CA2395885A1 - Nucleic acids, proteins, and antibodies - Google Patents

Nucleic acids, proteins, and antibodies Download PDF

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CA2395885A1
CA2395885A1 CA002395885A CA2395885A CA2395885A1 CA 2395885 A1 CA2395885 A1 CA 2395885A1 CA 002395885 A CA002395885 A CA 002395885A CA 2395885 A CA2395885 A CA 2395885A CA 2395885 A1 CA2395885 A1 CA 2395885A1
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seq
polypeptide
polynucleotide
cdna
sequence
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Craig A. Rosen
Steven C. Barash
Steven M. Ruben
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Human Genome Sciences Inc
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    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14Hydrolases (3)
    • C12N9/48Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6424Serine endopeptidases (3.4.21)
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K14/00Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/705Receptors; Cell surface antigens; Cell surface determinants
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
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    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12NMICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14Hydrolases (3)
    • C12N9/48Hydrolases (3) acting on peptide bonds (3.4)
    • C12N9/50Proteinases, e.g. Endopeptidases (3.4.21-3.4.25)
    • C12N9/64Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue
    • C12N9/6421Proteinases, e.g. Endopeptidases (3.4.21-3.4.25) derived from animal tissue from mammals
    • C12N9/6489Metalloendopeptidases (3.4.24)
    • CCHEMISTRY; METALLURGY
    • C12BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12QMEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • AHUMAN NECESSITIES
    • A01AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01KANIMAL HUSBANDRY; CARE OF BIRDS, FISHES, INSECTS; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
    • A01K2217/00Genetically modified animals
    • A01K2217/05Animals comprising random inserted nucleic acids (transgenic)
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/505Medicinal preparations containing antigens or antibodies comprising antibodies
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00Medicinal preparations containing peptides
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K48/00Medicinal preparations containing genetic material which is inserted into cells of the living body to treat genetic diseases; Gene therapy
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2319/00Fusion polypeptide
    • C07K2319/30Non-immunoglobulin-derived peptide or protein having an immunoglobulin constant or Fc region, or a fragment thereof, attached thereto
    • GPHYSICS
    • G01MEASURING; TESTING
    • G01NINVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00Screening for compounds of potential therapeutic value
    • YGENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02ATECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

The present invention relates to novel proteins. More specifically, isolated nucleic acid molecules are provided encoding novel polypeptides. Novel polypeptides and antibodies that bind to these polypeptides are provided. Also provided are vectors, host cells, and recombinant and synthetic methods for producing human polynucleotides and/or polypeptides, and antibodies. The invention further relates to diagnostic and therapeutic methods useful for diagnosing, treating, preventing and/or prognosing disorders related to these novel polypeptides. The invention further relates to screening methods for identifying agonists and antagonists of polynucleotides and polypeptides of the invention. The present invention further relates to methods and/or compositions for inhibiting or enhancing the production and function of the polypeptides of the present invention.

Description

DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

""~ TTENANT LES PAGES 1 (114 A ~514~
NOTE : Pour les tomes additionels, veuillez contacter 1e Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

