCSSAAQMDCSFSNTSAIVCLVNLTNTVTKDPTVMLLLSSSSNTCDFISM
VTYGKLPRTAITSSYFSSSRKCSRV YQKSIWKVYVVRLRLLKPQPNIIPTVKKIVL- LAGW
(SEQ ID NO:1130), and/or CHPPFVLFLLVSPCPSSAGCSSAAQMDC- SFSNTSA (SEQ
ID NO:1131).
[1170] Polynucleotides encoding these polypeptides are also
encompassed by the invention.
[1171] This gene is expressed primarily in Hodgkin's lymphoma, and
to a lesser extent, in testes.
[1172] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune or hematopoietic disorders, particularly cancer.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune system, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g., immune, hematopoietic, reproductive, testicular,
and cancerous and wounded tissues) or bodily fluids (e.g., lymph,
seminal fluid, serum, plasma, urine, synovial fluid and spinal
fluid), or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[1173] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 422 as residues: Val-37 to Pro-49, His-76 to Asp-82,
Thr-97 to Trp-105, Arg-158 to Asp-165, Glu-199 to Asp-214, Asn-229
to Pro-236, Thr-261 to Gln-266, Arg-292 to Glu-298, Glu-335 to
Lys-351, Glu-372 to Glu-377, Leu-398 to Asn-405, Glu-437 to
Pro-480, Gln-487 to Gln-495, Lys-507 to Ala-555, Ser-563 to
Arg-569, Pro-588 to Glu-593, Lys-618 to Val-623, Pro-630 to
Asn-635, Ser-644 to Gly-649, Lys-664 to Trp-673, Gly-679 to
Phe-689, Asp-691 to Asp-704.
[1174] The tissue distribution in Hodgkin's lymphoma, combined with
the homology to dnaJ and sec63 indicates that the protein product
of this gene is useful as a diagnostic for cancer, that the protein
may be useful in regulating gene expression levels, and that it is
essential for normal protein metabolism. Therefore, protein
products of this gene may show utility as an anticancer agent, or
even serve to protect from viral or bacterial infections, based
upon its homologous function as a protein chaperone. Protein, as
well as, antibodies directed against the protein may show utility
as a tumor marker and/or immunotherapy targets for the above listed
tissues.
[1175] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:184 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 3360 of SEQ ID NO:184, b is an
integer of 15 to 3374, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:184, and where
b is greater than or equal to a+14.
[1176] Features of Protein Encoded by Gene No: 175
[1177] The gene encoding the disclosed cDNA is believed to reside
on chromosome 5. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
5. Contact of cells with supernatant expressing the product of this
gene has been shown to increase the permeability of the plasma
membrane of chondrocytes to calcium. Thus it is likely that the
product of this gene is involved in a signal transduction pathway
that is initiated when the product binds a receptor on the surface
of the plasma membrane of both chondrocytes, in addition to other
cell-lines or tissue cell types. Thus, polynucleotides and
polypeptides have uses which include, but are not limited to,
activating chondrocytes.
[1178] This gene is expressed primarily in endothelial cells, and
to a lesser extent, in bone marrow stromal cells.
[1179] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune, hematopoietic, ebdothelial, or vascular
disorders, such as diseases involving angiogenic abnormalities
including diabetic retinopathy, macular degeneration, and other
diseases including arterioscerosis and cancer. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
vascular system, expression of this gene at significantly higher or
lower levels may be routinely detected in certain tissues or cell
types (e.g., immune, hematopoietic, ebdothelial, vascular, and
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[1180] The tissue distribution in endothelial cells indicates that
the protein products of this gene are useful for treating diseases
where an increase or decrease in angiogenesis is indicated and as a
factor in the wound healing process. In addition, the protein
product of this gene may show utility in the treatment, detection,
and/or prevention of a variety of vascular disorders, which
include, but are not limited to microvascular disease, embolism,
thrombosis, atherosclerosis, aneurysm, or stroke. Moreover, the
protein product of this gene is useful for the treatment and
diagnosis of hematopoetic related disorders such as anemia,
pancytopenia, leukopenia, thrombocytopenia or leukemia since
stromal cells are important in the production of cells of
hematopoietic lineages. The uses include bone marrow cell ex vivo
culture, bone marrow transplantation, bone marrow reconstitution,
radiotherapy or chemotherapy of neoplasia. The gene product may
also be involved in lymphopoiesis, therefore, it can be used in
immune disorders such as infection, inflammation, allergy,
immunodeficiency etc. In addition, this gene product may have
commercial utility in the expansion of stem cells and committed
progenitors of various blood lineages, and in the differentiation
and/or proliferation of various cell types. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[1181] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:185 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1323 of SEQ ID NO:185, b is an
integer of 15 to 1337, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:185, and where
b is greater than or equal to a+14.
[1182] Features of Protein Encoded by Gene No: 176
[1183] The translation product of this gene shares sequence
homology with both the RIC and MAT8 proteins (mouse), which are
thought to be important in regulating chloride conductance in cells
by modulating the response mediated by cAMP and protein kinase C to
extracellular signals. In specific embodiments, polypeptides of the
invention comprise the following amino acid sequence:
52 GTSLDAAATAASLSPRGCRLRTPSSD (SEQ ID NO:1132), QIQRHTRAPKQLI (SEQ
ID NO:1133), PLMTPRRSLRDHPQA QTSRQTPRPSSHLVFMRMTPSSMMNTPSGNGGCWSQ
LCCSSQASSSSPVASAGSCPGYAGIIAGE- SIRNR S PRRSLRDHPQA QTSRQTPRPSSHLVFM
(SEQ ID NO:1134), THPPETGAVGRSCAVHHRHHHPHQWQVQAAVPVMPESLQVSPSETG
ADNXLGTRRPSPLP (SEQ ID NO:1135),
AHRAQPPASPRRAWPEREDTDDEAGARAAGPSLLPPPTLPAPEGYLA- PWGLSL KLS
PLLRQKVKHCGLC PESLQVSPSETG ADNXLGTRRPSPLPAHRAQPPASP (SEQ ID
NO:1136), GTAPKAPGSLQGRAGLGEVGDSDRQP (SEQ ID NO:1137), WLQLHHLC
LPSLARLFEGMQEAGHGELAGGLVFGCPAGCQLLFLMDSPAMIPA
GEVGDSDRQPWLQHHLCLPSLARLFEGMQEAGH (SEQ ID NO: 1138),
GSGGLSGRLCLGMVSQRASWCHQWDELLWCSCVSLD (SEQ ID NO:1139), and/or
LSLEAHPFLP VAGSGSGVVVFHQQARLGLERWAGVLCRLHLGLVSGPECP
QWDELLWCSCVSLDLSLEAHPFLP VAGSGSGVVVFHQQARL (SEQ ID NO:1140).
[1184] Polynucleotides encoding these polypeptides are also
encompassed by the invention. The gene encoding the disclosed cDNA
is believed to reside on chromosome 19. Accordingly,
polynucleotides related to this invention are useful as a marker in
linkage analysis for chromosome 19.
[1185] This gene is expressed primarily in amniotic cells and
hematopoeitic cells including macrophages, neutrophils, T cells,
TNF induced aortic endothelium, and to a lesser extent in testes,
TNF induced epithelial cells, and smooth muscle.
[1186] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune or hematopoietic disorders, particularly
inflammatory responses mediated by T cells, macrophages, and/or
neutrophils, particularly those involving TNF, and also cancer.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune system, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g., immune, hematopoietic, developmental, and
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[1187] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 424 as residues: Thr-19 to Ala-33, Leu-54 to Asp-82,
Pro-89 to Ala-97, Pro-100 to Lys-125, Ser-127 to Phe-135, Gly-164
to Leu-169, Cys-173 to Arg-178.
[1188] The tissue distribution in hematopoietic cells, combined
with the homology to the RIC and mat-8 genes, indicates that the
protein product of this gene is useful for modifying inflammatory
responses to cytokines such as TNF, and thus modifying the duration
and/or severity of inflammation. Polynucleotides and polypeptides
derived from this gene are thought to be useful in the diagnosis
and treatment of cancer. The protein product of this gene is useful
for the treatment and diagnosis of hematopoetic related disorders
such as anemia, pancytopenia, leukopenia, thrombocytopenia or
leukemia, since stromal cells are important in the production of
cells of hematopoietic lineages. The uses include bone marrow cell
ex vivo culture, bone marrow transplantation, bone marrow
reconstitution, radiotherapy or chemotherapy of neoplasia. The gene
product may also be involved in lymphopoiesis, therefore, it can be
used in immune disorders such as infection, inflammation, allergy,
immunodeficiency etc. In addition, this gene product may have
commercial utility in the expansion of stem cells and committed
progenitors of various blood lineages, and in the differentiation
and/or proliferation of various cell types. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[1189] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO: 186 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 927 of SEQ ID NO:186, b is an integer
of 15 to 941, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:186, and where b is greater
than or equal to a+14.
[1190] Features of Protein Encoded by Gene No: 177
[1191] This gene is expressed primarily in endothelial cells.
[1192] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, vascular disorders, including vascular restenosis.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the vascular system, expression of this gene at significantly
higher or lower levels may be routinely detected in certain tissues
or cell types (e.g., vascular, endothelial, and cancerous and
wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[1193] The tissue distribution in endothelial tissue indicates that
the protein product of this gene is useful for treating diseases
associated with vascular responses to injury such as vascular
restenosis following angioplasty. Moreover, the protein product of
this gene is useful for the treatment, detection, and/or prevention
of a variety of other vascular disorders, which include, but are
not limited to microvascular disease, embolism, thrombosis,
atherosclerosis, aneurysm, or stroke. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[1194] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:187 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 664 of SEQ ID NO:187, b is an integer
of 15 to 678, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:187, and where b is greater
than or equal to a+14.
[1195] Features of Protein Encoded by Gene No: 178
[1196] This gene appears to be chimeric. There are two ORFs of
interest. The first ORF-1 encodes a polypeptide preferrably
comprising one of the following polypeptide sequences:
53 MRPDWKAGAGPGGPPQKPAPSSQRKPPARPSAAAAAIAVAAAEEERRLRQRN (SEQ ID
NO:1141); and/or RLRLEEDKPAVERCLEELVFGDVENDEDALLRRLRGPRVQEHEDSGDS-
EVENEA KGNFPPQKKPVWVDEEDEDEEMVDMMNNRFRKDMMKNASESKLSKDNLKK
RLKEEFQHAMGGVPAWAETTKRKTSSDDESEEDEDDLLQRTGNFISTSTSLPRG
ILKMKNCQHANAERPTVARISICAVPSRCTDCDGCWD
CLEELVFGDVENDEDALLRRLRGPRVQEHEDSGDSEVENEAKGNF (SEQ ID NO:1142).
PPQKKPVWVDEEDEDEEMVDMMNNRFRKDMMKNASESKLSKDNLKKRLKE
EFQHAMGGVPAWAETTKRKTSSDDESEEDEDDLLQRTGNFISTSTSLPRGILKM
KNCQHANAERPTVARISICAVPSRCTDCDGC
[1197] ORF-2 encodes a polypeptide preferrably comprising one of
the following polypeptide sequences:
54 LKEKIVRSFEVSPDGSFLLINGIAGYLHLLAMKTKELIGSMKINGRVAASTFSSD (SEQ ID
NO:1143); and/or SKKVYASSGDGEVYVWDVNSRKCLNRFVDEGSLYGLSIATSRNGQYVA-
CGSN CGVVNIYNQDSCLQETNPKPIKAIMNLVTGVTSLTFNPTTEILAIASEKMKEAVR
LVHLPSCTVFSNFPVIKNKNISHVHTMDFSPRSGYFALGNEKGKALMYRLHH YSDF
KINGRVAASTFSSDSKKVYASSGDGEVYVW (SEQ ID NO:1144).
DVNSRKCLNRFVDEGSLYGLSIATSRNGQYVACGSNCGVVNIYNQDSCLQETN
PKPIKAIMNLVTGVTSLTFNPTTEILAIASEKMKEAVRLVHLPSCTVFSNEPVIK
NKNISHVHTMDFSPRSGYFAIGNEKGKAL
[1198] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
55 WLLGLDNAVSLFQVDGKTNPKIQSIYLERFPIFKACFSANGE (SEQ ID NO:1145),
EVLATSTHSKVLYVYD LVFGDVENDEDALLRRLRGPRVQ (SEQ ID NO:1146),
KNASESKLSKDNLKKRLKEEFQHAMGGVP (SEQ ID NO:1147), and/or
SLPRGILKMKNCQHANAERPTVA (SEQ ID NO:1148).
[1199] Polynucleotides encoding these polypeptides are also
encompassed by the invention. Moreover, the translation product of
this gene shares homology with the transcriptional repressor TUPI
of Candida albicans (See Genbank Accession No. gi.vertline.2245634
(AF005741)), which is thought to modulate the expression levels of
cellular filiment and may implicate this protein as serving a
useful role in the amelioration of proliferating cells and
tissues.
[1200] This gene is expressed primarily in epidydimus and
endometrial tumors, and to a lesser extent, in T cell lymphoma and
cell lines derived from colon cancer.
[1201] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, reproductive or developmental conditions, which include
tumors of the reproductive organs, including testis and endometrial
cells. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the reproductive system, expression of this gene at significantly
higher or lower levels may be routinely detected in certain tissues
or cell types (e.g., reproductive, developmental, and cancerous and
wounded tissues) or bodily fluids (e.g., lymph, amniotic fluid,
seminal fluid, serum, plasma, urine, synovial fluid and spinal
fluid) or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[1202] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 426 as residues: Ser-67 to Lys-72, Val-87 to Leu-93,
Tyr-128 to Pro-141, Asp-204 to Gly-210.
[1203] The tissue distribution in reproductive tissue cancers,
combined with the homology to a transcriptional repressor protein,
indicates that the protein products of this gene are useful for
treating tumors of the endometrium or epithelial tumors of the
reproductive system. Moreover, the protein may also be useful as a
contraceptive. Protein, as well as, antibodies directed against the
protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[1204] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:188 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1834 of SEQ ID NO:188, b is an
integer of 15 to 1848, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:188, and where
b is greater than or equal to a+14.
[1205] Features of Protein Encoded by Gene No: 179
[1206] Preferred polypeptides encoded by this gene comprise the
following amino acid sequence:
56 MRILQLILLALATGLVGGETRIIKGFECKLHSQPWQAALFEKTRLLCGATLIAPR (SEQ ID
NO:1149); WLLTAAHCLKPRYIVHLGQHNLQKEEGCEQTRTATESFPHPGFNNSLPNKDH
RNDIMLVKMASPVSITWAVRPLTLSSRCVTAGTSCSFPAGAARPDPSYACLTPC
DAPTSPSLSTRSVRTPTPATSQTPWCVPACRKGARTPARVTPGALWSVTSLFKA
LSPGARIRVRSPESLVSTRKSANMWTGSRRR ETRIIKGFECKLHSQPWQAALFEKT-
RLLCGATLIAPRWLLTAAHCLKPRYIVHLGQHNLQK (SEQ ID NO:1150); and/or
EEGCEQTRTATESFPHPGFNNSLPNKDHRNDIMLVKMASPVSITWAVRPLTLSS
RCVTAGTSCSFPAGAARPDPSYACLTPCDAPTSPSLSTRSVRTPTPATSQTPWC
VPACRKGARTPARVTPGALWSVTSLFKALSPGARIRVRSPESLVSTRKSANMW TGSRRR
CKLHSQPWQAALFEKTRLLCGATLIAPRW (SEQ ID NO:1151).
LLTAAHCLKPRYIVHLGQHNLQKEEGCEQTRTATESFPHPGFNNS
[1207] The translation product of this gene shares sequence
homology with neuropsin, a novel serine protease, which is thought
to be important in modulating extracellular signalling pathways in
the brain. Owing to the structural similarity to other serine
proteases, the protein products of this gene are expected to have
serine protease activity which may be assayed by methods known in
the art and described elsewhere herein. Moreover, this protein has
been shown to also have homology to PSA (prostate specific
antigen). PSA is a serum marker for prostate cancer and it is a
member of the kallikrein family. The members of the kallikrein
family are secreted serine proteases and some of them are good
tissue specific markers. This new member of the kallikrein family
has been detected twice in endometrial tumor cDNA library and
therefore is a good candidate as a serum marker for endometrial
tumor.
[1208] This gene is expressed primarily in endometrial tumor, and
to a lesser extent, in colon cancer, benign hypertrophic prostate,
and thymus.
[1209] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, reproductive, immune, or endocrine disorders,
particularly cancers of the endometrium or colon and benign
hypertrophy of the prostate. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the urogenital or reproductive
systems, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g., reproductive, immune, endocrine, gastrointestinal, and
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, seminal fluid, plasma, urine, synovial fluid and spinal
fluid) or another tissue or cell sample taken from an individual
having such a disorder, relative to the standard gene expression
level, i.e., the expression level in healthy tissue or bodily fluid
from an individual not having the disorder.
[1210] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 427 as residues: Glu-27 to Trp-35, Leu-77 to Ala-89,
Pro-96 to Asn-109, Ser-149 to Arg-156, Gln-172 to Ile-182, Glu-193
to Gly-204, Glu-245 to Asn-250.
[1211] The tissue distribution in proliferative reproductive
tissues, combined with the homology to serine proteases indicates
that the protein product of this gene is useful for diagnosing,
treating, and/or preventing hyperproliferative disorders such as
cancer of the endometrium or colon and hyperplasia of the prostate.
Similarly, expression within cellular sources marked by
proliferating cells indicates that this protein may play a role in
the regulation of cellular division, and may show utility in the
diagnosis and treatment of cancer and other proliferative
disorders. Similarly, developmental tissues rely on decisions
involving cell differentiation and/or apoptosis in pattern
formation. Thus this protein may also be involved in apoptosis or
tissue differentiation and could again be useful in cancer therapy.
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[1212] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:189 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1278 of SEQ ID NO:189, b is an
integer of 15 to 1292, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO: 189, and where
b is greater than or equal to a+14.
[1213] Features of Protein Encoded by Gene No: 180
[1214] Preferred polypeptides encoded by this gene comprise the
following amino acid sequence:
57 VLQGRYFSPILEMRRLRPEGXXNLPGGSRAQKEPRQDLTLVLWPHCPHFAMTR (SEQ ID
NO:1152), and/or SYVPTKQCMVQGSFYCIFIFKGPVQNWC CPRRRTCVR
VEKSRPFQCQLHSIS (SEQ ID NO:1153).
[1215] Polynucleotides encoding such polypeptides are also
provided.
[1216] This gene is expressed primarily in fetal brain.
[1217] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neural disorders, particularly neurodegenerative
conditions, in addition to identifying and expanding stem cells in
the CNS. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the nervous system, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g., neural, developmental, and cancerous and wounded
tissues) or bodily fluids (e.g., lymph, amniotic fluid, serum,
plasma, urine, synovial fluid and spinal fluid) or another tissue
or cell sample taken from an individual having such a disorder,
relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[1218] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 428 as residues: Met-1 to Lys-9, Glu-26 to Lys-37,
Lys-39 to Lys-48.
[1219] The tissue distribution in fetal brain indicates that the
protein products of this gene are useful for detecting and
expanding stem cell populations in the (or of the) central nervous
system. Moreover, the protein product of this gene is useful for
the detection/treatment of neurodegenerative disease states,
behavioural disorders, or inflammatory conditions which include,
but are not limited to Alzheimers Disease, Parkinsons Disease,
Huntingtons Disease, Tourette Syndrome, meningitis, encephalitis,
demyelinating diseases, peripheral neuropathies, neoplasia, trauma,
congenital malformations, spinal cord injuries, ischemia and
infarction, aneurysms, hemorrhages, schizophrenia, mania, dementia,
paranoia, obsessive compulsive disorder, depression, panic
disorder, learning disabilities, ALS, psychoses, autism, and
altered behaviors, including disorders in feeding, sleep patterns,
balance, and perception. In addition, elevated expression of this
gene product in regions of the brain indicates that it plays a role
in normal neural function. Potentially, this gene product is
involved in synapse formation, neurotransmission, learning,
cognition, homeostasis, or neuronal differentiation or survival.
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[1220] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:190 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 892 of SEQ ID NO:190, b is an integer
of 15 to 906, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:190, and where b is greater
than or equal to a+14.
[1221] Features of Protein Encoded by Gene No: 181
[1222] In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
58 PKEPGVPE (SEQ ID NO:1154), LQLKPRDPFSTLGPNAVL (SEQ ID NO:1155),
SPQRLVLETLSKLSIQDNNVDLILATPPFSRLEKLYSTMVRFLSDRKN- PVCR
RWLWYCWPTWLRGTAWQLVPLQCRRAVSATSWAS RDPFSTLGPNAVLSPQRLVLETLSKLS (SEQ
ID NO:1156), EVISGLFIQSRRRERGQ (SEQ ID NO:1157), and/or GVVGSHM
ILWGKSLFFFSPQRLTKNIFKNYSLLLTQRFLFPCETLLLQY VYSIRCTVQYMKGSTLYCTGLSS-
EQGLF TTANFLAPARL IRCTVQYMKGSTLYCTGLSSEQG (SEQ ID NO:1158).
[1223] Polynucleotides encoding these polypeptides are also
encompassed by the invention.
[1224] This gene is expressed primarily in early stage human brain,
fetal liver/spleen, and stromal cells.
[1225] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, developmental abnormalities, neural, immune, or
hematopoietic disorders. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the central nervous system,
expression of this gene at significantly higher or lower levels may
be routinely detected in certain tissues or cell types (e.g.,
developmental, neural, immune, hematopoietic, and cancerous and
wounded tissues) or bodily fluids (e.g., lymph, amniotic fluid,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[1226] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 429 as residues: Gln-42 to Gln-47, Gln-54 to
Pro-60.
[1227] The tissue distribution in embryonic brain and fetal liver
indicates that the protein products of this gene play a role in the
development of the central nervous and hematopoietic systems.
Therefore this gene and its products are useful for diagnosing or
treating developmental abnormalities of the central nervous system.
Moreover, the protein product of this gene is useful for the
treatment and diagnosis of hematopoetic related disorders such as
anemia, pancytopenia, leukopenia, thrombocytopenia or leukemia
since stromal cells are important in the production of cells of
hematopoietic lineages. The uses include bone marrow cell ex vivo
culture, bone marrow transplantation, bone marrow reconstitution,
radiotherapy or chemotherapy of neoplasia. The gene product may
also be involved in lymphopoiesis, therefore, it can be used in
immune disorders such as infection, inflammation, allergy,
immunodeficiency etc. In addition, this gene product may have
commercial utility in the expansion of stem cells and committed
progenitors of various blood lineages, and in the differentiation
and/or proliferation of various cell types. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[1228] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:191 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer,between 1 to 1927 of SEQ ID NO:191, b is an
integer of 15 to 1941, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:191, and where
b is greater than or equal to a+14.
[1229] Features of Protein Encoded by Gene No: 182
[1230] Preferred polypeptides encoded by this gene comprise the
following amino acid sequence:
59 MPIIDQVNPELHDFMQSAEVGTIFALSWLITWFGHVLSDFRHVVRLYDFFLACH (SEQ ID
NO:1159; "ORB-1"); or PLMPIYFAAVIVLYREQEVLDCDCDMASVHHLLSQIPQDLPYE-
TLISRXETFLFSF PHPNLLGRPLPNSKLRGRQPLLSKTLSWHQPSRGLIWCCGSGXRGLLRPEDRT
KDVLTKPRTNRFVKLAVMGLTVALGAAALAVVKSALEWAPKFQLQLFP
CPEFFIPATLPCPFVFAFTSEASSRAYLTQRGPGG (SEQ ID NO:1160; "ORF-2").
LAQNLMPLPVGFWMGSLPPPWCWRKWVSEACSCFC
[1231] "ORF-2"). ORF-2 is structurally similar to various TGF-beta
family members. Thus, this polypeptide is expected to have a
variety of activities in the modulation of cell growth and
proliferation. In specific embodiments, polypeptides of the
invention comprise the following amino acid sequence:
60 CRQAGAVRGHPMFQFTFYGVTXRFPVTRAAQAQQVAKAAASFRNPLPPTPGR (SEQ ID
NO:1161), WQRAHPKAHWERHKILC QAPRSPLCQVGSATGL
HILNYLMPIIDQVNPELHDFMQSAEVGTIFALSWLITWFGHVLSDFRHVVRLYDFFLAC (SEQ ID
NO:1162), HPLMPIYFAAV IVLYREQEVLDCDCDMASVHHLLSQIPQDLPYETLISR XETF
LFSFPHPNLLGRPLPNSKLRGRQPLLSK TLSWHQPSRGLIWCCGSGXRGLLR
PEDRTKDVLTKPRTNRFVKLAVMGLTVALGAAALAVVKSALEWAPK FQLQLFP
AEVGTIFALSWLITWFGHVLSDFRHVVRLYD (SEQ ID NO:1163), and/or
VLTKPRTNRFVKLAVMGLTVALGAAALAVVKSA (SEQ ID NO:1164).
[1232] Polynucleotides encoding these polypeptides are also
encompassed by the invention. The gene encoding the disclosed cDNA
is believed to reside on chromosome 20. Accordingly,
polynucleotides related to this invention are useful as a marker in
linkage analysis for chromosome 20.
[1233] This gene is expressed primarily in osteoclastoma,
microvascular endothelium, and bone marrow derived cell lines.
[1234] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, skeletal, vascular, or hematological diseases,
particularly those involving aberrant proliferation of stem cells.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune system, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g., skeletal, vascular, immune, hematological, and
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[1235] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 430 as residues: Ser-33 to Ala-39.
[1236] The tissue distribution in bone marrow and endothelial cells
indicates that the protein products of this gene is useful for
treating disorders of the progenitors of the immune system.
Applications include in vivo expansion of progenitor cells, ex vivo
expansion of progenitor cells, or the treatment of tumors of the
circulatory system, such as lymphomas. Moreover, the protein
product of this gene may also show utility in either the
enhancement or inhibition of immune cell localization or targeting
at sites of inflammation or injury. The protein product of this
gene may be useful in the treatment, detection, and/or prevention
of a variety of vascular disorders, which include, but are not
limited to microvascular disease, embolism, aneurysm,
atherosclerosis, or stroke. Protein, as well as, antibodies
directed against the protein may show utility as a tumor marker
and/or immunotherapy targets for the above listed tissues.
[1237] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:192 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 2104 of SEQ ID NO:192, b is an
integer of 15 to 2118, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO: 192, and where
b is greater than or equal to a+14.
[1238] Features of Protein Encoded by Gene No: 183
[1239] In specific embodiments, polypeptides of the invention
comprise the sequence: GFGSVSAAGRRSGGTWQPVQ (SEQ ID NO:1165),
PGGLAVGSRW WSRSLT (SEQ ID NO:1166), LEPSRQRRPRRRGGTSRPETDQRAKCWRQL
(SEQ ID NO:1167), and/or VCLRCQNRMEN (SEQ ID NO:1168). In further
specific embodiments, polypeptides of the invention comprise the
sequence: MAACTARRPGRGQPLVVPVADXGPVAKAALCAAXAGAFSPASTTTTRRHLSS
RNRPEGKVLETVGVFEVPKQNGKYETGQLFLHSIFGYRGVVLFPWQARLXDR
DVASAAPEKAENPAGHGSKEVKGKTHTYYQVLIDARDCPHISQRSQTEAVTFL
ANHDDSRALYAIPGLDYVSHEDILPYTSTDQVPIQHELFERFLLYDQTKAPPFVA
RETLRAWQEKNHPWLELSDVHRETTENIRVTVIPFYMGMREAQNSHVYWWRY
CIRLENLDSDVVQLRERHWRIFSLSGTLETVRGRGVVGREPVLSKEQPAFQYSS
HVSLQASSGHMWGTFRFERPDGSHFDVRIPPFSLESNKDEKTPPSGLHW (SEQ ID NO:1169),
MAACTARRPGRGQPLVVPVADXGPVAKAALCAA (SEQ ID NO:1170),
MAACTARRPGRGQPLVVPVADXGPVAKAALCAA (SEQ ID NO:1171),
MAACTARRPGRGQPLVVPVADXGPVAKAALCAA (SEQ ID NO:1172),
MAACTARRPGRGQPLVVPVADXGPVAKAALCAA (SEQ ID NO:1173),
MAACTARRPGRGQPLVVPVADXGPVAKAALCAA (SEQ ID NO:1174),
VLETVGVFEVPKQNGKYETGQLFLHSIFGYRGVVL (SEQ ID NO:1175),
GLDYVSHEDILPYTST (SEQ ID NO:1176), DVHRETTENIRVTVIPFY M (SEQ ID
NO:1177), WWRYCIRLENLDSDVVQLRER (SEQ ID NO:1178), PAFQ
YSSHVSLQASSGHMWGTFRFER (SEQ ID NO:1179), RLPSHKRRCFCLVIQ
KKSFKEFMLDGNLISGGVGEDVFMADIVQAWDGIEGPTVIMVSQ- EGHSFCLRS
LRYMWAVTSINQHLIVSVSFAFHLLGAMASRVLCFFWSCRSHIPVXQSGLPGK
QDDTSVAKNAMKERLPGLIFSILFWHLKHTNCLQHFALWSVSGREVPPRR
RGRRWREGSSXGRAQSGLGHRAXVSDRDHQRLPTARPPGCTGCHVPPERR PAADTEPNP (SEQ
ID NO:1180), KEFMLDGNLISGGVGEDVFMADIVQAWDGIE (SEQ ID NO:1181),
AVTSINQHLIVSVSFAFHLLGAMASRVLC (SEQ ID NO:1182), and/or
TARPPGCTGCHVPPERRPAA (SEQ ID NO:1183). Polynucleotides encoding
these polypeptides are also encompassed by the invention. The gene
encoding the disclosed cDNA is believed to reside on chromosome 17.
Accordingly, polynucleotides related to this invention are useful
as a marker in linkage analysis for chromosome 17.
[1240] This gene is expressed primarily in gall bladder, prostate,
and fetal brain, and to a lesser extent, in tumor and fetal
tissues.
[1241] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, gastrointestinal, reproductive, neural, or growth
related disorders such as cancers. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the prostate, gall bladder, and
fetal brain, expression of this gene at significantly higher or
lower levels may be routinely detected in certain tissues or cell
types (e.g., gastrointestinal, reproductive, neural, developmental,
and cancerous and wounded tissues) or bodily fluids (e.g., lymph,
amniotic fluid, bile, serum, plasma, urine, synovial fluid and
spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[1242] The tissue distribution in fetal brain and tumor tissues
indicates that the protein product of this gene is useful for the
diagnosis and treatment of growth-related disorders, such as
cancers. Moreover, the protein product of this gene is useful for
the detection/treatment of neurodegenerative disease states,
behavioural disorders, or inflammatory conditions which include,
but are not limited to Alzheimers Disease, Parkinsons Disease,
Huntingtons Disease, Tourette Syndrome, meningitis, encephalitis,
demyelinating diseases, peripheral neuropathies, neoplasia, trauma,
congenital malformations, spinal cord injuries, ischemia and
infarction, aneurysms, hemorrhages, schizophrenia, mania, dementia,
paranoia, obsessive compulsive disorder, depression, panic
disorder, learning disabilities, ALS, psychoses, autism, and
altered behaviors, including disorders in feeding, sleep patterns,
balance, and perception. In addition, elevated expression of this
gene product in regions of the brain indicates that it plays a role
in normal neural function. Potentially, this gene product is
involved in synapse formation, neurotransmission, learning,
cognition, homeostasis, or neuronal differentiation or survival, in
addition to metabolic, or reproductive disorders. Protein, as well
as, antibodies directed against the protein may show utility as a
tumor marker and/or immunotherapy targets for the above listed
tissues.
[1243] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:193 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1524 of SEQ ID NO:193, b is an
integer of 15 to 1538, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:193, and where
b is greater than or equal to a+14.
[1244] Features of Protein Encoded by Gene No: 184
[1245] In specific embodiments, polypeptides of the invention
comprise the sequence: SLCCPEGAEGC (SEQ ID NO:1184), QLKKTHYDRPCP
(SEQ ID NO:1185), QLKKTHYDRPCP (SEQ ID NO:1186), MNRPCPFCLWKVFP
LLLLLHEELFPLPVP (SEQ ID NO:1187), and/or KEKTFTPRNSLCCPEG
AEGCIAGGDLQLKKTHY (SEQ ID NO:1188). Polynucleotides encoding these
polypeptides are also encompassed by the invention.
[1246] This gene is expressed primarily in stromal cell, tonsil,
and glioblastoma.
[1247] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, hematopoietic, immune and inflammatory disorders, in
addition to neural disorders, such as glioblastoma. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
stromal cells, tonsil, and glioblastoma expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., immune, hematopoietic, neural,
and cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder. Additionally, it is believed
that the product of this gene regulates pancreatic cell
differentiation into beta cells. Accordingly, polynucleotides and
polypeptides of the invention are useful in the treatment of
insulin-dependent diabetes mellitus and associated conditions e.g.
pancreatic hypofunction and the prevention, as well as the
treatment of undifferentiated type pancreatic cancers.
[1248] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 432 as residues: Pro-27 to Ala-32.
[1249] The tissue distribution in stromal cells and tonsils
indicates that the protein product of this gene is useful for
diagnosis and treatment of immune and inflammatory disorders and
glioblastoma. Similarly, the protein product of this gene is useful
for the treatment and diagnosis of hematopoetic related disorders
such as anemia, pancytopenia, leukopenia, thrombocytopenia or
leukemia since stromal cells are important in the production of
cells of hematopoietic lineages. The uses include bone marrow cell
ex vivo culture, bone marrow transplantation, bone marrow
reconstitution, radiotherapy or chemotherapy of neoplasia. The gene
product may also be involved in lymphopoiesis, therefore, it can be
used in immune disorders such as infection, inflammation, allergy,
immunodeficiency etc. In addition, this gene product may have
commercial utility in the expansion of stem cells and committed
progenitors of various blood lineages, and in the differentiation
and/or proliferation of various cell types. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[1250] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:194 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1084 of SEQ ID NO:194, b is an
integer of 15 to 1098, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:194, and where
b is greater than or equal to a+14.
[1251] Features of Protein Encoded by Gene No: 185
[1252] This gene is expressed primarily in hepatocellular
carcinoma.
[1253] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, hepatic or metabolic diseases. Similarly, polypeptides
and antibodies directed to these polypeptides are useful in
providing immunological probes for differential identification of
the tissue(s) or cell type(s). For a number of disorders of the
above tissues or cells, particularly of the liver, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g., hepatic,
metabolic, immune, hematopoietic, and cancerous and wounded
tissues) or bodily fluids (e.g., lymph, serum, bile, plasma, urine,
synovial fluid and spinal fluid) or another tissue or cell sample
taken from an individual having such a disorder, relative to the
standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[1254] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 433 as residues: Gly-32 to Lys-39.
[1255] The tissue distribution in hepatocellular carcinoma tissue
indicates that the protein product of this gene is useful for
diagnosis and treatment of liver diseases. Moreover, the protein
product of this gene is useful for the detection and treatment of
liver disorders and cancers (e.g. hepatoblastoma, jaundice,
hepatitis, liver metabolic diseases and conditions that are
attributable to the differentiation of hepatocyte progenitor
cells). In addition the protein may have a useful role in treating,
detecting, or preventing developmental abnormalities, fetal
deficiencies, pre-natal disorders and various would-healing models
and/or tissue trauma. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[1256] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:195 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 987 of SEQ ID NO:195, b is an integer
of 15 to 1001, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:195, and where b is greater
than or equal to a+14.
[1257] Features of Protein Encoded by Gene No: 186
[1258] This gene is expressed primarily in hippocampus.
[1259] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neuronal or endocrine disorders, particularly
behavioral and mood disorders. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the hippocampus, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g., neural, endocrine,
and cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[1260] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 434 as residues: Ser-14 to Tyr-20.
[1261] The tissue distribution in hippocampus indicates that the
protein product of this gene is useful for the diagnosis and
treatment of neuronal disorders. Moreover, the protein product of
this gene is useful for the detection/treatment of
neurodegenerative disease states, behavioural disorders, or
inflammatory conditions which include, but are not limited to
Alzheimers Disease, Parkinsons Disease, Huntingtons Disease,
Tourette Syndrome, meningitis, encephalitis, demyelinating
diseases, peripheral neuropathies, neoplasia, trauma, congenital
malformations, spinal cord injuries, ischemia and infarction,
aneurysms, hemorrhages, schizophrenia, mania, dementia, paranoia,
obsessive compulsive disorder, depression, panic disorder, learning
disabilities, ALS, psychoses, autism, and altered behaviors,
including disorders in feeding, sleep patterns, balance, and
perception. In addition, elevated expression of this gene product
in regions of the brain indicates that it plays a role in normal
neural function. Potentially, this gene product is involved in
synapse formation, neurotransmission, learning, cognition,
homeostasis, or neuronal differentiation or survival. Protein, as
well as, antibodies directed against the protein may show utility
as a tumor marker and/or immunotherapy targets for the above listed
tissues.
[1262] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:196 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1444 of SEQ ID NO:196, b is an
integer of 15 to 1458, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:196, and where
b is greater than or equal to a+14.
