Translational Control of Radiation-Induced Apoptosis

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DESCRIPTION (provided by applicant): This research will be done primarily at the Institute of Protein Research, Russian Academy of Sciences, Puschino, Russia, in collaboration with professor A. S. Spirin as an extension of NIH grant No. RC1 AI078513. We have recently discovered a novel intracellular signal transduction pathway involved in the regulation of radiation sensitivity in mammals. This pathway is mediated by the elongation factor 2 kinase (eEF2K), a key regulator of global protein synthesis. We found that inactivation of this pathway in mice can confer resistance to the lethal effects of gamma radiation and also protects against radiation-induced hair graying and radiation- induced apoptosis in intestinal cells. The goal of the parent proposal is to characterize this novel signal transduction pathway and to develop new approaches that can be used to protect tissues particularly of gastrointestinal tract from radiation damage. In our preliminary experiments we found that downregulation of anti-apoptotic proteins FLIP and XIAP is blocked in cells lacking eEF2K, suggesting that phosphorylation of eEF2 by eEF2K stimulates radiation-induced apoptosis by inhibiting synthesis of short-lived anti-apoptotic proteins. We further provided evidence that eEF2K regulates expression of anti-apoptotic proteins at the level of translation. The goal of this proposal is to determine the molecular mechanism by which eEF2 phosphorylation controls translation of short-lived anti-apoptotic proteins. This will be achieved by using various cell-free translation systems and methods developed at the Institute of Protein Research by A. S. Spirin and his colleagues. PUBLIC HEALTH RELEVANCE: Translational control of radiation-induced apoptosis. We have recently found that inactivation of a protein synthesis regulator eEF2 kinase in mice can confer resistance to the lethal effects of gamma radiation and also protects against radiation-induced hair graying and radiation-induced apoptosis in intestinal cells. In our preliminary experiments we found that knockout of eEF2 kinase protects cells from radiation-induced apoptosis by preventing down-regulation of short-lived anti- apoptotic proteins. The goal of this proposal is to determine the molecular mechanism by which eEF2 kinase controls translation of short-lived anti-apoptotic proteins and therefore modulates radiation resistance. This research will be done in collaboration with the Institute of Protein Research, Russian Academy of Sciences, Puschino, Russia, in collaboration with professor A. S. Spirin as an extension of NIH grant No. RC1 AI078513.