It has long been understood that programmed cell death is an active process that requires protein synthesis. Although overall rates of translation are decreased in apoptosis, a subset of proteins bucks the trend and continues to be made, or is even more abundant, in cells destined to die. Bushell et al. explored how the mRNAs encoding these proteins are differentially regulated. They screened polysomal RNAs on microarrays to identify those whose translation was maintained or increased in cells of the human breast cancer-derived cell line MCF7 that were induced to undergo apoptosis by treatment with the cytokine TRAIL (tumor necrosis factor-related apoptosis-inducing ligand). About 3% of all mRNAs were maintained or recruited onto polysomes in the TRAIL-treated cells. Of these, about a third encoded proteins known to function in organization of chromatin or regulation of transcription. Also overrepresented were mRNAs encoding proteins of the Notch signaling pathway. Of 11 mRNAs examined in detail, 8 contained internal ribosomal entry sites (IRESs) that allow internal recruitment of ribosomes for initiation of translation. There is specificity within the IRES sequences, however, as not all mRNAs with functional IRESs were maintained on polysomes in the apoptotic cells. The function of the IRESs that promoted synthesis in the apoptotic cells appeared to require PTB (polypyrimidine tract-binding protein), a factor known to enhance IRES function. Expression of PTB was increased in TRAIL-treated cells. Furthermore, reduced expression of PTB after treatment of cells with siRNA inhibited apoptosis in response to TRAIL. Thus IRESs, which are often activated in conditions of cell stress, provide one mechanism by which translation is maintained of proteins that accumulate during cell death.
M. Bushell, M. Stoneley, Y. W. Kong, T. L. Hamilton, K. A. Spriggs, H. C. Dobbyn, X. Qin, P. Sarnow, A. E. Willis, Polypyrimidine tract binding protein regulates IRES-mediated gene expression during apoptosis. Mol. Cell 23, 401-412 (2006). [PubMed]