[1263] Features of Protein Encoded by Gene No: 187
[1264] This gene is expressed primarily in bone cancer and
hippocampus, and to a lesser extent, in osteoclastoma.
[1265] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, bone-related disorders and neuronal diseases.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the bone, ostoeclast, and hippocampus, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g., neural, skeletal, and
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[1266] The tissue distribution in hippocampus and skeletal tissues
indicates that the protein product of this gene is useful for
diagnosis and treatment of bone-related disorders and neuronal
diseases. Similarly, this gene product is useful in the detection
and treatment of disorders and conditions affecting the skeletal
system, in particular osteoporosis, bone cancer, as well as,
disorders afflicting connective tissues (e.g. arthritis, trauma,
tendonitis, chrondomalacia and inflammation), such as in the
diagnosis or treatment of various autoimmune disorders such as
rheumatoid arthritis, lupus, scleroderma, and dermatomyositis as
well as dwarfism, spinal deformation, and specific joint
abnormalities as well as chondrodysplasias (ie. spondyloepiphyseal
dysplasia congenita, familial osteoarthritis, Atelosteogenesis type
II, metaphyseal chondrodysplasia type Schmid). Alternatively, the
protein product of this gene is useful for the detection/treatment
of neurodegenerative disease states, behavioural disorders, or
inflammatory conditions. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[1267] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:197 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1268 of SEQ ID NO:197, b is an
integer of 15 to 1282, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:197, and where
b is greater than or equal to a+14.
[1268] Features of Protein Encoded by Gene No: 188
[1269] The gene encoding the disclosed cDNA is thought to reside on
chromosome 4. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
4.
[1270] This gene is expressed primarily in neuronal tissues such as
hippocampus, spinal cord, and hypothalamus.
[1271] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neuronal diseases. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the neuronal tissues, expression
of this gene at significantly higher or lower levels may be
routinely detected in certain tissues or cell types (e.g. neuronal,
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[1272] The tissue distribution in neuronal tissues indicates that
the protein product of this gene is useful for diagnosis and
treatment of neuronal disorders, such as Alzheimers Disease,
Parkinsons Disease, Huntingtons Disease, Tourette Syndrome,
schizophrenia, mania, dementia, paranoia, obsessive compulsive
disorder, panic disorder, learning disabilities, ALS, psychoses,
autism, and altered bahaviors; including disorders in feeding,
sleep patterns, balance, and perception. In addition, the gene or
gene product may also play a role in the treatment and/or detection
of developmental disorders associated with the developing embryo,
or sexually-linked disorders. Protein, as well as, antibodies
directed against the protein may show utility as a tumor marker
and/or immunotherapy targets for the above listed tissues.
[1273] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:198 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 937 of SEQ ID NO:198, b is an integer
of 15 to 951, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:198, and where b is greater
than or equal to a+14.
[1274] Features of Protein Encoded by Gene No. 189
[1275] The gene encoding the disclosed cDNA is thought to reside on
chromosome 10. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
10.
[1276] This gene is expressed primarily in neuronal tissues and
immune tissues.
[1277] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, neuronal and immune-related disorders. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
neuronal and immune-related tissues, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. neuronal, immune, cancerous and
wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[1278] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 437 as residues: Pro-19 to Asp-25.
[1279] The tissue distribution neuronal and immune tissues
indicates that the protein product of this gene is useful for the
diagnosis and treatment of neuronal and immune-related disorders.
Furthermore, the tissue distribution indicates that the protein
product of this gene is useful for the detection/treatment of
neurodegenerative disease states, neuronal disorders, and
behavioural disorders such as Alzheimers Disease, Parkinsons
Disease, Huntingtons Disease, Tourette Syndrome, schizophrenia,
mania, dementia, paranoia, obsessive compulsive disorder, panic
disorder, learning disabilities, ALS, psychoses, autism, and
altered bahaviors, including disorders in feeding, sleep patterns,
balance, and perception. In addition, the gene or gene product may
also play a role in the treatment and/or detection of developmental
disorders associated with the developing embryo, or sexually-linked
disorders. Additionally, this gene product may be involved in the
regulation of cytokine production, antigen presentation, or other
processes that may also suggest a usefulness in the treatment of
cancer (e.g. by boosting, immune responses). Since the gene is
expressed in cells of lymphoid origin, the gene or protein, as well
as, antibodies directed against the protein may show utility as a
tumor marker and/or immunotherapy targets for the above listed
tissues. Therefore it may be also used as an agent for
immunological disorders including arthritis, asthma, immune
deficiency diseases such as AIDS, leukemia, rheumatoid arthritis,
inflammatory bowel disease, sepsis, acne, and psoriasis. In
addition, this gene product may have commercial utility in the
expansion of stem cells and committed progenitors of various blood
lineages, and in the differentiation and/or proliferation of
various cell types. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[1280] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:199 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1726 of SEQ ID NO:199, b is an
integer of 15 to 1740, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:199, and where
b is greater than or equal to a+14.
[1281] Features of Protein Encoded by Gene No: 190
[1282] The translation product of this gene shares sequence
homology with human N33, a gene located in a homozygously deleted
region of human metastatic prostate cancer, which is thought to be
important in prevention of prostate cancer. The gene and its
translation product also share sequence homology with an isolated
prostate/colon tumour suppressor gene (PSTG) product
(W)952214-A1.). In specific embodiments, polypeptides of the
invention comprise the sequence: AQRKKEMVLSEKVSQLMEWTNKRPVIRMNGDKF-
RRLVKAPPRNYSVIVMFTA
LQLHRQCVVCKQADEEFQILANSWRYSSAFTNRIFFAMVDFDEGSDVFQMLNM
NSAPTFINFPAKGKPKRGDTYELQVRGRSAEQLARWIADRTDVNIRVIRPPNMA ARWRFWCVSVT
(SEQ ID NO:1189), MVVALLIVCDVPSAS (SEQ ID NO:1190),
AQRKKEMVLSEKVSQL (SEQ ID NO:1191), MEWTNKRPVIRMNGDKF (SEQ ID:1192),
RRLVKAPPRNYSVIVMFTALQLHRQCVVCK- QADEEFQILANSWRY SSAFTNRIFFA (SEQ ID
NO:1193), MVDFDEGSDVFQMLNMNSAPTFTNFPA KGKP (SEQ ID NO:1194),
KRGDTYELQVRGFSAEQIARWIADRTDVNIRVIRPPN (SEQ ID NO:1195), and/or
YAGPLMLGLLLAVIGGLVYLRRVIWNFSLIKLD GLLQLCVLCLL (SEQ ID NO:1196).
Polynucleotides encoding these polypeptides are also encompassed by
the invention.
[1283] This gene is expressed primarily in infant adrenal gland,
prostate cell line, and to a lesser extent in adrenal gland.
[1284] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, prostate cancer and endocrine disorders. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
prostate and adrenal gland, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. prostate, endocrine, cancerous
and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[1285] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 438 as residues: Pro-34 to Gly-43, Arg-l 13 to
Pro-120.
[1286] The tissue distribution infant adrenal gland, combined with
the homology to N33 and prostate/colon tumour suppressor gene
(PSTG) indicates that the protein product of this gene is useful
for the diagnosis and treatment for prostate cancer and endocrine
disorders, and that the nucleic acids and proteins of this gene can
be used in the diagnosis and treatment of prostate, endocrine and
colorectal cancers. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and
immunotherapy targets for the above listed tumors and tissues.
[1287] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:200 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1693 of SEQ ID NO:200, b is an
integer of 15 to 1707, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:200, and where
b is greater than or equal to a+14.
[1288] Features of Protein Encoded by Gene No: 191
[1289] This gene is expressed primarily in T-cell, and to a lesser
extent in fetal lung.
[1290] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune and respiratory disorders. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the immune
and respiratory systems, expression of this gene at significantly
higher or lower levels may be routinely detected in certain tissues
or cell types (e.g. immune, respiratory, cancerous and wounded
tissues) or bodily fluids (e.g., lymph, serum, plasma, urine,
synovial fluid and spinal fluid) or another tissue or cell sample
taken from an individual having such a disorder, relative to the
standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[1291] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 439 as residues: Trp-3 to Phe-9.
[1292] The tissue distribution in T-cells and fetal lung indicates
that the protein product of this gene is useful for the diagnosis
and treatment of immune and respiratory disorders. Furthermore,
this gene product may be involved in the regulation of cytokine
production, antigen presentation, or other processes that may also
suggest a usefulness in the treatment of cancer (e.g. by boosting
immune responses). Since the gene is expressed in cells of lymphoid
origin, the gene or protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues. Therefore it
may be also used as an agent for immunological disorders including
arthritis, asthma, immune deficiency diseases such as AIDS,
leukemia, rheumatoid arthritis, inflammatory bowel disease, sepsis,
acne, and psoriasis. In addition, this gene product may have
commercial utility in the expansion of stem cells and committed
progenitors of various blood lineages, and in the differentiation
and or proliferation of various cell types. Expression of this gene
product in T cells also strongly indicates a role for this protein
in immune function and immune surveillance. The tissue distribution
also indicates that the protein product of this gene is useful for
the detection and treatment of disorders associated with developing
lungs, particularly in premature infants where the lungs are the
last tissues to develop. The tissue distribution indicates that the
protein product of this gene is useful for the diagnosis and
intervention of lung tumors, since the gene may be involved in the
regulation of cell division, particularly since it is expressed in
fetal tissue. Protein, as well as, antibodies directed against the
protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[1293] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:201 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 765 of SEQ ID NO:201, b is an integer
of 15 to 779, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:201, and where b is greater
than or equal to a+14.
[1294] Features of Protein Encoded by Gene No: 192
[1295] The gene encoding the disclosed cDNA is thought to reside on
chromosome 6. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
6. The translation product of this gene shares significant homology
with the rat protein Neuritin, and in fact appears to be a human
ortholog of the rat protein. It is believed that this gene is
induced in rats by neural activity and neurotrophins, and that it
promotes neuritogenesis. Neural activity and neurotrophins induce
synaptic remodeling in part by altering gene expression. This gene
is believed to be a glycosylphoshatidylinositol-anc- hored protein
encoded by a hippocampal gene, and to possess neural activity. This
molecule is believed to be expressed in postmitotic-differentiating
neurons of the developing nervous system and neuronal structures
associated with plasticity in the adult. Message of this gene is
believed to be induced by neuronal activity and by the
activity-regulated neurotrophins BDNF and NT-3. The product of this
gene is believed to stimulate neurite outgrowth and arborization in
primary embryonic hippocampal and cortical cultures, and to act as
a downstream effector of activity-induced neurite outgrowth. In
specific embodiments, polypeptides of the invention comprise the
sequence: DAVFKGFSDCLLKLGDS (SEQ ID NO:1197), CQEGAKDMWDKLRKESKNLN
(SEQ ID NO:1198), VLLVSLSA ALATWLSF (SEQ ID NO:1199),
MGLKLNGRYISLILAVQIAYLVQAVRAAGKCD AVFKGFSDCLLKLGDS (SEQ ID NO:1200),
PAAWDDKTNIKTVCTYWEDFHS
CTVTALTKCQEGAKDMWDKLRKESKNLNIQGSLFELCGSGNGAAGSLLPAFP
VLLVSLSAALATWLSF (SEQ ID NO:1201), and/or MGLKLNGRYISLILAVQIAY
LVQAVRAAGKCKAVFKGFSDCLLKLGD- SXXXXXPAAWDDKTNIKTVCTYWE
DFHSCTVTALTDCQEGAKDMWDKLRKESKNLNIQGSLFELCGSGNGAAG- SLL
PAFPVLLVSLSAZALATWLSF (SEQ ID NO:1202). Polynucleotides encoding
this polypeptide are also encompassed by the invention.
[1296] This gene is expressed primarily in human placenta,
endometrial tumor and tissues of the central nervous system
(CNS).
[1297] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, relating to reproductive disorders, cancers and
neurological diseases. Similarly, polypeptides and antibodies
directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the reproductive and neurological
disorders, expression of this gene at significantly higher or lower
levels may be routinely detected in certain tissues or cell types
(e.g. reproductive, neurological, cancerous and wounded tissues) or
bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[1298] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 440 as residues: Asp-47 to Asp-63, His-75 to Tyr-80,
Pro-83 to Tyr-89.
[1299] The tissue distribution indicates that the protein product
of this gene is useful for the diagnosis and treatment of
reproductive disorders such as endometrial tumors. Expression of
this gene in tissues of the CNS, and its strong homology to
Neuritin, suggest that the protein product from this gene is also
useful in the treatment and diagnosis of neurological disorders and
in the regeneration of neural tissues, e.g., following injury.
[1300] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:202 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1603 of SEQ ID NO:202, b is an
integer of 15 to 1617, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:202, and where
b is greater than or equal to a+14.
[1301] Features of Protein Encoded by Gene No: 193
[1302] The translation product of this gene shares sequence
homology with tenascin, which is thought to be important in
development. The translation product of this gene is believed to be
a ligand of the fibroblast growth factor family. FGF ligand
activity is known in the art and can be assayed by methods known in
the art and disclosed elsewhere herein.
[1303] Northern analysis indicates that a 2.5 kb band is expressed
in brain and lung.
[1304] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, cancers, growth disorders of the brain and lung.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the cancer tissues, brain, lung, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. brain, lung, cancerous and
wounded tissues) or bodily fluids (e.g., lymph, serum, plasma.
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[1305] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 441 as residues: Gly-29 to Glu-34, Arg-71 to Arg-76,
Thr-176 to Cys-182, Gly-184 to Glu-199.
[1306] The tissue distribution in brain and lung, combined with the
homology to tenascin indicates that the protein product of this
gene is useful for diagnosis and treatment of cancers.
Alternatively, given the tissue distribution indicated by Northern
analysis, the translation product of this gene is thought to be a
growth factor functioning in the brain and lung that may be useful
in treating neurodegneration and lung disorder. For example, the
protein product of this gene is useful for the detection and
treatment of disorders associated with developing lungs,
particularly in premature infants where the lungs are the last
tissues to develop. Furthermore, the tissue distribution indicates
that the protein product of this gene is useful for the diagnosis
and intervention of lung tumors, since the gene may be involved in
the regulation of cell division. Additionally, expression in the
brain indicates that it may be involved in neuronal survival;
synapse formation; conductance; neural differentiation, etc. Such
involvement may impact many processes, such as learning and
cognition. It may also be useful in the treatment of such
neurodegenerative disorders as schizophrenia; ALS; or Alzheimer's.
Protein, as well as, antibodies directed against the protein may
show utility as a tissue-specific marker and/or immunotherapy
target for the above listed tissues.
[1307] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:203 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1960 of SEQ ID NO:203, b is an
integer of 15 to 1974, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:203, and where
b is greater than or equal to a+14.
[1308] Features of Protein Encoded by Gene No: 194
[1309] In specific embodiments, polypeptides of the invention
comprise the sequence: MNSAAGFSHLDRRERVLKLGESFEKQPRCASTLC (SEQ ID
NO:1203). Polynucleotides encoding these polypeptides are also
encompassed by the invention.
[1310] This gene is expressed primarily in fetal human lung and
neutrophils.
[1311] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, lung development and respiratory disorders. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
respiratory system, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g. respiratory, immune, cancerous and wounded
tissues) or bodily fluids (e.g., lymph, serum, plasma, urine,
synovial fluid and spinal fluid) or another tissue or cell sample
taken from an individual having such a disorder, relative to the
standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[1312] The tissue distribution in fetal lung and neutrophils
indicates that the protein product of this gene is useful for the
diagnosis and treatment of lung and immunity related diseases, for
example, lung cancer, viral, fungal or bacterial infections (e.g.
lesions caused by tuberculosis), inflammation (e.g. pneumonia),
metabolic lesions etc. Furthermore, the tissue distribution
indicates that the protein product of this gene is useful for the
detection and treatment of disorders associated with developing
lungs, particularly in premature infants where the lungs are the
last tissues to develop. The tissue distribution indicates that the
protein product of this gene is useful for the diagnosis and
intervention of lung tumors, since the gene may be involved in the
regulation of cell division, particularly since it is expressed in
fetal tissue. Protein, as well as, antibodies directed against the
protein may show utility as a tumor marker and immunotherapy
targets for the above listed tumors and tissues.
[1313] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:204 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1043 of SEQ ID NO:204, b is an
integer of 15 to 1057, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:204, and where
b is greater than or equal to a+14.
[1314] Features of Protein Encoded by Gene No: 195
[1315] This gene is expressed primarily in breast lymph node, and
to a lesser extent in synovial tissues.
[1316] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune and skeletal disorders. Similarly, polypeptides
and antibodies directed to these polypeptides are useful in
providing immunological probes for differential identification of
the tissue(s) or cell type(s). For a number of disorders of the
above tissues or cells, particularly of the immune system and
skeletal system, expression of this gene at significantly higher or
lower levels may be routinely detected in certain tissues or cell
types (e.g. immune, skeletal, cancerous and wounded tissues) or
bodily fluids (e.g., lymph, serum, plasma, urine, synovial fluid
and spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[1317] The tissue distribution in breast lymph node and synovial
indicates that the protein product of this gene is useful for the
diagnosis and treatment of immune and skeletal disorders.
Furthermore, this gene product may be involved in the regulation of
cytokine production, antigen presentation, or other processes that
may also suggest a usefulness in the treatment of cancer (e.g. by
boosting immune responses). Since the gene is expressed in cells of
lymphoid origin, the gene or protein, as well as, antibodies
directed against the protein may show utility as a tumor marker
and/or immunotherapy targets for the above listed tissues.
Therefore it may be also used as an agent for immunological
disorders including arthritis, asthma, immune deficiency diseases
such as AIDS, leukemia, rheumatoid arthritis, inflammatory bowel
disease, sepsis, acne, and psoriasis. In addition, this gene
product may have commercial utility in the expansion of stem cells
and committed progenitors of various blood lineages, and in the
differentiation and/or proliferation of various cell types.
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues. The expression of this gene product in
synovial indicates a role in the detection and treatment of
disorders and conditions affecting the skeletal system, in
particular osteoporosis as well as disorders afflicting connective
tissues (e.g. arthritis, trauma, tendonitis, chrondomalacia and
inflammation), such as in the diagnosis or treatment of various
autoimmune disorders such as rheumatoid arthritis, lupus,
scleroderma, and dermatomyositis as well as dwarfism, spinal
deformation, and specific joint abnormalities as well as
chondrodysplasias (ie. spondyloepiphyseal dysplasia congenita,
familial osteoarthritis, Atelosteogenesis type II, metaphyseal
chondrodysplasia type Schmid). Protein, as well as, antibodies
directed against the protein may show utility as a tumor marker
and/or immunotherapy targets for the above listed tissues.
[1318] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:205 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 707 of SEQ ID NO:205, b is an integer
of 15 to 721, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:205, and where b is greater
than or equal to a+14.
[1319] Features of Protein Encoded by Gene No: 196
[1320] The gene encoding the disclosed cDNA is thought to reside on
chromosome 5. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
5. The translation product of this gene shares sequence homology
with human M-phase phosphoprotein 4, which is thought to be
important in the phosphorylation and signal transduction processes.
In specific embodiments, polypeptides of the invention comprise the
sequence: TIYPTEEELQAVQKIVSITERALKLVSD (SEQ ID NO:1204), RALKGVLR
VGVLAKGLLLRGDRNVNLVLLC (SEQ ID NO:1205), ALAALRHAKWFQARAN
GLQSCVIIIRILRDLCQRVPTWS (SEQ ID NO:1206), GDALRRVFECISSGIIL (SEQ ID
NO:1207), LAFRQIHKVLGMDPLP (SEQ ID NO:1208), and/or TIYPTEEE
LQAVQKIVSITERALKLVSDSLSEHEKNKNKEGDDKKEGGKDRALDGVLRVG
VLAKGLLLRGDRNVNLVLLCSEKPSKTLLSRIAENLPKQLAVISPEKYDIKCAV
SEAAIILNSCVEPKMQVTITLTSPIIREENMREGDVTSGMVKDPPDVLDRQKCLD
ALAALRHAKWFQARANGLQSCVIIIRILRDLCQRVPTWSDFPSWAMELLVEKAI
SSASSPQSPGDALRRVFECISSGIILKGSPGLLDPCEKDPFDTLATMTDQQREDIT
SSAQFALRLLAFRQIHKVLGMDPLPQMSQRFNIHNNRKRRRDSDGVDGFEAEG KKDKKDYDNF
(SEQ ID NO:1209), MERHPKKKMCSD (SEQ ID NO:1210), and/or
GENSSSDFFPLFLFYFLVALASPPI- FVSFIN (SEQ ID NO:1211). Polynucleotides
encoding these polypeptides are also encompassed by the
invention.
[1321] This gene is expressed primarily in human hippocampus, and
to a lesser extent in prostate and human frontal cortex.
[1322] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, disorders related to the reproductive and nervous
systems. Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the reproductive and nervous systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. reproductive, CNS, cancerous
and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[1323] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 444 as residues: Arg-13 to Asp-21, Lys-28 to Lys-38,
Val-76 to Asp-81, Ser-99 to Ala-107, Pro-130 to Phe-136, Thr-143 to
Ile-150, Pro-176 to Phe-182, Asn-186 to Gly-196, Ala-202 to
Phe-214.
[1324] The tissue distribution in human hippocampus, prostate, and
frontal cortex, combined with the homology to human M-phase
phosphoprotein 4 indicates that the protein product of this gene is
useful for the diagnosis and treatment of reproductive and nervous
system disorders. Furthermore, elevated expression of this gene
product within the frontal cortex of the brain indicates that it
may be involved in neuronal survival; synapse formation;
conductance; neural differentiation, etc. Such involvement may
impact many processes, such as learning and cognition. It may also
be useful in the treatment of such neurodegenerative disorders as
schizophrenia; ALS; or Alzheimer's. Protein, as well as, antibodies
directed against the protein may show utility as a tissue-specific
marker and/or immunotherapy target for the above listed
tissues.
[1325] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:206 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 2451 of SEQ ID NO:206, b is an
integer of 15 to 2465, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:206, and where
b is greater than or equal to a+14.
[1326] Features of Protein Encoded by Gene No: 197
[1327] In specfic embodiments, polypeptides of the invention
comprise the sequence: MGSQHSAAARPSSCRRKQEDDRDG (SEQ ID NO:1212),
LLAEREQEEAIAQ FPYVEFTGRDSITCLTC (SEQ ID NO:1213), and/or
QGTGYIPTEQVNELVALI PHSDQRLRPQRTKQYV (SEQ ID NO:1214).
Polynucleotides encoding these polypeptides are also encompassed by
the invention.
[1328] This gene is expressed primarily in human primary breast
cancer, and to a lesser extent, in human adult spleen, Hodgkin's
lymphoma I, and salivary gland.
[1329] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, cancer, as well as immune disorders. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly cancers and
the immune system, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g. immune, cancerous and wounded tissues) or bodily
fluids (e.g., lymph, serum, plasma, urine, synovial fluid and
spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[1330] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 445 as residues: Ser-126 to Gly-138.
[1331] The tissue distribution in tumors of breast origins
indicates that the protein product of this gene is useful for the
diagnosis and intervention of these tumors, in addition to other
tumors where expression has been indicated. Furthermore, the
expression in hematopoietic cells and tissues indicates that this
protein may play a role in the proliferation, differentiation,
and/or survival of hematopoietic cell lineages. In such an event,
this gene may be useful in the treatment of lymphoproliferative
disorders, and in the maintenance and differentiation of various
hematopoietic lineages from early hematopoietic stem and committed
progeniltor cells. Protein, as well as, antibodies directed against
the protein may show utility as a tissue-specific marker and/or
immunotherapy target for the above listed tissues.
[1332] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:207 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1466 of SEQ ID NO:207, b is an
integer of 15 to 1480, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:207, and where
b is greater than or equal to a+14.
[1333] Features of Protein Encoded by Gene No: 198
[1334] This gene is expressed primarily in monocytes.
[1335] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, blood cell disorders. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the immune system, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g. immune, cancerous
and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[1336] The tissue distribution in monocytes indicates that the
protein product of this gene is useful for the diagnosis and
treatment of blood cell disorders. Furthermore, expression of this
gene product in monocytes also-strongly indicates a role for this
protein in immune function and immune surveillance. Protein, as
well as, antibodies directed against the protein may show utility
as a tumor marker and/or immunotherapy targets for the above listed
tissues.
[1337] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:208 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 858 of SEQ ID NO:208, b is an integer
of 15 to 872, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:208, and where b is greater
than or equal to a+14.
[1338] Features of Protein Encoded by Gene No: 199
[1339] The gene encoding the disclosed cDNA is thought to reside on
chromosome 6. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
6.
[1340] This gene is expressed primarily in human ovary and synovia,
and to a lesser extent in human 8 week whole embryo.
[1341] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, reproductive and developmental disorders. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
reproductive and developmental systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. reproductive, developmental,
cancerous and wounded tissues) or bodily fluids (e.g., lymph,
serum, plasma, urine, synovial fluid and spinal fluid) or another
tissue or cell sample taken from an individual having such a
disorder, relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[1342] The tissue distribution in human ovary and human 8 week
whole embryo indicates that the protein product of this gene is
useful for the diagnosis and treatment of reproductive and
developmental disorders. Similarly, expression within embryonic
tissue and other cellular sources marked by proliferating cells
indicates that this protein may play a role in the regulation of
cellular division, and may show utility in the diagnosis and
treatment of cancer and other proliferative disorders. Similarly,
embryonic development also involves decisions involving cell
differentiation and/or apoptosis in pattern formation. Thus this
protein may also be involved in apoptosis or tissue differentiation
and could again be useful in cancer therapy. Protein, as well as,
antibodies directed against the protein may show utility as a tumor
marker and/or immunotherapy targets for the above listed
tissues.
[1343] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:209 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1765 of SEQ ID NO:209, b is an
integer of 15 to 1779, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:209, and where
b is greater than or equal to a+14.
[1344] Features of Protein Encoded by Gene No: 200
[1345] The gene encoding the disclosed cDNA is thought to reside on
chromosome 8. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
8. The translation product of this gene shares limited sequence
homology with collagen proline rich domain.
[1346] This gene is expressed primarily in CNS.
[1347] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to. neurological diseases. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the nervous system, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g. CNS, cancerous and
wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[1348] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 448 as residues: Pro-35 to Asp-41.
[1349] The tissue distribution in tissues of the central nervous
system indicates that the protein product of this gene is useful
for the diagnosis and treatment of neurological diseases and
disorders, such as Alzheimers Disease, Parkinsons Disease,
Huntingtons Disease, Tourette Syndrome, schizophrenia, mania,
dementia, paranoia, obsessive compulsive disorder, panic disorder,
learning disabilities, ALS, psychoses, autism, and altered
bahaviors, including disorders in feeding, sleep patterns, balance,
and perception. In addition, the gene or gene product may also play
a role in the treatment and/or detection of developmental disorders
associated with the developing embryo, or sexually-linked
disorders. Protein, as well as, antibodies directed against the
protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[1350] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:210 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 2096 of SEQ ID NO:210, b is an
integer of 15 to 2110, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:210, and where
b is greater than or equal to a+14.
[1351] Features of Protein Encoded by Gene No: 201
[1352] The translation product of this gene shares homology with a
mammalian histone H1a protein. One embodiment for this gene is the
polypeptide fragments comprising the following amino acid sequence:
ARLNVGRESLKREMLKSQGVKVSESPMGARHSSWPEGAAFCKKVQGAQMQF PPRR (SEQ ID
NO:1215), ARLNVGRESLKREML (SEQ ID NO:1216), LKSQGV KVSESPMGARHSSW
(SEQ ID NO:1217), AFCKKVQGAQMQFPPRR (SEQ ID NO:1218), and/or
AFCKKVQGAQMQFPPRR (SEQ ID NO:1219). An additional embodiment is the
polynucleotide fragments encoding these polypeptide fragments.(See
Genbank Accession No. pir.vertline.S24178).
[1353] This gene is expressed primarily in neutrophils.
[1354] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune disorders. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the immune system, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g. immune, cancerous
and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[1355] The tissue distribution in neutrophils indicates that the
protein product of this gene is useful for the diagnosis and
treatment of immune disorders. Since the gene is expressed in cells
of lymphoid origin, the natural gene product may be involved in
vital immune functions. Therefore it may be also used as an agent
for immunological disorders including arthritis, asthma, immune
deficiency diseases such as AIDS, and leukemia. Furthermore,
expression of this gene product in neutrophils also strongly
indicates a role for this protein in immune function and immune
surveillance. Protein, as well as, antibodies directed against the
protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[1356] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:211 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 924 of SEQ ID NO:211, b is an integer
of 15 to 938, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:211, and where b is greater
than or equal to a+14.
[1357] Features of Protein Encoded by Gene No: 202
[1358] This gene is expressed primarily in neutrophils.
[1359] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune disorders. Similarly, polypeptides and
antibodies directed to these polypeptides are useful in providing
immunological probes for differential identification of the
tissue(s) or cell type(s). For a number of disorders of the above
tissues or cells, particularly of the immune system, expression of
this gene at significantly higher or lower levels may be routinely
detected in certain tissues or cell types (e.g. immune, cancerous
and wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[1360] The tissue distribution in neutrophils indicates that the
protein product of this gene is useful for the diagnosis and
treatment of immune disorders. Since the gene is expressed in cells
of lymphoid origin, the natural gene product may be involved in
immune functions. Therefore it may be also used as an agent for
immunological disorders including arthritis, asthma, immune
deficiency diseases such as AIDS, and leukemia. Furthermore,
expression of this gene product in neutrophils also strongly
indicates a role for this protein in immune function and immune
surveillance. Protein, as well as, antibodies directed against the
protein may show utility as a tumor marker and/or immunotherapy
targets for the above listed tissues.
[1361] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:212 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1537 of SEQ ID NO:212, b is an
integer of 15 to 1551, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:212, and where
b is greater than or equal to a+14.
[1362] Features of Protein Encoded by Gene No: 203
[1363] This gene is expressed primarily in neutrophils.
[1364] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, infectious disorders, immune disorders, and cancers.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune system, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g. immune, cancerous and wounded tissues) or bodily
fluids (e.g., lymph, serum, plasma, urine, synovial fluid and
spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[1365] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 451 as residues: Thr-31 to Lys-36.
[1366] The tissue distribution in neutrophils indicates that the
protein product of this gene is useful for the diagnosis and
treatment of infectious disorders, immune disorders, and cancers.
Since the gene is expressed in cells of lymphoid origin, the
natural gene product may be involved in immune functions. Therefore
it may be also used as an agent for immunological disorders
including arthritis, asthma, immune deficiency diseases such as
AIDS, and leukemia. Expression of this gene product in neutrophils
also strongly indicates a role for this protein in immune function
and immune surveillance. Protein, as well as, antibodies directed
against the protein may show utility as a tumor marker and/or
immunotherapy targets for the above listed tissues.
[1367] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:213 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 983 of SEQ ID NO:213, b is an integer
of 15 to 997, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:213, and where b is greater
than or equal to a+14.
[1368] Features of Protein Encoded by Gene No: 204
[1369] The gene encoding the disclosed cDNA is thought to reside on
chromosome 16. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
16. The translation product of this gene shares sequence homology
with lactate dehydrogenase, which is thought to be important in
lactate metabolism.
[1370] This gene is expressed primarily in human tonsils, and to a
lesser extent, in spleen, and neutrophils.
[1371] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, immune disorders, infectious disorders, and cancers.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the immune disorders, infectious disorders, and cancers, expression
of this gene at significantly higher or lower levels may be
routinely detected in certain tissues or cell types (e.g. tonsils,
immune, cancerous and wounded tissues) or bodily fluids (e.g.,
lymph, serum, plasma, urine, synovial fluid and spinal fluid) or
another tissue or cell sample taken from an individual having such
a disorder, relative to the standard gene expression level, i.e.,
the expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[1372] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 452 as residues: Gly-7 to Ser-12.
[1373] The tissue distribution in human tonsils, spleen, and
neutrophils, combined with the homology to lactate dehydrogenase
gene indicates that the protein product of this gene is useful for
the diagnosis and treatment of immune disorders, infectious
disorders, and cancers. Furthermore, expression of this gene
product in tonsils indicates a role in the regulation of the
proliferation; survival; differentiation; and/or activation of
potentially all hematopoietic cell lineages, including blood stem
cells. This gene product may be involved in the regulation of
cytokine production, antigen presentation, or other processes that
may also suggest a usefulness in the treatment of cancer (e.g. by
boosting immune responses). Since the gene is expressed in cells of
lymphoid origin, the gene or protein, as well as, antibodies
directed against the protein may show utility as a tumor marker
and/or immunotherapy targets for the above listed tissues.
Therefore it may be also used as an agent for immunological
disorders including arthritis, asthma, immune deficiency diseases
such as AIDS, leukemia, rheumatoid arthritis, inflammatory bowel
disease, sepsis, acne, and psoriasis. In addition, this gene
product may have commercial utility in the expansion of stem cells
and committed progenitors of various blood lineages, and in the
differentiation and/or proliferation of various cell types.
Protein, as well as, antibodies directed against the protein may
show utility as a tumor marker and/or immunotherapy targets for the
above listed tissues.
[1374] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:214 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1482 of SEQ ID NO:214, b is an
integer of 15 to 1496, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:214, and where
b is greater than or equal to a+14.
[1375] Features of Protein Encoded by Gene No: 205
[1376] The translation product of this gene shares sequence
homology with Gcap1 protein which is developmentally regulated in
brain. In specific embodiments, polypeptides of the invention
comprise the following amino acid sequence:
NFFFVCLFKSSLRLVNSSYTPILCVL (SEQ ID NO:1220). Polynucleotides
encoding these polypeptides are also encompassed by the
invention.The gene encoding the disclosed cDNA is thought to reside
on chromosome 7. Accordingly, polynucleotides related to this
invention are useful as a marker in linkage analysis for chromosome
7.
[1377] This gene is expressed primarily in placenta and endometrial
tumors.
[1378] Therefore polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, vasculogenesis/angiogenesis and tumorigenesis.
Similarly, polypeptides and antibodies directed to these
polypeptides are useful in providing immunological probes for
differential identification of the tissue(s) or cell type(s). For a
number of disorders of the above tissues or cells, particularly of
the vascular system and tumors, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. placental, cancerous and
wounded tissues) or bodily fluids (e.g., lymph, serum, plasma,
urine, synovial fluid and spinal fluid) or another tissue or cell
sample taken from an individual having such a disorder, relative to
the standard gene expression level, i.e., the expression level in
healthy tissue or bodily fluid from an individual not having the
disorder.
[1379] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 453 as residues: Lys-9 to Gln-16.
[1380] The tissue distribution placenta and endometrial tumors,
combined with the homology to Gcap1 protein indicates that the
protein product of this gene is useful for the diagnosis and
treatment of disorders or dysfunctions of the vascular system,
which incude, but are not limited to atherosclerosis, hypertension,
embolism, thrombosis, microvascular disease, aneurysm, or stroke,
or tumorigenesis. Furthermore, the tissue distribution indicates
that the protein product of this gene is useful for the diagnosis
and/or treatment of disorders of the placenta. Specific expression
within the placenta indicates that this gene product may play a
role in the proper establishment and maintenance of placental
function. Alternately, this gene product may be produced by the
placenta and then transported to the embryo, where it may play a
crucial role in the development and/or survival of the developing
embryo or fetus. Expression of this gene product in a vascular-rich
tissue such as the placenta also indicates that this gene product
may be produced more generally in endothelial cells or within the
circulation. In such instances, it may play more generalized roles
in vascular function, such as in angiogenesis. It may also be
produced in the vasculature and have effects on other cells within
the circulation, such as hematopoietic cells. It may serve to
promote the proliferation, survival, activation, and/or
differentiation of hematopoietic cells, as well as other cells
throughout the body.
[1381] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:215 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1294 of SEQ ID NO:215, b is an
integer of 15 to 1308, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:215, and where
b is greater than or equal to a+14.
[1382] Features of Protein Encoded by Gene No: 206
[1383] The translation product of this gene shares sequence
homology with a C. elegans protein of unknown function (F23B2.4
[Caenorhabditis elegans]). In specific embodiments, polypeptides of
the invention comprise the following amino acid sequence:
ARLNVGRESLKREMLKSQGVKVSESPMGA- RHSSWPEGAAFCKKVQGAQMQF PPRR (SEQ ID
NO:1215), ARLNVGRESLKREML (SEQ ID NO:1216), LKSQGV KVSESPMGARHSSW
(SEQ ID NO:1217), AFCKKVQGAQMQFPPRR (SEQ ID NO:1218), and/or
AFCKKVQGAQMQFPPRR (SEQ ID NO:1219). Polynucleotides encoding these
polypeptides are also encompassed by the invention.
[1384] This gene is expressed primarily in testes.
[1385] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, male reproductive and endocrine disorders. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
reproductive and endocrine systems, expression of this gene at
significantly higher or lower levels may be routinely detected in
certain tissues or cell types (e.g. testes, cancerous and wounded
tissues) or bodily fluids (e.g., lymph, serum, seminal fluid,
plasma, urine, synovial fluid and spinal fluid) or another tissue
or cell sample taken from an individual having such a disorder,
relative to the standard gene expression level, i.e., the
expression level in healthy tissue or bodily fluid from an
individual not having the disorder.
