Human tumor necrosis factor receptors TR13 and TR14

Abstract

The present invention relates to two novel proteins, TR13 and TR14, which are members of the tumor necrosis factor (TNF) receptor superfamily. In particular, isolated nucleic acid molecules are provided encoding the human TR13 and TR14 proteins. TR13 and TR14 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 TR13 and TR14.

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 1 to about 750 in SEQ ID NO: 1;    (b) a nucleotide sequence encoding a polypeptide comprising amino acids from about 1 to about 750 in SEQ ID NO:1;    (c) a nucleotide sequence encoding a polypeptide comprising amino acids from about 1 to about 750 in SEQ ID NO:1;    (d) a nucleotide sequence encoding a polypeptide having the amino acid sequence encoded by the cDNA clone contained in ATCC Deposit No. PTA-349;    (e) a nucleotide sequence encoding the mature TR13 polypeptide having the amino acid sequence encoded by the cDNA clone contained in ATCC Deposit No. PTA-349;    (f) a nucleotide sequence encoding a polypeptide comprising amino acids from about 1 to about 1001 in SEQ ID NO:40;    (g) a nucleotide sequence encoding a polypeptide comprising amino acids from about 2 to about 1001 in SEQ ID NO:40;    (h) a nucleotide sequence encoding a polypeptide comprising amino acids from about 42 to about 1001 in SEQ ID NO:40;    (i) a nucleotide sequence encoding a polypeptide having the amino acid sequence encoded by the cDNA clone contained in ATCC Deposit No. PTA-507;    (j) a nucleotide sequence encoding the mature TR13 polypeptide having the amino acid sequence encoded by the cDNA clone contained in ATCC Deposit No. PTA-507;    (k) a nucleotide sequence encoding the TR13 extracellular domain;    (l) a nucleotide sequence encoding the TR13 transmembrane domain;    (m) a nucleotide sequence encoding the TR13 intracellular domain;    (n) a nucleotide sequence encoding the TR13 receptor extracellular and intracellular domains with all or part of the transmembrane domain deleted; and    (o) a nucleotide sequence complementary to any of the nucleotide sequences in (a), (b), (c), (d), (e), (f), (g), (h), (i), (j) (k), (l), (m), (n) or (o).    
   
   
       2 . An isolated nucleic acid molecule comprising a polynucleotide which encodes the amino acid sequence of an epitope-bearing portion of a TR13 receptor having an amino acid sequence in (a), (b), (c), (d), (e), (f), (g), (h), (i), (j), (k), (l), (m), (n) or (o) of  claim 1 .  
   
   
       3 . The isolated nucleic acid molecule of  claim 2 , which encodes an epitope-bearing portion of a TR13 receptor selected from the group consisting of: a polypeptide comprising amino acid residues from about 2 to about 170 in SEQ ID NO:2; a polypeptide comprising amino acid residues from about 210 to about 318 in SEQ ID NO:2; a polypeptide comprising amino acid residues from about 343 to about 480 in SEQ ID NO:2; a polypeptide comprising amino acid residues from about 548 to about 592 in SEQ ID NO:2; or a polypeptide comprising amino acid residues from about 632 to about 742 in SEQ ID NO:2, or a polypeptide comprising amino acid residues from about 1 to about 262 in SEQ ID NO:40, or a polypeptide comprising amino acid residues from about 264 to about 423 in SEQ ID NO:40, or a polypeptide comprising amino acid residues from about 437 to about 789 in SEQ ID NO:40, or a polypeptide comprising amino acid residues from about 791 to about 1001 in SEQ ID NO:40.  
   
   
       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 . A method of making a recombinant host cell comprising introducing the recombinant vector of  claim 5  into a host cell.  
   
   
       7 . A recombinant host cell produced by the method of  claim 6 .  
   
   
       8 . A recombinant method for producing a TR13 polypeptide, comprising culturing the recombinant host cell of  claim 7  under conditions such that said polypeptide is expressed, and recovering said polypeptide.  
   
   
       9 . An isolated TR13 polypeptide having an amino acid sequence at least 95% identical to a sequence selected from the group consisting of: 
 (a) amino acids from about 1 to about 750 in SEQ ID NO:2;    (b) amino acids from about 2 to about 750 in SEQ ID NO:2;    (c) amino acids from about 1 to about 1001 in SEQ ID NO:40;    (d) amino acids from about 2 to about 1001 in SEQ ID NO:40;    (e) the amino acid sequence of the TR13 polypeptide having the amino acid sequence encoded by the cDNA clone contained in ATCC Deposit No. PTA-349,    (f) the amino acid sequence of the TR13 polypeptide having the amino acid sequence encoded by the cDNA clone contained in ATCC Deposit No. PTA-507,    (g) the amino acid sequence of the mature TR13 polypeptide having the amino acid sequence encoded by the cDNA clone contained in ATCC Deposit No. PTA-349;    (h) the amino acid sequence of the mature TR13 polypeptide having the amino acid sequence encoded by the cDNA clone contained in ATCC Deposit No. PTA-507; and    (i) the amino acid sequence of an epitope-bearing portion of any one of the polypeptides of (a), (b), (c), (d), (e), (f), (g), or (h).    
   
   
       10 . An isolated polypeptide comprising an epitope-bearing portion of the TR13 receptor protein, wherein said portion is selected from the group consisting of: a polypeptide comprising amino acid residues from about 2 to about 170 in SEQ ID NO:2; a polypeptide comprising amino acid residues from about 210 to about 318 in SEQ ID NO:2; a polypeptide comprising amino acid residues from about 343 to about 480 in SEQ ID NO:2; a polypeptide comprising amino acid residues from about 545 to about 592 in SEQ ID NO:2; a polypeptide comprising amino acid residues from about 632 to about 742 in SEQ ID NO:2; a polypeptide comprising amino acid residues from about 1 to about 262 in SEQ ID NO:40; a polypeptide comprising amino acid residues from about 264 to about 423 in SEQ ID NO:40; a polypeptide comprising amino acid residues from about 437 to about 789 in SEQ ID NO:40; a polypeptide comprising amino acid residues from about 791 to about 1001 in SEQ ID NO:40.  
   
   
       11 . An isolated antibody that binds specifically to a TR13 receptor polypeptide of  claim 9 .  
   
   
       12 . A method of treating diseases and disorders associated with the inhibition of apoptosis comprising administering an effective amount of an agonist of the polypeptide as claimed in  claim 9 , to a patient in need thereof.  
   
   
       13 . A method of treating inflammatory diseases and disorders comprising administering to a patient in need thereof an effective amount of an antagonist of the polypeptide as claimed in  claim 9 .  
   
   
       14 . A method of treating cancer comprising administering an effective amount of an agonist of the polypeptide as claimed in  claim 9 , to a patient in need thereof.  
   
   
       15 . The method of  claim 14  wherein the agonist is an anti-TR13 antibody.  
   
   
       16 . The method of  claim 14  wherein the cancer is a cancer of the gastrointestinal system.  
   
   
       17 . The method of  claim 14  wherein the cancer is a cancer of the reproductive system.  
   
   
       18 . The method of  claim 14  wherein the cancer is a cancer of the immune system.  
   
   
       19 . A method of inhibiting Fas ligand activity in a patient comprising administering to said patient an effective amount of the polypeptide as claimed in  claim 9.