TRUNCATED VARIANT OF THE MAMMALIAN TARGET FOR RAPAMYCIN (mTOR) PROTEIN

Abstract

The invention relates to mTORbeta, a splice form of mTOR, nucleic acids encoding mTOR beta, and antibodies against mTOR beta. The invention also relates to methods of producing mTOR beta and methods of screening for an agent that modulates mTOR beta expression and/or activity. The invention further relates to a method of treating a disease associated with aberrant expression of mTOR beta by administration of an agent that alters mTOR activity and/or expression.

1 . An isolated polypeptide which phosphorylates S6K1 and/or 4E-BP1 selected from the group consisting of:
 (a) an isolated polypeptide comprising the amino acid sequence of SEQ ID NO: 2;   (b) an isolated polypeptide comprising an amino acid sequence having at least 75% sequence identity with the amino acid sequence of SEQ ID NO: 2; and   (c) an isolated polypeptide comprising the amino acid sequence encoded by SEQ ID NO: 1.   
     
     
         2 . An isolated polynucleotide selected from the group consisting of:
 (a) a polynucleotide encoding a polypeptide according to  claim 1 ;   (b) a polynucleotide comprising the nucleotide sequence of SEQ ID NO: 1 or the complement thereof;   (c) a polynucleotide comprising a nucleic acid sequence having at least 80% sequence identity over the entire contiguous sequence of SEQ ID NO: 1 and encoding a protein that phosphorylates S6K1 and/or 4E-BP1; and   (d) an isolated nucleic acid molecule which hybridizes to the nucleotide sequence of SEQ ID NO: 1 or the complement thereof under conditions which employ 0.1×SSC at 68° C. and encoding a protein which phosphorylates S6K1 and/or 4E-BP1.   
     
     
         3 . A polynucleotide according to  claim 2 , wherein said polynucleotide is operably linked to one or more expression control elements. 
     
     
         4 . A vector comprising a polynucleotide according to  claim 2 . 
     
     
         5 . A host cell comprising a polynucleotide according to  claim 2 . 
     
     
         6 . An isolated antibody that specifically binds to a polypeptide according to  claim 1 . 
     
     
         7 . An antibody according to  claim 6 , wherein said antibody is monoclonal. 
     
     
         8 . An antibody according to  claim 6 , wherein the antibody is humanized. 
     
     
         9 . A method for producing a polypeptide comprising culturing a host cell according to  claim 5  under conditions in which is expressed. 
     
     
         10 . A method of screening for an agent that modulates mTORbeta activity, comprising the following steps:
 (a) contacting a polypeptide according to  claim 1 ;
 with a test agent; and 
   (b) detecting any change in the activity of said polypeptide, wherein a change in activity is indicative of an agent capable of modulating mTORbeta activity.   
     
     
         11 . A method according to  claim 10 , wherein the activity is detected by measuring S6K1 and/or 4E-BP1 phosphorylation. 
     
     
         12 . A method according to  claim 10 , wherein the activity is detected by measuring expression of c-Myc protein. 
     
     
         13 . A method of screening for an agent that modulates mTORbeta expression and/or activity, comprising the following steps:
 (a) providing a host cell according to  claim 5 ;   (b) contacting said host cell with a test agent; and   (c) detecting any change in the expression and/or activity of said polypeptide, wherein a change in expression and/or activity is indicative of an agent capable of modulating mTORbeta expression and/or activity.   
     
     
         14 . A method according to  claim 13 , wherein the activity is detected by measuring S6K1 and/or 4E-BP-1 phosphorylation. 
     
     
         15 . A method according to  claim 13 , wherein the activity is detected by measuring expression of c-Myc protein. 
     
     
         16 . A method according to  claim 13 , wherein the expression is detected by measuring the level of a nucleic acid comprising SEQ ID NO: 1. 
     
     
         17 . A method of treating a disease associated with aberrant expression of a polypeptide according to  claim 1  comprising administration of an effective amount of an agent to a subject in need thereof, wherein said agent alters the activity and/or expression of said polypeptide. 
     
     
         18 . A method according to  claim 17 , wherein the agent is an antibody that specifically binds to a polypeptide selected from the group consisting of:
 (a) an isolated polypeptide comprising the amino acid sequence of SEQ ID NO: 2;   (b) an isolated polypeptide comprising an amino acid sequence having at least 75% sequence identity with the amino acid sequence of SEQ ID NO: 2; and   (c) an isolated polypeptide comprising the amino acid sequence encoded by SEQ ID NO: 1.   
     
     
         19 . A host cell comprising a polypeptide of  claim 1 .