[1386] The tissue distribution in testes indicates that the protein
product of this gene is useful for the treatment of male
reproductive and endocrine disorders. Furthermore, the tissue
distribution indicates that the protein product of this gene is
useful for the treatment and diagnosis of conditions concerning
proper testicular function (e.g. endocrine function, sperm
maturation), as well as cancer. Therefore, this gene product is
useful in the treatment of male infertility and/or impotence. This
gene product is also useful in assays designed to identify binding
agents, as such agents (antagonists) are useful as male
contraceptive agents. Similarly, the protein is believed to be
useful in the treatment and/or diagnosis of testicular cancer. The
testes are also a site of active gene expression of transcripts
that may be expressed, particularly at low levels, in other tissues
of the body. Therefore, this gene product may be expressed in other
specific tissues or organs where it may play related functional
roles in other processes, such as hematopoiesis, inflammation, bone
formation, and kidney function, to name a few possible target
indications.
[1387] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:216 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 1691 of SEQ ID NO:216, b is an
integer of 15 to 1705, where both a and b correspond to the
positions of nucleotide residues shown in SEQ ID NO:216, and where
b is greater than or equal to a+14.
[1388] Features of Protein Encoded by Gene No. 207
[1389] This gene is expressed in fetal lung.
[1390] Therefore, polynucleotides and polypeptides of the invention
are useful as reagents for differential identification of the
tissue(s) or cell type(s) present in a biological sample and for
diagnosis of diseases and conditions which include, but are not
limited to, lung diseases such as cystic fibrosis. Similarly,
polypeptides and antibodies directed to these polypeptides are
useful in providing immunological probes for differential
identification of the tissue(s) or cell type(s). For a number of
disorders of the above tissues or cells, particularly of the
respiratory system, expression of this gene at significantly higher
or lower levels may be routinely detected in certain tissues or
cell types (e.g. respiratory, cancerous and wounded tissues) or
bodily fluids (e.g., serum, plasma, urine, synovial fluid and
spinal fluid) or another tissue or cell sample taken from an
individual having such a disorder, relative to the standard gene
expression level, i.e., the expression level in healthy tissue or
bodily fluid from an individual not having the disorder.
[1391] Preferred epitopes include those comprising a sequence shown
in SEQ ID NO: 455 as residues: Tyr-49 to Cys-54.
[1392] The tissue distribution in fetal lung indicates that the
protein product of this gene is useful for the detection and
treatment of disorders associated with developing lungs,
particularly in premature infants where the lungs are the last
tissues to develop. The tissue distribution indicates that the
protein product of this gene is useful for the diagnosis and
intervention of lung tumors, since the gene may be involved in the
regulation of cell division, particularly since it is expressed in
fetal tissue. Protein, as well as, antibodies directed against the
protein may show utility as a tumor marker and immunotherapy
targets for the above listed tumors and tissues.
[1393] Many polynucleotide sequences, such as EST sequences, are
publicly available and accessible through sequence databases. Some
of these sequences are related to SEQ ID NO:217 and may have been
publicly available prior to conception of the present invention.
Preferably, such related polynucleotides are specifically excluded
from the scope of the present invention. To list every related
sequence is cumbersome. Accordingly, preferably excluded from the
present invention are one or more polynucleotides comprising a
nucleotide sequence described by the general formula of a-b, where
a is any integer between 1 to 985 of SEQ ID NO:217, b is an integer
of 15 to 999, where both a and b correspond to the positions of
nucleotide residues shown in SEQ ID NO:217, and where b is greater
than or equal to a+14.
61 NT 5' NT ATCC SEQ 5' NT of First First AA Last Deposit ID Total
of 3' NT 5' NT AA of AA First Last of AA Gene cDNA Nr and NO: NT
Clone of Clone of Start Signal SEQ ID AA of AA of Secreted of No.
Clone ID Date Vector X Seq. Seq. Seq. Codon Pep NO: Y Sig Pep Sig
Pep Portion ORF 1 HLHDS67 97979 Uni-ZAP XR 11 2526 427 2526 458 458
249 1 30 31 30 03/27/97 2 HLHDZ58 97979 Uni-ZAP XR 12 1131 1 1131
129 129 250 1 14 15 115 03/27/97 3 HLMMJ13 97979 Lambda ZAP 13 941
39 941 62 62 251 1 44 45 102 03/27/97 II 3 HLMMJ13 97979 Lambda ZAP
218 941 39 941 245 245 456 1 35 36 41 03/27/97 II 4 HLTEI25 97979
Uni-ZAP XR 14 843 1 843 155 155 252 1 19 20 42 03/27/97 5 HMSJX24
97979 Uni-ZAP XR 15 1018 1 1018 90 90 253 1 18 19 36 03/27/97 6
HNFED65 97979 Uni-ZAP XR 16 661 1 661 76 76 254 1 28 29 127
03/27/97 7 HNHDX07 97979 Uni-ZAP XR 17 553 1 553 106 106 255 1 23
24 66 03/27/97 8 HNHGC82 97979 Uni-ZAP XR 18 869 1 869 101 101 256
1 21 22 68 03/27/97 9 HNHGO09 97979 Uni-ZAP XR 19 959 1 959 176 176
257 1 21 22 43 03/27/97 10 HOUBE18 97979 Uni-ZAP XR 20 1446 1 1446
101 101 258 1 27 28 50 03/27/97 11 HOUDL69 97979 Uni-ZAP XR 21 1471
579 1460 692 692 259 1 31 32 42 03/27/97 12 HPMFI71 97979 Uni-ZAP
XR 22 1402 242 1402 401 401 260 1 32 33 60 03/27/97 13 HPMGQ55
97979 Uni-ZAP XR 23 1047 1 1047 164 164 261 1 26 27 35 03/27/97 14
HPQAC69 97979 Lambda ZAP 24 990 1 988 82 82 262 1 20 21 37 03/27/97
II 15 HPTBB03 97979 Uni-ZAP XR 25 1208 350 1173 398 398 263 1 29 30
210 03/27/97 16 HPTWA66 97979 pBluescript 26 1922 1381 1922 24 24
264 1 33 34 547 03/27/97 16 HPTWA66 97979 pBluescript 219 575 1 575
148 148 457 1 22 23 65 03/27/97 17 HPTWC08 97979 pBluescript 27
1951 1422 1874 219 219 265 1 19 20 299 03/27/97 18 HRGCZ46 97979
Uni-ZAP XR 28 3989 2635 3989 2748 266 1 16 17 39 03/27/97 19
HSAVU34 97979 Uni-ZAP XR 29 3735 2966 3735 272 272 267 1 30 31 594
03/27/97 19 HSAVU31 97979 Uni-ZAP XR 220 3018 1929 3018 26 26 458 1
1 2 156 03/27/97 20 HSDFW61 97974 Uni-ZAP XR 30 1667 59 1625 138
138 268 1 32 33 130 04/04/97 209080 05/29/97 21 HSDGP60 97974
Uni-ZAP XR 31 1408 1 1408 285 285 269 1 20 04/04/97 209080 05/29/97
22 HSOAJ55 97974 Uni-ZAP XR 32 3186 2402 3186 302 302 270 1 43 44
159 04/04/97 209080 05/29/97 22 HSOAJ55 97974 Uni-ZAP XR 221 2031
1273 2031 1285 1285 459 1 29 30 30 04/04/97 209080 05/29/97 23
HSQEO84 97974 Uni-ZAP XR 33 971 13 971 91 91 271 1 19 20 218
04/04/97 209080 05/29/97 23 HSQEO84 97974 Uni-ZAP XR 222 968 8 968
86 86 460 1 20 21 56 04/04/97 209080 05/29/97 24 HSXAM05 97974
Uni-ZAP XR 34 1792 369 1792 470 470 272 1 26 27 49 04/04/97 209080
05/29/97 25 HSXAS67 97974 Uni-ZAP XR 35 896 1 896 96 96 273 1 32 33
121 04/04/97 209080 05/29/97 26 HTDAF28 97974 pSport1 36 912 1 912
38 38 274 1 22 23 87 04/04/97 209080 05/29/97 27 HTEGQ64 97974
Uni-ZAP XR 37 1382 67 1382 271 271 275 1 25 04/04/97 209080
05/29/97 28 HTGEU09 97974 Uni-ZAP XR 38 872 1 872 74 74 276 1 18 19
28 04/04/97 209080 05/29/97 29 HTOAM21 97974 Uni-ZAP XR 39 812 1
812 41 41 277 1 30 31 43 04/04/97 209080 05/29/97 30 HTPBW79 209511
Uni-ZAP XR 40 1515 118 1507 302 302 278 1 24 25 362 12/03/97 30
HTSEV09 97974 pBluescript 223 1404 1 1265 92 92 461 1 19 20 415
04/04/97 209080 05/29/97 31 HJPCD40 97974 Uni-ZAP XR 41 704 22 704
117 279 1 18 19 127 04/04/97 209080 05/29/97 32 HTWBY48 97974
pSport1 42 1094 1 1094 32 32 280 1 34 35 53 04/04/97 209080
05/29/97 33 HTWCI46 97974 pSport1 43 1821 892 1647 56 56 281 1 26
27 29 04/04/97 209080 05/29/97 34 HTXGI75 97974 Uni-ZAP XR 44 1024
30 1024 167 282 1 20 21 25 04/04/97 209080 05/29/97 35 HWTBF59
97974 Uni-ZAP XR 45 983 779 983 85 85 283 1 30 31 221 04/04/97
209080 05/29/97 35 HWTBF59 97974 Uni-ZAP XR 224 707 488 707 514 514
462 1 41 42 64 04/04/97 209080 05/29/97 36 HADAE74 97974 pSport1 46
2421 664 1587 2110 2110 284 1 33 34 40 04/04/97 209080 05/29/97 37
HAGFB60 97974 Uni-ZAP XR 47 840 1 840 97 97 285 1 30 31 48 04/04/97
209080 05/29/97 38 HATEF60 97974 Uni-ZAP XR 48 2432 1193 2246 1491
1491 286 1 17 18 51 04/04/97 209080 05/29/97 39 HBMSN25 97974
Uni-ZAP XR 49 1742 1165 1742 1207 1207 287 1 23 24 31 04/04/97
209080 05/29/97 40 HCDAR68 97974 Uni-ZAP XR 50 1487 181 1455 325
325 288 1 35 36 56 04/04/97 209080 05/29/97 41 HCE3J79 97974
Uni-ZAP XR 51 1328 251 1328 525 525 289 1 21 04/04/97 209080
05/29/97 42 HMDAN54 97974 Uni-ZAP XR 52 1856 725 1853 928 928 290 1
33 34 50 04/04/97 209080 05/29/97 43 HCECA49 97974 Uni-ZAP XR 53
1558 310 1408 109 109 291 1 30 31 98 04/04/97 209080 05/29/97 44
HCEEC15 97974 Uni-ZAP XR 54 948 1 948 9 9 292 1 23 24 65 04/04/97
209080 05/29/97 45 HCESF40 97974 pBluescript 55 990 99 990 193 193
293 1 32 33 256 04/04/97 209080 05/29/97 45 HCESF40 97974
pBluescript 225 1384 99 1384 193 193 463 1 32 33 205 04/04/97
209080 05/29/97 46 HCFMV39 97974 pSport1 56 1603 1 1296 96 96 294 1
29 30 102 04/04/97 209080 05/29/97 47 HCMSX86 97975 Uni-ZAP XR 57
1052 5 786 12 12 295 1 28 29 32 04/04/97 209081 05/29/97 48 HCNAP62
97975 Lambda ZAP 58 814 1 558 93 93 296 1 22 23 42 04/04/97 II
209081 05/29/97 49 HCRAF32 97975 Uni-ZAP XR 59 1215 257 1215 356
297 1 19 20 20 04/04/97 209081 05/29/97 50 HCUDC07 97975 ZAP
Express 60 478 1 478 147 147 298 1 36 37 69 04/04/97 209081
05/29/97 51 HCWBB42 97975 ZAP Express 61 618 1 618 212 212 299 1 35
36 74 04/04/97 209081 05/29/97 52 HDTAB05 97975 pCMVSport 62 751 1
751 257 257 300 1 21 22 32 04/04/97 2.0 209081 05/29/97 53 HE2AV74
97975 Uni-ZAP XR 63 780 283 780 433 301 1 16 04/04/97 209081
05/29/97 54 HE2AY71 97975 Uni-ZAP XR 64 588 21 588 169 169 302 1 16
04/04/97 209081 05/29/97 55 HE2GS36 97975 Uni-ZAP XR 65 945 1 349
520 520 303 1 39 40 111 04/04/97 209081 05/29/97 55 HE2GS36 97975
Uni-ZAP XR 226 774 272 774 445 445 464 1 37 04/04/97 209081
05/29/97 56 HE2OF09 97975 Uni-ZAP XR 66 1866 1313 1866 1596 1596
304 1 11 04/04/97 209081 05/29/97 57 HE6EU50 97975 Uni-ZAP XR 67
1152 117 686 237 237 305 1 20 21 34 04/04/97 209081 05/29/97 58
HE9HU17 97975 Uni-ZAP XR 68 2483 1577 2448 1620 1620 306 1 14
04/04/97 209081 05/29/97 59 HE9ND48 97975 Uni-ZAP XR 69 536 1 536
83 83 307 1 36 37 43 04/04/97 209081 05/29/97 60 HEBBW11 97975
Uni-ZAP XR 70 574 97 564 109 109 308 1 55 56 137 04/04/97 209081
05/29/97 60 HEBBW11 97975 Uni-ZAP XR 227 865 647 865 388 465 1 30
31 135 04/04/97 209081 05/29/97 61 HELDY74 97975 Uni-ZAP XR 71 932
1 932 201 201 309 1 17 18 33 04/04/97 209081 05/29/97 62 HEMAE80
97975 Uni-ZAP XR 72 996 1 945 12 12 310 1 24 25 136 04/04/97 209081
05/29/97 63 HFEBA88 97975 Uni-ZAP XR 73 785 464 785 356 356 311 1
29 30 57 04/04/97 209081 05/29/97 64 HFGAB89 97975 Uni-ZAP XR 74
1069 196 1047 295 295 312 1 32 33 34 04/04/97 209081 05/29/97 65
HFVHY45 97975 pBluescript 75 831 1 831 50 50 313 1 36 37 89
04/04/97 209081 05/29/97 66 HGBAJ93 97975 Uni-ZAP XR 76 590 1 590
233 233 314 1 38 39 94 04/04/97 209081 05/29/97 67 HGBBQ69 97975
Uni-ZAP XR 77 1274 1 1273 105 105 315 1 24 25 43 04/04/97 209081
05/29/97 68 HHFCF08 97975 Uni-ZAP XR 78 1133 4 1042 175 175 316 1
23 24 30 04/04/97 209081 05/29/97 69 HHFHJ59 97975 Uni-ZAP XR 79
661 1 661 192 192 317 1 29 30 112 04/04/97 209081 05/29/97 70
HHFHR32 97975 Uni-ZAP XR 80 1378 1 1378 58 58 318 1 25 26 235
04/04/97 209081 05/29/97 71 HHGCN69 97975 Lambda ZAP 81 1440 298
1440 532 532 319 1 23 24 34 04/04/97 II 209081 05/29/97 72 HHGDO13
97975 Lambda ZAP 82 1381 766 1371 993 993 320 1 23 24 34 04/04/97
II 209081 05/29/97 73 HHPFD63 97975 Uni-ZAP XR 83 1706 182 1644 257
257 321 1 24 25 81 04/04/97 209081 05/29/97 74 HHSEG23 97976
Uni-ZAP XR 84 573 1 573 160 160 322 1 18 19 71 04/04/97 75 HJPAV06
97976 Uni-ZAP XR 85 684 199 684 323 323 323 1 27 28 33 04/04/97 76
HKIXL73 97976 pBluescript 86 1036 591 1036 690 690 324 1 32 33 114
04/04/97 77 HKMNC43 97976 pBluescript 87 908 1 908 139 139 325 1 18
19 108 04/04/97 78 HMEJE31 97976 Lambda ZAP 88 655 1 655 165 165
326 1 33 34 64 04/04/97 II 79 HMSKS35 97976 Uni-ZAP XR 89 1102 1
1102 228 228 327 1 23 24 49 04/04/97 79 HMSKS35 97976 Uni-ZAP XR
228 1102 1 1102 228 228 466 1 26 27 49 04/04/97 80 HNFAE54 97976
Uni-ZAP XR 90 1533 665 1518 347 347 328 1 26 27 293 04/04/97 81
HNFJH45 97976 Uni-ZAP XR 91 575 1 575 275 275 329 1 30 31 67
04/04/97 82 HNGBT31 97976 Uni-ZAP XR 92 639 1 639 224 224 330 1 28
29 104 04/04/97 83 HNGIN60 97976 Uni-ZAP XR 93 858 1 858 239 239
331 1 23 24 58 04/04/97 83 HNGIN60 97976 Uni-ZAP XR 229 744 1 744
225 225 467 1 43 44 70 04/04/97 84 HNGJG84 97976 Uni-ZAP XR 94 526
1 526 268 268 332 1 29 30 38 04/04/97 85 HNHDW42 97976 Uni-ZAP XR
95 426 1 426 168 168 333 1 28 29 71 04/04/97 86 HNHFL57 97976
Uni-ZAP XR 96 844 1 844 98 98 334 1 25 26 61 04/04/97 87 HOGAR52
97977 pCMVSport 97 1985 453 1985 533 533 335 1 17 18 285 04/04/97
2.0 209082 05/29/97 88 HOSBZ55 97977 Uni-ZAP XR 98 1416 69 1416 246
246 336 1 32 33 54 04/04/97 209082 05/29/97 89 HOSDI92 97977
Uni-ZAP XR 99 1760 1469 1760 934 934 337 1 22 23 59 04/04/97 209082
05/29/97 89 HOSDI92 97977 Uni-ZAP XR 230 1935 141 772 274 468 1 20
21 58 04/04/97 209082 05/29/97 90 HPBCU51 97977 pBluescript 100 599
1 599 86 86 338 1 27 28 119 04/04/97 SK- 209082 05/29/97 91 HPCAL49
97977 Uni-ZAP XR 101 784 1 784 113 113 339 1 36 37 38 04/04/97
209082 05/29/97 92 HPFCR13 97977 Uni-ZAP XR 102 404 1 404 266 266
340 1 30 31 46 04/04/97 209082 05/29/97 92 HPFCR13 97977 Uni-ZAP XR
231 1035 602 1035 859 859 469 1 32 33 58 04/04/97 209082 05/29/97
93 HPHAC83 97977 Uni-ZAP XR 103 2218 840 2182 1035 1035 341 1 17 18
17 04/04/97 209082 05/29/97 93 HOFNZ45 209568 pCMVSport 232 760 1
728 86 86 470 1 36 37 61 01/06/98 2.0 94 HPMBQ32 97977 Uni-ZAP XR
104 1351 1 1351 18 18 342 1 23 24 86 04/04/97 209082 05/29197 95
HPWAN23 97977 Uni-ZAP XR 105 2066 51 2052 270 270 343 1 29 30 537
04/04/97 209082 05/29/97 95 HPWAN23 97977 Uni-ZAP XR 233 2057 1
1954 220 220 471 1 29 30 315 04/04/97 209082 05/29/97 96 HRDFB85
97977 Uni-ZAP XR 106 1705 23 1697 233 233 344 1 21 22 201 04/04/97
209082 05/29/97 97 HRGBR28 97977 Uni-ZAP XR 107 1167 1 557 604 604
345 1 22 23 122 04/04/97 209082 05/29/97 98 HSKGN81 97977
pBluescript 108 1907 151 1432 353 353 346 1 23 24 260 04/04/97
209082 05/29/97 98 HSKGN81 97977 pBluescript 234 2084 335 2084 537
537 472 1 19 20 23 04/04/97 209082 05/29/97 99 HSPAH56 97977
pSport1 109 611 1 576 229 229 347 1 25 26 47 04/04/97 209082
05/29/97 100 HE8EU04 209746 Uni-ZAP XR 110 2632 294 2632 337 337
348 1 25 26 333 04/07/98 100 HSXBT86 97977 Uni-ZAP XR 235 2143 53
1096 235 235 473 1 9 04/04/97 209082 05/29/97 101 HSXCS62 97977
Uni-ZAP XR 111 2249 1 1953 90 90 349 1 18 19 199 04/04/97 209082
05/29/97 102 HTEFU09 97977 Uni-ZAP XR 112 2198 228 2158 400 400 350
1 23 04/04/97 209082 05/29/97 103 HTEKM35 97977 Uni-ZAP XR 113 1043
40 1043 320 320 351 1 20 21 142 04/04/97 209082 05/29/97 104
HTGEP89 97977 Uni-ZAP XR 114 703 1 703 285 285 352 1 29 30 94
04/04/97 209082 05/29/97 105 HTGEW91 97977 Uni-ZAP XR 115 3684 526
1338 584 584 353 1 24 25 37 04/04/97 209082 05/29/97 106 HTOEY16
97977 Uni-ZAP XR 116 1965 127 1915 202 202 354 1 27 28 38 04/04/97
209082 05/29/97 107 HTPCN79 97977 Uni-ZAP XR 117 503 1 503 1 355 1
7 8 70 04/04/97 209082 05/29/97 108 HTSGM54 97977 pBluescript 118
1071 50 981 29 29 356 1 30 31 227 04/04/97 209082 05/29/97 108
HTSGM54 97977 pBluescript 236 1133 316 1069 423 474 1 12 13 84
04/04/97 209082 05/29/97 109 HTSHE40 97977 pBluescript 119 1101 118
956 218 218 357 1 31 32 89 04/04/97 209082 05/29/97 110 HTWAF58
97977 Lambda ZAP 120 282 1 282 137 137 358 1 25 26 48 04/04/97 II
209082 05/29/97 111 HTWBY29 97977 pSport1 121 2635 1593 2489 1654
1654 359 1 25 26 55 04/04/97 209082 05/29/97 112 HUKFC71 209007
Lambda ZAP 122 994 1 932 272 360 1 15 16 221 04/28/97 II 209083
05/29/97 113 HCE3Q10 209007 Uni-ZAP XR 123 1542 1 1542 143 143 361
1 25 26 63 04/28/97 209083 05/29/97 114 HCEVR60 209007 Uni-ZAP XR
124 1390 82 1390 127 127 362 1 32 33 153 04/28/97 209083 05/29/97
115 HDTAW95 209007 pCMVSport 125 1288 412 1288 571 571 363 1 16
04/28/97 2.0 209083 05/29/97 116 HE6EL90 209007 Uni-ZAP XR 126 1517
1 1452 243 243 364 1 9 04/28/97 209083 05/29/97 117 HELBU29 209007
Uni-ZAP XR 127 1073 198 1073 776 365 1 13 04/28/97 209083 05/29/97
118 HERAH36 209007 Uni-ZAP XR 128 300 155 300 202 202 366 1 17
04/28/97 209083 05/29/97 119 HFXBW82 209007 Lambda ZAP 129 1275 1
1275 56 56 367 1 23 24 61 04/28/97 II 209083 05/29/97 120 HHPTD20
209007 Uni-ZAP XR 130 472 51 472 243 368 1 32 04/28/97 209083
05/29/97 121 HIBED17 209007 Other 131 1950 284 1927 395 395 369 1
72 73 245 04/28/97 209083 05/29/97 122 HLTER03 209007 Uni-ZAP XR
132 990 1 990 78 78 370 1 22 23 34 04/28/97 209083 05/29/97 123
HOABL56 209007 Uni-ZAP XR 133 1720 565 1720 660 660 371 1 18 19 21
04/28/97 209083 05/29/97 124 HPMCJ92 209007 Uni-ZAP XR 134 705 28
705 106 106 372 1 28 29 98 04/28/97 209083 05/29/97 125 HPWAZ95
209007 Uni-ZAP XR 135 323 1 323 88 88 373 1 27 28 78 04/28/97
209083 05/29/97 126 HRGBR18 209007 Uni-ZAP XR 136 582 1 582 16 374
1 17 18 30 04/28/97 209083 05/29/97 127 HSUBW09 209007 Uni-ZAP XR
137 1021 1 1021 153 153 375 1 32 33 56 04/28/97 209083 05/29/97 128
HUKCO64 209007 Lambda ZAP 138 1777 1 1339 198 198 376 1 23 24 63
04/28/97 II 209083 05/29/97 129 H6EAA53 209007 Uni-ZAP XR 139 643
303 643 306 306 377 1 14 15 38 04/28/97 209083 05/29/97 130 HAGAI11
209007 Uni-ZAP XR 140 1220 1 1220 567 567 378 1 50 51 98 04/28/97
209083 05/29/97 131 HAGAO39 209007 Uni-ZAP XR 141 721 1 721 415 379
1 14 04/28/97 209083 05/29/97 132 HALSK07 209007 Uni-ZAP XR 142
1468 125 1468 210 210 380 1 29 30 33 04/28/97 209083 05/29/97 133
HALSQ59 209007 Uni-ZAP XR 143 300 4 300 101 101 381 1 22 23 66
04/28/97 209083 05/29/97 134 HAIBP89 209877 Uni-ZAP XR 144 2243
173 2243 311 311 382 1 27 28 317 05/18/98 134 HBGCB91 209007
Uni-ZAP XR 237 1025 409 1025 624 624 475 1 20 21 25 04/28/97 209083
05/29/97 135 HBMTD81 209008 Uni-ZAP XR 145 1082 163 1082 357 357
383 1 30 04/28/97 209084 05/29/97 136 HBXGK12 209008 ZAP Express
146 4313 1153 4313 1313 1313 384 1 18 19 42 04/28/97 209084
05/29/97 137 HFKFJ07 209010 Uni-ZAP XR 147 1183 1 1183 149 149 385
1 41 42 254 04/28/97 209085 05/29/97 138 HCQAI40 209008 Lambda ZAP
148 734 1 734 285 285 386 1 19 04/28/97 II 209084 05/29/97 139
HCWHZ24 209008 ZAP Express 149 1405 1 1405 108 108 387 1 34 35 63
04/28/97 209084 05/29/97 140 HE2GT20 209008 Uni-ZAP XR 150 2890
1178 2890 1178 1178 388 1 31 32 39 04/28/97 209084 05/29/97 141
HE8EY43 209008 Uni-ZAP XR 151 2399 1181 2399 1265 1265 389 1 30 31
34 04/28/97 209084 05/29/97 142 HFCEB37 209008 Uni-ZAP XR 152 802
352 802 487 390 1 10 04/28/97 209084 05/29/97 143 HFTCT67 209008
Uni-ZAP XR 153 461 24 461 145 145 391 1 37 38 63 04/28/97 209084
05/29/97 144 HGLAM46 209008 Uni-ZAP XR 154 2388 818 2388 648 648
392 1 18 04/28/97 209084 05/29/97 145 HHGBR15 209008 Lambda ZAP 155
642 322 642 369 369 393 1 41 42 43 04/28/97 II 209084 05/29/97 146
HJAAU36 209008 pBluescript 156 1251 583 1251 933 394 1 16 17 16
04/28/97 SK- 209084 05/29/97 147 HUSIT49 209008 pSport1 157 2127
247 2127 383 383 395 1 47 48 83 04/28/97 209084 05/29/97 148
HKLAB16 209008 Lambda ZAP 158 1625 817 1625 1012 1012 396 1 18 19
20 04/28/97 II 209084 05/29/97 149 HLMMU76 209008 Lambda ZAP 159
1687 1307 1687 1296 1296 397 1 28 29 28 04/28/97 II 209084 05/29/97
150 HMSKQ35 209008 Uni-ZAP XR 160 1842 172 1463 319 319 398 1 30 31
33 04/28/97 209084 05/29/97 151 HNHED86 209008 Uni-ZAP XR 161 770 1
770 30 30 399 1 31 32 46 04/28/97 209084 05/29/97 152 HNHEJ88
209008 Uni-ZAP XR 162 519 1 519 242 242 400 1 17 18 24 04/28/97
209084 05/29/97 153 HNHFQ63 209008 Uni-ZAP XR 163 753 1 753 164 164
401 1 17 18 67 04/28/97 209084 05/29/97 154 HOECU83 209009 Uni-ZAP
XR 164 1893 1 1211 1637 1637 402 1 28 29 85 04/28/97 154 HOECU83
209009 Uni-ZAP XR 238 1400 189 1400 508 476 1 22 23 33 04/28/97 155
HPTRC15 209009 pBluescript 165 2153 594 2153 57 57 403 1 26 27 82
04/28/97 156 HSKCP69 209009 Uni-ZAP XR 166 1251 219 1120 49 49 404
1 27 28 286 04/28/97 156 HSKCP69 209009 Uni-ZAP XR 239 1250 223
1250 393 393 477 1 32 33 171 04/28/97 157 H6EAE26 209009 Uni-ZAP XR
167 882 48 882 155 155 405 1 33 34 153 04/28/97 158 HAGBX03 209009
Uni-ZAP XR 168 1208 1 1208 290 290 406 1 20 21 37 04/28/97 159
HAGDQ47 209009 Uni-ZAP XR 169 1258 1 1258 44 44 407 1 22 23 60
04/28/97 159 HAGDQ47 209009 Uni-ZAP XR 240 1307 1 1307 44 44 478 1
22 23 60 04/28/97 160 HAICP19 209009 Uni-ZAP XR 170 1624 89 1483
128 128 408 1 18 19 446 04/28/97 161 HAUAE83 209009 Uni-ZAP XR 171
2003 889 2003 957 957 409 1 29 30 64 04/28/97 162 HBHAD12 209009
Uni-ZAP XR 172 786 1 786 176 410 1 17 18 23 04/28/97 163 HBMTY28
209009 Uni-ZAP XR 173 1758 962 1758 1184 1184 411 1 27 28 34
04/28/97 164 HBMVP04 209009 Uni-ZAP XR 174 1369 29 557 947 947 412
1 33 34 41 04/28/97 164 HBMVP04 209009 Uni-ZAP XR 241 888 330 862
546 479 1 2 04/28/97 165 HCDDB78 209009 Uni-ZAP XR 175 2379 750
2379 901 901 413 1 18 19 24 04/28/97 166 HCEQA68 209010 Uni-ZAP XR
176 1348 1 1348 12 12 414 1 28 29 78 04/28/97 209085 05/29/97 167
HCEZS40 209010 Uni-ZAP XR 177 1502 178 1502 388 388 415 1 31 32 51
04/28/97 209085 05/29/97 168 HCFNF11 209010 pSport1 178 1637 26
1607 152 152 416 1 44 45 257 04/28/97 209085 05/29/97 169 HCRBL20
209010 Uni-ZAP XR 179 2911 1103 2858 192 192 417 1 32 33 424
04/28/97 209085 05/29/97 169 HCRBL20 209010 Uni-ZAP XR 242 1811 20
1811 93 93 480 1 36 37 95 04/28/97 209085 05/29/97 170 HCUBL62
209010 ZAP Express 180 519 1 519 57 57 418 1 28 29 32 04/28/97
209085 05/29/97 171 HDSAP81 209010 Uni-ZAP XR 181 968 320 968 476
476 419 1 27 28 79 04/28/97 209085 05/29/97 172 HE2CT29 209010
Uni-ZAP XR 182 1128 1 1128 111 111 420 1 26 27 94 04/28/97 209085
05/29/97 173 HE8MG65 209010 Uni-ZAP XR 183 2276 48 2276 88 88 421 1
37 38 257 04/28/97 209085 05/29/97 173 HE8MG65 209010 Uni-ZAP XR
243 2271 56 2232 79 79 481 1 43 44 170 04/28/97 209085 05/29/97 174
HE9FB42 209010 Uni-ZAP XR 184 3374 86 1705 277 277 422 1 40 41 704
04/28/97 209085 05/29/97 174 HE9FB42 209010 Uni-ZAP XR 244 2500 76
1693 518 518 482 1 1 2 623 04/28/97 209085 05/29/97 175 HEMAM41
209010 Uni-ZAP XR 185 1337 60 1328 175 175 423 1 39 40 190 04/28/97
209085 05/29/97 175 HEMAM41 209010 Uni-ZAP XR 245 1338 33 1327 175
175 483 1 32 33 91 04/28/97 209085 05/29/97 176 HEMCV19 209010
Uni-ZAP XR 186 941 33 931 79 79 424 1 23 24 178 04/28/97 209085
05/29/97 177 HEMDX17 209010 Uni-ZAP XR 187 678 1 678 131 131 425 1
21 22 40 04/28/97 209085 05/29/97 177 HEMDX17 209010 Uni-ZAP XR 246
654 1 654 137 137 484 1 12 04/28/97 209085 05/29/97 178 HETAR54
209010 Uni-ZAP XR 188 1848 454 1848 948 948 426 1 14 15 232
04/28/97 209085 05/29/97 179 HETBX14 209010 Uni-ZAP XR 189 1292 303
1292 207 207 427 1 18 19 250 04/28/97 209085 05/29/97 179 HETBX14
209010 Uni-ZAP XR 247 1146 157 1146 74 485 1 14 15 53 04/28/97
209085 05/29/97 180 HFGAB48 209010 Uni-ZAP XR 190 906 156 906 628
628 428 1 23 24 58 04/28/97 209085 05/29/97 181 HFKFI40 209010
Uni-ZAP XR 191 1941 120 1002 213 213 429 1 18 19 218 04/28/97
209085 05/29/97 182 HFXHN68 209010 Lambda ZAP 192 2118 777 2118 966
966 430 1 23 24 50 04/28/97 II 209085 05/29/97 183 HGBFO79 209011
Uni-ZAP XR 193 1538 259 1538 273 273 431 1 23 24 49 04/28/97 184
HGLAM56 209011 Uni-ZAP XR 194 1098 68 1098 185 432 1 28 29 69
04/28/97 185 HHLBA89 209011 pBluescript 195 1001 1 1001 324 324 433
1 25 26 39 04/28/97 SK- 186 HHPDW05 209011 Uni-ZAP XR 196 1458 1
1458 254 254 434 1 17 18 104 04/28/97 186 HHPDW05 209011 Uni-ZAP XR
248 1443 1 1443 246 246 486 1 21 22 21 04/28/97 187 HHPSD37 209011
pBluescript 197 1282 66 1282 171 171 435 1 19 20 37 04/28/97 188
HHPSF70 209011 pBluescript 198 951 26 951 162 436 1 16 17 34
04/28/97 189 HHSAK25 209011 Uni-ZAP XR 199 1740 1390 1740 1534 1534
437 1 19 20 31 04/28/97 190 HIASB53 209011 pBluescript 200 1707 401
1195 652 652 438 1 26 27 126 04/28/97 191 HJABZ65 209011
pBluescript 201 779 1 779 23 23 439 1 26 27 68 04/28/97 SK- 192
HJPBB39 209011 Uni-ZAP XR 202 1617 188 1605 182 182 440 1 28 29 91
04/28/97 193 HLHSK94 209011 pBluescript 203 1974 1 1794 112 112 441
1 26 27 379 04/28/97 194 HLHTC70 209011 pBluescript 204 1057 229
1057 365 365 442 1 23 24 22 04/28/97 195 HLMIW92 209011 Lambda ZAP
205 721 1 721 244 244 443 1 25 26 46 04/28/97 II 196 HLTCY93 209011
Uni-ZAP XR 206 2465 988 2465 387 387 444 1 27 28 214 04/28/97 197
HLTDB65 209011 Uni-ZAP XR 207 1480 1 1480 371 445 1 15 16 143
04/28/97 198 HMSHM43 209011 Uni-ZAP XR 208 872 1 872 35 35 446 1 18
19 36 04/28/97 199 HMSHQ24 209011 Uni-ZAP XR 209 1779 16 1779 148
148 447 1 24 25 36 04/28/97 200 HNFAH08 209011 Uni-ZAP XR 210 2110
592 2110 611 611 448 1 18 19 191 04/28/97 201 HNGAO10 209011
Uni-ZAP XR 211 938 1 938 107 107 449 1 27 28 30 04/28/97 202
HNGBE45 209011 Uni-ZAP XR 212 1551 1 1551 114 114 450 1 21 22 100
04/28/97 203 HNHAZ16 209011 Uni-ZAP XR 213 997 1 997 202 202 451 1
24 25 36 04/28/97 204 HNHCM59 209011 Uni-ZAP XR 214 1496 1 1132 165
452 1 28 29 41 04/28/97 205 HOSFM22 97977 Uni-ZAP XR 215 1308 501
1308 1081 1081 453 1 46 47 48 04/04/97 209082 05/29/97 206 HPHAC88
97977 Uni-ZAP XR 216 1705 384 1705 549 549 454 1 23 24 24 04/04/97
209082 05/29/97 207 HCDEO95 209007 Uni-ZAP XR 217 999 608 999 273
273 455 1 22 23 54 04/28/97 209083 05/29/97
[1394] Table 1 summarizes the information corresponding to each
"Gene No." described above. The nucleotide sequence identified as
"NT SEQ ID NO:X" was assembled from partially homologous
("overlapping") sequences obtained from the "cDNA clone ID"
identified in Table 1 and, in some cases, from additional related
DNA clones. The overlapping sequences were assembled into a single
contiguous sequence of high redundancy (usually three to five
overlapping sequences at each nucleotide position), resulting in a
final sequence identified as SEQ ID NO:X.
