Methods and means for increasing resistance to cell damage

Abstract

Methods are provided to increase resistance to cell damage in a subject. The increase in resistance to cell damage in a subject in the subject is accomplished by decreasing activity of eEF2 kinase in the subject. The eEF2 kinase activity can be decreased by decreasing the amount of functional eEF2 kinase produced by the subject, including contacting the eEF2 kinase with a compound that inhibits phosphorylation of eEF2 kinase substrate or decreasing the amount of functional eEF2 kinase is decreased by reducing expression of a gene encoding the eEF2 kinase.

1 . A method of increasing resistance to cell damage in a subject caused by a cytotoxic agent, the method comprising
 identifying a subject that has been, or is suspected of having been, or is expected to be, exposed to a cytotoxic agent,   administering to the subject an amount of a compound that decreases phosphorylation of an eEF2 kinase substrate by an eEF2 kinase, wherein said amount is effective to increase protein turnover in a cell of the subject at a rate effective to increase resistance to cell damage.   
     
     
         2 . The method of  claim 1 , wherein said phosphorylation of said eEF2 kinase substrate is decreased by decreasing eEF2 kinase catalytic activity in said cell. 
     
     
         3 . The method of  claim 2 , wherein said eEF2 kinase catalytic activity is decreased by contacting the eEF2 kinase with the compound. 
     
     
         4 . The method of  claim 4 , wherein said phosphorylation of the eEF2 kinase substrate is decreased by reducing expression of a gene encoding the eEF2 kinase in said cell. 
     
     
         5 . The method of  claim 4 , wherein said expression of the gene encoding the eEF2 kinase is reduced by altering said gene such that the gene encodes a dysfunctional or non-functional eEF2 kinase. 
     
     
         6 . The method of  claim 4 , wherein said expression of the gene encoding the eEF2 kinase is reduced by contacting said gene, or an mRNA transcribed from said gene, with the compound, the compound comprising a polynucleotide selected from the group consisting of an antisense oligonucleotide, a ribozyme, an siRNA, and an shRNA. 
     
     
         7 . The method of  claim 6 , wherein said compound comprises a polynucleotide comprising a nucleotide sequence complementary to a nucleotide sequence encoding a polypeptide comprising the amino acid sequence of SEQ ID NO: 2. 
     
     
         8 . The method of  claim 7 , wherein said compound comprises a nucleotide sequence complementary to a nucleotide sequence comprising the nucleotide sequence of SEQ ID NO: 1. 
     
     
         9 . The method of  claim 4 , wherein the cytotoxic agent is selected from the group consisting of treatment increased acidity, oxidative stress, a chemotherapy agent, ionizing radiation, ultraviolet radiation, and free radicals. 
     
     
         10 . The method of  claim 9 , wherein the chemotherapy agent is camptothecin (CPT), doxorubicin (DOX), or taxol.