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B.S., Wuhan University - 2007
Thesis Advisor: Alexey G. Ryazanov, Ph.D.
Graduate Program in Molecular & Cellular Pharmacology
RWJMS 4th floor Conference Room
Monday, May 6, 2013
Eukaryotic elongation factor-2 kinase (eEF2K) is an evolutionarily conserved protein kinase. The phosphorylation of elongation factor-2 (eEF2) by eEF2K represents a ubiquitous regulatory mechanism to arrest protein synthesis. Although multiple nutrient and stress signals have been shown to regulate eEF2K activity, the physiological significance of this protein kinase is still unclear.
To study the physiological function of eEF2K, we performed immunohistochemistry studies in various mouse tissues, and the phosphorylation level of eEF2 was used as an indicator for kinase activity. Surprisingly, the most intense staining of eEF2 was found in mouse ovaries. Knockout of eEF2K reduced the level of granulosa cell death in atretic follicles and altered estrous cycle progression. As a result, menopause onset was delayed in Eef2K-/- mice. Interestingly, the function of eEF2K in the germline was conserved in nematode Caenorhabditis elegans, where it also mediated germ cell death. Even more importantly, deletion of EFK-1, a homolog of eEF2K in C. elegans, lead to a significant decrease in embryo production and oocyte quality, presumably reflecting an evolutionarily conserved function of eEF2K in germline maintenance.
In addition to follicle atresia, eEF2K also mediated apoptosis under stress conditions. Knockout of eEF2K reduced apoptosis in bone marrow and intestinal crypts after Õ-irradiation. Thus, eEF2K-deificient mice were resistant to low-dose radiation. However, following high dose Õ-irradiation, apoptosis reduction in the crypts had limited contribution to the intestinal stem cell viability. Under these conditions, the deletion of eEF2K caused mitotic catastrophe, thereby depleting the stem cell pool and leading to a more severe gastrointestinal syndrome.
Overall, our results suggest that eEF2K regulates cell death programs under both physiological and stress conditions and plays key roles in maintaining normal physiology of various organ s