[1395] The cDNA Clone ID was deposited on the date and given the
corresponding deposit number listed in "ATCC Deposit No:Z and
Date." Some of the deposits contain multiple different clones
corresponding to the same gene. "Vector" refers to the type of
vector contained in the cDNA Clone ID.
[1396] "Total NT Seq." refers to the total number of nucleotides in
the contig identified by "Gene No." The deposited clone may contain
all or most of these sequences, reflected by the nucleotide
position indicated as "5' NT of Clone Seq." and the "3' NT of Clone
Seq." of SEQ ID NO:X. The nucleotide position of SEQ ID NO:X of the
putative start codon (methionine) is identified as "5' NT of Start
Codon." Similarly, the nucleotide position of SEQ ID NO:X of the
predicted signal sequence is identified as "5' NT of First AA of
Signal Pep."
[1397] The translated amino acid sequence, beginning with the
methionine, is identified as "AA SEQ ID NO:Y," although other
reading frames can also be easily translated using known molecular
biology techniques. The polypeptides produced by these alternative
open reading frames are specifically contemplated by the present
invention.
[1398] The first and last amino acid position of SEQ ID NO:Y of the
predicted signal peptide is identified as "First AA of Sig Pep" and
"Last AA of Sig Pep." The predicted first amino acid position of
SEQ ID NO:Y of the secreted portion is identified as "Predicted
First AA of Secreted Portion." Finally, the amino acid position of
SEQ ID NO:Y of the last amino acid in the open reading frame is
identified as "Last AA of ORF."
[1399] SEQ ID NO:X and the translated SEQ ID NO:Y are sufficiently
accurate and otherwise suitable for a variety of uses well known in
the art and described further below. For instance, SEQ ID NO:X is
useful for designing nucleic acid hybridization probes that will
detect nucleic acid sequences contained in SEQ ID NO:X or the cDNA
contained in the deposited clone. These probes will also hybridize
to nucleic acid molecules in biological samples, thereby enabling a
variety of forensic and diagnostic methods of the invention.
Similarly, polypeptides identified from SEQ ID NO:Y may be used to
generate antibodies which bind specifically to the secreted
proteins encoded by the cDNA clones identified in Table 1.
[1400] Nevertheless, DNA sequences generated by sequencing
reactions can contain sequencing errors. The errors exist as
misidentified nucleotides, or as insertions or deletions of
nucleotides in the generated DNA sequence. The erroneously inserted
or deleted nucleotides cause frame shifts in the reading frames of
the predicted amino acid sequence. In these cases, the predicted
amino acid sequence diverges from the actual amino acid sequence,
even though the generated DNA sequence may be greater than 99.9%
identical to the actual DNA sequence (for example, one base
insertion or deletion in an open reading frame of over 1000
bases).
[1401] Accordingly, for those applications requiring precision in
the nucleotide sequence or the amino acid sequence, the present
invention provides not only the generated nucleotide sequence
identified as SEQ ID NO:X and the predicted translated amino acid
sequence identified as SEQ ID NO:Y, but also a sample of plasmid
DNA containing a human cDNA of the invention deposited with the
ATCC, as set forth in Table 1. The nucleotide sequence of each
deposited clone can readily be determined by sequencing the
deposited clone in accordance with known methods. The predicted
amino acid sequence can then be verified from such deposits.
Moreover, the amino acid sequence of the protein encoded by a
particular clone can also be directly determined by peptide
sequencing or by expressing the protein in a suitable host cell
containing the deposited human cDNA, collecting the protein, and
determining its sequence.
[1402] The present invention also relates to the genes
corresponding to SEQ ID NO:X, SEQ ID NO:Y, or the deposited clone.
The corresponding gene can be isolated in accordance with known
methods using the sequence information disclosed herein. Such
methods include preparing probes or primers from the disclosed
sequence and identifying or amplifying the corresponding gene from
appropriate sources of genomic material.
[1403] Also provided in the present invention are species homologs.
Species homologs may be isolated and identified by making suitable
probes or primers from the sequences provided herein and screening
a suitable nucleic acid source for the desired homologue.
[1404] The polypeptides of the invention can be prepared in any
suitable manner. Such polypeptides include isolated naturally
occurring polypeptides, recombinantly produced polypeptides,
synthetically produced polypeptides, or polypeptides produced by a
combination of these methods. Means for preparing such polypeptides
are well understood in the art.
[1405] The polypeptides may be in the form of the secreted protein,
including the mature form, or may be a part of a larger protein,
such as a fusion protein (see below). It is often advantageous to
include an additional amino acid sequence which contains secretory
or leader sequences, pro-sequences, sequences which aid in
purification, such as multiple histidine residues, or an additional
sequence for stability during recombinant production.
[1406] The polypeptides of the present invention are preferably
provided in an isolated form, and preferably are substantially
purified. A recombinantly produced version of a polypeptide,
including the secreted polypeptide, can be substantially purified
by the one-step method described in Smith and Johnson, Gene
67:31-40 (1988). Polypeptides of the invention also can be purified
from natural or recombinant sources using antibodies of the
invention raised against the secreted protein in methods which are
well known in the art.
[1407] Signal Sequences
[1408] Methods for predicting whether a protein has a signal
sequence, as well as the cleavage point for that sequence, are
available. For instance, the method of McGeoch, Virus Res.
3:271-286 (1985), uses the information from a short N-terminal
charged region and a subsequent uncharged region of the complete
(uncleaved) protein. The method of von Heinje, Nucleic Acids Res.
14:4683-4690 (1986) uses the information from the residues
surrounding the cleavage site, typically residues -13 to +2, where
+1 indicates the amino terminus of the secreted protein. The
accuracy of predicting the cleavage points of known mammalian
secretory proteins for each of these methods is in the range of
75-80%. (von Heinje, supra.) However, the two methods do not always
produce the same predicted cleavage point(s) for a given
protein.
[1409] In the present case, the deduced amino acid sequence of the
secreted polypeptide was analyzed by a computer program called
SignalP (Henrik Nielsen et al., Protein Engineering 10:1-6 (1997)),
which predicts the cellular location of a protein based on the
amino acid sequence. As part of this computational prediction of
localization, the methods of McGeoch and von Heinje are
incorporated. The analysis of the amino acid sequences of the
secreted proteins described herein by this program provided the
results shown in Table 1.
[1410] As one of ordinary skill would appreciate, however, cleavage
sites sometimes vary from organism to organism and cannot be
predicted with absolute certainty. Accordingly, the present
invention provides secreted polypeptides having a sequence shown in
SEQ ID NO:Y which have an N-terminus beginning within 5 residues
(i.e., + or -5 residues) of the predicted cleavage point.
Similarly, it is also recognized that in some cases, cleavage of
the signal sequence from a secreted protein is not entirely
uniform, resulting in more than one secreted species. These
polypeptides, and the polynucleotides encoding such polypeptides,
are contemplated by the present invention.
[1411] Moreover, the signal sequence identified by the above
analysis may not necessarily predict the naturally occurring signal
sequence. For example, the naturally occurring signal sequence may
be further upstream from the predicted signal sequence. However, it
is likely that the predicted signal sequence will be capable of
directing the secreted protein to the ER. These polypeptides, and
the polynucleotides encoding such polypeptides, are contemplated by
the present invention.
[1412] Polynucleotide and Polypeptide Variants
[1413] "Variant" refers to a polynucleotide or polypeptide
differing from the polynucleotide or polypeptide of the present
invention, but retaining essential properties thereof. Generally,
variants are overall closely similar, and, in many regions,
identical to the polynucleotide or polypeptide of the present
invention.
[1414] By a polynucleotide having a nucleotide sequence at least,
for example, 95% "identical" to a reference nucleotide sequence of
the present invention, it is intended that the nucleotide sequence
of the polynucleotide is identical to the reference sequence except
that the polynucleotide sequence may include up to five point
mutations per each 100 nucleotides of the reference nucleotide
sequence encoding the polypeptide. In other words, to obtain a
polynucleotide having a nucleotide sequence at least 95% identical
to a reference nucleotide sequence, up to 5% of the nucleotides in
the reference sequence may be deleted or substituted with another
nucleotide, or a number of nucleotides up to 5% of the total
nucleotides in the reference sequence may be inserted into the
reference sequence. The query sequence may be an entire sequence
shown in Table 1, the ORF (open reading frame), or any fragement
specified as described herein.
[1415] As a practical matter, whether any particular nucleic acid
molecule or polypeptide is at least 90%, 95%, 96%, 97%, 98% or 99%
identical to a nucleotide sequence of the presence invention can be
determined conventionally using known computer programs. A
preferred method for determining the best overall match between a
query sequence (a sequence of the present invention) and a subject
sequence, also referred to as a global sequence alignment, can be
determined using the FASTDB computer program based on the algorithm
of Brutlag et al. (Comp. App. Biosci. (1990) 6:237-245). In a
sequence alignment the query and subject sequences are both DNA
sequences. An RNA sequence can be compared by converting U's to
T's. The result of said global sequence alignment is in percent
identity. Preferred parameters used in a FASTDB alignment of DNA
sequences to calculate percent identiy are: Matrix=Unitary,
k-tuple=4, Mismatch Penalty=1, Joining Penalty=30, Randomization
Group Length=0, Cutoff Score=1, Gap Penalty=5, Gap Size Penalty
0.05, Window Size=500 or the lenght of the subject nucleotide
sequence, whichever is shorter.
[1416] If the subject sequence is shorter than the query sequence
because of 5' or 3' deletions, not because of internal deletions, a
manual correction must be made to the results. This is because the
FASTDB program does not account for 5' and 3' truncations of the
subject sequence when calculating percent identity. For subject
sequences truncated at the 5' or 3' ends, relative to the the query
sequence, the percent identity is corrected by calculating the
number of bases of the query sequence that are 5' and 3' of the
subject sequence, which are not matched/aligned, as a percent of
the total bases of the query sequence. Whether a nucleotide is
matched/aligned is determined by results of the FASTDB sequence
alignment. This percentage is then subtracted from the percent
identity, calculated by the above FASTDB program using the
specified parameters, to arrive at a final percent identity score.
This corrected score is what is used for the purposes of the
present invention. Only bases outside the 5' and 3' bases of the
subject sequence, as displayed by the FASTDB alignment, which are
not matched/aligned with the query sequence, are calculated for the
purposes of manually adjusting the percent identity score.
[1417] For example, a 90 base subject sequence is aligned to a 100
base query sequence to determine percent identity. The deletions
occur at the 5' end of the subject sequence and therefore, the
FASTDB alignment does not show a matched/alignement of the first 10
bases at 5' end. The 10 unpaired bases represent 10% of the
sequence (number of bases at the 5' and 3' ends not matched/total
number of bases in the query sequence) so 10% is subtracted from
the percent identity score calculated by the FASTDB program. If the
remaining 90 bases were perfectly matched the final percent
identity would be 90%. In another example, a 90 base subject
sequence is compared with a 100 base query sequence. This time the
deletions are internal deletions so that there are no bases on the
5' or 3' of the subject sequence which are not matched/aligned with
the query. In this case the percent identity calculated by FASTDB
is not manually corrected. Once again, only bases 5' and 3' of the
subject sequence which are not matched/aligned with the query
sequence are manually corrected for. No other manual corrections
are to made for the purposes of the present invention.
[1418] By a polypeptide having an amino acid sequence at least, for
example, 95% "identical" to a query amino acid sequence of the
present invention, it is intended that the amino acid sequence of
the subject polypeptide is identical to the query sequence except
that the subject polypeptide sequence may include up to five amino
acid alterations per each 100 amino acids of the query amino acid
sequence. In other words, to obtain a polypeptide having an amino
acid sequence at least 95% identical to a query amino acid
sequence, up to 5% of the amino acid residues in the subject
sequence may be inserted, deleted, (indels) or substituted with
another amino acid. These alterations of the reference sequence may
occur at the amino or carboxy terminal positions of the reference
amino acid sequence or anywhere between those terminal positions,
interspersed either individually among residues in the reference
sequence or in one or more contiguous groups within the reference
sequence.
[1419] As a practical matter, whether any particular polypeptide is
at least 90%, 95%, 96%, 97%, 98% or 99% identical to, for instance,
the amino acid sequences shown in Table 1 or to the amino acid
sequence encoded by deposited DNA clone can be determined
conventionally using known computer programs. A preferred method
for determing the best overall match between a query sequence (a
sequence of the present invention) and a subject sequence, also
referred to as a global sequence alignment, can be determined using
the FASTDB computer program based on the algorithm of Brutlag et
al. (Comp. App. Biosci. (1990) 6:237-245). In a sequence alignment
the query and subject sequences are either both nucleotide
sequences or both amino acid sequences. The result of said global
sequence alignment is in percent identity. Preferred parameters
used in a FASTDB amino acid alignment are: Matrix=PAM 0, k-tuple=2,
Mismatch Penalty=1, Joining Penalty=20, Randomization Group
Length=0, Cutoff Score=1, Window Size=sequence length, Gap
Penalty=5, Gap Size Penalty=0.05, Window Size=500 or the length of
the subject amino acid sequence, whichever is shorter.
[1420] If the subject sequence is shorter than the query sequence
due to N- or C-terminal deletions, not because of internal
deletions, a manual correction must be made to the results. This is
because the FASTDB program does not account for N- and C-terminal
truncations of the subject sequence when calculating global percent
identity. For subject sequences truncated at the N- and C-termini,
relative to the the query sequence, the percent identity is
corrected by calculating the number of residues of the query
sequence that are N- and C-terminal of the subject sequence, which
are not matched/aligned with a corresponding subject residue, as a
percent of the total bases of the query sequence. Whether a residue
is matched/aligned is determined by results of the FASTDB sequence
alignment. This percentage is then subtracted from the percent
identity, calculated by the above FASTDB program using the
specified parameters, to arrive at a final percent identity score.
This final percent identity score is what is used for the purposes
of the present invention. Only residues to the N- and C-termini of
the subject sequence, which are not matched/aligned with the query
sequence, are considered for the purposes of manually adjusting the
percent identity score. That is, only query residue positions
outside the farthest N- and C-terminal residues of the subject
sequence.
[1421] For example, a 90 amino acid residue subject sequence is
aligned with a 100 residue query sequence to determine percent
identity. The deletion occurs at the N-terminus of the subject
sequence and therefore, the FASTDB alignment does not show a
matching/alignment of the first 10 residues at the N-terminus. The
10 unpaired residues represent 10% of the sequence (number of
residues at the N- and C-termini not matched/total number of
residues in the query sequence) so 10% is subtracted from the
percent identity score calculated by the FASTDB program. If the
remaining 90 residues were perfectly matched the final percent
identity would be 90%. In another example, a 90 residue subject
sequence is compared with a 100 residue query sequence. This time
the deletions are internal deletions so there are no residues at
the N- or C-termini of the subject sequence which are not
matched/aligned with the query. In this case the percent identity
calculated by FASTDB is not manually corrected. Once again, only
residue positions outside the N- and C-terminal ends of the subject
sequence, as displayed in the FASTDB alignment, which are not
matched/aligned with the query sequence are manually corrected for.
No other manual corrections are to made for the purposes of the
present invention.
[1422] The variants may contain alterations in the coding regions,
non-coding regions, or both. Especially preferred are
polynucleotide variants containing alterations which produce silent
substitutions, additions, or deletions, but do not alter the
properties or activities of the encoded polypeptide. Nucleotide
variants produced by silent substitutions due to the degeneracy of
the genetic code are preferred. Moreover, variants in which 5-10,
1-5, or 1-2 amino acids are substituted, deleted, or added in any
combination are also preferred. Polynucleotide variants can be
produced for a variety of reasons, e.g., to optimize codon
expression for a particular host (change codons in the human mRNA
to those preferred by a bacterial host such as E. coli).
[1423] Naturally occurring variants are called "allelic variants,"
and refer to one of several alternate forms of a gene occupying a
given locus on a chromosome of an organism. (Genes II, Lewin, B.,
ed., John Wiley & Sons, New York (1985).) These allelic
variants can vary at either the polynucleotide and/or polypeptide
level. Alternatively, non-naturally occurring variants may be
produced by mutagenesis techniques or by direct synthesis.
[1424] Using known methods of protein engineering and recombinant
DNA technology, variants may be generated to improve or alter the
characteristics of the polypeptides of the present invention. For
instance, one or more amino acids can be deleted from the
N-terminus or C-terminus of the secreted protein without
substantial loss of biological function. The authors of Ron et al.,
J. Biol. Chem. 268: 2984-2988 (1993), reported variant KGF proteins
having heparin binding activity even after deleting 3, 8, or 27
amino-terminal amino acid residues. Similarly, Interferon gamma
exhibited up to ten times higher activity after deleting 8-10 amino
acid residues from the carboxy terminus of this protein. (Dobeli et
al., J. Biotechnology 7:199-216 (1988).)
[1425] Moreover, ample evidence demonstrates that variants often
retain a biological activity similar to that of the naturally
occurring protein. For example, Gayle and coworkers (J. Biol. Chem
268:22105-22111 (1993)) conducted extensive mutational analysis of
human cytokine IL-1a. They used random mutagenesis to generate over
3,500 individual IL-1a mutants that averaged 2.5 amino acid changes
per variant over the entire length of the molecule. Multiple
mutations were examined at every possible amino acid position. The
investigators found that "[m]ost of the molecule could be altered
with little effect on either [binding or biological activity]."
(See, Abstract.) In fact, only 23 unique amino acid sequences, out
of more than 3,500 nucleotide sequences examined, produced a
protein that significantly differed in activity from wild-type.
[1426] Furthermore, even if deleting one or more amino acids from
the N-terminus or C-terminus of a polypeptide results in
modification or loss of one or more biological functions, other
biological activities may still be retained. For example, the
ability of a deletion variant to induce and/or to bind antibodies
which recognize the secreted form will likely be retained when less
than the majority of the residues of the secreted form are removed
from the N-terminus or C-terminus. Whether a particular polypeptide
lacking N- or C-terminal residues of a protein retains such
immunogenic activities can readily be determined by routine methods
described herein and otherwise known in the art.
[1427] Thus, the invention further includes polypeptide variants
which show substantial biological activity. Such variants include
deletions, insertions, inversions, repeats, and substitutions
selected according to general rules known in the art so as have
little effect on activity. For example, guidance concerning how to
make phenotypically silent amino acid substitutions is provided in
Bowie, J. U. et al., Science 247:1306-1310 (1990), wherein the
authors indicate that there are two main strategies for studying
the tolerance of an amino acid sequence to change.
[1428] The first strategy exploits the tolerance of amino acid
substitutions by natural selection during the process of evolution.
By comparing amino acid sequences in different species, conserved
amino acids can be identified. These conserved amino acids are
likely important for protein function. in contrast, the amino acid
positions where substitutions have been tolerated by natural
selection indicates that these positions are not critical for
protein function. Thus, positions tolerating amino acid
substitution could be modified while still maintaining biological
activity of the protein.
[1429] The second strategy uses genetic engineering to introduce
amino acid changes at specific positions of a cloned gene to
identify regions critical for protein function. For example, site
directed mutagenesis or alanine-scanning mutagenesis (introduction
of single alanine mutations at every residue in the molecule) can
be used. (Cunningham and Wells, Science 244:1081-1085 (1989).) The
resulting mutant molecules can then be tested for biological
activity.
[1430] As the authors state, these two strategies have revealed
that proteins are surprisingly tolerant of amino acid
substitutions. The authors further indicate which amino acid
changes are likely to be permissive at certain amino acid positions
in the protein. For example, most buried (within the tertiary
structure of the protein) amino acid residues require nonpolar side
chains, whereas few features of surface side chains are generally
conserved. Moreover, tolerated conservative amino acid
substitutions involve replacement of the aliphatic or hydrophobic
amino acids Ala, Val, Leu and Ile; replacement of the hydroxyl
residues Ser and Thr; replacement of the acidic residues Asp and
Glu; replacement of the amide residues Asn and Gln, replacement of
the basic residues Lys, Arg, and His; replacement of the aromatic
residues Phe, Tyr, and Trp, and replacement of the small-sized
amino acids Ala, Ser, Thr, Met, and Gly.
[1431] Besides conservative amino acid substitution, variants of
the present invention include (i) substitutions with one or more of
the non-conserved amino acid residues, where the substituted amino
acid residues may or may not be one encoded by the genetic code, or
(ii) substitution with one or more of amino acid residues having a
substituent group, or (iii) fusion of the mature polypeptide with
another compound, such as a compound to increase the stability
and/or solubility of the polypeptide (for example, polyethylene
glycol), or (iv) fusion of the polypeptide with additional amino
acids, such as an IgG Fc fusion region peptide, or leader or
secretory sequence, or a sequence facilitating purification. Such
variant polypeptides are deemed to be within the scope of those
skilled in the art from the teachings herein.
[1432] For example, polypeptide variants containing amino acid
substitutions of charged amino acids with other charged or neutral
amino acids may produce proteins with improved characteristics,
such as less aggregation. Aggregation of pharmaceutical
formulations both reduces activity and increases clearance due to
the aggregate's immunogenic activity. (Pinckard et al., Clin. Exp.
Immunol. 2:331-340 (1967); Robbins et al., Diabetes 36: 838-845
(1987); Cleland et al., Crit. Rev. Therapeutic Drug Carrier Systems
10:307-377 (1993).)
[1433] Polynucleotide and Polypeptide Fragments
[1434] In the present invention, a "polynucleotide fragment" refers
to a short polynucleotide having a nucleic acid sequence contained
in the deposited clone or shown in SEQ ID NO:X. The short
nucleotide fragments are preferably at least about 15 nt, and more
preferably at least about 20 nt, still more preferably at least
about 30 nt, and even more preferably, at least about 40 nt in
length. A fragment "at least 20 nt in length," for example, is
intended to include 20 or more contiguous bases from the cDNA
sequence contained in the deposited clone or the nucleotide
sequence shown in SEQ ID NO:X. These nucleotide fragments are
useful as diagnostic probes and primers as discussed herein. Of
course, larger fragments (e.g., 50, 150, 500, 600, 2000
nucleotides) are preferred.
[1435] Moreover, representative examples of polynucleotide
fragments of the invention, include, for example, fragments having
a sequence from about nucleotide number 1-50, 51-100, 101-150,
151-200, 201-250, 251-300, 301-350, 351-400, 401-450, 451-500,
501-550, 551-600, 651-700, 701-750, 751-800, 800-850, 851-900,
901-950, 951-1000, 1001-1050, 1051-1100, 1101-1150, 1151-1200,
1201-1250, 1251-1300, 1301-1350, 1351-1400, 1401-1450, 1451-1500,
1501-1550, 1551-1600, 1601-1650, 1651-1700, 1701-1750, 1751-1800,
1801-1850, 1851-1900, 1901-1950, 1951-2000, or 2001 to the end of
SEQ ID NO:X or the cDNA contained in the deposited clone. In this
context "about" includes the particularly recited ranges, larger or
smaller by several (5, 4, 3, 2, or 1) nucleotides, at either
terminus or at both termini. Preferably, these fragments encode a
polypeptide which has biological activity. More preferably, these
polynucleotides can be used as probes or primers as discussed
herein.
[1436] In the present invention, a "polypeptide fragment" refers to
a short amino acid sequence contained in SEQ ID NO:Y or encoded by
the cDNA contained in the deposited clone. Protein fragments may be
"free-standing," or comprised within a larger polypeptide of which
the fragment forms a part or region, most preferably as a single
continuous region. Representative examples of polypeptide fragments
of the invention, include, for example, fragments from about amino
acid number 1-20, 21-40, 41-60, 61-80, 81-100, 102-120, 121-140,
141-160, or 161 to the end of the coding region. Moreover,
polypeptide fragments can be about 20, 30, 40, 50, 60, 70, 80, 90,
100, 110, 120, 130, 140, or 150 amino acids in length. In this
context "about" includes the particularly recited ranges, larger or
smaller by several (5, 4, 3, 2, or 1) amino acids, at either
extreme or at both extremes.
[1437] Preferred polypeptide fragments include the secreted protein
as well as the mature form. Further preferred polypeptide fragments
include the secreted protein or the mature form having a continuous
series of deleted residues from the amino or the carboxy terminus,
or both. For example, any number of amino acids, ranging from 1-60,
can be deleted from the amino terminus of either the secreted
polypeptide or the mature form. Similarly, any number of amino
acids, ranging from 1-30, can be deleted from the carboxy terminus
of the secreted protein or mature form. Furthermore, any
combination of the above amino and carboxy terminus deletions are
preferred. Similarly, polynucleotide fragments encoding these
polypeptide fragments are also preferred.
[1438] Also preferred are polypeptide and polynucleotide fragments
characterized by structural or functional domains, such as
fragments that comprise alpha-helix and alpha-helix forming
regions, beta-sheet and beta-sheet-forming regions, turn and
turn-forming regions, coil and coil-forming regions, hydrophilic
regions, hydrophobic regions, alpha amphipathic regions, beta
amphipathic regions, flexible regions, surface-forming regions,
substrate binding region, and high antigenic index regions.
Polypeptide fragments of SEQ ID NO:Y falling within conserved
domains are specifically contemplated by the present invention.
Moreover, polynucleotide fragments encoding these domains are also
contemplated.
[1439] Other preferred fragments are biologically active fragments.
Biologically active fragments are those exhibiting activity
similar, but not necessarily identical, to an activity of the
polypeptide of the present invention. The biological activity of
the fragments may include an improved desired activity, or a
decreased undesirable activity.
[1440] Epitopes & Antibodies
[1441] In the present invention, "epitopes" refer to polypeptide
fragments having antigenic or immunogenic activity in an animal,
especially in a human. A preferred embodiment of the present
invention relates to a polypeptide fragment comprising an epitope,
as well as the polynucleotide encoding this fragment. A region of a
protein molecule to which an antibody can bind is defined as an
"antigenic epitope." In contrast, an "immunogenic epitope" is
defined as a part of a protein that elicits an antibody response.
(See, for instance, Geysen et al., Proc. Natl. Acad. Sci. USA
81:3998-4002 (1983).)
[1442] Fragments which function as epitopes may be produced by any
conventional means. (See, e.g., Houghten, R. A., Proc. Natl. Acad.
Sci. USA 82:5131-5135 (1985) further described in U.S. Pat. No.
4,631,211.)
[1443] In the present invention, antigenic epitopes preferably
contain a sequence of at least seven, more preferably at least
nine, and most preferably between about 15 to about 30 amino acids.
Antigenic epitopes are useful to raise antibodies, including
monoclonal antibodies, that specifically bind the epitope. (See,
for instance, Wilson et al., Cell 37:767-778 (1984); Sutcliffe, J.
G. et al., Science 219:660-666 (1983).)
[1444] Similarly, immunogenic epitopes can be used to induce
antibodies according to methods well known in the art. (See, for
instance, Sutcliffe et al., supra; Wilson et al., supra; Chow, M.
et al., Proc. Natl. Acad. Sci. USA 82:910-914; and Bittle, F. J. et
al., J. Gen. Virol. 66:2347-2354 (1985).) A preferred immunogenic
epitope includes the secreted protein. The immunogenic epitopes may
be presented together with a carrier protein, such as an albumin,
to an animal system (such as rabbit or mouse) or, if it is long
enough (at least about 25 amino acids), without a carrier. However,
immunogenic epitopes comprising as few as 8 to 10 amino acids have
been shown to be sufficient to raise antibodies capable of binding
to, at the very least, linear epitopes in a denatured polypeptide
(e.g., in Western blotting.)
[1445] As used herein, the term "antibody" (Ab) or "monoclonal
antibody" (Mab) is meant to include intact molecules as well as
antibody fragments (such as, for example, Fab and F(ab')2
fragments) which are capable of specifically binding to protein.
Fab and Fab')2 fragments lack the Fc fragment of intact antibody,
clear more rapidly from the circulation, and may have less
non-specific tissue binding than an intact antibody. (Wahl et al.,
J. Nucl. Med. 24:316-325 (1983).) Thus, these fragments are
preferred, as well as the products of a FAB or other immunoglobulin
expression library. Moreover, antibodies of the present invention
include chimeric, single chain, and humanized antibodies.
[1446] Fusion Proteins
[1447] Any polypeptide of the present invention can be used to
generate fusion proteins. For example, the polypeptide of the
present invention, when fused to a second protein, can be used as
an antigenic tag. Antibodies raised against the polypeptide of the
present invention can be used to indirectly detect the second
protein by binding to the polypeptide. Moreover, because secreted
proteins target cellular locations based on trafficking signals,
the polypeptides of the present invention can be used as targeting
molecules once fused to other proteins.
[1448] Examples of domains that can be fused to polypeptides of the
present invention include not only heterologous signal sequences,
but also other heterologous functional regions. The fusion does not
necessarily need to be direct, but may occur through linker
sequences.
[1449] Moreover, fusion proteins may also be engineered to improve
characteristics of the polypeptide of the present invention. For
instance, a region of additional amino acids, particularly charged
amino acids, may be added to the N-terminus of the polypeptide to
improve stability and persistence during purification from the host
cell or subsequent handling and storage. Also, peptide moieties may
be added to the polypeptide to facilitate purification. Such
regions may be removed prior to final preparation of the
polypeptide. The addition of peptide moieties to facilitate
handling of polypeptides are familiar and routine techniques in the
art.
[1450] Moreover, polypeptides of the present invention, including
fragments, and specifically epitopes, can be combined with parts of
the constant domain of immunoglobulins (IgG), resulting in chimeric
polypeptides. These fusion proteins facilitate purification and
show an increased half-life in vivo. One reported example describes
chimeric proteins consisting of the first two domains of the human
CD4-polypeptide and various domains of the constant regions of the
heavy or light chains of mammalian immunoglobulins. (EP A 394,827;
Traunecker et al., Nature 331:84-86 (1988).) Fusion proteins having
disulfide-linked dimeric structures (due to the IgG) can also be
more efficient in binding and neutralizing other molecules, than
the monomeric secreted protein or protein fragment alone.
(Fountoulakis et al., J. Biochem. 270:3958-3964 (1995).)
[1451] Similarly, EP-A-O 464 533 (Canadian counterpart 2045869)
discloses fusion proteins comprising various portions of constant
region of immunoglobulin molecules together with another human
protein or part thereof. In many cases, the Fc part in a fusion
protein is beneficial in therapy and diagnosis, and thus can result
in, for example, improved pharmacokinetic properties. (EP-A 0232
262.) Alternatively, deleting the Fc part after the fusion protein
has been expressed, detected, and purified, would be desired. For
example, the Fc portion may hinder therapy and diagnosis if the
fusion protein is used as an antigen for immunizations. In drug
discovery, for example, human proteins, such as hIL-5, have been
fused with Fc portions for the purpose of high-throughput screening
assays to identify antagonists of hIL-5. (See, D. Bennett et al.,
J. Molecular Recognition 8:52-58 (1995); K. Johanson et al., J.
Biol. Chem. 270:9459-9471 (1995).)
[1452] Moreover, the polypeptides of the present invention can be
fused to marker sequences, such as a peptide which facilitates
purification of the fused polypeptide. In preferred embodiments,
the marker amino acid sequence is a hexa-histidine peptide, such as
the tag provided in a pQE vector (QIAGEN, Inc., 9259 Eton Avenue,
Chatsworth, Calif., 91311), among others, many of which are
commercially available. As described in Gentz et al., Proc. Natl.
Acad. Sci. USA 86:821-824 (1989), for instance, hexa-histidine
provides for convenient purification of the fusion protein. Another
peptide tag useful for purification, the "HA" tag, corresponds to
an epitope derived from the influenza hemagglutinin protein.
(Wilson et al., Cell 37:767 (1984).)
[1453] Thus, any of these above fusions can be engineered using the
polynucleotides or the polypeptides of the present invention.
[1454] Vectors, Host Cells, and Protein Production
[1455] The present invention also relates to vectors containing the
polynucleotide of the present invention, host cells, and the
production of polypeptides by recombinant techniques. The vector
may be, for example, a phage, plasmid, viral, or retroviral vector.
Retroviral vectors may be replication competent or replication
defective. In the latter case, viral propagation generally will
occur only in complementing host cells.
[1456] The polynucleotides may be joined to a vector containing a
selectable marker for propagation in a host. Generally, a plasmid
vector is introduced in a precipitate, such as a calcium phosphate
precipitate, or in a complex with a charged lipid. If the vector is
a virus, it may be packaged in vitro using an appropriate packaging
cell line and then transduced into host cells.
[1457] The polynucleotide insert should be operatively linked to an
appropriate promoter, such as the phage lambda PL promoter, the E.
coli lac, trp, phoA and tac promoters, the SV40 early and late
promoters and promoters of retroviral LTRs, to name a few. Other
suitable promoters will be known to the skilled artisan. The
expression constructs will further contain sites for transcription
initiation, termination, and, in the transcribed region, a ribosome
binding site for translation. The coding portion of the transcripts
expressed by the constructs will preferably include a translation
initiating codon at the beginning and a termination codon (UAA, UGA
or UAG) appropriately positioned at the end of the polypeptide to
be translated.
[1458] As indicated, the expression vectors will preferably include
at least one selectable marker. Such markers include dihydrofolate
reductase, G418 or neomycin resistance for eukaryotic cell culture
and tetracycline, kanamycin or ampicillin resistance genes for
culturing in E. coli and other bacteria. Representative examples of
appropriate hosts include, but are not limited to, bacterial cells,
such as E. coli, Streptomyces and Salmonella typhimurium cells;
fungal cells, such as yeast cells; insect cells such as Drosophila
S2 and Spodoptera Sf9 cells; animal cells such as CHO, COS, 293,
and Bowes melanoma cells; and plant cells. Appropriate culture
mediums and conditions for the above-described host cells are known
in the art.
[1459] Among vectors preferred for use in bacteria include pQE70,
pQE60 and pQE-9, available from QIAGEN, Inc.; pBluescript vectors,
Phagescript vectors, pNH8A, pNH16a, pNH18A, pNH46A, available from
Stratagene Cloning Systems, Inc.; and ptrc99a, pKK223-3, pKK233-3,
pDR540, pRIT5 available from Pharmacia Biotech, Inc. Among
preferred eukaryotic vectors are pWLNEO, pSV2CAT, pOG44, pXT1 and
pSG available from Stratagene; and pSVK3, pBPV, pMSG and pSVL
available from Pharmacia. Other suitable vectors will be readily
apparent to the skilled artisan.
[1460] Introduction of the construct into the host cell can be
effected by calcium phosphate transfection, DEAE-dextran mediated
transfection, cationic lipid-mediated transfection,
electroporation, transduction, infection, or other methods. Such
methods are described in many standard laboratory manuals, such as
Davis et al., Basic Methods In Molecular Biology (1986). It is
specifically contemplated that the polypeptides of the present
invention may in fact be expressed by a host cell lacking a
recombinant vector.
[1461] A polypeptide of this invention can be recovered and
purified from recombinant cell cultures by well-known methods
including ammonium sulfate or ethanol precipitation, acid
extraction, anion or cation exchange chromatography,
phosphocellulose chromatography, hydrophobic interaction
chromatography, affinity chromatography, hydroxylapatite
chromatography and lectin chromatography. Most preferably, high
performance liquid chromatography ("HPLC") is employed for
purification.
[1462] Polypeptides of the present invention, and preferably the
secreted form, can also be recovered from: products purified from
natural sources, including bodily fluids, tissues and cells,
whether directly isolated or cultured; products of chemical
synthetic procedures; and products produced by recombinant
techniques from a prokaryotic or eukaryotic host, including, for
example, bacterial, yeast, higher plant, insect, and mammalian
cells. Depending upon the host employed in a recombinant production
procedure, the polypeptides of the present invention may be
glycosylated or may be non-glycosylated. In addition, polypeptides
of the invention may also include an initial modified methionine
residue, in some cases as a result of host-mediated processes.
Thus, it is well known in the art that the N-terminal methionine
encoded by the translation initiation codon generally is removed
with high efficiency from any protein after translation in all
eukaryotic cells. While the N-terminal methionine on most proteins
also is efficiently removed in most prokaryotes, for some proteins,
this prokaryotic removal process is inefficient, depending on the
nature of the amino acid to which the N-terminal methionine is
covalently linked.
[1463] Uses of the Polynucleotides
[1464] Each of the polynucleotides identified herein can be used in
numerous ways as reagents. The following description should be
considered exemplary and utilizes known techniques.
[1465] The polynucleotides of the present invention are useful for
chromosome identification. There exists an ongoing need to identify
new chromosome markers, since few chromosome marking reagents,
based on actual sequence data (repeat polymorphisms), are presently
available. Each polynucleotide of the present invention can be used
as a chromosome marker.
[1466] Briefly, sequences can be mapped to chromosomes by preparing
PCR primers (preferably 15-25 bp) from the sequences shown in SEQ
ID NO:X. Primers can be selected using computer analysis so that
primers do not span more than one predicted exon in the genomic
DNA. These primers are then used for PCR screening of somatic cell
hybrids containing individual human chromosomes. Only those hybrids
containing the human gene corresponding to the SEQ ID NO:X will
yield an amplified fragment.
