Novel human growth factors

Abstract

The present invention relates to huXAG-1, huXAG-2 and huXAG-3 proteins which are novel human growth factors. In particular, isolated nucleic acid molecules are provided encoding the huXAG-1, huXAG-2 and huXAG-3 proteins. huXAG-1, huXAG-2 and huXAG-3 polypeptides are also provided as are vectors, host cells and recombinant methods for producing the same. The invention further relates to screening methods for identifying agonists and antagonists of huXAG-1, huXAG-2 or huXAG-3 activity. Also provided are diagnostic and therapeutic uses of huXAG-1. huXAG-2 and huXAG-3.

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 nucleotide sequence encoding a polypeptide comprising amino acids from about −20 to about 155 in SEQ ID NO:2, or amino acids from about −23 to about 149 in SEQ ID NO:4, or amino acids from about −23 to about 143 in SEQ ID NO:6;   (b) a nucleotide sequence encoding a polypeptide comprising amino acids from about −19 to about 155 in SEQ ID NO:2, or amino acids from about −22 to about 149 in SEQ ID NO:4, or amino acids from about −22 to about 143 in SEQ ID NO:6;   (c) a nucleotide sequence encoding the polypeptide comprising amino acids from about 1 to about 155 in SEQ ID NO:2, or amino acids from about 1 to about 149 in SEQ ID NO:4 or amino acids from about 1 to about 143 in SEQ ID NO:6;   (d) a nucleotide sequence encoding a full-length polypeptide having the amino acid sequence encoded by the cDNA clone contained in ATCC™ Deposit No. 97641, or ATCC™ Deposit No. 209134 or ATCC™ Deposit No. 209137;   (e) a nucleotide sequence encoding a mature polypeptide having the amino acid sequence encoded by the cDNA clone contained in ATCC™ Deposit No. 97641, or ATCC™ Deposit No. 209134 or ATCC™ Deposit No. 209137; and   (f) a nucleotide sequence complementary to any of the nucleotide sequences in (a), (b), (c), (d), or (e).   
     
     
         2 . An isolated nucleic acid molecule, comprising a polynucleotide which hybridizes under stringent hybridization conditions to a polynucleotide having a nucleotide sequence identical to a nucleotide sequence in (a), (b), (c), (d), (e), or (f) of  claim 1  wherein said polynucleotide which does not hybridize under stringent hybridization conditions to a polynucleotide having a nucleotide sequence consisting of only A residues or of only T residues. 
     
     
         3 . An isolated nucleic acid molecule, comprising a polynucleotide having a sequence selected from the group consisting of:
 (a) a nucleotide sequence of a fragment of the sequence shown in SEQ ID NO:1, wherein said fragment comprises at least 50 contiguous nucleotides from SEQ ID NO:1, provided that said isolated nucleic acid molecule is not SEQ ID NO:9, SEQ ID NO:10, SEQ ID NO:11, SEQ ID NO:12, SEQ ID NO:13, SEQ ID NO:14, SEQ ID NO:15, SEQ ID NO:35, SEQ ID NO:36, SEQ ID NO:37, SEQ ID NO:38, SEQ ID NO: 39, or any subfragment thereof;   (b) a nucleotide sequence of a fragment of the sequence shown in SEQ ID NO:3, wherein said fragment comprises at least 50 contiguous nucleotides from SEQ ID NO:3, provided that said isolated nucleic acid molecule is not SEQ ID NO:16, SEQ ID NO:17, SEQ ID NO:18, SEQ ID NO:19, SEQ ID NO:20, SEQ ID NO:21, SEQ ID NO:22, SEQ ID NO:23, or any subfragment thereof;   (c) a nucleotide sequence of a fragment of the sequence shown in SEQ ID NO:5, wherein said fragment comprises at least 50 contiguous nucleotides from SEQ ID NO:5, provided that said isolated nucleic acid molecule is not SEQ ID NO:40 or SEQ ID NO:41, or any subfragment thereof; and   (d) a nucleotide sequence complementary to a nucleotide sequence in (a), (b), or (c).   
     
