? Apoptosis is a highly controlled, universal cellular suicide process of cells. Dysregulation of apoptosis has been linked to several diseases such as cancer, Alzheimers disease and Huntington's chorea. The process of apoptosis induces initial alterations in translation regulation followed by overt shutoff that may be required for the completion of cellular suicide. These changes in translation regulation are mediated by a complex series of caspase cleavages of certain initiation factors combined with phosphorylation of other regulatory factors. The individual modifications of factors which have been described are expected to result in complex changes in function, but for most factors the functional consequences are not yet clear. The challenge before us is to determine how the covalent modification of multiple factors results in changes in function in translation. We hypothesize that cell stress causes initial changes in translation initiation factors which favor capindependent translation of mRNAs containing IRES elements. Our research will focus on factors which control selection of the specific mRNAs that can compete for ribosomes. We will determine if specific classes of IRES elements respond differentially to stress-induced modifications in translation factors. We will isolate the functional effect of caspase-cleavage of the four initiation factors independently and test the effect on translational efficiency of specific mRNAs. This investigation will focus on eIF4G, 4E-BP1 which regulate mRNA selection and eIF4B, which likely functions in 5'-3' interactions in ribosome re-cycling. We have also isolated four new IRES elements which control synthesis of the anti-apoptotic proteins Bcl-2, BcI- 10, clAP1 and clAP2. We will characterize the cis-acting RNA regulatory elements in the 5' UTRs of two of these mRNAs, Bc1-2 and clAP-1, and determine how they variably control synthesis of anti-apoptotic proteins in response to different types of cell stress. The long term goal is to understand how translation factor modification can influence cell death and further our basic understanding of how protein synthesis is regulated in human cells. ? ? ?
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