[1467] Similarly, somatic hybrids provide a rapid method of PCR
mapping the polynucleotides to particular chromosomes. Three or
more clones can be assigned per day using a single thermal cycler.
Moreover, sublocalization of the polynucleotides can be achieved
with panels of specific chromosome fragments. Other gene mapping
strategies that can be used include in situ hybridization,
prescreening with labeled flow-sorted chromosomes, and preselection
by hybridization to construct chromosome specific-cDNA
libraries.
[1468] Precise chromosomal location of the polynucleotides can also
be achieved using fluorescence in situ hybridization (FISH) of a
metaphase chromosomal spread. This technique uses polynucleotides
as short as 500 or 600 bases; however, polynucleotides 2,000-4,000
bp are preferred. For a review of this technique, see Verma et al.,
"Human Chromosomes: a Manual of Basic Techniques," Pergamon Press,
New York (1988).
[1469] For chromosome mapping, the polynucleotides can be used
individually (to mark a single chromosome or a single site on that
chromosome) or in panels (for marking multiple sites and/or
multiple chromosomes). Preferred polynucleotides correspond to the
noncoding regions of the cDNAs because the coding sequences are
more likely conserved within gene families, thus increasing the
chance of cross hybridization during chromosomal mapping.
[1470] Once a polynucleotide has been mapped to a precise
chromosomal location, the physical position of the polynucleotide
can be used in linkage analysis. Linkage analysis establishes
coinheritance between a chromosomal location and presentation of a
particular disease. (Disease mapping data are found, for example,
in V. McKusick, Mendelian Inheritance in Man (available on line
through Johns Hopkins University Welch Medical Library).) Assuming
1 megabase mapping resolution and one gene per 20 kb, a cDNA
precisely localized to a chromosomal region associated with the
disease could be one of 50-500 potential causative genes.
[1471] Thus, once coinheritance is established, differences in the
polynucleotide and the corresponding gene between affected and
unaffected individuals can be examined. First, visible structural
alterations in the chromosomes, such as deletions or
translocations, are examined in chromosome spreads or by PCR. If no
structural alterations exist, the presence of point mutations are
ascertained. Mutations observed in some or all affected
individuals, but not in normal individuals, indicates that the
mutation may cause the disease. However, complete sequencing of the
polypeptide and the corresponding gene from several normal
individuals is required to distinguish the mutation from a
polymorphism. If a new polymorphism is identified, this polymorphic
polypeptide can be used for further linkage analysis.
[1472] Furthermore, increased or decreased expression of the gene
in affected individuals as compared to unaffected individuals can
be assessed using polynucleotides of the present invention. Any of
these alterations (altered expression, chromosomal rearrangement,
or mutation) can be used as a diagnostic or prognostic marker.
[1473] In addition to the foregoing, a polynucleotide can be used
to control gene expression through triple helix formation or
antisense DNA or RNA. Both methods rely on binding of the
polynucleotide to DNA or RNA. For these techniques, preferred
polynucleotides are usually 20 to 40 bases in length and
complementary to either the region of the gene involved in
transcription (triple helix--see Lee et al., Nucl. Acids Res.
6:3073 (1979); Cooney et al., Science 241:456 (1988); and Dervan et
al., Science 251:1360 (1991) ) or to the mRNA itself
(antisense--Okano, J. Neurochem. 56:560 (1991);
Oligodeoxy-nucleotides as Antisense Inhibitors of Gene Expression,
CRC Press, Boca Raton, Fla. (1988).) Triple helix formation
optimally results in a shut-off of RNA transcription from DNA,
while antisense RNA hybridization blocks translation of an mRNA
molecule into polypeptide. Both techniques are effective in model
systems, and the information disclosed herein can be used to design
antisense or triple helix polynucleotides in an effort to treat
disease.
[1474] Polynucleotides of the present invention are also useful in
gene therapy. One goal of gene therapy is to insert a normal gene
into an organism having a defective gene, in an effort to correct
the genetic defect. The polynucleotides disclosed in the present
invention offer a means of targeting such genetic defects in a
highly accurate manner. Another goal is to insert a new gene that
was not present in the host genome, thereby producing a new trait
in the host cell.
[1475] The polynucleotides are also useful for identifying
individuals from minute biological samples. The United States
military, for example, is considering the use of restriction
fragment length polymorphism (RFLP) for identification of its
personnel. In this technique, an individual's genomic DNA is
digested with one or more restriction enzymes, and probed on a
Southern blot to yield unique bands for identifying personnel. This
method does not suffer from the current limitations of "Dog Tags"
which can be lost, switched, or stolen, making positive
identification difficult. The polynucleotides of the present
invention can be used as additional DNA markers for RFLP.
[1476] The polynucleotides of the present invention can also be
used as an alternative to RFLP, by determining the actual
base-by-base DNA sequence of selected portions of an individual's
genome. These sequences can be used to prepare PCR primers for
amplifying and isolating such selected DNA, which can then be
sequenced. Using this technique, individuals can be identified
because each individual will have a unique set of DNA sequences.
Once an unique ID database is established for an individual,
positive identification of that individual, living or dead, can be
made from extremely small tissue samples.
[1477] Forensic biology also benefits from using DNA-based
identification techniques as disclosed herein. DNA sequences taken
from very small biological samples such as tissues, e.g., hair or
skin, or body fluids, e.g., blood, saliva, semen, etc., can be
amplified using PCR. In one prior art technique, gene sequences
amplified from polymorphic loci, such as DQa class II HLA gene, are
used in forensic biology to identify individuals. (Erlich, H., PCR
Technology, Freeman and Co. (1992).) Once these specific
polymorphic loci are amplified, they are digested with one or more
restriction enzymes, yielding an identifying set of bands on a
Southern blot probed with DNA corresponding to the DQa class II HLA
gene. Similarly, polynucleotides of the present invention can be
used as polymorphic markers for forensic purposes.
[1478] There is also a need for reagents capable of identifying the
source of a particular tissue. Such need arises, for example, in
forensics when presented with tissue of unknown origin. Appropriate
reagents can comprise, for example, DNA probes or primers specific
to particular tissue prepared from the sequences of the present
invention. Panels of such reagents can identify tissue by species
and/or by organ type. In a similar fashion, these reagents can be
used to screen tissue cultures for contamination.
[1479] In the very least, the polynucleotides of the present
invention can be used as molecular weight markers on Southern gels,
as diagnostic probes for the presence of a specific mRNA in a
particular cell type, as a probe to "subtract-out" known sequences
in the process of discovering novel polynucleotides, for selecting
and making oligomers for attachment to a "gene chip" or other
support, to raise anti-DNA antibodies using DNA immunization
techniques, and as an antigen to elicit an immune response.
[1480] Uses of the Polypeptides
[1481] Each of the polypeptides identified herein can be used in
numerous ways. The following description should be considered
exemplary and utilizes known techniques.
[1482] A polypeptide of the present invention can be used to assay
protein levels in a biological sample using antibody-based
techniques. For example, protein expression in tissues can be
studied with classical immunohistological methods. (Jalkanen, M.,
et al., J. Cell. Biol. 101:976-985 (1985); Jalkanen, M., et al., J.
Cell . Biol. 105:3087-3096 (1987).) Other antibody-based methods
useful for detecting protein gene expression include immunoassays,
such as the enzyme linked immunosorbent assay (ELISA) and the
radioimmunoassay (RIA). Suitable antibody assay labels are known in
the art and include enzyme labels, such as, glucose oxidase, and
radioisotopes, such as iodine (125I, 121I), carbon (14C), sulfur
(35S), tritium (3H), indium (112In), and technetium (99mTc), and
fluorescent labels, such as fluorescein and rhodamine, and
biotin.
[1483] In addition to assaying secreted protein levels in a
biological sample, proteins can also be detected in vivo by
imaging. Antibody labels or markers for in vivo imaging of protein
include those detectable by X-radiography, NMR or ESR. For
X-radiography, suitable labels include radioisotopes such as barium
or cesium, which emit detectable radiation but are not overtly
harmful to the subject. Suitable markers for NMR and ESR include
those with a detectable characteristic spin, such as deuterium,
which may be incorporated into the antibody by labeling of
nutrients for the relevant hybridoma.
[1484] A protein-specific antibody or antibody fragment which has
been labeled with an appropriate detectable imaging moiety, such as
a radioisotope (for example, 131I, 112In, 99mTc), a radio-opaque
substance, or a material detectable by nuclear magnetic resonance,
is introduced (for example, parenterally, subcutaneously, or
intraperitoneally) into the mammal. It will be understood in the
art that the size of the subject and the imaging system used will
determine the quantity of imaging moiety needed to produce
diagnostic images. In the case of a radioisotope moiety, for a
human subject, the quantity of radioactivity injected will normally
range from about 5 to 20 millicuries of 99mTc. The labeled antibody
or antibody fragment will then preferentially accumulate at the
location of cells which contain the specific protein. In vivo tumor
imaging is described in S. W. Burchiel et al.,
"Immunopharmacokinetics of Radiolabeled Antibodies and Their
Fragments." (Chapter 13 in Tumor Imaging: The Radiochemical
Detection of Cancer, S. W. Burchiel and B. A. Rhodes, eds., Masson
Publishing Inc. (1982).)
[1485] Thus, the invention provides a diagnostic method of a
disorder, which involves (a) assaying the expression of a
polypeptide of the present invention in cells or body fluid of an
individual; (b) comparing the level of gene expression with a
standard gene expression level, whereby an increase or decrease in
the assayed polypeptide gene expression level compared to the
standard expression level is indicative of a disorder.
[1486] Moreover, polypeptides of the present invention can be used
to treat disease. For example, patients can be administered a
polypeptide of the present invention in an effort to replace absent
or decreased levels of the polypeptide (e.g., insulin), to
supplement absent or decreased levels of a different polypeptide
(e.g., hemoglobin S for hemoglobin B), to inhibit the activity of a
polypeptide (e.g., an oncogene), to activate the activity of a
polypeptide (e.g., by binding to a receptor), to reduce the
activity of a membrane bound receptor by competing with it for free
ligand (e.g., soluble TNF receptors used in reducing inflammation),
or to bring about a desired response (e.g., blood vessel
growth).
[1487] Similarly, antibodies directed to a polypeptide of the
present invention can also be used to treat disease. For example,
administration of an antibody directed to a polypeptide of the
present invention can bind and reduce overproduction of the
polypeptide. Similarly, administration of an antibody can activate
the polypeptide, such as by binding to a polypeptide bound to a
membrane (receptor).
[1488] At the very least, the polypeptides of the present invention
can be used as molecular weight markers on SDS-PAGE gels or on
molecular sieve gel filtration columns using methods well known to
those of skill in the art. Polypeptides can also be used to raise
antibodies, which in turn are used to measure protein expression
from a recombinant cell, as a way of assessing transformation of
the host cell. Moreover, the polypeptides of the present invention
can be used to test the following biological activities.
[1489] Biological Activities
[1490] The polynucleotides and polypeptides of the present
invention can be used in assays to test for one or more biological
activities. If these polynucleotides and polypeptides do exhibit
activity in a particular assay, it is likely that these molecules
may be involved in the diseases associated with the biological
activity. Thus, the polynucleotides and polypeptides could be used
to treat the associated disease.
[1491] Immune Activity
[1492] A polypeptide or polynucleotide of the present invention may
be useful in treating deficiencies or disorders of the immune
system, by activating or inhibiting the proliferation,
differentiation, or mobilization (chemotaxis) of immune cells.
Immune cells develop through a process called hematopoiesis,
producing myeloid (platelets, red blood cells, neutrophils, and
macrophages) and lymphoid (B and T lymphocytes) cells from
pluripotent stem cells. The etiology of these immune deficiencies
or disorders may be genetic, somatic, such as cancer or some
autoimmune disorders, acquired (e.g., by chemotherapy or toxins),
or infectious. Moreover, a polynucleotide or polypeptide of the
present invention can be used as a marker or detector of a
particular immune system disease or disorder.
[1493] A polynucleotide or polypeptide of the present invention may
be useful in treating or detecting deficiencies or disorders of
hematopoietic cells. A polypeptide or polynucleotide of the present
invention could be used to increase differentiation and
proliferation of hematopoietic cells, including the pluripotent
stem cells, in an effort to treat those disorders associated with a
decrease in certain (or many) types hematopoietic cells. Examples
of immunologic deficiency syndromes include, but are not limited
to: blood protein disorders (e.g. agammaglobulinemia,
dysgammaglobulinemia), ataxia telangiectasia, common variable
immunodeficiency, Digeorge Syndrome, HIV infection, HTLV-BLV
infection, leukocyte adhesion deficiency syndrome, lymphopenia,
phagocyte bactericidal dysfunction, severe combined
immunodeficiency (SCIDs), Wiskott-Aldrich Disorder, anemia,
thrombocytopenia, or hemoglobinuria.
[1494] Moreover, a polypeptide or polynucleotide of the present
invention could also be used to modulate hemostatic (the stopping
of bleeding) or thrombolytic activity (clot formation). For
example, by increasing hemostatic or thrombolytic activity, a
polynucleotide or polypeptide of the present invention could be
used to treat blood coagulation disorders (e.g., afibrinogenemia,
factor deficiencies), blood platelet disorders (e.g.
thrombocytopenia), or wounds resulting from trauma, surgery, or
other causes. Alternatively, a polynucleotide or polypeptide of the
present invention that can decrease hemostatic or thrombolytic
activity could be used to inhibit or dissolve clotting. These
molecules could be important in the treatment of heart attacks
(infarction), strokes, or scarring.
[1495] A polynucleotide or polypeptide of the present invention may
also be useful in treating or detecting autoimmune disorders. Many
autoimmune disorders result from inappropriate recognition of self
as foreign material by immune cells. This inappropriate recognition
results in an immune response leading to the destruction of the
host tissue. Therefore, the administration of a polypeptide or
polynucleotide of the present invention that inhibits an immune
response, particularly the proliferation, differentiation, or
chemotaxis of T-cells, may be an effective therapy in preventing
autoimmune disorders.
[1496] Examples of autoimmune disorders that can be treated or
detected by the present invention include, but are not limited to:
Addison's Disease, hemolytic anemia, antiphospholipid syndrome,
rheumatoid arthritis, dermatitis, allergic encephalomyelitis,
glomerulonephritis, Goodpasture's Syndrome, Graves' Disease,
Multiple Sclerosis, Myasthenia Gravis, Neuritis, Ophthalmia,
Bullous Pemphigoid, Pemphigus, Polyendocrinopathies, Purpura,
Reiter's Disease, Stiff-Man Syndrome, Autoimmune Thyroiditis,
Systemic Lupus Erythematosus, Autoimmune Pulmonary Inflammation,
Guillain-Barre Syndrome, insulin dependent diabetes mellitis, and
autoimmune inflammatory eye disease.
[1497] Similarly, allergic reactions and conditions, such as asthma
(particularly allergic asthma) or other respiratory problems, may
also be treated by a polypeptide or polynucleotide of the present
invention. Moreover, these molecules can be used to treat
anaphylaxis, hypersensitivity to an antigenic molecule, or blood
group incompatibility.
[1498] A polynucleotide or polypeptide of the present invention may
also be used to treat and/or prevent organ rejection or
graft-versus-host disease (GVHD). Organ rejection occurs by host
immune cell destruction of the transplanted tissue through an
immune response. Similarly, an immune response is also involved in
GVHD, but, in this case, the foreign transplanted immune cells
destroy the host tissues. The administration of a polypeptide or
polynucleotide of the present invention that inhibits an immune
response, particularly the proliferation, differentiation, or
chemotaxis of T-cells, may be an effective therapy in preventing
organ rejection or GVHD.
[1499] Similarly, a polypeptide or polynucleotide of the present
invention may also be used to modulate inflammation. For example,
the polypeptide or polynucleotide may inhibit the proliferation and
differentiation of cells involved in an inflammatory response.
These molecules can be used to treat inflammatory conditions, both
chronic and acute conditions, including inflammation associated
with infection (e.g., septic shock, sepsis, or systemic
inflammatory response syndrome (SIRS)), ischemia-reperfusion
injury, endotoxin lethality, arthritis, complement-mediated
hyperacute rejection, nephritis, cytokine or chemokine induced lung
injury, inflammatory bowel disease, Crohn's disease, or resulting
from over production of cytokines (e.g., TNF or IL-1.)
[1500] Hyperproliferative Disorders
[1501] A polypeptide or polynucleotide can be used to treat or
detect hyperproliferative disorders, including neoplasms. A
polypeptide or polynucleotide of the present invention may inhibit
the proliferation of the disorder through direct or indirect
interactions. Alternatively, a polypeptide or polynucleotide of the
present invention may proliferate other cells which can inhibit the
hyperproliferative disorder.
[1502] For example, by increasing an immune response, particularly
increasing antigenic qualities of the hyperproliferative disorder
or by proliferating, differentiating, or mobilizing T-cells,
hyperproliferative disorders can be treated. This immune response
may be increased by either enhancing an existing immune response,
or by initiating a new immune response. Alternatively, decreasing
an immune response may also be a method of treating
hyperproliferative disorders, such as a chemotherapeutic agent.
[1503] Examples of hyperproliferative disorders that can be treated
or detected by a polynucleotide or polypeptide of the present
invention include, but are not limited to neoplasms located in the:
abdomen, bone, breast, digestive system, liver, pancreas,
peritoneum, endocrine glands (adrenal, parathyroid, pituitary,
testicles, ovary, thymus, thyroid), eye, head and neck, nervous
(central and peripheral), lymphatic system, pelvic, skin, soft
tissue, spleen, thoracic, and urogenital.
[1504] Similarly, other hyperproliferative disorders can also be
treated or detected by a polynucleotide or polypeptide of the
present invention. Examples of such hyperproliferative disorders
include, but are not limited to: hypergammaglobulinemia,
lymphoproliferative disorders, paraproteinemias, purpura,
sarcoidosis, Sezary Syndrome, Waldenstron's Macroglobulinemia,
Gaucher's Disease, histiocytosis, and any other hyperproliferative
disease, besides neoplasia, located in an organ system listed
above.
[1505] Infectious Disease
[1506] A polypeptide or polynucleotide of the present invention can
be used to treat or detect infectious agents. For example, by
increasing the immune response, particularly increasing the
proliferation and differentiation of B and/or T cells, infectious
diseases may be treated. The immune response may be increased by
either enhancing an existing immune response, or by initiating a
new immune response. Alternatively, the polypeptide or
polynucleotide of the present invention may also directly inhibit
the infectious agent, without necessarily eliciting an immune
response.
[1507] Viruses are one example of an infectious agent that can
cause disease or symptoms that can be treated or detected by a
polynucleotide or polypeptide of the present invention. Examples of
viruses, include, but are not limited to the following DNA and RNA
viral families: Arbovirus, Adenoviridae, Arenaviridae, Arterivirus,
Birnaviridae, Bunyaviridae, Caliciviridae, Circoviridae,
Coronaviridae, Flaviviridae, Hepadnaviridae (Hepatitis),
Herpesviridae (such as, Cytomegalovirus, Herpes Simplex, Herpes
Zoster), Mononegavirus (e.g., Paramyxoviridae, Morbillivirus,
Rhabdoviridae), Orthomyxoviridae (e.g., Influenza), Papovaviridae,
Parvoviridae, Picornaviridae, Poxviridae (such as Smallpox or
Vaccinia), Reoviridae (e.g., Rotavirus), Retroviridae (HTLV-II,
HTLV-II, Lentivirus), and Togaviridae (e.g., Rubivirus). Viruses
falling within these families can cause a variety of diseases or
symptoms, including, but not limited to: arthritis, bronchiollitis,
encephalitis, eye infections (e.g., conjunctivitis, keratitis),
chronic fatigue syndrome, hepatitis (A, B, C, E, Chronic Active,
Delta), meningitis, opportunistic infections (e.g., AIDS),
pneumonia, Burkitt's Lymphoma, chickenpox, hemorrhagic fever,
Measles, Mumps, Parainfluenza, Rabies, the common cold, Polio,
leukemia, Rubella, sexually transmitted diseases, skin diseases
(e.g., Kaposi's, warts), and viremia. A polypeptide or
polynucleotide of the present invention can be used to treat or
detect any of these symptoms or diseases.
[1508] Similarly, bacterial or fungal agents that can cause disease
or symptoms and that can be treated or detected by a polynucleotide
or polypeptide of the present invention include, but not limited
to, the following Gram-Negative and Gram-positive bacterial
families and fungi: Actinomycetales (e.g., Corynebacterium,
Mycobacterium, Norcardia), Aspergillosis, Bacillaceae (e.g.,
Anthrax, Clostridium), Bacteroidaceae, Blastomycosis, Bordetella,
Borrelia, Brucellosis, Candidiasis, Campylobacter,
Coccidioidomycosis, Cryptococcosis, Dermatocycoses,
Enterobacteriaceae (Klebsiella, Salmonella, Serratia, Yersinia),
Erysipelothrix, Helicobacter, Legionellosis, Leptospirosis,
Listeria, Mycoplasmatales, Neisseriaceae (e.g., Acinetobacter,
Gonorrhea, Menigococcal), Pasteurellacea Infections (e.g.,
Actinobacillus, Heamophilus, Pasteurella), Pseudomonas,
Rickettsiaceae, Chlamydiaceae, Syphilis, and Staphylococcal. These
bacterial or fungal families can cause the following diseases or
symptoms, including, but not limited to: bacteremia, endocarditis,
eye infections (conjunctivitis, tuberculosis, uveitis), gingivitis,
opportunistic infections (e.g., AIDS related infections),
paronychia, prosthesis-related infections, Reiter's Disease,
respiratory tract infections, such as Whooping Cough or Empyema,
sepsis, Lyme Disease, Cat-Scratch Disease, Dysentery, Paratyphoid
Fever, food poisoning, Typhoid, pneumonia, Gonorrhea, meningitis,
Chlamydia, Syphilis, Diphtheria, Leprosy, Paratuberculosis,
Tuberculosis, Lupus, Botulism, gangrene, tetanus, impetigo,
Rheumatic Fever, Scarlet Fever, sexually transmitted diseases, skin
diseases (e.g., cellulitis, dermatocycoses), toxemia, urinary tract
infections, wound infections. A polypeptide or polynucleotide of
the present invention can be used to treat or detect any of these
symptoms or diseases.
[1509] Moreover, parasitic agents causing disease or symptoms that
can be treated or detected by a polynucleotide or polypeptide of
the present invention include, but not limited to, the following
families: Amebiasis, Babesiosis, Coccidiosis, Cryptosporidiosis,
Dientamoebiasis, Dourine, Ectoparasitic, Giardiasis, Helminthiasis,
Leishmaniasis, Theileriasis, Toxoplasmosis, Trypanosomiasis, and
Trichomonas. These parasites can cause a variety of diseases or
symptoms, including, but not limited to: Scabies, Trombiculiasis,
eye infections, intestinal disease (e.g., dysentery, giardiasis),
liver disease, lung disease, opportunistic infections (e.g., AIDS
related), Malaria, pregnancy complications, and toxoplasmosis. A
polypeptide or polynucleotide of the present invention can be used
to treat or detect any of these symptoms or diseases.
[1510] Preferably, treatment using a polypeptide or polynucleotide
of the present invention could either be by administering an
effective amount of a polypeptide to the patient, or by removing
cells from the patient, supplying the cells with a polynucleotide
of the present invention, and returning the engineered cells to the
patient (ex vivo therapy). Moreover, the polypeptide or
polynucleotide of the present invention can be used as an antigen
in a vaccine to raise an immune response against infectious
disease.
[1511] Regeneration
[1512] A polynucleotide or polypeptide of the present invention can
be used to differentiate, proliferate, and attract cells, leading
to the regeneration of tissues. (See, Science 276:59-87 (1997).)
The regeneration of tissues could be used to repair, replace, or
protect tissue damaged by congenital defects, trauma (wounds,
burns, incisions, or ulcers), age, disease (e.g. osteoporosis,
osteocarthritis, periodontal disease, liver failure), surgery,
including cosmetic plastic surgery, fibrosis, reperfusion injury,
or systemic cytokine damage.
[1513] Tissues that could be regenerated using the present
invention include organs (e.g., pancreas, liver, intestine, kidney,
skin, endothelium), muscle (smooth, skeletal or cardiac), vascular
(including vascular endothelium), nervous, hematopoietic, and
skeletal (bone, cartilage, tendon, and ligament) tissue.
Preferably, regeneration occurs without or decreased scarring.
Regeneration also may include angiogenesis.
[1514] Moreover, a polynucleotide or polypeptide of the present
invention may increase regeneration of tissues difficult to heal.
For example, increased tendon/ligament regeneration would quicken
recovery time after damage. A polynucleotide or polypeptide of the
present invention could also be used prophylactically in an effort
to avoid damage. Specific diseases that could be treated include of
tendinitis, carpal tunnel syndrome, and other tendon or ligament
defects. A further example of tissue regeneration of non-healing
wounds includes pressure ulcers, ulcers associated with vascular
insufficiency, surgical, and traumatic wounds.
[1515] Similarly, nerve and brain tissue could also be regenerated
by using a polynucleotide or polypeptide of the present invention
to proliferate and differentiate nerve cells. Diseases that could
be treated using this method include central and peripheral nervous
system diseases, neuropathies, or mechanical and traumatic
disorders (e.g., spinal cord disorders, head trauma,
cerebrovascular disease, and stoke). Specifically, diseases
associated with peripheral nerve injuries, peripheral neuropathy
(e.g., resulting from chemotherapy or other medical therapies),
localized neuropathies, and central nervous system diseases
(e.g.,Alzheimer's disease, Parkinson's disease, Huntington's
disease, amyotrophic lateral sclerosis, and Shy-Drager syndrome),
could all be treated using the polynucleotide or polypeptide of the
present invention.
[1516] Chemotaxis
[1517] A polynucleotide or polypeptide of the present invention may
have chemotaxis activity. A chemotaxic molecule attracts or
mobilizes cells (e.g., monocytes, fibroblasts, neutrophils,
T-cells, mast cells, eosinophils, epithelial and/or endothelial
cells) to a particular site in the body, such as inflammation,
infection, or site of hyperproliferation. The mobilized cells can
then fight off and/or heal the particular trauma or
abnormality.
[1518] A polynucleotide or polypeptide of the present invention may
increase chemotaxic activity of particular cells. These chemotactic
molecules can then be used to treat inflammation, infection,
hyperproliferative disorders, or any immune system disorder by
increasing the number of cells targeted to a particular location in
the body. For example, chemotaxic molecules can be used to treat
wounds and other trauma to tissues by attracting immune cells to
the injured location. Chemotactic molecules of the present
invention can also attract fibroblasts, which can be used to treat
wounds.
[1519] It is also contemplated that a polynucleotide or polypeptide
of the present invention may inhibit chemotactic activity. These
molecules could also be used to treat disorders. Thus, a
polynucleotide or polypeptide of the present invention could be
used as an inhibitor of chemotaxis.
[1520] Binding Activity
[1521] A polypeptide of the present invention may be used to screen
for molecules that bind to the polypeptide or for molecules to
which the polypeptide binds. The binding of the polypeptide and the
molecule may activate (agonist), increase, inhibit (antagonist), or
decrease activity of the polypeptide or the molecule bound.
Examples of such molecules include antibodies, oligonucleotides,
proteins (e.g., receptors), or small molecules.
[1522] Preferably, the molecule is closely related to the natural
ligand of the polypeptide, e.g., a fragment of the ligand, or a
natural substrate, a ligand, a structural or functional mimetic.
(See, Coligan et al., Current Protocols in Immunology 1(2):Chapter
5 (1991).) Similarly, the molecule can be closely related to the
natural receptor to which the polypeptide binds, or at least, a
fragment of the receptor capable of being bound by the polypeptide
(e.g., active site). In either case, the molecule can be rationally
designed using known techniques.
[1523] Preferably, the screening for these molecules involves
producing appropriate cells which express the polypeptide, either
as a secreted protein or on the cell membrane. Preferred cells
include cells from mammals, yeast, Drosophila, or E. coli. Cells
expressing the polypeptide (or cell membrane containing the
expressed polypeptide) are then preferably contacted with a test
compound potentially containing the molecule to observe binding,
stimulation, or inhibition of activity of either the polypeptide or
the molecule.
[1524] The assay may simply test binding of a candidate compound to
the polypeptide, wherein binding is detected by a label, or in an
assay involving competition with a labeled competitor. Further, the
assay may test whether the candidate compound results in a signal
generated by binding to the polypeptide.
[1525] Alternatively, the assay can be carried out using cell-free
preparations, polypeptide/molecule affixed to a solid support,
chemical libraries, or natural product mixtures. The assay may also
simply comprise the steps of mixing a candidate compound with a
solution containing a polypeptide, measuring polypeptide/molecule
activity or binding, and comparing the polypeptide/molecule
activity or binding to a standard.
[1526] Preferably, an ELISA assay can measure polypeptide level or
activity in a sample (e.g., biological sample) using a monoclonal
or polyclonal antibody. The antibody can measure polypeptide level
or activity by either binding, directly or indirectly, to the
polypeptide or by competing with the polypeptide for a
substrate.
[1527] All of these above assays can be used as diagnostic or
prognostic markers. The molecules discovered using these assays can
be used to treat disease or to bring about a particular result in a
patient (e.g., blood vessel growth) by activating or inhibiting the
polypeptide/molecule. Moreover, the assays can discover agents
which may inhibit or enhance the production of the polypeptide from
suitably manipulated cells or tissues.
[1528] Therefore, the invention includes a method of identifying
compounds which bind to a polypeptide of the invention comprising
the steps of: (a) incubating a candidate binding compound with a
polypeptide of the invention; and (b) determining if binding has
occurred. Moreover, the invention includes a method of identifying
agonists/antagonists comprising the steps of: (a) incubating a
candidate compound with a polypeptide of the invention, (b)
assaying a biological activity , and (b) determining if a
biological activity of the polypeptide has been altered.
[1529] Other Activities
[1530] A polypeptide or polynucleotide of the present invention may
also increase or decrease the differentiation or proliferation of
embryonic stem cells, besides, as discussed above, hematopoietic
lineage.
[1531] A polypeptide or polynucleotide of the present invention may
also be used to modulate mammalian characteristics, such as body
height, weight, hair color, eye color, skin, percentage of adipose
tissue, pigmentation, size, and shape (e.g., cosmetic surgery).
Similarly, a polypeptide or polynucleotide of the present invention
may be used to modulate mammalian metabolism affecting catabolism,
anabolism, processing, utilization, and storage of energy.
[1532] A polypeptide or polynucleotide of the present invention may
be used to change a mammal's mental state or physical state by
influencing biorhythms, caricadic rhythms, depression (including
depressive disorders), tendency for violence, tolerance for pain,
reproductive capabilities (preferably by Activin or Inhibin-like
activity), hormonal or endocrine levels, appetite, libido, memory,
stress, or other cognitive qualities.
[1533] A polypeptide or polynucleotide of the present invention may
also be used as a food additive or preservative, such as to
increase or decrease storage capabilities, fat content, lipid,
protein, carbohydrate, vitamins, minerals, cofactors or other
nutritional components.
[1534] Other Preferred Embodiments
[1535] Other preferred embodiments of the claimed invention include
an isolated nucleic acid molecule comprising a nucleotide sequence
which is at least 95% identical to a sequence of at least about 50
contiguous nucleotides in the nucleotide sequence of SEQ ID NO:X
wherein X is any integer as defined in Table 1.
[1536] Also preferred is a nucleic acid molecule wherein said
sequence of contiguous nucleotides is included in the nucleotide
sequence of SEQ ID NO:X in the range of positions beginning with
the nucleotide at about the position of the 5' Nucleotide of the
Clone Sequence and ending with the nucleotide at about the position
of the 3' Nucleotide of the Clone Sequence as defined for SEQ ID
NO:X in Table 1.
[1537] Also preferred is a nucleic acid molecule wherein said
sequence of contiguous nucleotides is included in the nucleotide
sequence of SEQ ID NO:X in the range of positions beginning with
the nucleotide at about the position of the 5' Nucleotide of the
Start Codon and ending with the nucleotide at about the position of
the 3' Nucleotide of the Clone Sequence as defined for SEQ ID NO:X
in Table 1.
[1538] Similarly preferred is a nucleic acid molecule wherein said
sequence of contiguous nucleotides is included in the nucleotide
sequence of SEQ ID NO:X in the range of positions beginning with
the nucleotide at about the position of the 5' Nucleotide of the
First Amino Acid of the Signal Peptide and ending with the
nucleotide at about the position of the 3' Nucleotide of the Clone
Sequence as defined for SEQ ID NO:X in Table 1.
[1539] Also preferred is an isolated nucleic acid molecule
comprising a nucleotide sequence which is at least 95% identical to
a sequence of at least about 150 contiguous nucleotides in the
nucleotide sequence of SEQ ID NO:X.
[1540] Further preferred is an isolated nucleic acid molecule
comprising a nucleotide sequence which is at least 95% identical to
a sequence of at least about 500 contiguous nucleotides in the
nucleotide sequence of SEQ ID NO:X.
[1541] A further preferred embodiment is a nucleic acid molecule
comprising a nucleotide sequence which is at least 95% identical to
the nucleotide sequence of SEQ ID NO:X beginning with the
nucleotide at about the position of the 5' Nucleotide of the First
Amino Acid of the Signal Peptide and ending with the nucleotide at
about the position of the 3' Nucleotide of the Clone Sequence as
defined for SEQ ID NO:X in Table 1.
[1542] A further preferred embodiment is an isolated nucleic acid
molecule comprising a nucleotide sequence which is at least 95%
identical to the complete nucleotide sequence of SEQ ID NO:X.
[1543] Also preferred is an isolated nucleic acid molecule which
hybridizes under stringent hybridization conditions to a nucleic
acid molecule, wherein said nucleic acid molecule which hybridizes
does not hybridize under stringent hybridization conditions to a
nucleic acid molecule having a nucleotide sequence consisting of
only A residues or of only T residues.
[1544] Also preferred is a composition of matter comprising a DNA
molecule which comprises a human cDNA clone identified by a cDNA
Clone Identifier in Table 1, which DNA molecule is contained in the
material deposited with the American Type Culture Collection and
given the ATCC Deposit Number shown in Table 1 for said cDNA Clone
Identifier.
[1545] Also preferred is an isolated nucleic acid molecule
comprising a nucleotide sequence which is at least 95% identical to
a sequence of at least 50 contiguous nucleotides in the nucleotide
sequence of a human cDNA clone identified by a cDNA Clone
Identifier in Table 1, which DNA molecule is contained in the
deposit given the ATCC Deposit Number shown in Table 1.
[1546] Also preferred is an isolated nucleic acid molecule, wherein
said sequence of at least 50 contiguous nucleotides is included in
the nucleotide sequence of the complete open reading frame sequence
encoded by said human cDNA clone.
[1547] Also preferred is an isolated nucleic acid molecule
comprising a nucleotide sequence which is at least 95% identical to
sequence of at least 150 contiguous nucleotides in the nucleotide
sequence encoded by said human cDNA clone.
[1548] A further preferred embodiment is an isolated nucleic acid
molecule comprising a nucleotide sequence which is at least 95%
identical to sequence of at least 500 contiguous nucleotides in the
nucleotide sequence encoded by said human cDNA clone.
[1549] A further preferred embodiment is an isolated nucleic acid
molecule comprising a nucleotide sequence which is at least 95%
identical to the complete nucleotide sequence encoded by said human
cDNA clone.
[1550] A further preferred embodiment is a method for detecting in
a biological sample a nucleic acid molecule comprising a nucleotide
sequence which is at least 95% identical to a sequence of at least
50 contiguous nucleotides in a sequence selected from the group
consisting of: a nucleotide sequence of SEQ ID NO:X wherein X is
any integer as defined in Table 1; and a nucleotide sequence
encoded by a human cDNA clone identified by a cDNA Clone Identifier
in Table 1 and contained in the deposit with the ATCC Deposit
Number shown for said cDNA clone in Table 1; which method comprises
a step of comparing a nucleotide sequence of at least one nucleic
acid molecule in said sample with a sequence selected from said
group and determining whether the sequence of said nucleic acid
molecule in said sample is at least 95% identical to said selected
sequence.
[1551] Also preferred is the above method wherein said step of
comparing sequences comprises determining the extent of nucleic
acid hybridization between nucleic acid molecules in said sample
and a nucleic acid molecule comprising said sequence selected from
said group. Similarly, also preferred is the above method wherein
said step of comparing sequences is performed by comparing the
nucleotide sequence determined from a nucleic acid molecule in said
sample with said sequence selected from said group. The nucleic
acid molecules can comprise DNA molecules or RNA molecules.
[1552] A further preferred embodiment is a method for identifying
the species, tissue or cell type of a biological sample which
method comprises a step of detecting nucleic acid molecules in said
sample, if any, comprising a nucleotide sequence that is at least
95% identical to a sequence of at least 50 contiguous nucleotides
in a sequence selected from the group consisting of: a nucleotide
sequence of SEQ ID NO:X wherein X is any integer as defined in
Table 1; and a nucleotide sequence encoded by a human cDNA clone
identified by a cDNA Clone Identifier in Table 1 and contained in
the deposit with the ATCC Deposit Number shown for said cDNA clone
in Table 1.