CONTAINING PAGES 1 (1 I 4 TO 1514 NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME
NOTE POUR LE TOME / VOLUME NOTE:
Nucleic Acids, Proteins, and Antibodies [1] This application refers to a "Sequence Listing" that is provided only on electronic media in computer readable form pursuant to Administrative Instructions Section 801(a)(i).
The Sequence Listing forms a part of this description pursuant to Rule 5.2 and Administrative Instructions Sections 801 to 806, and is hereby incorporated in its entirety.
[2] The Sequence Listing is provided as an electronic file (PTZ23PCT
seqList.txt, 3,853,294 bytes in size, created on January 13, 2001) on four identical compact discs (CD-R), labeled "COPY 1," "COPY 2," "COPY 3,'.' and "CRF." The Sequence Listing complies with Annex C of the Administrative Instructions, and may be viewed, for example, on an IBM-PC machine running the MS-Windows operating system by using the V viewer software, version 2000 (see World Wide Web URL: http://www.fileviewer.com).
Field of the Inve~ztioh [3] The present invention relates to novel proteins. More specifically, isolated nucleic acid molecules are provided encoding novel polypeptides. Novel polypeptides and antibodies that bind to these polypeptides are provided. Also provided are vectors, host cells, and recombinant and synthetic methods for producing human polynucleotides and/or polypeptides, and antibodies. The invention further relates to diagnostic and therapeutic methods useful for diagnosing, treating, preventing and/or prognosing disorders related to these novel polypeptides. The invention further relates to screening methods for identifying agonists and antagonists of polynucleotides and polypeptides of the invention.
The present invention further relates to methods and/or compositions ,for inhibiting or enhancing the production and function of the polypeptides of the present invention.
Background of the Invention [4] While the human genome. encodes tens of thousands of functional proteins, it is believed that individual cells express only a subset of the total genetic repertoire. This selective gene expression underlies the diversity of cellular phenotypes found in the body.
For example, many genes exhibit tissue-specific expression profiles which are thought to contribute to functions and properties, as well as disease states, unique to the tissue [Maeda et al., Gene 190: 227-35 (1997); Cha et al., J. Biol. Chem. 275: 18358-65 (2000); Perou et al., Nature 406: 747-52 (2000)]. Furthermore, the subset of genes expressed in a given cell may vary in response to extracellular signalling molecules, across developmental stages, or in pathological conditions.
[5] The precise coordination of gene expression depends on regulatory proteins known as transcription factors [see Chapter 9, Molecular Biology of the Cell, Third Edition, Albert et al. Editors]. These factors, often functioning as homo- or hetero-dimers, interact with the basal transcriptional machinery of the cell (including RNA
polymerases and associated factors) by binding short stretches of defined DNA sequences. Well-characterized examples of such DNA regulatory regions are the cAMP response element (CRE), the TPA response element (TRE), and the serum response element (SRE).
In this way, transcription factors can act as activators or suppressors of gene expression.
(6] Transcription factors can be classified according .to structural motifs contained within the DNA-binding region of the polypeptide. These motifs can determine the DNA
sequence binding specificity, as well as the nature of the transcriptional control (i.e.
activation or repression).
(7] One of the most common DNA-binding motifs, the Helix-Turn-Helix (HTH), is composed of two alpha helices linked by a short amino acid chain (the "turn").
The carboxyl-terminal helix contributes to the DNA-recognition properties of the transcription factor. An important subset of HTH domain-containing transcription factors are the homeodomain proteins, which comprise a large class of transcription factors thought to be involved in developmental regulation of gene expression.
[8] Another major class of transcription regulatory proteins incorporate zinc as structural features of the polypeptide. Among important examples of these so-called zinc finger proteins are the intracellular hormone receptors (e.g. Vitamin D
receptor, estrogen receptors, progesterone receptors, thyroid hormone receptors), SpI, and Egr/KROX
proteins. This class of regulatory proteins has been implicated in a number of processes, including cell proliferation and differentiation; signal transduction; and adaptive cellular responses, such as long term potentiation of neural synapses.
[9] . The leucine zipper motif defines another class of transcription factors.
Repetitive stretches of leucine residues at every seventh position allow dimerization with other leucine zipper motifs. Dimerized leucine zipper proteins form a Y-shaped structure which can bind DNA and regulate transciption. Both homodimers and heterodimers may be formed, with the .specific amino acid sequence of the leucine zipper domain determining the dimerization specificity of the protein.. Noteable examples of leucine zipper transcription factors are CREB and CREM, which bind the cAMP Response Element DNA regulatory region; and the proto-oncogenes Fos and Jun, which are involved in normal transcriptional control as well as transformation of normal cells into highly proliferative cancerous cells.
[10] Because of the fundamental importance of gene regulatory control in development, signal transduction, cellular adaptative responses, aging, neoplastic diseases, as well as many other normal and pathological processes, transcription factors are a major focus of biomedical research. Improved understanding of how gene expression is coordinated under normal and pathological conditions, as well as in different tissues, will allow a more sophisticated approach to the treatment of human disease. .
[1l] Thus there exists a clear need for identifying and exploiting novel transcription factor polynucleotides and polypeptides. Although structurally related, such proteins may possess diverse and multifaceted functions in a variety of cell and tissue types. The purified transcription factor polypeptides of the invention are research tools useful for the identification, characterization and purif cation of additional proteins involved in the regulation of gene transcription. Furthermore, the identificafion~of new transcription factor polynucleotides and polypeptides permits the development of a range of derivatives, agonists and antagonists at the nucleic acid and protein levels which in turn have applications in the treatment and diagnosis of a range of conditions such as, for example, developmental and neoplastic disorders, amongst other conditions.
Summary of the Invention [12] The present invention relates to novel proteins. More specifically, isolated nucleic acid molecules are provided encoding novel polypeptides. Novel polypeptides and antibodies that bind to these polypeptides are provided. Also provided are vectors, host cells, and recombinant and synthetic methods for producing human polynucleotides and/or polypeptides, and antibodies. The invention further relates to diagnostic and therapeutic methods useful for diagnosing, treating, preventing and/or prognosing disorders related to these novel polypeptides. The invention further relates to screening methods for identifying agonists and antagonists of polynucleotides and. polypeptides of the invention. The present invention further relates to methods and/or compositions for inhibiting or enhancing the production and function of the polypeptides of the present invention.
Detailed Description Tables [13] Table 1A summarizes some of the polynucleotides encompassed by the invention (including cDNA clones ielated to the sequences (Clone m NO:Z), contig sequences (contig identifier (Contig m:) and contig nucleotide sequence identifier (SEQ
m NO:X)) and further summarizes certain characteristics of these polynucleotides and the polypeptides encoded thereby. The. first column provides the gene number in the application for each clone identifier. The second column provides a unique clone identifier, "Clone m NO:Z", for a cDNA clone related to each contig sequence disclosed in Table 1A. The third column provides a unique contig identifier, "Contig m:" for each of the contig sequences disclosed in Table 1A. The fourth column provides the sequence identifier, "SEQ m NO:X", for each of the contig sequences disclosed in Table 1A. The fifth column, "ORF
(From-To)", provides the location ~ (i.e., nucleotide position numbers) within the polynucleotide sequence of SEQ m NO:X that delineate the preferred open reading frame (ORF) that encodes the amino acid sequence shown in the sequence listing and referenced in Table 1A
as SEQ ID NO:Y (cohunn 6). Column _ 7 lists residues comprising predicted epitopes contained in the polypeptides encoded by each of the preferred ORFs (SEQ m NO:Y).

Identification of potential immunogenic regions was performed according to the method of Jameson and Wolf (CABIOS, 4; 181-186 (1988)); specifically, the Genetics Computer Group (GCG) implementation of this algorithm, embodied in the program PEPTIDESTRUCTURE (Wisconsin Package v10.0, Genetics Computer Group (GCG), Madison, Wisc.). This method returns a measure of the probability that a given residue is found on the surface of the protein. Regions where the antigenic index score is greater than 0.9~ over at least 6 amino acids are indicated in Table 1A as "Predicted Epitopes". In particular embodiments, polypeptides of the invention comprise, or alternatively consist of, one, two, three, four, five or more of the predicted epitopes described in Table 1A. It will be appreciated that depending on the analytical criteria used to predict antigenic determinants, the exact address of the determinant may vary slightly. Column.
8, "Tissue Distribution" shows the expression profile of tissue, cells, and/or cell line libraries which express the polynucleotides of the invention. The first number in column 8 (preceding the colon), represents the tissue/cell source identifier code corresponding to the key provided in Table 4. Expression of these polynucleotides was not observed in the other tissues and/or cell libraries tested. For those identifier codes in which the first two letters are not "AR", the second number in column 8 (following the colon), represents the number of times a sequence corresponding to the reference polynucleotide sequence (e.g., SEQ ID
NO:X) was identified in the tissue/cell source. Those .tissue/cell source identifier codes in which the first two letters are "AR" designate information generated using DNA array technology.
Utilizing this technology,.cDNAs were amplified by PCR and then transferred,.in duplicate, onto the array. Gene expression was assayed through hybridization of first strand cDNA
probes to the DNA array. cDNA probes were generated from total RNA extracted from a variety of different tissues and cell lines. Probe synthesis was performed in the presence of ssP dCTP, using oligo(dT) to prime reverse transcription. After hybridization, high stringency washing conditions were employed to remove non-specific hybrids from the array. The remaining signal, emanating from each gene target, was measured using a Phosphorimager. Gene expression was reported 'as Phosphor Stimulating Luminescence (PSL) which reflects the level of phosphor signal generated from the probe hybridized to each of the gene targets represented on the ariay. A local background signal subtraction was performed before the total signal generated from each array was used to normalize gene expression between the different hybridizations. The value presented after "[array code]:"
represents the mean of the duplicate values, following background subtraction and probe normalization. One of skill i~n the art could routinely use this information to identify normal and/or diseased tissues) which show a predominant expression pattern of the corresponding polynucleotide of the invention or ,to identify polynucleotides which show predominant and/or specific tissue and/or cell expression. Column 9 provides the chromosomal location of polynucleotides corresponding to SEQ ID NO:X. Chromosomal location was determined by finding exact matches to EST and cDNA sequences contained ~in the NCBI
(National Center for Biotechnology Information) UniGene database. Given a presumptive chromosomal location, disease locus association was determined by comparison with the Morbid Map, derived from Online Mendelian Inheritance 'in Man (Online Mendelian Inheritance in Man, OMIMTM. McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine (Bethesda, MD) 2000. World Wide Web URL:
http:l/www.ncbi.nlm.nih.gov/omim~. If the putative chromosomal location of the Query overlaps with the chromosomal location of a Morbid Map entry, an OMIlVI
identification number is disclosed in column 10 labeled "OMIM Disease References)". A key to the OMIM reference identification numbers is provided in Table 5.
[14] Table 1B summarizes additional polynucleotides encompassed by the invention (including ,cDNA clones related to the sequences (Clone ID NO:Z), contig sequences (contig identifier (Contig ff~:) contig nucleotide sequence identifiers (SEQ
ID NO:X)), and genomic sequences (SEQ ID NO:B). The first column provides a unique clone identifier, "Clone ID NO:Z", for a cDNA clone related to each contig sequence. The second column provides the sequence identif er, "SEQ ID NO:X", for each contig sequence. The third column provides a unique contig identifier, "Contig ID:" for each contig sequence. The fourth column, provides a BAC identifier "BAC ID NO:A" for, the BAC clone referenced in the corresponding row of the table. The fifth column provides the nucleotide sequence identifier, "SEQ ID NO:B" for a fragment of the BAC clone identified in column four of the corresponding row of the table. The sixth column, "Exon From-To", provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence of SEQ W
NO:B which delineate certain polynucleotides of the invention that are also exemplary members of polynucleotide sequences that encode polypeptides of the invention (e.g., polypeptides containing amino acid sequences encoded by the polynucleotide sequences delineated in column six, and fragments and variants thereof). .