     
         4 . A method for making a recombinant vector, comprising inserting an isolated nucleic acid molecule of  claim 1  into a vector. 
     
     
         5 . A recombinant vector produced by the method of  claim 4 . 
     
     
         6 . An isolated polypeptide having an amino acid sequence at least 95% identical to a sequence selected from the group consisting of:
 (a) amino acids from about −20 to about 155 in SEQ ID NO:2, or amino acids from about −23 to about 149 in SEQ ID NO:4, or amino acids from about −23 to about 143 in SEQ ID NO:6;   (b) amino acids from about −19 to about 155 in SEQ ID NO:2, or amino acids from about −22 to about 149 in SEQ ID NO:4, or amino acids from about −22 to about 143 in SEQ ID NO:6;   (c) amino acids from about 1 to about 155 in SEQ ID NO:2, or amino acids from about 1 to about 149 in SEQ ID NO:4, or amino acids from about 1 to about 143 in SEQ ID NO:6;   (d) the amino acid sequence of a full-length polypeptide having the amino acid sequence encoded by the cDNA clone contained in ATCC™ Deposit No. 97641, or ATCC™ Deposit No. 209134 or ATCC™ Deposit No. 209137;   (e) the amino acid sequence of a mature polypeptide having the amino acid sequence encoded by the cDNA clone contained in ATCC™ Deposit No. 97641, or ATCC™ Deposit No. 209134 or ATCC™ Deposit No. 209137; and   (f) the amino acid sequence of an epitope-bearing portion of any one of the polypeptides of (a), (b), (c), (d), or (e).   
     
     
         7 . An isolated polypeptide of  claim 6 , comprising an epitope-bearing portion of huXAG-1, huXAG-2 or huXAG-3 polypeptide, wherein said portion is selected from the group consisting of: a polypeptide comprising amino acid residues from about −1 to about 23 in SEQ ID NO:2; a polypeptide comprising amino acid residues from about 24 to about 32 in SEQ ID NO:2; a polypeptide comprising amino acid residues from about 41 to about 52 in SEQ ID NO:2; a polypeptide comprising amino acid residues from about 70 to about 83 in SEQ ID NO:2; a polypeptide comprising amino acid residues from about 93 to about 105 in SEQ ID NO:2; a polypeptide comprising amino acid residues from about 118 to about 130 in SEQ ID NO:2; a polypeptide comprising amino acid residues from about −1 to about 15 in SEQ ID NO:4; a polypeptide comprising amino acid residues from about 20 to 30 about in SEQ ID NO:4; a polypeptide comprising amino acid residues from about 71 to about 89 in SEQ ID NO:4; a polypeptide comprising amino acid residues from about 97 to about 115 in SEQ ID NO:4; a polypeptide comprising amino acid residues from about 2 to about 21 in SEQ ID NO:6; a polypeptide comprising amino acid residues from about 81 to about 92 in SEQ ID NO:6; and a polypeptide comprising amino acid residues from about 109 to about 127 in SEQ ID NO:6. 
     
     
         8 . An isolated polypeptide of  claim 6 , which is produced or contained in a recombinant host cell. 
     
     
         9 . An isolated nucleic acid molecule, comprising a polynucleotide encoding a huXAG-1, huXAG-2 or huXAG-3 polypeptide wherein, except for one to fifty conservative amino acid substitutions, said polypeptide has a sequence selected from the group consisting of:
 (a) a nucleotide sequence encoding a polypeptide comprising amino acids from about −20 to about 155 in SEQ ID NO:2, or amino acids from about −23 to about 149 in SEQ ID NO:4, or amino acids from about −23 to about 143 in SEQ ID NO:6;   (b) a nucleotide sequence encoding a polypeptide comprising amino acids from about −19 to about 155 in SEQ ID NO:2, or amino acids from about −22 to about 149 in SEQ ID NO:4, or amino acids from about −22 to about 143 in SEQ ID NO:6;   (c) a nucleotide sequence encoding the polypeptide comprising amino acids from about 1 to about 155 in SEQ ID NO:2, or amino acids from about 1 to about 149 in SEQ ID NO:4 or amino acids from about 1 to about 143 in SEQ ID NO:6;   (d) a nucleotide sequence encoding a full-length polypeptide having the amino acid sequence encoded by the cDNA clone contained in ATCC™ Deposit No. 97641, or ATCC™ Deposit No. 209134 or ATCC™ Deposit No. 209137;   (e) a nucleotide sequence encoding a mature polypeptide having the amino acid sequence encoded by the cDNA clone contained in ATCC™ Deposit No. 97641, or ATCC™ Deposit No. 209134 or ATCC™ Deposit No. 209137; and   (f) a nucleotide sequence complementary to any of the nucleotide sequences in (a), (b), (c), (d), or (e).   
     