[1553] The method for identifying the species, tissue or cell type
of a biological sample can comprise a step of detecting nucleic
acid molecules comprising a nucleotide sequence in a panel of at
least two nucleotide sequences, wherein at least one sequence in
said panel is at least 95% identical to a sequence of at least 50
contiguous nucleotides in a sequence selected from said group.
[1554] Also preferred is a method for diagnosing in a subject a
pathological condition associated with abnormal structure or
expression of a gene encoding a secreted protein identified in
Table 1, which method comprises a step of detecting in a biological
sample obtained from said subject nucleic acid molecules, if any,
comprising a nucleotide sequence that is at least 95% identical to
a sequence of at least 50 contiguous nucleotides in a sequence
selected from the group consisting of: a nucleotide sequence of SEQ
ID NO:X wherein X is any integer as defined in Table 1; and a
nucleotide sequence encoded by a human cDNA clone identified by a
cDNA Clone Identifier in Table 1 and contained in the deposit with
the ATCC Deposit Number shown for said cDNA clone in Table 1.
[1555] The method for diagnosing a pathological condition can
comprise a step of detecting nucleic acid molecules comprising a
nucleotide sequence in a panel of at least two nucleotide
sequences, wherein at least one sequence in said panel is at least
95% identical to a sequence of at least 50 contiguous nucleotides
in a sequence selected from said group.
[1556] Also preferred is a composition of matter comprising
isolated nucleic acid molecules wherein the nucleotide sequences of
said nucleic acid molecules comprise a panel of at least two
nucleotide sequences, wherein at least one sequence in said panel
is at least 95% identical to a sequence of at least 50 contiguous
nucleotides in a sequence selected from the group consisting of: a
nucleotide sequence of SEQ ID NO:X wherein X is any integer as
defined in Table 1; and a nucleotide sequence encoded by a human
cDNA clone identified by a cDNA Clone Identifier in Table 1 and
contained in the deposit with the ATCC Deposit Number shown for
said cDNA clone in Table 1. The nucleic acid molecules can comprise
DNA molecules or RNA molecules.
[1557] Also preferred is an isolated polypeptide comprising an
amino acid sequence at least 90% identical to a sequence of at
least about 10 contiguous amino acids in the amino acid sequence of
SEQ ID NO:Y wherein Y is any integer as defined in Table 1.
[1558] Also preferred is a polypeptide, wherein said sequence of
contiguous amino acids is included in the amino acid sequence of
SEQ ID NO:Y in the range of positions beginning with the residue at
about the position of the First Amino Acid of the Secreted Portion
and ending with the residue at about the Last Amino Acid of the
Open Reading Frame as set forth for SEQ ID NO:Y in Table 1.
[1559] Also preferred is an isolated polypeptide comprising an
amino acid sequence at least 95% identical to a sequence of at
least about 30 continuous amino acids in the amino acid sequence of
SEQ ID NO:Y.
[1560] Further preferred is an isolated polypeptide comprising an
amino acid sequence at least 95% identical to a sequence of at
least about 100 contiguous amino acids in the amino acid sequence
of SEQ ID NO:Y.
[1561] Further preferred is an isolated polypeptide comprising an
amino acid sequence at least 95% identical to the complete amino
acid sequence of SEQ ID NO:Y.
[1562] Further preferred is an isolated polypeptide comprising an
amino acid sequence at least 90% identical to a sequence of at
least about 10 contiguous amino acids in the complete amino acid
sequence of a secreted protein encoded by a human cDNA clone
identified by a cDNA Clone Identifier in Table 1 and contained in
the deposit with the ATCC Deposit Number shown for said cDNA clone
in Table 1.
[1563] Also preferred is a polypeptide wherein said sequence of
contiguous amino acids is included in the amino acid sequence of a
secreted portion of the secreted protein encoded by a human cDNA
clone identified by a cDNA Clone Identifier in Table 1 and
contained in the deposit with the ATCC Deposit Number shown for
said cDNA clone in Table 1.
[1564] Also preferred is an isolated polypeptide comprising an
amino acid sequence at least 95% identical to a sequence of at
least about 30 contiguous amino acids in the amino acid sequence of
the secreted portion of the protein encoded by a human cDNA clone
identified by a cDNA Clone Identifier in Table 1 and contained in
the deposit with the ATCC Deposit Number shown for said cDNA clone
in Table 1.
[1565] Also preferred is an isolated polypeptide comprising an
amino acid sequence at least 95% identical to a sequence of at
least about 100 contiguous amino acids in the amino acid sequence
of the secreted portion of the protein encoded by a human cDNA
clone identified by a cDNA Clone Identifier in Table 1 and
contained in the deposit with the ATCC Deposit Number shown for
said cDNA clone in Table 1.
[1566] Also preferred is an isolated polypeptide comprising an
amino acid sequence at least 95% identical to the amino acid
sequence of the secreted portion of the protein encoded by a human
cDNA clone identified by a cDNA Clone Identifier in Table 1 and
contained in the deposit with the ATCC Deposit Number shown for
said cDNA clone in Table 1.
[1567] Further preferred is an isolated antibody which binds
specifically to a polypeptide comprising an amino acid sequence
that is at least 90% identical to a sequence of at least 10
continuous amino acids in a sequence selected from the group
consisting of: an amino acid sequence of SEQ ID NO:Y wherein Y is
any integer as defined in Table 1; and a complete amino acid
sequence of a protein encoded by a human cDNA clone identified by a
cDNA Clone Identifier in Table 1 and contained in the deposit with
the ATCC Deposit Number shown for said cDNA clone in Table 1.
[1568] Further preferred is a method for detecting in a biological
sample a polypeptide comprising an amino acid sequence which is at
least 90% identical to a sequence of at least 10 contiguous amino
acids in a sequence selected from the group consisting of: an amino
acid sequence of SEQ ID NO:Y wherein Y is any integer as defined in
Table 1; and a complete amino acid sequence of a protein encoded by
a human cDNA clone identified by a cDNA Clone Identifier in Table 1
and contained in the deposit with the ATCC Deposit Number shown for
said cDNA clone in Table 1; which method comprises a step of
comparing an amino acid sequence of at least one polypeptide
molecule in said sample with a sequence selected from said group
and determining whether the sequence of said polypeptide molecule
in said sample is at least 90% identical to said sequence of at
least 10 contiguous amino acids.
[1569] Also preferred is the above method wherein said step of
comparing an amino acid sequence of at least one polypeptide
molecule in said sample with a sequence selected from said group
comprises determining the extent of specific binding of
polypeptides in said sample to an antibody which binds specifically
to a polypeptide comprising an amino acid sequence that is at least
90% identical to a sequence of at least 10 contiguous amino acids
in a sequence selected from the group consisting of: an amino acid
sequence of SEQ ID NO:Y wherein Y is any integer as defined in
Table 1; and a complete amino acid sequence of a protein encoded by
a human cDNA clone identified by a cDNA Clone Identifier in Table 1
and contained in the deposit with the ATCC Deposit Number shown for
said cDNA clone in Table 1.
[1570] Also preferred is the above method wherein said step of
comparing sequences is performed by comparing the amino acid
sequence determined from a polypeptide molecule in said sample with
said sequence selected from said group.
[1571] Also preferred is a method for identifying the species,
tissue or cell type of a biological sample which method comprises a
step of detecting polypeptide molecules in said sample, if any,
comprising an amino acid sequence that is at least 90% identical to
a sequence of at least 10 contiguous amino acids in a sequence
selected from the group consisting of: an amino acid sequence of
SEQ ID NO:Y wherein Y is any integer as defined in Table 1; and a
complete amino acid sequence of a secreted protein encoded by a
human cDNA clone identified by a cDNA Clone Identifier in Table 1
and contained in the deposit with the ATCC Deposit Number shown for
said cDNA clone in Table 1.
[1572] Also preferred is the above method for identifying the
species, tissue or cell type of a biological sample, which method
comprises a step of detecting polypeptide molecules comprising an
amino acid sequence in a panel of at least two amino acid
sequences, wherein at least one sequence in said panel is at least
90% identical to a sequence of at least 10 contiguous amino acids
in a sequence selected from the above group.
[1573] Also preferred is a method for diagnosing in a subject a
pathological condition associated with abnormal structure or
expression of a gene encoding a secreted protein identified in
Table 1, which method comprises a step of detecting in a biological
sample obtained from said subject polypeptide molecules comprising
an amino acid sequence in a panel of at least two amino acid
sequences, wherein at least one sequence in said panel is at least
90% identical to a sequence of at least 10 continuous amino acids
in a sequence selected from the group consisting of: an amino acid
sequence of SEQ ID NO:Y wherein Y is any integer as defined in
Table 1; and a complete amino acid sequence of a secreted protein
encoded by a human cDNA clone identified by a cDNA Clone Identifier
in Table 1 and contained in the deposit with the ATCC Deposit
Number shown for said cDNA clone in Table 1.
[1574] In any of these methods, the step of detecting said
polypeptide molecules includes using an antibody.
[1575] Also preferred is an isolated nucleic acid molecule
comprising a nucleotide sequence which is at least 95% identical to
a nucleotide sequence encoding a polypeptide wherein said
polypeptide comprises an amino acid sequence that is at least 90%
identical to a sequence of at least 10 contiguous amino acids in a
sequence selected from the group consisting of: an amino acid
sequence of SEQ ID NO:Y wherein Y is any integer as defined in
Table 1; and a complete amino acid sequence of a secreted protein
encoded by a human cDNA clone identified by a cDNA Clone Identifier
in Table 1 and contained in the deposit with the ATCC Deposit
Number shown for said cDNA clone in Table 1.
[1576] Also preferred is an isolated nucleic acid molecule, wherein
said nucleotide sequence encoding a polypeptide has been optimized
for expression of said polypeptide in a prokaryotic host.
[1577] Also preferred is an isolated nucleic acid molecule, wherein
said polypeptide comprises an amino acid sequence selected from the
group consisting of: an amino acid sequence of SEQ ID NO:Y wherein
Y is any integer as defined in Table 1; and a complete amino acid
sequence of a secreted protein encoded by a human cDNA clone
identified by a cDNA Clone Identifier in Table 1 and contained in
the deposit with the ATCC Deposit Number shown for said cDNA clone
in Table 1.
[1578] Further preferred is a method of making a recombinant vector
comprising inserting any of the above isolated nucleic acid
molecule into a vector. Also preferred is the recombinant vector
produced by this method. Also preferred is a method of making a
recombinant host cell comprising introducing the vector into a host
cell, as well as the recombinant host cell produced by this
method.
[1579] Also preferred is a method of making an isolated polypeptide
comprising culturing this recombinant host cell under conditions
such that said polypeptide is expressed and recovering said
polypeptide. Also preferred is this method of making an isolated
polypeptide, wherein said recombinant host cell is a eukaryotic
cell and said polypeptide is a secreted portion of a human secreted
protein comprising an amino acid sequence selected from the group
consisting of: an amino acid sequence of SEQ ID NO:Y beginning with
the residue at the position of the First Amino Acid of the Secreted
Portion of SEQ ID NO:Y wherein Y is an integer set forth in Table 1
and said position of the First Amino Acid of the Secreted Portion
of SEQ ID NO:Y is defined in Table 1; and an amino acid sequence of
a secreted portion of a protein encoded by a human cDNA clone
identified by a cDNA Clone Identifier in Table 1 and contained in
the deposit with the ATCC Deposit Number shown for said cDNA clone
in Table 1. The isolated polypeptide produced by this method is
also preferred.
[1580] Also preferred is a method of treatment of an individual in
need of an increased level of a secreted protein activity, which
method comprises administering to such an individual a
pharmaceutical composition comprising an amount of an isolated
polypeptide, polynucleotide, or antibody of the claimed invention
effective to increase the level of said protein activity in said
individual.
[1581] Having generally described the invention, the same will be
more readily understood by reference to the following examples,
which are provided by way of illustration and are not intended as
limiting.
EXAMPLES
Example 1
Isolation of a Selected cDNA Clone from the Deposited Sample
[1582] Each cDNA clone in a cited ATCC deposit is contained in a
plasmid vector. Table 1 identifies the vectors used to construct
the cDNA library from which each clone was isolated. In many cases,
the vector used to construct the library is a phage vector from
which a plasmid has been excised. The table immediately below
correlates the related plasmid for each phage vector used in
constructing the cDNA library. For example, where a particular
clone is identified in Table 1 as being isolated in the vector
"Lambda Zap," the corresponding deposited clone is in
"pBluescript."
62 Vector Used to Construct Library Corresponding Deposited Plasmid
Lambda Zap pBluescript (pBS) Uni-Zap XR pBluescript (pBS) Zap
Express pBK lafmid BA plafmid BA pSport1 pSport1 pCMVSport 2.0
pCMVSport 2.0 pCMVSport 3.0 pCMVSport 3.0 pCR .RTM.2.1 pCR
.RTM.2.1
[1583] Vectors Lambda Zap (U.S. Pat. Nos. 5,128,256 and 5,286,636),
Uni-Zap XR (U.S. Pat. Nos. 5,128,256 and 5,286,636), Zap Express
(U.S. Pat. Nos. 5,128,256 and 5,286,636), pBluescript (pBS) (Short,
J. M. et al., Nucleic Acids Res. 16:7583-7600 (1988); Alting-Mees,
M. A. and Short, J. M., Nucleic Acids Res. 17:9494 (1989)) and pBK
(Alting-Mees, M. A. et al., Strategies 5:58-61 (1992)) are
commercially available from Stratagene Cloning Systems, Inc., 11011
N. Torrey Pines Road, La Jolla, Calif., 92037. pBS contains an
ampicillin resistance gene and pBK contains a neomycin resistance
gene. Both can be transformed into E. coli strain XL-1 Blue, also
available from Stratagene. pBS comes in 4 forms SK+, SK-, KS+ and
KS. The S and K refers to the orientation of the polylinker to the
T7 and T3 primer sequences which flank the polylinker region ("S"
is for SacI and "K" is for KpnI which are the first sites on each
respective end of the linker). "+" or "-" refer to the orientation
of the f1 origin of replication ("ori"), such that in one
orientation, single stranded rescue initiated from the f1 ori
generates sense strand DNA and in the other, antisense.
[1584] Vectors pSport1, pCMVSport 2.0 and pCMVSport 3.0, were
obtained from Life Technologies, Inc., P. O. Box 6009,
Gaithersburg, Md. 20897. All Sport vectors contain an ampicillin
resistance gene and may be transformed into E. coli strain DH10B,
also available from Life Technologies. (See, for instance, Gruber,
C. E., et al., Focus 15:59 (1993).) Vector lafmid BA (Bento Soares,
Columbia University, NY) contains an ampicillin resistance gene and
can be transformed into E. coli strain XL-1 Blue. Vector
pCR.RTM.2.1, which is available from Invitrogen, 1600 Faraday
Avenue, Carlsbad, Calif. 92008, contains an ampicillin resistance
gene and may be transformed into E. coli strain DH10B, available
from Life Technologies. (See, for instance, Clark, J. M., Nuc.
Acids Res. 16:9677-9686 (1988) and Mead, D. et al., Bio/Technology
9: (1991).) Preferably, a polynucleotide of the present invention
does not comprise the phage vector sequences identified for the
particular clone in Table 1, as well as the corresponding plasmid
vector sequences designated above.
[1585] The deposited material in the sample assigned the ATCC
Deposit Number cited in Table 1 for any given cDNA clone also may
contain one or more additional plasmids, each comprising a cDNA
clone different from that given clone. Thus, deposits sharing the
same ATCC Deposit Number contain at least a plasmid for each cDNA
clone identified in Table 1. Typically, each ATCC deposit sample
cited in Table 1 comprises a mixture of approximately equal amounts
(by weight) of about 50 plasmid DNAs, each containing a different
cDNA clone; but such a deposit sample may include plasmids for more
or less than 50 cDNA clones, up to about 500 cDNA clones.
[1586] Two approaches can be used to isolate a particular clone
from the deposited sample of plasmid DNAs cited for that clone in
Table 1. First, a plasmid is directly isolated by screening the
clones using a polynucleotide probe corresponding to SEQ ID
NO:X.
[1587] Particularly, a specific polynucleotide with 30-40
nucleotides is synthesized using an Applied Biosystems DNA
synthesizer according to the sequence reported. The oligonucleotide
is labeled, for instance, with .sup.32P-.gamma.-ATP using T4
polynucleotide kinase and purified according to routine methods.
(E.g., Maniatis et al., Molecular Cloning: A Laboratory Manual,
Cold Spring Harbor Press, Cold Spring, N.Y. (1982).) The plasmid
mixture is transformed into a suitable host, as indicated above
(such as XL-1 Blue (Stratagene)) using techniques known to those of
skill in the art, such as those provided by the vector supplier or
in related publications or patents cited above. The transformants
are plated on 1.5% agar plates (containing the appropriate
selection agent, e.g., ampicillin) to a density of about 150
transformants (colonies) per plate. These plates are screened using
Nylon membranes according to routine methods for bacterial colony
screening (e.g., Sambrook et al., Molecular Cloning: A Laboratory
Manual, 2nd Edit., (1989), Cold Spring Harbor Laboratory Press,
pages 1.93 to 1.104), or other techniques known to those of skill
in the art.
[1588] Alternatively, two primers of 17-20 nucleotides derived from
both ends of the SEQ ID NO:X (i.e., within the region of SEQ ID
NO:X bounded by the 5' NT and the 3' NT of the clone defined in
Table 1) are synthesized and used to amplify the desired cDNA using
the deposited cDNA plasmid as a template. The polymerase chain
reaction is carried out under routine conditions, for instance, in
25 .mu.l of reaction mixture with 0.5 ug of the above cDNA
template. A convenient reaction mixture is 1.5-5 mM MgCl.sub.2,
0.01% (w/v) gelatin, 20 .mu.M each of dATP, dCTP, dGTP, dTTP, 25
pmol of each primer and 0.25 Unit of Taq polymerase. Thirty five
cycles of PCR (denaturation at 94.degree. C. for 1 min; annealing
at 55.degree. C. for 1 min; elongation at 72.degree. C. for 1 min)
are performed with a Perkin-Elmer Cetus automated thermal cycler.
The amplified product is analyzed by agarose gel electrophoresis
and the DNA band with expected molecular weight is excised and
purified. The PCR product is verified to be the selected sequence
by subcloning and sequencing the DNA product.
[1589] Several methods are available for the identification of the
5' or 3' non-coding portions of a gene which may not be present in
the deposited clone. These methods include but are not limited to,
filter probing, clone enrichment using specific probes, and
protocols similar or identical to 5' and 3' "RACE" protocols which
are well known in the art. For instance, a method similar to 5'
RACE is available for generating the missing 5' end of a desired
full-length transcript. (Fromont-Racine et al., Nucleic Acids Res.
21(7):1683-1684 (1993).)
[1590] Briefly, a specific RNA oligonucleotide is ligated to the 5'
ends of a population of RNA presumably containing full-length gene
RNA transcripts. A primer set containing a primer specific to the
ligated RNA oligonucleotide and a primer specific to a known
sequence of the gene of interest is used to PCR amplify the 5'
portion of the desired full-length gene. This amplified product may
then be sequenced and used to generate the full length gene.
[1591] This above method starts with total RNA isolated from the
desired source, although poly-A+ RNA can be used. The RNA
preparation can then be treated with phosphatase if necessary to
eliminate 5' phosphate groups on degraded or damaged RNA which may
interfere with the later RNA ligase step. The phosphatase should
then be inactivated and the RNA treated with tobacco acid
pyrophosphatase in order to remove the cap structure present at the
5' ends of messenger RNAs. This reaction leaves a 5' phosphate
group at the 5' end of the cap cleaved RNA which can then be
ligated to an RNA oligonucleotide using T4 RNA ligase.
[1592] This modified RNA preparation is used as a template for
first strand cDNA synthesis using a gene specific oligonucleotide.
The first strand synthesis reaction is used as a template for PCR
amplification of the desired 5' end using a primer specific to the
ligated RNA oligonucleotide and a primer specific to the known
sequence of the gene of interest. The resultant product is then
sequenced and analyzed to confirm that the 5' end sequence belongs
to the desired gene.
Example 2
Isolation of Genomic Clones Corresponding to a Polynucleotide
[1593] A human genomic P1 library (Genomic Systems, Inc.) is
screened by PCR using primers selected for the cDNA sequence
corresponding to SEQ ID NO:X., according to the method described in
Example 1. (See also, Sambrook.)
Example 3
Tissue Distribution of Polypeptide
[1594] Tissue distribution of mRNA expression of polynucleotides of
the present invention is determined using protocols for Northern
blot analysis, described by, among others, Sambrook et al. For
example, a cDNA probe produced by the method described in Example 1
is labeled with P.sup.32 using the rediprime.TM. DNA labeling
system (Amersham Life Science), according to manufacturer's
instructions. After labeling, the probe is purified using CHROMA
SPIN-100.TM. column (Clontech Laboratories, Inc.), according to
manufacturer's protocol number PT1200-1. The purified labeled probe
is then used to examine various human tissues for mRNA
expression.
[1595] Multiple Tissue Northern (MTN) blots containing various
human tissues (H) or human immune system tissues (IM) (Clontech)
are examined with the labeled probe using ExpressHyb.TM.
hybridization solution (Clontech) according to manufacturer's
protocol number PT1190-1. Following hybridization and washing, the
blots are mounted and exposed to film at -70.degree. C. overnight,
and the films developed according to standard procedures.
Example 4
Chromosomal Mapping of the Polynucleotides
[1596] An oligonucleotide primer set is designed according to the
sequence at the 5' end of SEQ ID NO:X. This primer preferably spans
about 100 nucleotides. This primer set is then used in a polymerase
chain reaction under the following set of conditions: 30 seconds,
95.degree. C.; 1 minute, 56.degree. C.; 1 minute, 70.degree. C.
This cycle is repeated 32 times followed by one 5 minute cycle at
70.degree. C. Human, mouse, and hamster DNA is used as template in
addition to a somatic cell hybrid panel containing individual
chromosomes or chromosome fragments (Bios, Inc). The reactions is
analyzed on either 8% polyacrylamide gels or 3.5% agarose gels.
Chromosome mapping is determined by the presence of an
approximately 100 bp PCR fragment in the particular somatic cell
hybrid.
Example 5
Bacterial Expression of a Polypeptide
[1597] A polynucleotide encoding a polypeptide of the present
invention is amplified using PCR oligonucleotide primers
corresponding to the 5' and 3' ends of the DNA sequence, as
outlined in Example 1, to synthesize insertion fragments. The
primers used to amplify the cDNA insert should preferably contain
restriction sites, such as BamHI and XbaI, at the 5' end of the
primers in order to clone the amplified product into the expression
vector. For example, BamHI and XbaI correspond to the restriction
enzyme sites on the bacterial expression vector pQE-9. (Qiagen,
Inc., Chatsworth, Calif.). This plasmid vector encodes antibiotic
resistance (Amp.sup.r), a bacterial origin of replication (ori), an
IPTG-regulatable promoter/operator (P/O), a ribosome binding site
(RBS), a 6-histidine tag (6-His), and restriction enzyme cloning
sites.
[1598] The pQE-9 vector is digested with BamHI and XbaI and the
amplified fragment is ligated into the pQE-9 vector maintaining the
reading frame initiated at the bacterial RBS. The ligation mixture
is then used to transform the E. coli strain M15/rep4 (Qiagen,
Inc.) which contains multiple copies of the plasmid pREP4, which
expresses the lacI repressor and also confers kanamycin resistance
(Kan.sup.r). Transformants are identified by their ability to grow
on LB plates and ampicillin/kanamycin resistant colonies are
selected. Plasmid DNA is isolated and confirmed by restriction
analysis.
[1599] Clones containing the desired constructs are grown overnight
(O/N) in liquid culture in LB media supplemented with both Amp (100
ug/ml) and Kan (25 ug/ml). The O/N culture is used to inoculate a
large culture at a ratio of 1:100 to 1:250. The cells are grown to
an optical density 600 (O.D..sup.600) of between 0.4 and 0.6. IPTG
(Isopropyl-B-D-thiogalacto pyranoside) is then added to a final
concentration of 1 mM. IPTG induces by inactivating the lacI
repressor, clearing the P/O leading to increased gene
expression.
[1600] Cells are grown for an extra 3 to 4 hours. Cells are then
harvested by centrifugation (20 mins at 6000.times. g). The cell
pellet is solubilized in the chaotropic agent 6 Molar Guanidine HCl
by stirring for 3-4 hours at 4.degree. C. The cell debris is
removed by centrifugation, and the supernatant containing the
polypeptide is loaded onto a nickel-nitrilo-tri-acetic acid
("Ni--NTA") affinity resin column (available from QIAGEN, Inc.,
supra). Proteins with a 6.times. His tag bind to the Ni--NTA resin
with high affinity and can be purified in a simple one-step
procedure (for details see: The QIAexpressionist (1995) QIAGEN,
Inc., supra).
[1601] Briefly, the supernatant is loaded onto the column in 6 M
guanidine-HCl, pH 8, the column is first washed with 10 volumes of
6 M guanidine-HCl, pH 8, then washed with 10 volumes of 6 M
guanidine-HCl pH 6, and finally the polypeptide is eluted with 6 M
guanidine-HCl, pH 5.
[1602] The purified protein is then renatured by dialyzing it
against phosphate-buffered saline (PBS) or 50 mM Na-acetate, pH 6
buffer plus 200 mM NaCl. Alternatively, the protein can be
successfully refolded while immobilized on the Ni--NTA column. The
recommended conditions are as follows: renature using a linear
6M-1M urea gradient in 500 mM NaCl, 20% glycerol, 20 mM Tris/HCl pH
7.4, containing protease inhibitors. The renaturation should be
performed over a period of 1.5 hours or more. After renaturation
the proteins are eluted by the addition of 250 mM immidazole.
Immidazole is removed by a final dialyzing step against PBS or 50
mM sodium acetate pH 6 buffer plus 200 mM NaCl. The purified
protein is stored at 4.degree. C. or frozen at -80.degree. C.
[1603] In addition to the above expression vector, the present
invention further includes an expression vector comprising phage
operator and promoter elements operatively linked to a
polynucleotide of the present invention, called pHE4a. (ATCC
Accession Number 209645, deposited on Feb. 25, 1998.) This vector
contains: 1) a neomycinphosphotransferase gene as a selection
marker, 2) an E. coli origin of replication, 3) a T5 phage promoter
sequence, 4) two lac operator sequences, 5) a Shine-Delgarno
sequence, and 6) the lactose operon repressor gene (lacIq). The
origin of replication (oriC) is derived from pUC 19 (LTI,
Gaithersburg, Md.). The promoter sequence and operator sequences
are made synthetically.
[1604] DNA can be inserted into the pHEa by restricting the vector
with NdeI and XbaI, BamHI, XhoI, or Asp718, running the restricted
product on a gel, and isolating the larger fragment (the stuffer
fragment should be about 310 base pairs). The DNA insert is
generated according to the PCR protocol described in Example 1,
using PCR primers having restriction sites for NdeI (5' primer) and
XbaI, BamHI, XhoI, or Asp718 (3' primer). The PCR insert is gel
purified and restricted with compatible enzymes. The insert and
vector are ligated according to standard protocols.
[1605] The engineered vector could easily be substituted in the
above protocol to express protein in a bacterial system.
Example 6
Purification of a Polypeptide from an Inclusion Body
[1606] The following alternative method can be used to purify a
polypeptide expressed in E Coli when it is present in the form of
inclusion bodies. Unless otherwise specified, all of the following
steps are conducted at 4-10.degree. C.
[1607] Upon completion of the production phase of the E. Coli
fermentation, the cell culture is cooled to 4-10.degree. C. and the
cells harvested by continuous centrifugation at 15,000 rpm (Heraeus
Sepatech). On the basis of the expected yield of protein per unit
weight of cell paste and the amount of purified protein required,
an appropriate amount of cell paste, by weight, is suspended in a
buffer solution containing 100 mM Tris, 50 mM EDTA, pH 7.4. The
cells are dispersed to a homogeneous suspension using a high shear
mixer.
[1608] The cells are then lysed by passing the solution through a
microfluidizer (Microfuidics, Corp. or APV Gaulin, Inc.) twice at
4000-6000 psi. The homogenate is then mixed with NaCl solution to a
final concentration of 0.5 M NaCl, followed by centrifugation at
7000.times. g for 15 min. The resultant pellet is washed again
using 0.5M NaCl, 100 mM Tris, 50 mM EDTA, pH 7.4.
[1609] The resulting washed inclusion bodies are solubilized with
1.5 M guanidine hydrochloride (GuHCl) for 2-4 hours. After
7000.times. g centrifugation for 15 min., the pellet is discarded
and the polypeptide containing supernatant is incubated at
4.degree. C. overnight to allow further GuHCl extraction.
[1610] Following high speed centrifugation (30,000.times. g) to
remove insoluble particles, the GuHCl solubilized protein is
refolded by quickly mixing the GuHCl extract with 20 volumes of
buffer containing 50 mM sodium, pH 4.5, 150 mM NaCl, 2 mM EDTA by
vigorous stirring. The refolded diluted protein solution is kept at
4.degree. C. without mixing for 12 hours prior to further
purification steps.
[1611] To clarify the refolded polypeptide solution, a previously
prepared tangential filtration unit equipped with 0.16 .mu.m
membrane filter with appropriate surface area (e.g., Filtron),
equilibrated with 40 mM sodium acetate, pH 6.0 is employed. The
filtered sample is loaded onto a cation exchange resin (e.g., Poros
HS-50, Perseptive Biosystems). The column is washed with 40 mM
sodium acetate, pH 6.0 and eluted with 250 mM, 500 mM, 1000 mM, and
1500 mM NaCl in the same buffer, in a stepwise manner. The
absorbance at 280 nm of the effluent is continuously monitored.
Fractions are collected and further analyzed by SDS-PAGE.
[1612] Fractions containing the polypeptide are then pooled and
mixed with 4 volumes of water. The diluted sample is then loaded
onto a previously prepared set of tandem columns of strong anion
(Poros HQ-50, Perseptive Biosystems) and weak anion (Poros CM-20,
Perseptive Biosystems) exchange resins. The columns are
equilibrated with 40 mM sodium acetate, pH 6.0. Both columns are
washed with 40 mM sodium acetate, pH 6.0, 200 mM NaCl. The CM-20
column is then eluted using a 10 column volume linear gradient
ranging from 0.2 M NaCl, 50 mM sodium acetate, pH 6.0 to 1.0 M
NaCl, 50 mM sodium acetate, pH 6.5. Fractions are collected under
constant A.sub.2.sub.280 monitoring of the effluent. Fractions
containing the polypeptide (determined, for instance, by 16%
SDS-PAGE) are then pooled.
[1613] The resultant polypeptide should exhibit greater than 95%
purity after the above refolding and purification steps. No major
contaminant bands should be observed from Commassie blue stained
16% SDS-PAGE gel when 5 .mu.g of purified protein is loaded. The
purified protein can also be tested for endotoxin/LPS
contamination, and typically the LPS content is less than 0.1 ng/ml
according to LAL assays.
Example 7
Cloning and Expression of a Polypeptide in a Baculovirus Expression
System
[1614] In this example, the plasmid shuttle vector pA2 is used to
insert a polynucleotide into a baculovirus to express a
polypeptide. This expression vector contains the strong polyhedrin
promoter of the Autographa californica nuclear polyhedrosis virus
(AcMNPV) followed by convenient restriction sites such as BamHI,
Xba I and Asp718. The polyadenylation site of the simian virus 40
("SV40") is used for efficient polyadenylation. For easy selection
of recombinant virus, the plasmid contains the beta-galactosidase
gene from E. coli under control of a weak Drosophila promoter in
the same orientation, followed by the polyadenylation signal of the
polyhedrin gene. The inserted genes are flanked on both sides by
viral sequences for cell-mediated homologous recombination with
wild-type viral DNA to generate a viable virus that express the
cloned polynucleotide.
[1615] Many other baculovirus vectors can be used in place of the
vector above, such as pAc373, pVL941, and pAcIM1, as one skilled in
the art would readily appreciate, as long as the construct provides
appropriately located signals for transcription, translation,
secretion and the like, including a signal peptide and an in-frame
AUG as required. Such vectors are described, for instance, in
Luckow et al., Virology 170:31-39 (1989).
[1616] Specifically, the cDNA sequence contained in the deposited
clone, including the AUG initiation codon and the naturally
associated leader sequence identified in Table 1, is amplified
using the PCR protocol described in Example 1. If the naturally
occurring signal sequence is used to produce the secreted protein,
the pA2 vector does not need a second signal peptide.
Alternatively, the vector can be modified (pA2 GP) to include a
baculovirus leader sequence, using the standard methods described
in Summers et al., "A Manual of Methods for Baculovirus Vectors and
Insect Cell Culture Procedures," Texas Agricultural Experimental
Station Bulletin No. 1555 (1987).
[1617] The amplified fragment is isolated from a 1% agarose gel
using a commercially available kit ("Geneclean," BIO 101 Inc., La
Jolla, Calif.). The fragment then is digested with appropriate
restriction enzymes and again purified on a 1% agarose gel.
[1618] The plasmid is digested with the corresponding restriction
enzymes and optionally, can be dephosphorylated using calf
intestinal phosphatase, using routine procedures known in the art.
The DNA is then isolated from a 1% agarose gel using a commercially
available kit ("Geneclean" BIO 101 Inc., La Jolla, Calif.).
[1619] The fragment and the dephosphorylated plasmid are ligated
together with T4 DNA ligase. E. coli HB101 or other suitable E.
coli hosts such as XL-1 Blue (Stratagene Cloning Systems, La Jolla,
Calif.) cells are transformed with the ligation mixture and spread
on culture plates. Bacteria containing the plasmid are identified
by digesting DNA from individual colonies and analyzing the
digestion product by gel electrophoresis. The sequence of the
cloned fragment is confirmed by DNA sequencing.
[1620] Five .mu.g of a plasmid containing the polynucleotide is
co-transfected with 1.0 .mu.g of a commercially available
linearized baculovirus DNA ("BaculoGold.TM. baculovirus DNA",
Pharmingen, San Diego, Calif.), using the lipofection method
described by Felgner et al., Proc. Natl. Acad. Sci. USA
84:7413-7417 (1987). One .mu.g of BaculoGold.TM. virus DNA and 5
.mu.g of the plasmid are mixed in a sterile well of a microtiter
plate containing 50 .mu.l of serum-free Grace's medium (Life
Technologies Inc., Gaithersburg, Md.). Afterwards, 10 .mu.l
Lipofectin plus 90 .mu.l Grace's medium are added, mixed and
incubated for 15 minutes at room temperature. Then the transfection
mixture is added drop-wise to Sf9 insect cells (ATCC CRL 1711)
seeded in a 35 mm tissue culture plate with 1 ml Grace's medium
without serum. The plate is then incubated for 5 hours at
27.degree. C. The transfection solution is then removed from the
plate and 1 ml of Grace's insect medium supplemented with 10% fetal
calf serum is added. Cultivation is then continued at 27.degree. C.
for four days.
[1621] After four days the supernatant is collected and a plaque
assay is performed, as described by Summers and Smith, supra. An
agarose gel with "Blue Gal" (Life Technologies Inc., Gaithersburg)
is used to allow easy identification and isolation of
gal-expressing clones, which produce blue-stained plaques. (A
detailed description of a "plaque assay" of this type can also be
found in the user's guide for insect cell culture and
baculovirology distributed by Life Technologies Inc., Gaithersburg,
page 9-10.) After appropriate incubation, blue stained plaques are
picked with the tip of a micropipettor (e.g., Eppendorf). The agar
containing the recombinant viruses is then resuspended in a
microcentrifuge tube containing 200 .mu.l of Grace's medium and the
suspension containing the recombinant baculovirus is used to infect
Sf9 cells seeded in 35 mm dishes. Four days later the supernatants
of these culture dishes are harvested and then they are stored at
4.degree. C.
[1622] To verify the expression of the polypeptide, Sf9 cells are
grown in Grace's medium supplemented with 10% heat-inactivated FBS.
The cells are infected with the recombinant baculovirus containing
the polynucleotide at a multiplicity of infection ("MOI") of about
2. If radiolabeled proteins are desired, 6 hours later the medium
is removed and is replaced with SF900 II medium minus methionine
and cysteine (available from Life Technologies Inc., Rockville,
Md.). After 42 hours, 5 .mu.Ci of .sup.35S-methionine and 5 .mu.Ci
.sup.35S-cysteine (available from Amersham) are added. The cells
are further incubated for 16 hours and then are harvested by
centrifugation. The proteins in the supernatant as well as the
intracellular proteins are analyzed by SDS-PAGE followed by
autoradiography (if radiolabeled).
[1623] Microsequencing of the amino acid sequence of the amino
terminus of purified protein may be used to determine the amino
terminal sequence of the produced protein.
Example 8
Expression of a Polypeptide in Mammalian Cells
[1624] The polypeptide of the present invention can be expressed in
a mammalian cell. A typical mammalian expression vector contains a
promoter element, which mediates the initiation of transcription of
mRNA, a protein coding sequence, and signals required for the
termination of transcription and polyadenylation of the transcript.