[15] Table 2 summarizes homology and features of some of the polypeptides of the invention. The first column provides a unique clone identifier, "Clone. ID
NO:Z", corresponding to a cDNA clone disclosed in Table 1A. The second column.
provides the unique contig identifier, "Contig ID:" corresponding to contigs in Table 1A
and allowing for correlation with the information in Table 1A. The third column provides the sequence identifier, "SEQ ID NO:X", for the contig polynucleotide sequence. The fourth column provides the analysis method by which the homology/identity disclosed in the Table was determined. Comparisons were made between polypeptides encoded by the polynucleotides of the invention and either a non-redundant protein database (herein referred to as "NR"), or a database of protein families (herein referred to as "PFAM") as further described below.
The fifth column provides a description of the PFA1VI/NR hit having a significant match to a t polypeptide of the invention. Column six provides the accession number of the PFAM/NR
hit disclosed in the fifth column. Column seven, "Score/Percent Identity", provides a quality score or the percent identity, of the hit disclosed in columns five and six.
Columns 8 and 9, "NT From" and "NT To" respectively, delineate the polynucleotides in "SEQ ID
NO:X"
that encode a polypeptide having a significant match to the PFAM/NR database as disclosed in the fifth and sixth columns. In specific embodiments polypeptides of the invention comprise, or alternatively consist of, an amino acid sequence encoded by a polynucleotide in SEQ ID NO:X as delineated in columns 8 and 9, or fragments or variants thereof.
[16] Table 3 provides polynucleotide sequences that may be disclaimed according to certain embodiments of the invention. The first column provides a unique clone identifier, "Clone ID", for a cDNA clone related to contig sequences disclosed in Table 1A. The second column provides the sequence identifier, "SEQ ID NO:X", for contig sequences disclosed in Table 1A. The third column provides the unique contig identifier, "Contig ID:", for contigs disclosed in Table 1A. The fourth column provides a unique integer 'a' where 'a' is any integer between 1 and the final nucleotide minus 15 of SEQ ID
NO:X, and the fifth column provides a unique integer 'b' where 'b' is any integer between 15 and the final nucleotide of SEQ ID NO:X, where both a and b correspond to the positions of nucleotide residues shown in SEQ ID NO:X, and where b is greater than or equal to a + 14.
For each of the polynucleotides shown as SEQ ID NO:X, the uniquely defined integers can be substituted into the general formula of a-b, and used ~to describe polynucleotides which may be preferably excluded from the invention. In certain embodiments, preferably excluded from the invention are at least one, two, three, four, five, ten, or more of the polynucleotide sequences) having the accession numbers) disclosed in the sixth column of this Table (including for example, published sequence in connection with a particular BAC
clone). In further embodiments, preferably excluded from the invention are the specific polynucleotide sequences) contained in the clones corresponding to at least one, two, three, four, five, ten, or more of the available material having the accession numbers identified in the sixth column of this Table (including for example, the actual sequence contained in an identified BAC clone).
[17] Table 4. provides a key to the tissue/cell source identifier code disclosed in Table 1A, column 8. Column 1 provides the tissue/cell source identifier code disclosed in Table 1A, Column 8. Columns 2-5 provide a description of the tissue or cell source.
Codes corresponding to diseased tissues are indicated in column 6 with the word "disease". The use of the word "disease" in column 6 is non-limiting. The tissue or cell source may be specific (e.g. a neoplasm), or may be disease-associated (e.g., a tissue sample from a normal portion of a diseased organ). Furthermore, tissues and/or cells.lacking the "disease"
designation may still be derived from sources directly or indirectly involved in a disease state or disorder, and therefore may have a further utility in that disease state or disorder. In numerous cases where the tissue/cell source is a library, column 7 identif es the vector used to generate the library.
[18] Table 5 provides a key to the OMIM reference identification numbers disclosed in Table 1A, column 10. OMIM reference identification numbers (Column 1) were derived from Online Mendelian Inheritance in Man (Online Mendelian Inheritance in Man, OMIM.
McKusick-Nathans Institute for Genetic Medicine, Johns Hopkins University (Baltimore, MD) and National Center for Biotechnology Information, National Library of Medicine, (Bethesda, MD) 2000. World Wide Web URL: http://www.ncbi.nlm.nih.gov/omirn~.
Column 2 provides diseases associated with the cytologic band disclosed in Table 1A, column 9, as determined using the Morbid Map database.
[19] Table 6 summarizes ATCC Deposits, Deposit dates, and ATCC designation numbers of deposits made with the ATCC in connection with the present application.
[20] Table 7 shows the cDNA libraries sequenced, and ATCC designation numbers and vector information relating to these cDNA libraries.
[21] Table 8 provides .a physical characterization of clones. encompassed by the invention. The first column provides the unique clone identifier, "Clone ID
NO:Z", for 8.

