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by Hsueh-Ping Chu MS, 2002 National Yang Ming University Thesis Advisor: Alexey G. Ryazanov, PhD Graduate Program: Cellular and Molecular Pharmacology Monday, September 14, 2009 1:00 pm Abstract Phosphorylation of elongation factor 2 (eEF2) by eEF2 kinase (eEF2K) is a ubiquitous mechanism of global protein synthesis regulation. Here we report that phosphorylation of eEF2 occurs specifically in cells undergoing apoptosis. We generated eEF2K knockout mice that lack phosphorylation of eEF2 and found that cells derived from Eef2K-/- mice displayed an increase in resistance to apoptosis induced by oxidative stress and DNA damage. We demonstrate that eEF2K plays an important role in the regulation of apoptosis by mediating global translational arrest, leading to the inhibition in translation of short-lived anti-apoptotic proteins XIAP and FLIPL. Investigation of radiation sensitivity showed that eEF2K deficiency results in increased resistance of mice to the lethal effects of gamma radiation, prevents hair graying after irradiation and protects intestinal stem cells from radiation-induced apoptosis. Intriguingly, analysis of long-term survival and mortality rate of mice revealed that eEF2K deficiency increases maximum lifespan and slows down the age-dependent mortality rate. Our results suggest that eEF2K is a positive regulator of apoptosis and its inactivation confers radiation resistance and an extended lifespan. |
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