Additional elements include enhancers, Kozak sequences and
intervening sequences flanked by donor and acceptor sites for RNA
splicing. Highly efficient transcription is achieved with the early
and late promoters from SV40, the long terminal repeats (LTRs) from
Retroviruses, e.g., RSV, HTLVI, HIVI and the early promoter of the
cytomegalovirus (CMV). However, cellular elements can also be used
(e.g., the human actin promoter).
[1625] Suitable expression vectors for use in practicing the
present invention include, for example, vectors such as pSVL and
pMSG (Pharmacia, Uppsala, Sweden), pRSVcat (ATCC 37152), pSV2dhfr
(ATCC 37146), pBC12MI (ATCC 67109), pCMVSport 2.0, and pCMVSport
3.0. Mammalian host cells that could be used include, human Hela,
293, H9 and Jurkat cells, mouse NIH3T3 and C127 cells, Cos 1, Cos 7
and CV1, quail QC1-3 cells, mouse L cells and Chinese hamster ovary
(CHO) cells.
[1626] Alternatively, the polypeptide can be expressed in stable
cell lines containing the polynucleotide integrated into a
chromosome. The co-transfection with a selectable marker such as
dhfr, gpt, neomycin, hygromycin allows the identification and
isolation of the transfected cells.
[1627] The transfected gene can also be amplified to express large
amounts of the encoded protein. The DHFR (dihydrofolate reductase)
marker is useful in developing cell lines that carry several
hundred or even several thousand copies of the gene of interest.
(See, e.g., Alt, F. W., et al., J. Biol. Chem. 253:1357-1370
(1978); Hamlin, J. L. and Ma, C., Biochem. et Biophys. Acta,
1097:107-143 (1990); Page, M. J. and Sydenham, M. A., Biotechnology
9:64-68 (1991).) Another useful selection marker is the enzyme
glutamine synthase (GS) (Murphy et al., Biochem J. 227:277-279
(1991); Bebbington et al., Bio/Technology 10:169-175 (1992). Using
these markers, the mammalian cells are grown in selective medium
and the cells with the highest resistance are selected. These cell
lines contain the amplified gene(s) integrated into a chromosome.
Chinese hamster ovary (CHO) and NSO cells are often used for the
production of proteins.
[1628] Derivatives of the plasmid pSV2-dhfr (ATCC Accession No.
37146), the expression vectors pC4 (ATCC Accession No. 209646) and
pC6 (ATCC Accession No.209647) contain the strong promoter (LTR) of
the Rous Sarcoma Virus (Cullen et al., Molecular and Cellular
Biology, 438-447 (March, 1985)) plus a fragment of the CMV-enhancer
(Boshart et al., Cell 41:521-530 (1985).) Multiple cloning sites,
e.g., with the restriction enzyme cleavage sites BamHI, XbaI and
Asp718, facilitate the cloning of the gene of interest. The vectors
also contain the 3' intron, the polyadenylation and termination
signal of the rat preproinsulin gene, and the mouse DHFR gene under
control of the SV40 early promoter.
[1629] Specifically, the plasmid pC6, for example, is digested with
appropriate restriction enzymes and then dephosphorylated using
calf intestinal phosphates by procedures known in the art. The
vector is then isolated from a 1% agarose gel.
[1630] A polynucleotide of the present invention is amplified
according to the protocol outlined in Example 1. If the naturally
occurring signal sequence is used to produce the secreted protein,
the vector does not need a second signal peptide. Alternatively, if
the naturally occurring signal sequence is not used, the vector can
be modified to include a heterologous signal sequence. (See, e.g.,
WO 96/34891.)
[1631] The amplified fragment is isolated from a 1% agarose gel
using a commercially available kit ("Geneclean," BIO 101 Inc., La
Jolla, Calif.). The fragment then is digested with appropriate
restriction enzymes and again purified on a 1% agarose gel.
[1632] The amplified fragment is then digested with the same
restriction enzyme and purified on a 1% agarose gel. The isolated
fragment and the dephosphorylated vector are then ligated with T4
DNA ligase. E. coli HB101 or XL-1 Blue cells are then transformed
and bacteria are identified that contain the fragment inserted into
plasmid pC6 using, for instance, restriction enzyme analysis.
[1633] Chinese hamster ovary cells lacking an active DHFR gene is
used for transfection. Five .mu.g of the expression plasmid pC6 is
cotransfected with 0.5 .mu.g of the plasmid pSVneo using lipofectin
(Felgner et al., supra). The plasmid pSV2-neo contains a dominant
selectable marker, the neo gene from Tn5 encoding an enzyme that
confers resistance to a group of antibiotics including G418. The
cells are seeded in alpha minus MEM supplemented with 1 mg/ml G418.
After 2 days, the cells are trypsinized and seeded in hybridoma
cloning plates (Greiner, Germany) in alpha minus MEM supplemented
with 10, 25, or 50 ng/ml of metothrexate plus 1 mg/ml G418. After
about 10-14 days single clones are trypsinized and then seeded in
6-well petri dishes or 10 ml flasks using different concentrations
of methotrexate (50 nM, 100 nM, 200 nM, 400 nM, 800 nM). Clones
growing at the highest concentrations of methotrexate are then
transferred to new 6-well plates containing even higher
concentrations of methotrexate (1 .mu.M, 2 .mu.M, 5 .mu.M, 10 mM,
20 mM). The same procedure is repeated until clones are obtained
which grow at a concentration of 100-200 .mu.M. Expression of the
desired gene product is analyzed, for instance, by SDS-PAGE and
Western blot or by reversed phase HPLC analysis.
Example 9
Protein Fusions
[1634] The polypeptides of the present invention are preferably
fused to other proteins. These fusion proteins can be used for a
variety of applications. For example, fusion of the present
polypeptides to His-tag, HA-tag, protein A, IgG domains, and
maltose binding protein facilitates purification. (See Example 5;
see also EP A 394,827; Traunecker, et al., Nature 331:84-86
(1988).) Similarly, fusion to IgG-1, IgG-3, and albumin increases
the halflife time in vivo. Nuclear localization signals fused to
the polypeptides of the present invention can target the protein to
a specific subcellular localization, while covalent heterodimer or
homodimers can increase or decrease the activity of a fusion
protein. Fusion proteins can also create chimeric molecules having
more than one function. Finally, fusion proteins can increase
solubility and/or stability of the fused protein compared to the
non-fused protein. All of the types of fusion proteins described
above can be made by modifying the following protocol, which
outlines the fusion of a polypeptide to an IgG molecule, or the
protocol described in Example 5.
[1635] Briefly, the human Fc portion of the IgG molecule can be PCR
amplified, using primers that span the 5' and 3' ends of the
sequence described below. These primers also should have convenient
restriction enzyme sites that will facilitate cloning into an
expression vector, preferably a mammalian expression vector.
[1636] For example, if pC4 (See Genbank Accession No. 209646) is
used, the human Fc portion can be ligated into the BamHI cloning
site. Note that the 3' BamHI site should be destroyed. Next, the
vector containing the human Fc portion is re-restricted with BamHI,
linearizing the vector, and a polynucleotide of the present
invention, isolated by the PCR protocol described in Example 1, is
ligated into this BamHI site. Note that the polynucleotide is
cloned without a stop codon, otherwise a fusion protein will not be
produced.
[1637] If the naturally occurring signal sequence is used to
produce the secreted protein, pC4 does not need a second signal
peptide. Alternatively, if the naturally occurring signal sequence
is not used, the vector can be modified to include a heterologous
signal sequence. (See, e.g., WO 96/34891.)
[1638] Human IgG Fc region:
63 Human IgG Fc region: GGGATCCGGAGCCCAAATCTTCTGACAAAACTCAC- AC
(SEQ ID NO:1) ATGCCCACCGTGCCCAGCACCTGAATTCGAGGGTGCA
CCGTCAGTCTTCCTCTTCCCCCCAAAACCCAAGGACA
CCCTCATGATCTCCCGGACTCCTGAGGTCACATGCGT
GGTGGTGGACGTAAGCCACGAAGACCCTGAGGTCAAG
TTCAACTGGTACGTGGACGGCGTGGAGGTGCATAATG
CCAAGACAAAGCCGCGGGAGGAGCAGTACAACAGCAC
GTACCGTGTGGTCAGCGTCCTCACCGTCCTGCACCAG
GACTGGCTGAATGGCAAGGAGTACAAGTGCAAGGTCT
CCAACAAAGCCCTCCCAACCCCCATCGAGAAAACCAT
CTCCAAAGCCAAAGGGCAGCCCCGAGAACCACAGGTG
TACACCCTGCCCCCATCCCGGGATGAGCTGACCAAGA
ACCAGGTCAGCCTGACCTGCCTGGTCAAAGGCTTCTA
TCCAAGCGACATCGCCGTGGAGTGGGAGAGCAATGGG
CAGCCGGAGAACAACTACAAGACCACGCCTCCCGTGC
TGGACTCCGACGGCTCCTTCTTCCTCTACAGCAAGCT
CACCGTGGACAAGAGCAGGTGGCAGCAGGGGAACGTC
TTCTCATGCTCCGTGATGCATGAGGCTCTGCACAACC
ACTACACGCAGAAGAGCCTCTCCCTGTCTCCGGGTAA
ATGAGTGCGACGGCCGCGACTCTAGAGGAT
Example 10
Production of an Antibody from a Polypeptide
[1639] The antibodies of the present invention can be prepared by a
variety of methods. (See, Current Protocols, Chapter 2.) For
example, cells expressing a polypeptide of the present invention is
administered to an animal to induce the production of sera
containing polyclonal antibodies. In a preferred method, a
preparation of the secreted protein is prepared and purified to
render it substantially free of natural contaminants. Such a
preparation is then introduced into an animal in order to produce
polyclonal antisera of greater specific activity.
[1640] In the most preferred method, the antibodies of the present
invention are monoclonal antibodies (or protein binding fragments
thereof). Such monoclonal antibodies can be prepared using
hybridoma technology. (Kohler et al., Nature 256:495 (1975); Kohler
et al., Eur. J. Immunol. 6:511 (1976); Kohler et al., Eur. J.
Immunol. 6:292 (1976); Hammerling et al., in: Monoclonal Antibodies
and T-Cell Hybridomas, Elsevier, N.Y., pp. 563-681 (1981).) In
general, such procedures involve immunizing an animal (preferably a
mouse) with polypeptide or, more preferably, with a secreted
polypeptide-expressing cell. Such cells may be cultured in any
suitable tissue culture medium; however, it is preferable to
culture cells in Earle's modified Eagle's medium supplemented with
10% fetal bovine serum (inactivated at about 56.degree. C.), and
supplemented with about 10 g/l of nonessential amino acids, about
1,000 U/mil of penicillin, and about 100 .mu.g/ml of
streptomycin.
[1641] The splenocytes of such mice are extracted and fused with a
suitable myeloma cell line. Any suitable myeloma cell line may be
employed in accordance with the present invention; however, it is
preferable to employ the parent myeloma cell line (SP2O), available
from the ATCC. After fusion, the resulting hybridoma cells are
selectively maintained in HAT medium, and then cloned by limiting
dilution as described by Wands et al. (Gastroenterology 80:225-232
(1981).) The hybridoma cells obtained through such a selection are
then assayed to identify clones which secrete antibodies capable of
binding the polypeptide.
[1642] Alternatively, additional antibodies capable of binding to
the polypeptide can be produced in a two-step procedure using
anti-idiotypic antibodies. Such a method makes use of the fact that
antibodies are themselves antigens, and therefore, it is possible
to obtain an antibody which binds to a second antibody. In
accordance with this method, protein specific antibodies are used
to immunize an animal, preferably a mouse. The splenocytes of such
an animal are then used to produce hybridoma cells, and the
hybridoma cells are screened to identify clones which produce an
antibody whose ability to bind to the protein-specific antibody can
be blocked by the polypeptide. Such antibodies comprise
anti-idiotypic antibodies to the protein-specific antibody and can
be used to immunize an animal to induce formation of further
protein-specific antibodies.
[1643] It will be appreciated that Fab and Fab')2 and other
fragments of the antibodies of the present invention may be used
according to the methods disclosed herein. Such fragments are
typically produced by proteolytic cleavage, using enzymes such as
papain (to produce Fab fragments) or pepsin (to produce Fab')2
fragments). Alternatively, secreted protein-binding fragments can
be produced through the application of recombinant DNA technology
or through synthetic chemistry.
[1644] For in vivo use of antibodies in humans, it may be
preferable to use "humanized" chimeric monoclonal antibodies. Such
antibodies can be produced using genetic constructs derived from
hybridoma cells producing the monoclonal antibodies described
above. Methods for producing chimeric antibodies are known in the
art. (See, for review, Morrison, Science 229:1202 (1985); Oi et
al., BioTechniques 4:214 (1986); Cabilly et al., U.S. Pat. No.
4,816,567; Taniguchi et al., EP 171496; Morrison et al., EP 173494;
Neuberger et al., WO 8601533; Robinson et al., WO 8702671;
Boulianne et al., Nature 312:643 (1984); Neuberger et al., Nature
314:268 (1985).)
Example 11
Production of Secreted Protein For High-Throughput Screening
Assays
[1645] The following protocol produces a supernatant containing a
polypeptide to be tested. This supernatant can then be used in the
Screening Assays described in Examples 13-20.
[1646] First, dilute Poly-D-Lysine (644 587 Boehringer-Mannheim)
stock solution (1 mg/ml in PBS) 1:20 in PBS (w/o calcium or
magnesium 17-516F Biowhittaker) for a working solution of 50 ug/ml.
Add 200 ul of this solution to each well (24 well plates) and
incubate at RT for 20 minutes. Be sure to distribute the solution
over each well (note: a 12-channel pipetter may be used with tips
on every other channel). Aspirate off the Poly-D-Lysine solution
and rinse with 1 ml PBS (Phosphate Buffered Saline). The PBS should
remain in the well until just prior to plating the cells and plates
may be poly-lysine coated in advance for up to two weeks.
[1647] Plate 293T cells (do not carry cells past P+20) at 2.times.
10.sup.5 cells/well in 0.5 ml DMEM(Dulbecco's Modified Eagle
Medium)(with 4.5 G/L glucose and L-glutamine (12-604F
Biowhittaker))/10% heat inactivated FBS(14-503F
Biowhittaker)/1.times.Penstrep(17-602E Biowhittaker). Let the cells
grow overnight.
[1648] The next day, mix together in a sterile solution basin: 300
ul Lipofectamine (18324-012 Gibco/BRL) and 5 ml Optimem I (31985070
Gibco/BRL)/96-well plate. With a small volume multi-channel
pipetter, aliquot approximately 2 ug of an expression vector
containing a polynucleotide insert, produced by the methods
described in Examples 8 or 9, into an appropriately labeled 96-well
round bottom plate. With a multi-channel pipetter, add 50 ul of the
Lipofectamine/Optimem I mixture to each well. Pipette up and down
gently to mix. Incubate at RT 15-45 minutes. After about 20
minutes, use a multi-channel pipetter to add 150 ul Optimem I to
each well. As a control, one plate of vector DNA lacking an insert
should be transfected with each set of transfections.
[1649] Preferably, the transfection should be performed by
tag-teaming the following tasks. By tag-teaming, hands on time is
cut in half, and the cells do not spend too much time on PBS.
First, person A aspirates off the media from four 24-well plates of
cells, and then person B rinses each well with 0.5-1 ml PBS. Person
A then aspirates off PBS rinse, and person B, using a12-channel
pipetter with tips on every other channel, adds the 200 ul of
DNA/Lipofectamine/Optimem I complex to the odd wells first, then to
the even wells, to each row on the 24-well plates. Incubate at
37.degree. C. for 6 hours.
[1650] While cells are incubating, prepare appropriate media,
either 1%BSA in DMEM with 1.times. penstrep, or CHO-5 media (116.6
mg/L of CaCl2 (anhyd); 0.00130 mg/L CuSO.sub.4--5H.sub.2O; 0.050
mg/L of Fe(NO.sub.3).sub.3--9H.sub.2O; 0.417 mg/L of
FeSO.sub.4--7H.sub.2O; 311.80 mg/L of Kcl; 28.64 mg/L of
MgCl.sub.2; 48.84 mg/L of MgSO.sub.4; 6995.50 mg/L of NaCl; 2400.0
mg/L of NaHCO.sub.3; 62.50 mg/L of NaH.sub.2PO.sub.4--H.sub.2O;
71.02 mg/L of Na.sub.2HPO4; 0.4320 mg/L of ZnSO.sub.4--7H.sub.2O;
0.002 mg/L of Arachidonic Acid; 1.022 mg/L of Cholesterol; 0.070
mg/L of DL-alpha-Tocopherol-Acetate; 0.0520 mg/L of Linoleic Acid;
0.010 mg/L of Linolenic Acid; 0.010 mg/L of Myristic Acid; 0.010
mg/L of Oleic Acid; 0.010 mg/L of Palmitric Acid; 0.010 mg/L of
Palmitic Acid; 100 mg/L of Pluronic F-68; 0.010 mg/L of Stearic
Acid; 2.20 mg/L of Tween 80; 4551 mg/L of D-Glucose; 130.85 mg/ml
of L-Alanine; 147.50 mg/ml of L-Arginine-HCL; 7.50 mg/ml of
L-Asparagine-H.sub.2O; 6.65 mg/ml of L-Aspartic Acid; 29.56 mg/ml
of L-Cystine-2HCL--H.sub.2O; 31.29 mg/ml of L-Cystine-2HCL; 7.35
mg/ml of L-Glutamic Acid; 365.0 mg/ml of L-Glutamine; 18.75 mg/ml
of Glycine; 52.48 mg/ml of L-Histidine-HCL-H.sub.2O; 106.97 mg/ml
of L-Isoleucine; 111.45 mg/ml of L-Leucine; 163.75 mg/ml of
L-Lysine HCL; 32.34 mg/ml of L-Methionine; 68.48 mg/ml of
L-Phenylalainine; 40.0 mg/ml of L-Proline; 26.25 mg/ml of L-Serine;
101.05 mg/ml of L-Threonine; 19.22 mg/ml of L-Tryptophan; 91.79
mg/ml of L-Tryrosine-2Na--2H.sub.2O; 99.65 mg/ml of L-Valine;
0.0035 mg/L of Biotin; 3.24 mg/L of D-Ca Pantothenate; 11.78 mg/L
of Choline Chloride; 4.65 mg/L of Folic Acid; 15.60 mg/L of
i-Inositol; 3.02 mg/L of Niacinamide; 3.00 mg/L of Pyridoxal HCL;
0.031 mg/L of Pyridoxine HCL; 0.319 mg/L of Riboflavin; 3.17 mg/L
of Thiamine HCL; 0.365 mg/L of Thymidine; and 0.680 mg/L of Vitamin
B.sub.12; 25 mM of HEPES Buffer; 2.39 mg/L of Na Hypoxanthine;
0.105 mg/L of Lipoic Acid; 0.081 mg/L of Sodium Putrescine-2HCL;
55.0 mg/L of Sodium Pyruvate; 0.0067 mg/L of Sodium Selenite; 20 uM
of Ethanolamine; 0.122 mg/L of Ferric Citrate; 41.70 mg/L of
Methyl-B-Cyclodextrin complexed with Linoleic Acid; 33.33 mg/L of
Methyl-B-Cyclodextrin complexed with Oleic Acid; and 10 mg/L of
Methyl-B-Cyclodextrin complexed with Retinal) with 2 mm glutamine
and 1.times.penstrep. (BSA (81-068-3 Bayer) 100 gm dissolved in 1 L
DMEM for a 10% BSA stock solution). Filter the media and collect 50
.mu.l for endotoxin assay in 15 ml polystyrene conical.
[1651] The transfection reaction is terminated, preferably by
tag-teaming, at the end of the incubation period. Person A
aspirates off the transfection media, while person B adds 1.5 ml
appropriate media to each well. Incubate at 37.degree. C. for 45 or
72 hours depending on the media used: 1%BSA for 45 hours or CHO-5
for 72 hours.
[1652] On day four, using a 300 ul multichannel pipetter, aliquot
600 ul in one 1 ml deep well plate and the remaining supernatant
into a 2 ml deep well. The supernatants from each well can then be
used in the assays described in Examples 13-20.
[1653] It is specifically understood that when activity is obtained
in any of the assays described below using a supernatant, the
activity originates from either the polypeptide directly (e.g., as
a secreted protein) or by the polypeptide inducing expression of
other proteins, which are then secreted into the supernatant. Thus,
the invention further provides a method of identifying the protein
in the supernatant characterized by an activity in a particular
assay.
Example 12
Construction of GAS Reporter Construct
[1654] One signal transduction pathway involved in the
differentiation and proliferation of cells is called the Jaks-STATs
pathway. Activated proteins in the Jaks-STATs pathway bind to gamma
activation site "GAS" elements or interferon-sensitive responsive
element ("ISRE"), located in the promoter of many genes. The
binding of a protein to these elements alter the expression of the
associated gene.
[1655] GAS and ISRE elements are recognized by a class of
transcription factors called Signal Transducers and Activators of
Transcription, or "STATs." There are six members of the STATs
family. Stat1 and Stat3 are present in many cell types, as is Stat2
(as response to IFN-alpha is widespread). Stat4 is more restricted
and is not in many cell types though it has been found in T helper
class I, cells after treatment with IL-12. Stat5 was originally
called mammary growth factor, but has been found at higher
concentrations in other cells including myeloid cells. It can be
activated in tissue culture cells by many cytokines.
[1656] The STATs are activated to translocate from the cytoplasm to
the nucleus upon tyrosine phosphorylation by a set of kinases known
as the Janus Kinase ("Jaks") family. Jaks represent a distinct
family of soluble tyrosine kinases and include Tyk2, Jak1, Jak2,
and Jak3. These kinases display significant sequence similarity and
are generally catalytically inactive in resting cells.
[1657] The Jaks are activated by a wide range of receptors
summarized in the Table below. (Adapted from review by Schidler and
Darnell, Ann. Rev. Biochem. 64:621-51 (1995).) A cytokine receptor
family, capable of activating Jaks, is divided into two groups: (a)
Class 1 includes receptors for IL-2, IL-3, IL-4, IL-6, IL-7, IL-9,
IL-11, IL-12, IL-15, Epo, PRL, GH, G-CSF, GM-CSF, LIF, CNTF, and
thrombopoietin; and (b) Class 2 includes IFN-a, IFN-g, and IL-10.
The Class 1 receptors share a conserved cysteine motif (a set of
four conserved cysteines and one tryptophan) and a WSXWS motif (a
membrane proxial region encoding Trp-Ser-Xxx-Trp-Ser (SEQ ID
NO:2)).
[1658] Thus, on binding of a ligand to a receptor, Jaks are
activated, which in turn activate STATs, which then translocate and
bind to GAS elements. This entire process is encompassed in the
Jaks-STATs signal transduction pathway.
[1659] Therefore, activation of the Jaks-STATs pathway, reflected
by the binding of the GAS or the ISRE element, can be used to
indicate proteins involved in the proliferation and differentiation
of cells. For example, growth factors and cytokines are known to
activate the Jaks-STATs pathway. (See Table below.) Thus, by using
GAS elements linked to reporter molecules, activators of the
Jaks-STATs pathway can be identified.
64 JAKs Ligand tyk2 Jak1 Jak2 Jak3 STATS GAS (elements) or ISRE IFN
family IFN-a/B + + - - 1,2,3 ISRE IFN-g + + - 1 GAS (IRF1 > Lys6
> IFP) Il-10 + ? ? - 1,3 gp130 family IL-6 (Pleiotrohic) + + + ?
1,3 GAS (IRF1 > Lys6 > IFP) Il-11 (Pleiotrohic) ? + ? ? 1,3
OnM (Pleiotrohic) ? + + ? 1,3 LIF (Pleiotrohic) ? + + ? 1,3 CNTF
(Pleiotrohic) -/+ + + ? 1,3 G-CSF (Pleiotrohic) ? + ? ? 1,3 IL-12
(Pleiotrohic) + - + + 1,3 g-C family IL-2 (lymphocytes) - + - +
1,3,5 GAS IL-4 (lymph/myeloid) - + - + 6 GAS (IRF1 = IFP > >
Ly6)(IgH) IL-7 (lymphocytes) - + - + 5 GAS IL-9 (lymphocytes) - + -
+ 5 GAS IL-13 (lymphocyte) - + ? ? 6 GAS IL-15 ? + ? + 5 GAS gp140
family IL-3 (myeloid) - - + - 5 GAS (IRF1 > IFP > > Ly6)
IL-5 (myeloid) - - + - 5 GAS GM-CSF (myeloid) - - + - 5 GAS Growth
hormone family GH ? - + - 5 PRL ? +/- + - 1,3,5 EPO ? - + - 5 GAS
(B-CAS > IRF1 = IFP > > Ly6) Receptor Tyrosine Kinases EGF
? + + - 1,3 GAS (IRF1) PDGF ? + + - 1,3 CSF-1 ? + + - 1,3 GAS (not
IRF1)
[1660] To construct a synthetic GAS containing promoter element,
which is used in the Biological Assays described in Examples 13-14,
a PCR based strategy is employed to generate a GAS-SV40 promoter
sequence. The 5' primer contains four tandem copies of the GAS
binding site found in the IRF1 promoter and previously demonstrated
to bind STATs upon induction with a range of cytokines (Rothman et
al., Immunity 1:457-468 (1994).), although other GAS or ISRE
elements can be used instead. The 5' primer also contains 18 bp of
sequence complementary to the SV40 early promoter sequence and is
flanked with an XhoI site. The sequence of the 5' primer is:
65 5':CTCGAGATTTCCCCGAAATCTAGATTTCCCCGAA (SEQ ID NO:5)
ATGATTTCCCCGAAATGATTTCCCCGAAATATCTGCC
ATCTCAATTAGTCAGCAACCATAGTCCCGCCCCTAAC
TCCGCCCATCCCGCCCCTAACTCCGCCCAGTTCCGCC
CATTCTCCGCCCCATGGCTGACTAATTTTTTTTATTT
ATGCAGAGGCCGAGGCCGCCTCGGCCTCTGAGCTATT
CCAGAAGTAGTGAGGAGGCTTTTTTGGAGGCCTAGGC TTTTGCAAAAAGCTT:3'
[1661] The downstream primer is complementary to the SV40 promoter
and is flanked with a Hind III site:
5':GCGGCAAGCTTTTTGCAAAGCCTAGGC:3' (SEQ ID NO:4)
[1662] PCR amplification is performed using the SV40 promoter
template present in the B-gal:promoter plasmid obtained from
Clontech. The resulting PCR fragment is digested with XhoI/Hind III
and subcloned into BLSK2-. (Stratagene.) Sequencing with forward
and reverse primers confirms that the insert contains the following
sequence:
66 5':CTCGAGATTTCCCCGAAATCTAGATTTCCCCGAAATGATTTCCCCGAAATG (SEQ ID
NO:5) ATTTCCCCGAAATATCTGCCATCTCAATTAGTCAGCAACCATAGTCCCGC- CC
CTAACTCCGCCCATCCCGCCCCTAACTCCGCCCAGTTCCGCCCATTCTCCGC
CCCATGGCTGACTAATTTTTTTTATTTATGCAGAGGCCGAGGCCGCCTCGGC
CTCTGAGCTATTCCAGAAGTAGTGAGGAGGCTTTTTTGGAGGCCTAGGCTTT
TGCAAAAAGCTT:3'
[1663] With this GAS promoter element linked to the SV40 promoter,
a GAS:SEAP2 reporter construct is next engineered. Here, the
reporter molecule is a secreted alkaline phosphatase, or "SEAP."
Clearly, however, any reporter molecule can be instead of SEAP, in
this or in any of the other Examples. Well known reporter molecules
that can be used instead of SEAP include chloramphenicol
acetyltransferase (CAT), luciferase, alkaline phosphatase,
B-galactosidase, green fluorescent protein (GFP), or any protein
detectable by an antibody.
[1664] The above sequence confirmed synthetic GAS-SV40 promoter
element is subcloned into the pSEAP-Promoter vector obtained from
Clontech using HindIII and XhoI, effectively replacing the SV40
promoter with the amplified GAS:SV40 promoter element, to create
the GAS-SEAP vector. However, this vector does not contain a
neomycin resistance gene, and therefore, is not preferred for
mammalian expression systems.
[1665] Thus, in order to generate mammalian stable cell lines
expressing the GAS-SEAP reporter, the GAS-SEAP cassette is removed
from the GAS-SEAP vector using SalI and NotI, and inserted into a
backbone vector containing the neomycin resistance gene, such as
pGFP-1 (Clontech), using these restriction sites in the multiple
cloning site, to create the GAS-SEAP/Neo vector. Once this vector
is transfected into mammalian cells, this vector can then be used
as a reporter molecule for GAS binding as described in Examples
13-14.
[1666] Other constructs can be made using the above description and
replacing GAS with a different promoter sequence. For example,
construction of reporter molecules containing NFK-B and EGR
promoter sequences are described in Examples 15 and 16. However,
many other promoters can be substituted using the protocols
described in these Examples. For instance, SRE, IL-2, NFAT, or
Osteocalcin promoters can be substituted, alone or in combination
(e.g., GAS/NF-KB/EGR, GAS/NF-KB, Il-2/NFAT, or NF-KB/GAS).
Similarly, other cell lines can be used to test reporter construct
activity, such as HELA (epithelial), HUVEC (endothelial), Reh
(B-cell), Saos-2 (osteoblast), HUVAC (aortic), or
Cardiomyocyte.
Example 13
High-Throughput Screening Assay for T-cell Activity
[1667] The following protocol is used to assess T-cell activity by
identifying factors, such as growth factors and cytokines, that may
proliferate or differentiate T-cells. T-cell activity is assessed
using the GAS/SEAP/Neo construct produced in Example 12. Thus,
factors that increase SEAP activity indicate the ability to
activate the Jaks-STATS signal transduction pathway. The T-cell
used in this assay is Jurkat T-cells (ATCC Accession No. TIB-152),
although Molt-3 cells (ATCC Accession No. CRL-1552) and Molt-4
cells (ATCC Accession No. CRL-1582) cells can also be used.
[1668] Jurkat T-cells are lymphoblastic CD4+Th1 helper cells. In
order to generate stable cell lines, approximately 2 million Jurkat
cells are transfected with the GAS-SEAP/neo vector using DMRIE-C
(Life Technologies)(transfection procedure described below). The
transfected cells are seeded to a density of approximately 20,000
cells per well and transfectants resistant to 1 mg/ml genticin
selected. Resistant colonies are expanded and then tested for their
response to increasing concentrations of interferon gamma. The dose
response of a selected clone is demonstrated.
[1669] Specifically, the following protocol will yield sufficient
cells for 75 wells containing 200 ul of cells. Thus, it is either
scaled up, or performed in multiple to generate sufficient cells
for multiple 96 well plates. Jurkat cells are maintained in
RPMI+10% serum with 1%Pen-Strep. Combine 2.5 mls of OPTI-MEM (Life
Technologies) with 10 ug of plasmid DNA in a T25 flask. Add 2.5 ml
OPTI-MEM containing 50 ul of DMRIE-C and incubate at room
temperature for 15-45 mins.
[1670] During the incubation period, count cell concentration, spin
down the required number of cells (10.sup.7 per transfection), and
resuspend in OPTI-MEM to a final concentration of 10.sup.7
cells/ml. Then add 1 ml of 1.times. 10.sup.7 cells in OPTI-MEM to
T25 flask and incubate at 37.degree. C. for 6 hrs. After the
incubation, add 10 ml of RPMI+15% serum.
[1671] The Jurkat:GAS-SEAP stable reporter lines are maintained in
RPIMI+10% serum, 1 mg/ml Genticin, and 1% Pen-Strep. These cells
are treated with supernatants containing a polypeptide as produced
by the protocol described in Example 11.
[1672] On the day of treatment with the supernatant, the cells
should be washed and resuspended in fresh RPMI+10% serum to a
density of 500,000 cells per ml. The exact number of cells required
will depend on the number of supernatants being screened. For one
96 well plate, approximately 10 million cells (for 10 plates, 100
million cells) are required.
[1673] Transfer the cells to a triangular reservoir boat, in order
to dispense the cells into a 96 well dish, using a 12 channel
pipette. Using a 12 channel pipette, transfer 200 ul of cells into
each well (therefore adding 100,000 cells per well).
[1674] After all the plates have been seeded, 50 l of the
supernatants are transferred directly from the 96 well plate
containing the supernatants into each well using a 12 channel
pipette. In addition, a dose of exogenous interferon gamma (0.1,
1.0, 10 ng) is added to wells H9, H10, and H11 to serve as
additional positive controls for the assay.
[1675] The 96 well dishes containing Jurkat cells treated with
supernatants are placed in an incubator for 48 hrs (note: this time
is variable between 48-72 hrs). 35 ul samples from each well are
then transferred to an opaque 96 well plate using a 12 channel
pipette. The opaque plates should be covered (using sellophene
covers) and stored at -20.degree. C. until SEAP assays are
performed according to Example 17. The plates containing the
remaining treated cells are placed at 4.degree. C. and serve as a
source of material for repeating the assay on a specific well if
desired.
[1676] As a positive control, 100 Unit/ml interferon gamma can be
used which is known to activate Jurkat T cells. Over 30 fold
induction is typically observed in the positive control wells.
Example 14
High-Throughput Screening Assay Identifying Myeloid Activity
[1677] The following protocol is used to assess myeloid activity by
identifying factors, such as growth factors and cytokines, that may
proliferate or differentiate myeloid cells. Myeloid cell activity
is assessed using the GAS/SEAP/Neo construct produced in Example
12. Thus, factors that increase SEAP activity indicate the ability
to activate the Jaks-STATS signal transduction pathway. The myeloid
cell used in this assay is U937, a pre-monocyte cell line, although
TF-1, HL60, or KG1 can be used.
[1678] To transiently transfect U937 cells with the GAS/SEAP/Neo
construct produced in Example 12, a DEAE-Dextran method (Kharbanda
et. al., 1994, Cell Growth & Differentiation, 5:259-265) is
used. First, harvest 2.times. 10e.sup.7 U937 cells and wash with
PBS. The U937 cells are usually grown in RPMI 1640 medium
containing 10% heat-inactivated fetal bovine serum (FBS)
supplemented with 100 units/ml penicillin and 100 mg/ml
streptomycin.
[1679] Next, suspend the cells in 1 ml of 20 mM Tris-HCl (pH 7.4)
buffer containing 0.5 mg/ml DEAE-Dextran, 8 ug GAS-SEAP2 plasmid
DNA, 140 nuM NaCl, 5 mM KCl, 375 uM Na.sub.2HPO.sub.4.7H.sub.2O, 1
mM MgCl.sub.2, and 675 uM CaCl.sub.2. Incubate at 37.degree. C. for
45 min.
[1680] Wash the cells with RPMI 1640 medium containing 10% FBS and
then resuspend in 10 ml complete medium and incubate at 37.degree.
C. for 36 hr.
[1681] The GAS-SEAP/U937 stable cells are obtained by growing the
cells in 400 ug/ml G418. The G418-free medium is used for routine
growth but every one to two months, the cells should be re-grown in
400 ug/ml G418 for couple of passages.
[1682] These cells are tested by harvesting 1.times. 10.sup.8 cells
(this is enough for ten 96-well plates assay) and wash with PBS.
Suspend the cells in 200 ml above described growth medium, with a
final density of 5.times. 10.sup.5 cells/ml. Plate 200 ul cells per
well in the 96-well plate (or 1.times. 10.sup.5 cells/well).
[1683] Add 50 ul of the supernatant prepared by the protocol
described in Example 11. Incubate at 37.degree. C. for 48 to 72 hr.
As a positive control, 100 Unit/ml interferon gamma can be used
which is known to activate U937 cells. Over 30 fold induction is
typically observed in the positive control wells. SEAP assay the
supernatant according to the protocol described in Example 17.
Example 15
High-Throughput Screening Assay Identifying Neuronal Activity
[1684] When cells undergo differentiation and proliferation, a
group of genes are activated through many different signal
transduction pathways. One of these genes, EGR1 (early growth
response gene 1), is induced in various tissues and cell types upon
activation. The promoter of EGR1 is responsible for such induction.
Using the EGR1 promoter linked to reporter molecules, activation of
cells can be assessed.
[1685] Particularly, the following protocol is used to assess
neuronal activity in PC12 cell lines. PC12 cells (rat
phenochromocytoma cells) are known to proliferate and/or
differentiate by activation with a number of mitogens, such as TPA
(tetradecanoyl phorbol acetate), NGF (nerve growth factor), and EGF
(epidermal growth factor). The EGR1 gene expression is activated
during this treatment. Thus, by stably transfecting PC12 cells with
a construct containing an EGR promoter linked to SEAP reporter,
activation of PC12 cells can be assessed.