certain cDNA clones of the invention, as described in Table 1A. The second column provides the size of the cDNA insert contained in the corresponding cDNA
clone.
Definitions [22] The following definitions are provided to facilitate understanding of certain terms used throughout this specification.
[23] 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 vector 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. The term "isolated" does not refer to genomic or cDNA
libraries, whole cell total or mRNA preparations, genomic DNA preparations (including those separated by electrophoresis and transferred onto blots), sheared whole cell genomic .
DNA preparations or other compositions where the art demonstrates no distinguishing features of the polynucleotide/sequences of the present invention.
(24] As used herein, a "polynucleotide" refers to a molecule having a nucleic acid sequence encoding SEQ m NO:Y or a fragment or variant thereof; a nucleic acid sequence contained in SEQ m NO:X (as' described in column 3 of Table 1A) or the complement thereof; a cDNA sequence contained in Clone ID NO:Z (as described in~ column 2 of Table 1A and contained within a library deposited with the ATCC); a nucleotide sequence encoding the polypeptide encoded by a nucleotide sequence in SEQ m NO:B as defined in column 6 of Table 1B or a fragment or variant thereof; or a nucleotide coding sequence in SEQ m NO:B as defined in column 6 of Table 1B or the complement thereof. 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, as well as fragments, epitopes, domains, and variants of the nucleic acid sequence.
Moreover, as used herein, a "polypeptide" refers to a molecule having an amino acid sequence encoded by a polynucleotide of the invention as broadly defined (obviously excluding poly-Phenylalanine or poly-Lysine peptide sequences which result from translation of a polyA tail of a sequence corresponding to a cDNA). ' [25] In the present invention, "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 m NO:X is deposited at Human Genome Sciences, Inc.
(HGS) in a catalogued and archived library. As shown, for example, in column 2 of Table 1A, each clone is identified by a cDNA Clone m (identifier generally referred to herein as Clone. m NO:Z). Each Clone m is unique to an individual clone and the Clone m is all the information needed to retrieve a given clone from the HGS library.
Furthermore, certain clones disclosed in this application have been deposited with the ATCC on October 5, 2000, having the ATCC designation numbers PTA 2574 and PTA 2575; and on January 5, 2001, having the depositor reference numbers TS-1, TS-2, AC-l, and AC-2. In addition to the individual cDNA clone deposits, most of the cDNA libraries from which the clones were derived were deposited. at the American Type Culture Collection (hereinafter "ATCC").
Table 7 provides a list of the deposited cDNA libraries. One can use the Clone ~ NO:Z to determine the library source by reference to Tables 6 and 7. Table 7 lists the deposited cDNA libraries by name and links each library to an ATCC Deposit. Library names contain four characters, for example, "HTWE." The name of a cDNA clone (Clone ll~) isolated from that library begins with the same four characters, for example "HTWEP07".
As mentioned below, Table 1A correlates the Clone m names with SEQ m NO:X. Thus, starting with an SEQ >D NO:X, one can use Tables 1, 6 and 7 to determine the corresponding Clone m, which library it came from and which ATCC deposit the library is contained in. Furthermore, it is possible to retrieve a given cDNA clone from the source library by techniques known in the art and described elsewhere herein. The ATCC is located at 10801 University Boulevard, Manassas, Virginia 20110-2209, USA. The ATCC
deposits were made pursuant to the terms of the Budapest Treaty on the international recognition of the deposit of microorganisms for the purposes of patent procedure.
[26] In specific embodiments, the polynucleotides of the invention are at least 15, at least 30, at least 50, at least 100, at least 125, at least 500, or at least 1000 continuous nucleotides but are less than or equal to 300 kb, 200 kb, 100 kb, 50 kb, 15 kb, 10 kb, 7.Skb, kb, 2.5 kb, 2.0 kb, or 1 kb, in length. In a further embodiment, polynucleotides of the invention comprise a portion of the coding sequences, as disclosed herein, but do not comprise all or a portion of any intron. In another embodiment, the polynucleotides comprising coding sequences do not contain coding sequences of a genomic flanking gene (i.e., 5' or 3' to the gene of interest in the genorne). In other embodiments, the polynucleotides of the invention do not contain the coding sequence of more than 1000., 500, 250, 100, 50, 25, 20, 15, 10, S, 4, 3, 2, or 1 genomic flanking gene(s).
. ' [27] - A "polynucleotide" of the present invention also includes those polynucleotides capable of hybridizing, undei stringent hybridization conditions, to sequences contained in SEQ 7D NO:X, or the complement thereof (e.g., the complement of any one, two, three, four, or more of the polynucleotide fragments described herein), the polynucleotide sequence delineated ~in columns 8 and 9 of Table 2 or the complement thereof,, and/or cDNA sequences contained in Clone m NO:Z (e.g., the complement of any one, two, three, four, or more of the polynucleotide fragments, or the cDNA clone within the pool of cDNA
clones deposited with the ATCC, described herein), and/or the polynucleotide sequence delineated in column 6 of Table 1B or the complement thereof. "Stringent hybridization conditions" refers to an overnight incubation at 42 degree C in a solution comprising 50%
formamide, 5x SSC (750 mM NaCl, 75 mM trisodium citrate), 50 mM sodium phosphate (pH 7.6), 5x Denhardt's solution, 10% dextran sulfate, and 20 ~,~ml denatured, sheared salmon sperm DNA, followed by washing the filters in O.lx SSC at about 65,degree C.
[28] 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 6X SSPE, (20X SSPE -- 3M NaCI; 0.2M NaH2P04; 0.02M EDTA, pH 7.4), 0.5% SDS, 30% formamide, 100 ug/xiil salmon sperm blocking DNA; followed by washes at 50 degree C with 1XSSPE, 0.1% SDS. In addition, to achieve even lower stringency, washes performed following stringent hybridization can be done at higher salt concentrations (e.g. 5X SSC). ' , [29] 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.