     
         10 . An isolated huXAG-1, huXAG-2 or huXAG-3 polypeptide wherein, except for one to fifty conservative amino acid substitutions, said polypeptide has a sequence selected from the group consisting of:
 (a) amino acids from about −20 to about 155 in SEQ ID NO:2, or amino acids from about −23 to about 149 in SEQ ID NO:4, or amino acids from about −23 to about 143 in SEQ ID NO:6;   (b) amino acids from about −19 to about 155 in SEQ ID NO:2, or amino acids from about −22 to about 149 in SEQ ID NO:4, or amino acids from about −22 to about 143 in SEQ ID NO:6;   (c) amino acids from about 1 to about 155 in SEQ ID NO:2, or amino acids from about 1 to about 149 in SEQ ID NO:4, or amino acids from about 1 to about 143 in SEQ ID NO:6;   (d) the amino acid sequence of a full-length polypeptide having the amino acid sequence encoded by the cDNA clone contained in ATCC™ Deposit No. 97641, or ATCC™ Deposit No. 209134 or ATCC™ Deposit No. 209137;   (e) the amino acid sequence of a mature polypeptide having the amino acid sequence encoded by the cDNA clone contained in ATCC™ Deposit No. 97641, or ATCC™ Deposit No. 209134 or ATCC™ Deposit No. 209137; and   (f) the amino acid sequence of an epitope-bearing portion of any one of the polypeptides of (a), (b), (c), (d), or (e).   
     
     
         11 . An isolated antibody or antibody fragment that binds specifically to a huXAG-1, huXAG-2 or huXAG-3 polypeptide of  claim 6 . 
     
     
         12 . A method for treating an individual in need of a decreased level of huXAG-1, huXAG-2 or huXAG-3, comprising administering to said individual a composition comprising the isolated antibody or antibody fragment of  claim 6 . 
     
     
         13 . A method for treating an individual in need of an increased level of huXAG-1, huXAG-2 or huXAG-3, comprising administering to said individual a composition comprising an isolated polypeptide of  claim 6 . 
     
     
         14 . A diagnostic method comprising:
 (a) measuring huXAG-1, huXAG-2 or huXAG-3 gene expression level in cells or body fluid of an individual; and   (b) comparing the huXAG-1, huXAG-2 or huXAG-3 gene expression level of said individual with a standard huXAG-1, huXAG-2 or huXAG-3 gene expression level, whereby an increase or decrease in the huXAG-1, huXAG-2 or huXAG-3 gene expression level over said standard is indicative of a huXAG-1-, huXAG-2- or huXAG-3-related disorder.   
     
     
         15 . A diagnostic method of  claim 14 , comprising:
 (a) measuring huXAG-1 gene expression level in colorectal cells or body fluid of an individual; and   (b) comparing the huXAG-1 gene expression level of said individual with a standard huXAG-1 gene expression level, whereby an increase in the huXAG-1 gene expression level over said standard is indicative of colon cancer.   
     
     
         16 . The method of  claim 15 , wherein said huXAG-1 gene expression level is assayed by detecting mRNA. 
     
     
         17 . The method of  claim 15 , wherein said huXAG-1 gene expression level is assayed by detecting huXAG-1 protein. 
     
     
         18 . The method of  claim 17 , wherein said protein is detected with an antibody.