[1686] The EGR/SEAP reporter construct can be assembled by the
following protocol. The EGR-1 promoter sequence (-633 to
+1)(Sakamoto K et al., Oncogene 6:867-871 (1991)) can be PCR
amplified from human genomic DNA using the following primers:
67 5'GCGCTCGAGGGATGACAGCGATAGAACCCCGG-3' (SEQ ID NO:6)
5'GCGAAGCTTCGCGACTCCCCGGATCCGCCTC-3' (SEQ ID NO:7)
[1687] Using the GAS:SEAP/Neo vector produced in Example 12, EGR1
amplified product can then be inserted into this vector. Linearize
the GAS:SEAP/Neo vector using restriction enzymes XhoI/HindIII,
removing the GAS/SV40 stuffer. Restrict the EGR1 amplified product
with these same enzymes. Ligate the vector and the EGR1
promoter.
[1688] To prepare 96 well-plates for cell culture, two mls of a
coating solution (1:30 dilution of collagen type I (Upstate Biotech
Inc. Cat#08-115) in 30% ethanol (filter sterilized)) is added per
one 10 cm plate or 50 ml per well of the 96-well plate, and allowed
to air dry for 2 hr.
[1689] PC12 cells are routinely grown in RPMI-1640 medium (Bio
Whittaker) containing 10% horse serum (JRH BIOSCIENCES, Cat. #
12449-78P), 5% heat-inactivated fetal bovine serum (FBS)
supplemented with 100 units/mil penicillin and 100 ug/ml
streptomycin on a precoated 10 cm tissue culture dish. One to four
split is done every three to four days. Cells are removed from the
plates by scraping and resuspended with pipetting up and down for
more than 15 times.
[1690] Transfect the EGR/SEAP/Neo construct into PC12 using the
Lipofectamine protocol described in Example 11. EGR-SEAP/PC12
stable cells are obtained by growing the cells in 300 ug/ml G418.
The G418-free medium is used for routine growth but every one to
two months, the cells should be re-grown in 300 ug/ml G418 for
couple of passages.
[1691] To assay for neuronal activity, a 10 cm plate with cells
around 70 to 80% confluent is screened by removing the old medium.
Wash the cells once with PBS (Phosphate buffered saline). Then
starve the cells in low serum medium (RPMI-1640 containing 1% horse
serum and 0.5% FBS with antibiotics) overnight.
[1692] The next morning, remove the medium and wash the cells with
PBS. Scrape off the cells from the plate, suspend the cells well in
2 ml low serum medium. Count the cell number and add more low serum
medium to reach final cell density as 5.times. 10.sup.5
cells/ml.
[1693] Add 200 ul of the cell suspension to each well of 96-well
plate (equivalent to 1.times. 10.sup.5 cells/well). Add 50 ul
supernatant produced by Example 11, 37.degree. C. for 48 to 72 hr.
As a positive control, a growth factor known to activate PC12 cells
through EGR can be used, such as 50 ng/ul of Neuronal Growth Factor
(NGF). Over fifty-fold induction of SEAP is typically seen in the
positive control wells. SEAP assay the supernatant according to
Example 17.
Example 16
[1694] High-Throughput Screening Assay for T-cell Activity
[1695] NF-.kappa.B (Nuclear Factor .kappa.B) is a transcription
factor activated by a wide variety of agents including the
inflammatory cytokines IL-1 and TNF, CD30 and CD40,
lymphotoxin-alpha and lymphotoxin-beta, by exposure to LPS or
thrombin, and by expression of certain viral gene products. As a
transcription factor, NF-.kappa.B regulates the expression of genes
involved in immune cell activation, control of apoptosis
(NF-.kappa.B appears to shield cells from apoptosis), B and T-cell
development, anti-viral and antimicrobial responses, and multiple
stress responses.
[1696] In non-stimulated conditions, NF-.kappa.B is retained in the
cytoplasm with I-.kappa.B (Inhibitor-.kappa.B). However, upon
stimulation, I-.kappa.B is phosphorylated and degraded, causing
NF-.kappa.B to shuttle to the nucleus, thereby activating
transcription of target genes. Target genes activated by
NF-.kappa.B include IL-2, IL-6, GM-CSF, ICAM-1 and class 1 MHC.
[1697] Due to its central role and ability to respond to a range of
stimuli, reporter constructs utilizing the NF-.kappa.B promoter
element are used to screen the supernatants produced in Example 11.
Activators or inhibitors of NF-.kappa.B would be useful in treating
diseases. For example, inhibitors of NF-.kappa.B could be used to
treat those diseases related to the acute or chronic activation of
NF-.kappa.B, such as rheumatoid arthritis.
[1698] To construct a vector containing the NF-.kappa.B promoter
element, a PCR based strategy is employed. The upstream primer
contains four tandem copies of the NF-.kappa.B binding site
(GGGGACTTTCCC) (SEQ ID NO:8), 18 bp of sequence complementary to
the 5' end of the SV40 early promoter sequence, and is flanked with
an XhoI site:
68 5':CTCGAGGGGACTTTCCCGGGGACTTTCCGGGGA (SEQ ID NO:10)
CTTTCCGGGACTTTCCATCTGCCATCTCAATTAGTC
AGCAACCATAGTCCCGCCCCTAACTCCGCCCATCCC
GCCCCTAACTCCGCCCAGTTCCGCCCATTCTCCGCC
CCATGGCTGACTAATTTTTTTTATTTATGCAGAGGC
CGAGGCCGCCTCGGCCTCTGAGCTATTCCAGAAGTA
GTGAGGAGGCTTTTTTGGAGGCCTAGGCTTTTGCAA AAAGCTT:3'
[1699] The downstream primer is complementary to the 3' end of the
SV40 promoter and is flanked with a Hind III site:
[1700] 5':GCGGCAAGCTTTTTGCAAAGCCTAGGC:3' (SEQ ID NO:4)
[1701] PCR amplification is performed using the SV40 promoter
template present in the pB-gal:promoter plasmid obtained from
Clontech. The resulting PCR fragment is digested with XhoI and Hind
III and subcloned into BLSK2-. (Stratagene) Sequencing with the T7
and T3 primers confirms the insert contains the following
sequence:
69 5':CTCGAGGGGACTTTCCCGGGGACTTTCCGGGGACTTTCCGGGACTTTCC (SEQ ID
NO:10) ATCTGCCATCTCAATTAGTCAGCAACCATAGTCCCGCCCCTAACTCCGC- CCA
TCCCGCCCCTAACTCCGCCCAGTTCCGCCCATTCTCCGCCCCATGGCTGACT
AATTTTTTTTATTTATGCAGAGGCCGAGGCCGCCTCGGCCTCTGAGCTATTC
CAGAAGTAGTGAGGAGGCTTTTTTGGAGGCCTAGGCTTTTGCAAAAAGCTT:3'
[1702] Next, replace the SV40 minimal promoter element present in
the pSEAP2-promoter plasmid (Clontech) with this NF-.kappa.B/SV40
fragment using XhoI and HindIII. However, this vector does not
contain a neomycin resistance gene, and therefore, is not preferred
for mammalian expression systems.
[1703] In order to generate stable mammalian cell lines, the
NF-.kappa.B/SV40/SEAP cassette is removed from the above
NF-.kappa.B/SEAP vector using restriction enzymes SalI and NotI,
and inserted into a vector containing neomycin resistance.
Particularly, the NF-.kappa.B/SV40/SEAP cassette was inserted into
pGFP-1 (Clontech), replacing the GFP gene, after restricting pGFP-1
with SalI and NotI.
[1704] Once ITF-.kappa.B/SV40/SEAP/Neo vector is created, stable
Jurkat T-cells are created and maintained according to the protocol
described in Example 13. Similarly, the method for assaying
supernatants with these stable Jurkat T-cells is also described in
Example 13. As a positive control, exogenous TNF alpha (0.1, 1, 10
ng) is added to wells H9, H10, and H11, with a 5-10 fold activation
typically observed.
Example 17
[1705] Assay for SEAP Activity
[1706] As a reporter molecule for the assays described in Examples
13-16, SEAP activity is assayed using the Tropix Phospho-light Kit
(Cat. BP-400) according to the following general procedure. The
Tropix Phospho-light Kit supplies the Dilution, Assay, and Reaction
Buffers used below.
[1707] Prime a dispenser with the 2.5.times. Dilution Buffer and
dispense 15 .mu.l of 2.5.times. dilution buffer into Optiplates
containing 35 .mu.l of a supernatant. Seal the plates with a
plastic sealer and incubate at 65.degree. C. for 30 min. Separate
the Optiplates to avoid uneven heating.
[1708] Cool the samples to room temperature for 15 minutes. Empty
the dispenser and prime with the Assay Buffer. Add 50 .mu.l Assay
Buffer and incubate at room temperature 5 min. Empty the dispenser
and prime with the Reaction Buffer (see the table below). Add 50
.mu.l Reaction Buffer and incubate at room temperature for 20
minutes. Since the intensity of the chemiluminescent signal is time
dependent, and it takes about 10 minutes to read 5 plates on
luminometer, one should treat 5 plates at each time and start the
second set 10 minutes later.
[1709] Read the relative light unit in the luminometer. Set H12 as
blank, and print the results. An increase in chemiluminescence
indicates reporter activity.
70 Reaction Buffer Formulation: # of plates Rxn buffer diluent (ml)
CSPD (ml) 10 60 3 11 65 3.25 12 70 3.5 13 75 3.75 14 80 4 15 85
4.25 16 90 4.5 17 95 4.75 18 100 5 19 105 5.25 20 110 5.5 21 115
5.75 22 120 6 23 125 6.25 24 130 6.5 25 135 6.75 26 140 7 27 145
7.25 28 150 7.5 29 155 7.75 30 160 8 31 165 8.25 32 170 8.5 33 175
8.75 34 180 9 35 185 9.25 36 190 9.5 37 195 9.75 38 200 10 39 205
10.25 40 210 10.5 41 215 10.75 42 220 11 43 225 11.25 44 230 11.5
45 235 11.75 46 240 12 47 245 12.25 48 250 12.5 49 255 12.75 50 260
13
Example 18
[1710] High-Throughput Screening Assay Identifying Changes in Small
Molecule Concentration and Membrane Permeability
[1711] Binding of a ligand to a receptor is known to alter
intracellular levels of small molecules, such as calcium,
potassium, sodium, and pH, as well as alter membrane potential.
These alterations can be measured in an assay to identify
supernatants which bind to receptors of a particular cell. Although
the following protocol describes an assay for calcium, this
protocol can easily be modified to detect changes in potassium,
sodium, pH, membrane potential, or any other small molecule which
is detectable by a fluorescent probe.
[1712] The following assay uses Fluorometric Imaging Plate Reader
("FLIPR") to measure changes in fluorescent molecules (Molecular
Probes) that bind small molecules. Clearly, any fluorescent
molecule detecting a small molecule can be used instead of the
calcium fluorescent molecule, fluo-3, used here.
[1713] For adherent cells, seed the cells at 10,000 -20,000
cells/well in a Co-star black 96-well plate with clear bottom. The
plate is incubated in a CO.sub.2 incubator for 20 hours. The
adherent cells are washed two times in Biotek washer with 200 ul of
HBSS (Hank's Balanced Salt Solution) leaving 100 ul of buffer after
the final wash.
[1714] A stock solution of 1 mg/ml fluo-3 is made in 10% pluronic
acid DMSO. To load the cells with fluo-3, 50 ul of 12 ug/ml fluo-3
is added to each well. The plate is incubated at 37.degree. C. in a
CO.sub.2 incubator for 60 min. The plate is washed four times in
the Biotek washer with HBSS leaving 100 ul of buffer.
[1715] For non-adherent cells, the cells are spun down from culture
media. Cells are re-suspended to 2-5.times. 10.sup.6 cells/ml with
HBSS in a 50-ml conical tube. 4 ul of 1 mg/ml fluo-3 solution in
10% pluronic acid DMSO is added to each ml of cell suspension. The
tube is then placed in a 37.degree. C. water bath for 30-60 min.
The cells are washed twice with HBSS, resuspended to 1.times.
10.sup.6 cells/ml, and dispensed into a microplate, 100 ul/well.
The plate is centrifuged at 1000 rpm for 5 min. The plate is then
washed once in Denley CellWash with 200 ul, followed by an
aspiration step to 100 ul final volume.
[1716] For a non-cell based assay, each well contains a fluorescent
molecule, such as fluo-3. The supernatant is added to the well, and
a change in fluorescence is detected.
[1717] To measure the fluorescence of intracellular calcium, the
FLIPR is set for the following parameters: (1) System gain is
300-800 mW; (2) Exposure time is 0.4 second; (3) Camera F/stop is
F/2; (4) Excitation is 488 nm; (5) Emission is 530 nm; and (6)
Sample addition is 50 ul. Increased emission at 530 nm indicates an
extracellular signaling event which has resulted in an increase in
the intracellular Ca.sup.++ concentration.
Example 19
[1718] High-Throughput Screening Assay Identifying Tyrosine Kinase
Activity
[1719] The Protein Tyrosine Kinases (PTK) represent a diverse group
of transmembrane and cytoplasmic kinases. Within the Receptor
Protein Tyrosine Kinase RPTK) group are receptors for a range of
mitogenic and metabolic growth factors including the PDGF, FGF,
EGF, NGF, HGF and Insulin receptor subfamilies. In addition there
are a large family of RPTKs for which the corresponding ligand is
unknown. Ligands for RPTKs include mainly secreted small proteins,
but also membrane-bound and extracellular matrix proteins.
[1720] Activation of RPTK by ligands involves ligand-mediated
receptor dimerization, resulting in transphosphorylation of the
receptor subunits and activation of the cytoplasmic tyrosine
kinases. The cytoplasmic tyrosine kinases include receptor
associated tyrosine kinases of the src-family (e.g., src, yes, lck,
lyn, fyn) and non-receptor linked and cytosolic protein tyrosine
kinases, such as the Jak family, members of which mediate signal
transduction triggered by the cytokine superfamily of receptors
(e.g., the Interleukins, Interferons, GM-CSF, and Leptin).
[1721] Because of the wide range of known factors capable of
stimulating tyrosine kinase activity, the identification of novel
human secreted proteins capable of activating tyrosine kinase
signal transduction pathways are of interest. Therefore, the
following protocol is designed to identify those novel human
secreted proteins capable of activating the tyrosine kinase signal
transduction pathways.
[1722] Seed target cells (e.g., primary keratinocytes) at a density
of approximately 25,000 cells per well in a 96 well Loprodyne
Silent Screen Plates purchased from Nalge Nunc (Naperville, Ill.).
The plates are sterilized with two 30 minute rinses with 100%
ethanol, rinsed with water and dried overnight. Some plates are
coated for 2 hr with 100 ml of cell culture grade type I collagen
(50 mg/ml), gelatin (2%) or polylysine (50 mg/ml), all of which can
be purchased from Sigma Chemicals (St. Louis, Mo.) or 10% Matrigel
purchased from Becton Dickinson (Bedford, Mass.), or calf serum,
rinsed with PBS and stored at 4.degree. C. Cell growth on these
plates is assayed by seeding 5,000 cells/well in growth medium and
indirect quantitation of cell number through use of alamarBlue as
described by the manufacturer Alamar Biosciences, Inc. (Sacramento,
Calif.) after 48 hr. Falcon plate covers #3071 from Becton
Dickinson (Bedford, Mass.) are used to cover the Loprodyne Silent
Screen Plates. Falcon Microtest III cell culture plates can also be
used in some proliferation experiments.
[1723] To prepare extracts, A431 cells are seeded onto the nylon
membranes of Loprodyne plates (20,000/200 ml/well) and cultured
overnight in complete medium. Cells are quiesced by incubation in
serum-free basal medium for 24 hr. After 5-20 minutes treatment
with EGF (60 ng/ml) or 50 ul of the supernatant produced in Example
11, the medium was removed and 100 ml of extraction buffer ((20 mM
HEPES pH 7.5, 0.15 M NaCl, 1% Triton X-100, 0.1% SDS, 2 mM Na3VO4,
2 mM Na4P2O7 and a cocktail of protease inhibitors (# 1836170)
obtained from Boeheringer Mannheim (Indianapolis, Ind.) is added to
each well and the plate is shaken on a rotating shaker for 5
minutes at 4.degree. C. The plate is then placed in a vacuum
transfer manifold and the extract filtered through the 0.45 mm
membrane bottoms of each well using house vacuum. Extracts are
collected in a 96-well catch/assay plate in the bottom of the
vacuum manifold and immediately placed on ice. To obtain extracts
clarified by centrifugation, the content of each well, after
detergent solubilization for 5 minutes, is removed and centrifuged
for 15 minutes at 4.degree. C. at 16,000.times. g.
[1724] Test the filtered extracts for levels of tyrosine kinase
activity. Although many methods of detecting tyrosine kinase
activity are known, one method is described here.
[1725] Generally, the tyrosine kinase activity of a supernatant is
evaluated by determining its ability to phosphorylate a tyrosine
residue on a specific substrate (a biotinylated peptide).
Biotinylated peptides that can be used for this purpose include
PSK1 (corresponding to amino acids 6-20 of the cell division kinase
cdc2-p34) and PSK2 (corresponding to amino acids 1-17 of gastrin).
Both peptides are substrates for a range of tyrosine kinases and
are available from Boehringer Mannheim.
[1726] The tyrosine kinase reaction is set up by adding the
following components in order. First, add 10 ul of 5 uM
Biotinylated Peptide, then 10 ul ATP/Mg.sub.2+ (5 mM ATP/50mM
MgCl.sub.2), then 10 ul of 5.times. Assay Buffer (40 mM imidazole
hydrochloride, pH7.3, 40 mM beta-glycerophosphate, 1 mM EGTA, 100
mM MgCl.sub.2, 5 mM MnCl.sub.2, 0.5 mg/ml BSA), then 5 ul of Sodium
Vanadate(1 mM), and then 5 ul of water. Mix the components gently
and preincubate the reaction mix at 30.degree. C. for 2 min.
Initial the reaction by adding loul of the control enzyme or the
filtered supernatant.
[1727] The tyrosine kinase assay reaction is then terminated by
adding 10 ul of 120 mm EDTA and place the reactions on ice.
[1728] Tyrosine kinase activity is determined by transferring 50 ul
aliquot of reaction mixture to a microtiter plate (MTP) module and
incubating at 37.degree. C. for 20 min. This allows the
streptavadin coated 96 well plate to associate with the
biotinylated peptide. Wash the MTP module with 300 ul/well of PBS
four times. Next add 75 ul of anti-phospotyrosine antibody
conjugated to horse radish peroxidase(anti-P-Tyr-POD(0.5 u/ml)) to
each well and incubate at 37.degree. C. for one hour. Wash the well
as above.
[1729] Next add 100 ul of peroxidase substrate solution (Boehringer
Mannheim) and incubate at room temperature for at least 5 mins (up
to 30 min). Measure the absorbance of the sample at 405 nm by using
ELISA reader. The level of bound peroxidase activity is quantitated
using an ELISA reader and reflects the level of tyrosine kinase
activity.
Example 20
[1730] High-Throughput Screening Assay Identifying Phosphorylation
Activity
[1731] As a potential alternative and/or compliment to the assay of
protein tyrosine kinase activity described in Example 19, an assay
which detects activation (phosphorylation) of major intracellular
signal transduction intermediates can also be used. For example, as
described below one particular assay can detect tyrosine
phosphorylation of the Erk-1 and Erk-2 kinases. However,
phosphorylation of other molecules, such as Raf, JNK, p38 MAP, Map
kinase kinase (MEK), MEK kinase, Src, Muscle specific kinase
(MuSK), IRAK, Tec, and Janus, as well as any other phosphoserine,
phosphotyrosine, or phosphothreonine molecule, can be detected by
substituting these molecules for Erk-1 or Erk-2 in the following
assay.
[1732] Specifically, assay plates are made by coating the wells of
a 96-well ELISA plate with 0.1 ml of protein G (1 ug/ml) for 2 hr
at room temp, (RT). The plates are then rinsed with PBS and blocked
with 3% BSA/PBS for 1 hr at RT. The protein G plates are then
treated with 2 commercial monoclonal antibodies (100 ng/well)
against Erk-1 and Erk-2 (1 hr at RT) (Santa Cruz Biotechnology).
(To detect other molecules, this step can easily be modified by
substituting a monoclonal antibody detecting any of the above
described molecules.) After 3-5 rinses with PBS, the plates are
stored at 4.degree. C. until use.
[1733] A431 cells are seeded at 20,000/well in a 96-well Loprodyne
filterplate and cultured overnight in growth medium. The cells are
then starved for 48 hr in basal medium (DMEM) and then treated with
EGF (6 ng/well) or 50 ul of the supernatants obtained in Example 11
for 5-20 minutes. The cells are then solubilized and extracts
filtered directly into the assay plate.
[1734] After incubation with the extract for 1 hr at RT, the wells
are again rinsed. As a positive control, a commercial preparation
of MAP kinase (10 ng/well) is used in place of A431 extract. Plates
are then treated with a commercial polyclonal (rabbit) antibody (1
ug/ml) which specifically recognizes the phosphorylated epitope of
the Erk-1 and Erk-2 kinases (1 hr at RT). This antibody is
biotinylated by standard procedures. The bound polyclonal antibody
is then quantitated by successive incubations with
Europium-streptavidin and Europium fluorescence enhancing reagent
in the Wallac DELFIA instrument (time-resolved fluorescence). An
increased fluorescent signal over background indicates a
phosphorylation.
Example 21
[1735] Method of Determining Alterations in a Gene Corresponding to
a Polynucleotide
[1736] RNA isolated from entire families or individual patients
presenting with a phenotype of interest (such as a disease) is be
isolated. cDNA is then generated from these RNA samples using
protocols known in the art. (See, Sambrook.) The cDNA is then used
as a template for PCR, employing primers surrounding regions of
interest in SEQ ID NO:X. Suggested PCR conditions consist of 35
cycles at 95.degree. C. for 30 seconds; 60-120 seconds at
52-58.degree. C.; and 60-120 seconds at 70.degree. C., using buffer
solutions described in Sidransky, D., et al., Science 252:706
(1991).
[1737] PCR products are then sequenced using primers labeled at
their 5' end with T4 polynucleotide kinase, employing SequiTherm
Polymerase. (Epicentre Technologies). The intron-exon borders of
selected exons is also determined and genomic PCR products analyzed
to confirm the results. PCR products harboring suspected mutations
is then cloned and sequenced to validate the results of the direct
sequencing.
[1738] PCR products is cloned into T-tailed vectors as described in
Holton, T. A. and Graham, M. W., Nucleic Acids Research, 19:1156
(1991) and sequenced with T7 polymerase (United States
Biochemical). Affected individuals are identified by mutations not
present in unaffected individuals.
[1739] Genomic rearrangements are also observed as a method of
determining alterations in a gene corresponding to a
polynucleotide. Genomic clones isolated according to Example 2 are
nick-translated with digoxigenindeoxy-uridine 5'-triphosphate
(Boehringer Manheim), and FISH performed as described in Johnson,
Cg. et al., Methods Cell Biol. 35:73-99 (1991). Hybridization with
the labeled probe is carried out using a vast excess of human cot-1
DNA for specific hybridization to the corresponding genomic
locus.
[1740] Chromosomes are counterstained with
4,6-diamino-2-phenylidole and propidium iodide, producing a
combination of C- and R-bands. Aligned images for precise mapping
are obtained using a triple-band filter set (Chroma Technology,
Brattleboro, Vt.) in combination with a cooled charge-coupled
device camera (Photometrics, Tucson, Ariz.) and variable excitation
wavelength filters. (Johnson, Cv. et al., Genet. Anal. Tech. Appl.,
8:75 (1991).) Image collection, analysis and chromosomal fractional
length measurements are performed using the ISee Graphical Program
System. (Inovision Corporation, Durham, N.C.) Chromosome
alterations of the genomic region hybridized by the probe are
identified as insertions, deletions, and translocations. These
alterations are used as a diagnostic marker for an associated
disease.
Example 22
[1741] Method of Detecting Abnormal Levels of a Polypeptide in a
Biological Sample
[1742] A polypeptide of the present invention can be detected in a
biological sample, and if an increased or decreased level of the
polypeptide is detected, this polypeptide is a marker for a
particular phenotype. Methods of detection are numerous, and thus,
it is understood that one skilled in the art can modify the
following assay to fit their particular needs.
[1743] For example, antibody-sandwich ELISAs are used to detect
polypeptides in a sample, preferably a biological sample. Wells of
a microtiter plate are coated with specific antibodies, at a final
concentration of 0.2 to 10 ug/ml. The antibodies are either
monoclonal or polyclonal and are produced by the method described
in Example 10. The wells are blocked so that non-specific binding
of the polypeptide to the well is reduced.
[1744] The coated wells are then incubated for >2 hours at RT
with a sample containing the polypeptide. Preferably, serial
dilutions of the sample should be used to validate results. The
plates are then washed three times with deionized or distilled
water to remove unbounded polypeptide.
[1745] Next, 50 ul of specific antibody-alkaline phosphatase
conjugate, at a concentration of 25-400 ng, is added and incubated
for 2 hours at room temperature. The plates are again washed three
times with deionized or distilled water to remove unbounded
conjugate.
[1746] Add 75 ul of 4-methylumbelliferyl phosphate (MUP) or
p-nitrophenyl phosphate (NPP) substrate solution to each well and
incubate 1 hour at room temperature. Measure the reaction by a
microtiter plate reader. Prepare a standard curve, using serial
dilutions of a control sample, and plot polypeptide concentration
on the X-axis (log scale) and fluorescence or absorbance of the
Y-axis (linear scale). Interpolate the concentration of the
polypeptide in the sample using the standard curve.
Example 23
[1747] Formulating a Polypeptide
[1748] The secreted polypeptide composition will be formulated and
dosed in a fashion consistent with good medical practice, taking
into account the clinical condition of the individual patient
(especially the side effects of treatment with the secreted
polypeptide alone), the site of delivery, the method of
administration, the scheduling of administration, and other factors
known to practitioners. The "effective amount" for purposes herein
is thus determined by such considerations.
[1749] As a general proposition, the total pharmaceutically
effective amount of secreted polypeptide administered parenterally
per dose will be in the range of about 1 .mu.g/kg/day to 10
mg/kg/day of patient body weight, although, as noted above, this
will be subject to therapeutic discretion. More preferably, this
dose is at least 0.01 mg/kg/day, and most preferably for humans
between about 0.01 and 1 mg/kg/day for the hormone. If given
continuously, the secreted polypeptide is typically administered at
a dose rate of about 1 .mu.g/kd/hour to about 50 .mu.g/kg/hour,
either by 1-4 injections per day or by continuous subcutaneous
infusions, for example, using a mini-pump. An intravenous bag
solution may also be employed. The length of treatment needed to
observe changes and the interval following treatment for responses
to occur appears to vary depending on the desired effect.
[1750] Pharmaceutical compositions containing the secreted protein
of the invention are administered orally, rectally, parenterally,
intracistemally, intravaginally, intraperitoneally, topically (as
by powders, ointments, gels, drops or transdermal patch), bucally,
or as an oral or nasal spray. "Pharmaceutically acceptable carrier"
refers to a non-toxic solid, semisolid or liquid filler, diluent,
encapsulating material or formulation auxiliary of any type. The
term "parenteral" as used herein refers to modes of administration
which include intravenous, intramuscular, intraperitoneal,
intrastemal, subcutaneous and intraarticular injection and
infusion.
[1751] The secreted polypeptide is also suitably administered by
sustained-release systems. Suitable examples of sustained-release
compositions include semi-permeable polymer matrices in the form of
shaped articles, e.g., films, or mirocapsules. Sustained-release
matrices include polylactides (U.S. Pat. No. 3,773,919, EP 58,481),
copolymers of L-glutamic acid and gamma-ethyl-L -glutamate (Sidman,
U. et al., Biopolymers 22:547-556 (1983)), poly (2- hydroxyethyl
methacrylate) (R. Langer et al., J. Biomed. Mater. Res. 15:167-277
(1981), and R. Langer, Chem. Tech. 12:98-105 (1982)), ethylene
vinyl acetate (R. Langer et al.) or poly-D-(-)-3-hydroxybutyric
acid (EP 133,988). Sustained-release compositions also include
liposomally entrapped polypeptides. Liposomes containing the
secreted polypeptide are prepared by methods known per se: U.S.
Pat. No. DE 3,218,121; Epstein et al., Proc. Natl. Acad. Sci. USA
82:3688-3692 (1985); Hwang et al., Proc. Natl. Acad. Sci. USA
77:4030-4034 (1980); EP 52,322; EP 36,676; EP 88,046; EP 143,949;
EP 142,641; Japanese Pat. Appl. 83-118008; U.S. Pat. Nos. 4,485,045
and 4,544,545; and EP 102,324. Ordinarily, the liposomes are of the
small (about 200-800 Angstroms) unilamellar type in which the lipid
content is greater than about 30 mol. percent cholesterol, the
selected proportion being adjusted for the optimal secreted
polypeptide therapy.
[1752] For parenteral administration, in one embodiment, the
secreted polypeptide is formulated generally by mixing it at the
desired degree of purity, in a unit dosage injectable form
(solution, suspension, or emulsion), with a pharmaceutically
acceptable carrier, i.e., one that is non-toxic to recipients at
the dosages and concentrations employed and is compatible with
other ingredients of the formulation. For example, the formulation
preferably does not include oxidizing agents and other compounds
that are known to be deleterious to polypeptides.
[1753] Generally, the formulations are prepared by contacting the
polypeptide uniformly and intimately with liquid carriers or finely
divided solid carriers or both. Then, if necessary, the product is
shaped into the desired formulation. Preferably the carrier is a
parenteral carrier, more preferably a solution that is isotonic
with the blood of the recipient. Examples of such carrier vehicles
include water, saline, Ringer's solution, and dextrose solution.
Non-aqueous vehicles such as fixed oils and ethyl oleate are also
useful herein, as well as liposomes.
[1754] The carrier suitably contains minor amounts of additives
such as substances that enhance isotonicity and chemical stability.
Such materials are non-toxic to recipients at the dosages and
concentrations employed, and include buffers such as phosphate,
citrate, succinate, acetic acid, and other organic acids or their
salts; antioxidants such as ascorbic acid; low molecular weight
(less than about ten residues) polypeptides, e.g., polyarginine or
tripeptides; proteins, such as serum albumin, gelatin, or
immunoglobulins; hydrophilic polymers such as polyvinylpyrrolidone;
amino acids, such as glycine, glutamic acid, aspartic acid, or
arginine; monosaccharides, disaccharides, and other carbohydrates
including cellulose or its derivatives, glucose, manose, or
dextrins; chelating agents such as EDTA; sugar alcohols such as
mannitol or sorbitol; counterions such as sodium; and/or nonionic
surfactants such as polysorbates, poloxamers, or PEG.
[1755] The secreted polypeptide is typically formulated in such
vehicles at a concentration of about 0.1 mg/ml to 100 mg/ml,
preferably 1-10 mg/ml, at a pH of about 3 to 8. It will be
understood that the use of certain of the foregoing excipients,
carriers, or stabilizers will result in the formation of
polypeptide salts.
[1756] Any polypeptide to be used for therapeutic administration
can be sterile. Sterility is readily accomplished by filtration
through sterile filtration membranes (e.g., 0.2 micron membranes).
Therapeutic polypeptide compositions generally are placed into a
container having a sterile access port, for example, an intravenous
solution bag or vial having a stopper pierceable by a hypodermic
injection needle.
[1757] Polypeptides ordinarily will be stored in unit or multi-dose
containers, for example, sealed ampoules or vials, as an aqueous
solution or as a lyophilized formulation for reconstitution. As an
example of a lyophilized formulation, 10-ml vials are filled with 5
ml of sterile-filtered 1% (w/v) aqueous polypeptide solution, and
the resulting mixture is lyophilized. The infusion solution is
prepared by reconstituting the lyophilized polypeptide using
bacteriostatic Water-for-Injection.
[1758] The invention also provides a pharmaceutical pack or kit
comprising one or more containers filled with one or more of the
ingredients of the pharmaceutical compositions of the invention.
Associated with such container(s) can be a notice in the form
prescribed by a governmental agency regulating the manufacture, use
or sale of pharmaceuticals or biological products, which notice
reflects approval by the agency of manufacture, use or sale for
human administration. In addition, the polypeptides of the present
invention may be employed in conjunction with other therapeutic
compounds.
Example 24
[1759] Method of Treating Decreased Levels of the Polypeptide
[1760] It will be appreciated that conditions caused by a decrease
in the standard or normal expression level of a secreted protein in
an individual can be treated by administering the polypeptide of
the present invention, preferably in the secreted form. Thus, the
invention also provides a method of treatment of an individual in
need of an increased level of the polypeptide comprising
administering to such an individual a pharmaceutical composition
comprising an amount of the polypeptide to increase the activity
level of the polypeptide in such an individual.
[1761] For example, a patient with decreased levels of a
polypeptide receives a daily dose 0.1-100 ug/kg of the polypeptide
for six consecutive days. Preferably, the polypeptide is in the
secreted form. The exact details of the dosing scheme, based on
administration and formulation, are provided in Example 23.
Example 25
[1762] Method of Treating Increased Levels of the Polypeptide
[1763] Antisense technology is used to inhibit production of a
polypeptide of the present invention. This technology is one
example of a method of decreasing levels of a polypeptide,
preferably a secreted form, due to a variety of etiologies, such as
cancer.
[1764] For example, a patient diagnosed with abnormally increased
levels of a polypeptide is administered intravenously antisense
polynucleotides at 0.5, 1.0, 1.5, 2.0 and 3.0 mg/kg day for 21
days. This treatment is repeated after a 7-day rest period if the
treatment was well tolerated. The formulation of the antisense
polynucleotide is provided in Example 23.
Example 26
[1765] Method of Treatment Using Gene Therapy
[1766] One method of gene therapy transplants fibroblasts, which
are capable of expressing a polypeptide, onto a patient. Generally,
fibroblasts are obtained from a subject by skin biopsy. The
resulting tissue is placed in tissue-culture medium and separated
into small pieces. Small chunks of the tissue are placed on a wet
surface of a tissue culture flask, approximately ten pieces are
placed in each flask. The flask is turned upside down, closed tight
and left at room temperature over night. After 24 hours at room
temperature, the flask is inverted and the chunks of tissue remain
fixed to the bottom of the flask and fresh media (e.g., Ham's F12
media, with 10% FBS, penicillin and streptomycin) is added. The
flasks are then incubated at 37.degree. C. for approximately one
week.
[1767] At this time, fresh media is added and subsequently changed
every several days. After an additional two weeks in culture, a
monolayer of fibroblasts emerge. The monolayer is trypsinized and
scaled into larger flasks.
[1768] pMV-7 (Kirschmeier, P. T. et al., DNA, 7:219-25 (1988)),
flanked by the long terminal repeats of the Moloney murine sarcoma
virus, is digested with EcoRI and HindIII and subsequently treated
with calf intestinal phosphatase. The linear vector is fractionated
on agarose gel and purified, using glass beads.
[1769] The cDNA encoding a polypeptide of the present invention can
be amplified using PCR primers which correspond to the 5' and 3'
end sequences respectively as set forth in Example 1. Preferably,
the 5' primer contains an EcoRI site and the 3' primer includes a
HindIII site. Equal quantities of the Moloney murine sarcoma virus
linear backbone and the amplified EcoRI and HindIII fragment are
added together, in the presence of T4 DNA ligase. The resulting
mixture is maintained under conditions appropriate for ligation of
the two fragments. The ligation mixture is then used to transform
bacteria HB 101, which are then plated onto agar containing
kanamycin for the purpose of confirming that the vector has the
gene of interest properly inserted.
[1770] The amphotropic pA317 or GP+am12 packaging cells are grown
in tissue culture to confluent density in Dulbecco's Modified
Eagles Medium (DMEM) with 10% calf serum (CS), penicillin and
streptomycin. The MSV vector containing the gene is then added to
the media and the packaging cells transduced with the vector. The
packaging cells now produce infectious viral particles containing
the gene (the packaging cells are now referred to as producer
cells).
[1771] Fresh media is added to the transduced producer cells, and
subsequently, the media is harvested from a 10 cm plate of
confluent producer cells. The spent media, containing the
infectious viral particles, is filtered through a millipore filter
to remove detached producer cells and this media is then used to
infect fibroblast cells. Media is removed from a sub-confluent
plate of fibroblasts and quickly replaced with the media from the
producer cells. This media is removed and replaced with fresh
media. If the titer of virus is high, then virtually all
fibroblasts will be infected and no selection is required. If the
titer is very low, then it is necessary to use a retroviral vector
that has a selectable marker, such as neo or his. Once the
fibroblasts have been efficiently infected, the fibroblasts are
analyzed to determine whether protein is produced.
[1772] The engineered fibroblasts are then transplanted onto the
host, either alone or after having been grown to confluence on
cytodex 3 microcarrier beads.
[1773] It will be clear that the invention may be practiced
otherwise than as particularly described in the foregoing
description and examples. Numerous modifications and variations of
the present invention are possible in light of the above teachings
and, therefore, are within the scope of the appended claims.
[1774] The entire disclosure of each document cited (including
patents, patent applications, journal articles, abstracts,
laboratory manuals, books, or other disclosures) in the Background
of the Invention, Detailed Description, and Examples is hereby
incorporated herein by reference. Further, the hard copy of the
sequence listing submitted herewith and the corresponding computer
readable form are both incorporated herein by reference in their
entireties.
Sequence CWU 0
0
* * * * *