[30] 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 LTJ 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 generated using oligo dT as a primer).
[31] The polynucleotide of the present invention can be composed of any polyribonucleotide or polydeoxribonucleotide, which may be unmodif ed RNA
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.
[32] 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, racemization, selenoylation, sulfation, txansfer-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. N.Y.
Acad. Sci. 663:48-62 (1992)). .
[33) "SEQ ID NO:X" refers to a polynucleotide sequence described, for example, in Tables lAor 2, while "SEQ ID NO:Y" refers to a polypeptide sequence described in column 6 of Table 1A. SEQ ID NO:X is identified by an integer specified in column 4 of Table 1A.
The polypeptide sequence SEQ ID NO:Y is a translated open reading frame (ORF) encoded by polynucleotide SEQ ID NO:X. "Clone ID NO:Z" refers to a cDNA clone described in column 2 of Table 1A.
[34] . "A polypeptide having functional activity" refers to a polypeptide capable of displaying one or more known functional activities associated with a full-length (complete) protein. Such functional activities include, but are not limited to, biological activity, antigenicity [ability to bind (or compete with a polypeptide for binding) ~ to an anti-polypeptide antibody], immunogenicity (ability to generate antibody which binds to a specific polypeptide of the invention), ability to form multimers with polypeptides of the invention, and ability to bind to a receptor or ligand for a polypeptide.
[35] The polypeptides of the invention can be assayed for functional activity (e.g.
biological activity) using or routinely modifying assays known in the art, as well as assays described herein. Specifically, one of skill in the art may routinely assay transcription factor polypeptides (including fragrrients and variants) of the invention for activity using assays as described in Examples 67, 68, 69, and 70.
., [36] "A polypeptide having biological activity" refers to a polypeptide exhibiting activity similar to, 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).
[37] Table 1A summarizes some of the polynucleotides encompassed by the invention (including contig sequences (SEQ m NO:X) and clones (Clone 1D NO:Z) and further.
summarizes certain characteristics of these polynucleotides and the polypeptides encoded thereby.

~ '..

a~

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y ", ~b o ea U

+.' N

N N N ,-i ,-i ,_; ~ ,~ ~ ,-; ,-i ,-~ ~-' r" .-i ~

:~ y O ~ d' ~ N oho ,.m-~ p~p ~ ~ N
H O ~ u'> o0 O~~ ~~i00~O000000000'C

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~ M N N '"' ~'' .--~ ,_, '"' ,--i ,-i ,-i ,-i ~-i ~ ';-; ,--~

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a, ~ N
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; .
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is a ' d' M M N N N N N N Wj ''~ '--i ~ r; r; r; r.; ,.~ ,-; ,_; '--i ,-i O l~ Q1 N V~ M d1 d' ~ 00 M d1 O V'1 ~ d' O N p f,j ~: ~1- O~ pp ~--, 00 00 I~
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M
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r~ r~ ~l ~ N ~i ~ ~ r~ x ~ x x ~i r~ 00 W
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l~ t~ t~ M d' O v~

