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The Role of Elongation Factor 2 Kinase in Germline Maintenance

by
James S. Novak
B.S., The University of Maryland - 2007

Thesis Advisor: Alexey G. Ryazanov, Ph.D.
Graduate Program in Cellular & Molecular Pharmacology

RWJMS Research Tower
4th floor Conference Room
Piscataway

Tuesday, May 14, 2013
1:00 p.m.


Abstract

Elongation factor 2 kinase (eEF2K) is a unique protein kinase that is regulated in response to Ca+2/Calmodulin and a variety of other cellular signals. eEF2K lacks homology to conventional protein kinases and is a member of the atypical family of -kinases. The sole substrate of eEF2K is elongation factor 2 (eEF2), and the phosphorylation of eEF2 at Threonine-56 inhibits this protein and blocks ribosomal translocation during protein translation elongation. Interestingly, we have found that eEF2K is highly active in the gonads of mice and Caenorhabditis elegans. Despite recent advances in the understanding of the regulation of this kinase, its physiological function has remained unknown.
C. elegans is a unique model system that has provided great insights into the molecular mechanisms regulating germ cell development and physiological apoptosis. We have found that the loss of the elongation factor 2 kinase homolog in C. elegans, efk-1, reduces germ cell apoptosis and leads to reduced oocyte quality. Existing evidence suggests that physiological germ cell apoptosis may be required for maintaining optimal germ cell quality and reproductive fitness. Our findings represent a novel function for elongation factor 2 kinase and translational regulation in the maintenance of germ cell development and physiological apoptosis.
Furthermore, we have discovered that elongation factor 2 kinase has additional functions in the development of the C. elegans germline. Intriguingly, EFK-1 is active throughout the gonads of both female and male C. elegans, despite an absence of apoptosis in the male germline. In addition, our results show that EFK-1 is critical for oocyte production and survival, and that both oocytes and sperm are compromised in the absence of EFK-1. Moreover, it was determined that EFK-1 is also highly active during embryogenesis and likely plays a role in translational regulation in the early embryo. We propose that the phosphorylation of elongation factor 2 by elongation factor 2 kinase represents a fundamental mechanism of translation regulation that is necessary for optimal germ cell development in C. elegans.


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