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O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O
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O ~ L~ l~ N l~ N N O ~O t~ ~ M d' M ~. ~O ~p ~ l0 d- l~ lW f' ~ ~ M l~ M ~D N
a O O O O O O O O O O O O O O O O O O O O O O O O O O O O O O
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O ~ M O ~ N ~n O
p M N M ~
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p N
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p ~ V) V7 ~ p O O M
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a O O O x O ~ O O
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a o o a ~ o o a a ,-a o 0 [38] The first column in Table lA provides the gene number in the application corresponding to the clone identifier. The second column in Table lA provides a unique "Clone ID NO:Z" for a cDNA clone related to each contig sequence. disclosed in Table lA.
This clone LD references the cDNA clone which contains at least the 5' most sequence of the assembled contig and at least a portion of SEQ ID NO:X was determined by directly sequencing the ~ referenced clone. The reference clone may have more sequence than described in the sequence listing or the clone may have less. In the vast majority of cases, however, the clone is believed to encode a full-length polypeptide. In the case where a clone is not full-length, a full-length cDNA can be obtained by methods described elsewhere herein.
[39] The third column in Table lA provides a unique "Contig ID"identification for each contig sequence. The fourth column provides the "SEQ ID NO:" identifier for each of the contig polynucleotide sequences disclosed in Table lA. The fifth column, "ORF
(From-To)", provides the location (i.e., nucleotide position numbers) within the polynucleotide sequence "SEQ ID NO:X" that delineate the preferred open reading frame (ORF) shown in the sequence listing and referenced in Table 1.A, column 6, as SEQ ID
NO:Y. Where the nucleotide position number "To" is lower than the nucleotide position number "From", the preferred ORF is the reverse complement of the referenced polynucleotide sequence. , [40] The sixth column in Table lA prQ,vides the corresponding SEQ ID NO:Y for the polypeptide sequence encoded by the preferred ORF delineated iri column 5. In one embodiment, the invention provides an amino acid sequence comprising, or alternatively consisting of, a polypeptide encoded~by the portion of SEQ ID NO:X delineated by "ORF
(From-To)". Also provided are polynucleotides encoding such amino acid sequences and a , the complementary strand thereto.
[41] Column 7 in Table lA lists residues comprising epitopes , contained in the polypeptides encoded by the preferred ~ ORF (SEQ ID NO:Y), as predicted using the algorithm of Jarneson and Wolf, (1988) Comp. Appl. Biosci. 4:181-186. The Jameson-Wolf antigenic analysis was performed using the computer program PROTEAN
(Version 3.11 for the Power Macintosh, DNASTAR, Inc., 1228 South Park Street' Madison, WI). In specific embodiments, polypeptides of the invention comprise, or alternatively consist of, at least one, two, three, four, five or more of the predicted epitopes as described~in Table lA.
294' It will be appreciated that depending on the analytical criteria used to predict antigenic determinants, the exact address of the determinant may vary slightly.
[42] Column 8 in Table 1A provides an expression profile and library code:
count for each of the contig sequences (SEQ 117 NO:X) disclosed in Table 1A, which can routinely be combined with the information provided in Table 4 and used to determine the tissues, cells, and/or cell line libraries which predominantly express the polynucleotides of the invention.
The first number in column 8 (preceding the colon), represents the tissuelcell source identifier code corresponding to the code and description provided in Table 4.
For those identifier codes in which the first two letters are not "AR", the second number in column 8 (following the colon) represents the number of times a sequence corresponding to the reference polynucleotide sequence was identified in the tissue/cell source.
Those tissue/cell source identifier codes in which the first two letters are "AR" designate information generated using DNA array technology. Utilizing this technology, cDNAs were amplified by PCR and then transferred, in duplicate, onto the array. Gene expression was assayed through hybridization of first strand cDNA probes to the DNA array. cDNA
probes were generated from total RNA extracted from a variety of different tissues and cell lines. Probe synthesis was performed in the presence of 33P dCTP, using bligo(dT) to prime reverse transcription. After hybridization, high stringency washing conditions were employed to remove non-specific hybrids from the array. The remaining signal, emanating from each gene target, was measured using a Phosphorimager. Gene expression was reported as Phosphor Stimulating Luminescence (PSL) which reflects the level of phosphor signal generated from the probe hybridized to each of the gene targets represented on the array. A
local background signal subtraction was performed before the total signal generated from each array was used to normalize gene expression between the different hybridizations. The value presented after "[array code]:" represents the mean of the duplicate values, following background subtraction and probe normalization. One of skill in the art could routinely use this information to identify normal and/or diseased tissues) which show a predominant expression pattern of the corresponding polynucleotide of the invention or to identify polynucleotides which show predominant and/or specific tissue and/or cell expression.
[43] Column 9 in Table 1A provides a chromosomal map location for certain polynucleotides of the invention. Chromosomal location was determined by finding exact matches to EST and cDNA sequences contained in the NCBI (National Center for Biotechnology Information) UniGene database. Each sequence in the UniGene database is assigned to a "cluster"; all of the ESTs, cDNAs, and STSs in a cluster are believed to be derived from a single gene. Chromosomal mapping data is often available for one or more sequences) in a UniGene cluster; this data (if consistent) is then applied to the cluster as a whole. Thus, it is possible to infer the chromosomal location of a new polynucleotide sequence by determining its identity with a mapped UniGene cluster.
[44] A modified version of the computer program BLASTN (Altshul et al., J.
Mol.
Biol. 215:403-410 (1990); and Gish and States, Nat. Genet. 3:266-272 (1993)) was used to search the UniGene database for .EST or cDNA sequences that contain exact or near-exact matches to a polynucleotide sequence of the invention (the 'Query'). A
sequence from the UniGene database (the 'Subject') was said to be an exact match if it contained a segment of 50 nucleotides in length such that 48 of those nucleotides were in the same order as found in the Query sequence. If all of the matches that met this criteria were in the same UniGene cluster, and mapping data was available for this cluster, it is indicated in Table 1A under the heading "Cytologic Band". Where a cluster had been further localized to a distinct cytologic band, that band is disclosed; where no banding information was available,,but the gene had been localized to a single chromosome, the chromosome is disclosed.
(45] Once a presumptive chromosomal location was determined for a polynucleotide of the invention, an associated disease locus was identified by comparison with a database of diseases which have been experimentally associated with genetic loci. The database used was the Morbid Map, derived from OMIMTM (supra). If the putative chromosomal location of ~a polynucleotide of the invention (Query sequence) was associated with a disease in the Morbid Map database, an OlVIIM reference identification number was noted in column 10, Table 1A, labelled "OMIlVI Disease References)". Table S is a key to the O1VIIM reference identification numbers (column 1), and provides a description of the associated disease in Column 2. ' Clone ID SEQ ID CONTIG BAC ID: SEQ ID EXON
A

NO:Z NO:X ID: NO:B From-To HEPBV26 28 . 965419 AL358253 1593 1-283 HOEOE25 46 907806 AC012342 _ 1-599 __ 162'73-16377 HDPRJ04 119 ' 909040 AL096677 1608 1-268 ~

HE8MA36 135 ~ 706858 AP001619 1613 1-46 HE8MA36 135 ~ 706858 AP001619 1615 ~ 1-1989 ' HE9CJ74 143 908903 AF166490 1619. 1-576 HFVI~AA93 162 908885 AC004017 1621 1-236 HMACX62. 196 908611 AC025162 1624 1-523 HMEIY94 199 ~ 908618 AC021848 1630 1-399 HMTMC64 2,03 909081 AL136109 1636 1-3030 1.23 I4-12965 HMTMC64 203 909081 AC022219 163$ 1-3030 9877-10.169 HNTBH53 220 909153 AC005b20 1646 1-124 ~

HSDFY86 266 908943 AJ009611 1658 '1-637 HSDFY86 266 908943 AJ009611 1661 l-941 945-lOS6 _ 3251-3659 ~

HTLDE64 285 9086.13 AC005087 1669 1-232 . 5511-9618 HWFT89 305 960524 AL132795 1673 1-253.

HUVFT89 305 960524 AL132795 1674 ~ 1-6181 HUVFT89 305 , 960524 AL132795 1675 1-287 . ' ' 3934-4654 , HOHAI78 384 811359 AC005076 1678 ' 1-100 .

11b69-11175 w 8305-8631 HE8NB30 393 ~ 899757 AL031387 1682 1-197 _ 6726-8918 HE8NB30 393 899757 AL031387. 1684 1-282 ' 305-384 HHEPQ28 401 694010 AC013663 1688 . 1-253 _ 16811-17.117 _ 18044-18361 ' 26364-26517 . 27957-28060 4305-5.345 11.599-11695 4404-456.6 HI~PAV32 407 847613 AC010552 1700 ~ 1-356 HFKFL92 409. 880139 AC018785 1701 1-1207 . 1997-2108 HFI~FL92 409 880139 AC037465 1705 1-34S

HWLGU06 410 882838 AC027440 1706 1-1366.

HWLGU06 410. 882838 AL390204 1708 1-902 ' 2961-3266.

HWLGU06 410 882838 AC021890 1710 . 1-S36 HWLGU06 410 882838 AC021890 1712 . 1-293 ' ' ~

. ~ 3199-3340 ' HE9PF14 413 908512 AC023I49 17.21 1-249 ' 2365-2402 _ 3679-3814 HPJEN26 428 909014 AC003006 1723 ' 1-408 ' 4147-4413 5186-531.1 HTEJR88 433 909033 AC010192 1728 ' 1-90 w 2483-2562 HTEJR88 433. 909033 AC026352 1729 1-90 HE2JI76 440 . 9,09110 AC078802 1732 1-803 HE2JI76 440 909110 AC078802 1733 ~ I-261 HDQHG17 443 909120 AP001458 1740 ~ . 1-304 HDQHG17 443 9091.20 APOOI458 1743 I-172 ~

.

HMWIU35 446 90916_7_ AL161903 1752 1-117 ~

HTTBX05 452 928079 AC011451 1754 ~ 1-277 .. 368-452 ' HDPSX40 453 ~ 935352 AC010815 1757 1-3938 ' 3960-4751 ~

uHASV05 457 948749 AC026954 1763 1-30 -~ 1820-2635 HHASV05_ 457 948749 ___ _ ~ 1-125 - ~ 3867-4682 HHASV05 457 948749 .AC003688 1766 1-718 ' HWBDS07 461 ~ 952796 AC016582 1768 1-38 . ' ~ ~ 8979-9149 ' 7515-8035 _ 8957-9127 ' 14170-14513 3114.5-31617 ' ' 31632-31805 HNTDI77 462 958279 AC008759 1773 . 1-318 ~

' ~ 1650-1802 .

HDPDN03 463 960952 AC005500 177.8 . 1-923 ~

HAGELOl 470 971510 ALI36439 1785 1-224 (46] Table 1B summarizes additional polynucleotides encompassed by the invention (including cDNA clones related to the sequences (Clone 117 NO:Z), contig sequences (c~ntig identifier (Contig ZD:) contig nucleotide sequence identifiers (SEQ ID
NO:X)), and genomic sequences (SEQ ID NO:B). The first column provides a unique clone identifier, "Clone ID NO:Z", for a cDNA clone related to each contig sequence. The second column provides the sequence identifier, "SEQ ID NO:X", for each contig sequence. The third column provides a unique contig identifier, "Contig ID:" for each contig sequence. The fourth column, provides a BAC identifier "BAC m NO:A" for the BAC clone referenced in the corresponding row of the table. The fifth column provides the nucleotide sequence identifier, "SEQ ID NO:B" for a fragment of the BAC clone identified in column four of the corresponding row of the table. The sixth column, "Exon From-To", provides the location (i.e.; nucleotide position numbers) within the polynucleotide sequence of SEQ ID
NO:B which delineate certain polynucleotides of the invention that are also exemplary members of polynucleotide sequences that encode polypeptides of the invention (e.g., polypeptides containing amino acid sequences encoded by the polynucleotide sequences delineated in column six, and fragments and variants thereof). .

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tn ~ d' d- N d1 N o0 M t~ 00 V7 ~
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'' "A' U U
-~~ ~ you a~ ~ ayn ~ r"' N O N pp N ~ N ~ N p ~ N O
M . ~ r' M ~ p '-i ~ M_ ~ ''~ M o ''~ M tO~p~ '..'' (''~ ~
fs.i ~ N O ~ ~ O d' "-~ O ~ ~ O ~ pOp p O
~ ,~ N f~ ~n f~ - 01 W . r, M fi, . ,~ 00 f~
a1 f~ by vo P-~ ~ ~A ~n W ~ ~4 N ~ b0 a1 P.~ bD oo ~ b1) O ~ ~N N ~N
' O, ~O~U~O~~~~0~ O~ O w O
a~ ~w ~ a~ .n ~, .~ N ,.fl . y'-' . y'-' ~ ~'~. v ~ n w 0~ ~', ~,~ tu0~
O ~ 00 N c~~'' N ~ ~ 'LS ~ ,-r +' ø, ~ b0.-wn b,0 ~ ~ ~ v~ 0o ~ ~ 00 O O U ~ O ~ ~ ~ ,.fl O ~ ~ t3' z~
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N N N
d' d' d' d' ' d' d' M Ch O ~ ~n o0 VM'W! t/7 O1 41 d1 d1 01 01 d' ~ , x x x ~- . ~ x DEMANDE OU BREVET VOLUMINEUX
LA PRESENTE PARTIE DE CETTE DEMANDE OU CE BREVET COMPREND
PLUS D'UN TOME.

""~ TTENANT LES PAGES 1 (114 A ~514~
NOTE : Pour les tomes additionels, veuillez contacter 1e Bureau canadien des brevets JUMBO APPLICATIONS/PATENTS
THIS SECTION OF THE APPLICATION/PATENT CONTAINS MORE THAN ONE
VOLUME

CONTAINING PAGES 1 (1 I 4 TO 1514 NOTE: For additional volumes, please contact the Canadian Patent Office NOM DU FICHIER / FILE NAME
NOTE POUR LE TOME / VOLUME NOTE:

Claims (24)

What Is Claimed Is:
1. An isolated nucleic acid molecule comprising a polynucleotide having a nucleotide sequence at least 95% identical to a sequence selected from the group consisting of:
(a) a polynucleotide fragment of SEQ ID NO:X or a polynucleotide fragment of the cDNA sequence contained in Clone ID NO:Z, which is hybridizable to SEQ ID
NO:X;
(b) a polynucleotide encoding a polypeptide fragment of SEQ ID NO:Y or a polypeptide fragment encoded by the cDNA sequence contained in cDNA Clone ID
NO:Z, which is hybridizable to SEQ ID NO:X;
(c) a polynucleotide encoding a polypeptide fragment of a polypeptide encoded by SEQ ID NO:X or a polypeptide fragment encoded by the cDNA sequence contained, in cDNA Clone ID NO:Z, which is hybridizable to SEQ ID NO:X;
(d) a polynucleotide encoding a polypeptide domain of SEQ ID NO:Y or a polypeptide domain encoded by the cDNA sequence contained in cDNA Clone ID
NO:Z, which is hybridizable to SEQ ID NO:X;
(e) a polynucleotide encoding a polypeptide epitope of SEQ ID NO:Y or a polypeptide epitope encoded by the cDNA sequence contained in cDNA Clone ID
NO:Z, which is hybridizable to SEQ ID NO:X;
(f) a polynucleotide encoding a polypeptide of SEQ ID NO:Y or the cDNA
sequence contained in cDNA Clone ID NO:Z, which is hybridizable to SEQ ID NO:X, having biological activity;
(g) a polynucleotide which is a variant of SEQ ID NO:X;
(h) a polynucleotide which is an allelic variant of SEQ ID NO:X;
(i) a polynucleotide which encodes a species homologue of the SEQ ID NO:Y;
(j) a polynucleotide capable of hybridizing under stringent conditions to any one of the polynucleotides specified in (a)-(i), wherein said polynucleotide does not hybridize under stringent conditions to a nucleic acid molecule having a nucleotide sequence of only A
residues or of only T residues.
2. The isolated nucleic acid molecule of claim 1, wherein the polynucleotide fragment comprises a nucleotide sequence encoding a protein.
3. The isolated nucleic acid molecule of claim 1, wherein the polynucleotide fragment comprises a nucleotide sequence encoding the sequence identified as SEQ ID NO:Y
or the polypeptide encoded by the cDNA sequence contained in cDNA Clone ID
NO:Z, which is hybridizable to SEQ ID NO:X.
4: The isolated nucleic acid molecule of claim 1, wherein the polynucleotide fragment comprises the entire nucleotide sequence of SEQ ID NO:X or the cDNA
sequence contained in cDNA Clone ID NO:Z, which is hybridizable to SEQ ID NO:X.
5. The isolated nucleic acid molecule of claim 2, wherein the nucleotide sequence comprises sequential nucleotide deletions from either the C-terminus or the N-terminus.
6. The isolated nucleic acid molecule of claim 3, wherein the nucleotide sequence comprises sequential nucleotide deletions from either the C-terminus or the N-terminus.
7. A recombinant vector comprising the isolated nucleic acid molecule of claim 1.
8. A method of making a recombinant host cell comprising the isolated nucleic acid molecule of claim 1.
9. A recombinant host cell produced by the method of claim 8.
10. The recombinant host cell of claim 9 comprising vector sequences.
11. An isolated polypeptide comprising an amino acid sequence at least 90%
identical to a sequence selected from the group consisting of:
(a) a polypeptide fragment of SEQ ID NO:Y or the encoded sequence contained in cDNA Clone ID NO:Z;
(b) a polypeptide fragment of SEQ ID, NO:Y or the encoded sequence contained in cDNA Clone ID NO:Z, having biological activity;

(c) a polypeptide domain of SEQ ID NO:Y or the encoded sequence contained in cDNA Clone ID NO:Z;

(d) a polypeptide epitope of SEQ ID NO:Y or the encoded sequence contained in cDNA Clone ID NO:Z;
(e) a full length protein of SEQ ID NO:Y or the encoded sequence contained in cDNA
Clone ID NO:Z;
(f) a variant of SEQ ID NO:Y;
(g) an allelic variant of SEQ ID NO:Y; or (h) a species homologue of the SEQ TD NO:Y.
12. The isolated polypeptide of claim 11, wherein the full length protein comprises sequential amino acid deletions from either the C-terminus or the N-terminus.
13. An isolated antibody that binds specifically to the isolated polypeptide of claim 11.
14. A recombinant host cell that expresses the isolated polypeptide of claim 11.
15. A method of making an isolated polypeptide comprising:
(a) culturing the recombinant host cell of claim 14 under conditions such that said polypeptide is expressed; and (b) recovering said polypeptide.
16. The polypeptide produced by claim 15.
17. A method for preventing, treating, or ameliorating a medical condition, comprising administering to a mammalian subject a therapeutically effective amount of the polynucleotide of claim 1.
18. A method of diagnosing a pathological condition or a susceptibility to a pathological condition in a subject comprising:
(a) determining the presence or absence of a mutation in the polynucleotide of claim 1; and (b) diagnosing a pathological condition or a susceptibility to a pathological condition based on the presence or absence of said mutation.
19. A method of diagnosing a pathological condition or a susceptibility to a pathological condition in a subject comprising:
(a) determining the presence or amount of expression of the polypeptide of claim 11 in a biological sample; and (b) diagnosing a pathological condition or a susceptibility to a pathological condition based on the presence or amount of expression of the polypeptide.
20. A method for identifying a binding partner to the polypeptide of claim 11 comprising:
(a) contacting the polypeptide of claim 11 with a binding partner; and (b) determining whether the binding partner effects an activity of the polypeptide.
21. The gene corresponding to the cDNA sequence of SEQ ID NO:Y.
22. A method of identifying an activity in a biological assay, wherein the method comprises:
(a) expressing SEQ ID NO:X in a cell;
(b) isolating the supernatant;
(c) detecting an activity in a biological assay; and identifying the protein in the supernatant having the activity.
23. The product produced by the method of claim 20.
24. A method for preventing, treating, or ameliorating a medical condition, comprising administering to a mammalian subject a therapeutically effective amount of the polypeptide of claim 11.
CA002395885A 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies Withdrawn CA2395885A1 (en)

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Publications (1)

Publication Number Publication Date
CA2395885A1 true CA2395885A1 (en) 2001-08-02

Family

ID=27587117

Family Applications (37)

Application Number Title Priority Date Filing Date
CA002395724A Pending CA2395724A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002395885A Withdrawn CA2395885A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002392398A Abandoned CA2392398A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002397839A Withdrawn CA2397839A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002393002A Withdrawn CA2393002A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002395693A Pending CA2395693A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002394039A Abandoned CA2394039A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002395858A Withdrawn CA2395858A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002395787A Withdrawn CA2395787A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002395849A Pending CA2395849A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002395666A Withdrawn CA2395666A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002395671A Withdrawn CA2395671A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002395734A Withdrawn CA2395734A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002395699A Pending CA2395699A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002392757A Abandoned CA2392757A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002392450A Abandoned CA2392450A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002394841A Withdrawn CA2394841A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002395178A Withdrawn CA2395178A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002395729A Pending CA2395729A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002395403A Withdrawn CA2395403A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002397407A Withdrawn CA2397407A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002393652A Withdrawn CA2393652A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002392751A Abandoned CA2392751A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002392438A Abandoned CA2392438A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002395816A Withdrawn CA2395816A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins and antibodies
CA002395827A Withdrawn CA2395827A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002395872A Withdrawn CA2395872A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002393912A Withdrawn CA2393912A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002395654A Withdrawn CA2395654A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002393618A Abandoned CA2393618A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002395398A Withdrawn CA2395398A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002398877A Withdrawn CA2398877A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002395295A Withdrawn CA2395295A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins and antibodies
CA002398411A Withdrawn CA2398411A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002395738A Withdrawn CA2395738A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002392428A Abandoned CA2392428A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002392422A Abandoned CA2392422A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies

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CA002395724A Pending CA2395724A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies

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CA002392398A Abandoned CA2392398A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002397839A Withdrawn CA2397839A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002393002A Withdrawn CA2393002A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
CA002395693A Pending CA2395693A1 (en) 2000-01-31 2001-01-17 Nucleic acids, proteins, and antibodies
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