title: Paradoxical Roles of Elongation Factor-2 Kinase in Stem Cell Survival.
abstract: Protein synthesis inhibition is an immediate response during stress to switch the composition of protein pool in order to adapt to the new environment. It was reported that this response could be either protective or deleterious. However, how cells choose to live or die upon protein synthesis inhibition is largely unknown. Previously, we have shown that elongation factor-2 kinase (eEF2K), a protein kinase that suppresses protein synthesis during elongation phase, is a positive regulator of apoptosis both in vivo and in vitro Consistently, here we report that knock-out of eEF2K protects mice from a lethal dose of whole-body ionizing radiation at 8 Gy by reducing apoptosis levels in both bone marrow and gastrointestinal tracts. Surprisingly, similar to the loss of p53, eEF2K deficiency results in more severe damage to the gastrointestinal tract at 20 Gy with the increased mitotic cell death in small intestinal stem cells. Furthermore, using epithelial cell lines, we showed that eEF2K is required for G2/M arrest induced by radiation to prevent mitotic catastrophe in a p53-independent manner. Specifically, we observed the elevation of Akt/ERK activity as well as the reduction of p21 expression in Eef2k(-/-) cells. Therefore, eEF2K also provides a protective strategy to maintain genomic integrity by arresting cell cycle in response to stress. Our results suggest that protective versus pro-apoptotic roles of eEF2K depend on the type of cells: eEF2K is protective in highly proliferative cells, such as small intestinal stem cells and cancer cells, which are more susceptible to mitotic catastrophe.
authors.affiliation: From the Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian 361102, China, the Department of Pharmacology, Robert Wood Johnson Medical School, and.
authors.forename: Yi
authors.initials: Y
authors.lastname: Liao
authors.affiliation: the Department of Pharmacology, Robert Wood Johnson Medical School, and the Department of Molecular Biology, Massachusetts General Hospital, Department of Genetics, Harvard Medical School, Boston, Massachusetts 02114.
authors.forename: Hsueh-Ping
authors.initials: HP
authors.lastname: Chu
authors.affiliation: the Department of Pharmacology, Robert Wood Johnson Medical School, and.
authors.forename: Zhixian
authors.initials: Z
authors.lastname: Hu
authors.affiliation: the Department of Pharmacology, Robert Wood Johnson Medical School, and.
authors.forename: Jason J
authors.initials: JJ
authors.lastname: Merkin
authors.affiliation: the Department of Cell Biology and Neuroscience, Rutgers University, Piscataway, New Jersey 08854.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Chen
authors.affiliation: From the Eye Institute of Xiamen University, Fujian Provincial Key Laboratory of Ophthalmology and Visual Science, Xiamen, Fujian 361102, China, the Affiliated Xiamen Eye Center of Xiamen University, Xiamen, Fujian 361102, China.
authors.forename: Zuguo
authors.initials: Z
authors.lastname: Liu
authors.affiliation: the Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, and.
authors.forename: Kurt
authors.initials: K
authors.lastname: Degenhardt
authors.affiliation: the Cancer Institute of New Jersey, New Brunswick, New Jersey 08903, and.
authors.forename: Eileen
authors.initials: E
authors.lastname: White
authors.affiliation: the Department of Pharmacology, Robert Wood Johnson Medical School, and ryazanag@rwjms.rutgers.edu.
authors.forename: Alexey G
authors.initials: AG
authors.lastname: Ryazanov
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000528:radiation effects; D002470:Cell Survival / Q000235:genetics / Q000528:radiation effects; D054736:Elongation Factor 2 Kinase / Q000235:genetics / Q000378:metabolism; D005720:Gamma Rays / Q000009:adverse effects*; D007421:Intestine, Small / Q000378:metabolism / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D008938:Mitosis / Q000235:genetics / Q000528:radiation effects; D011833:Radiation Injuries, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D011836:Radiation Tolerance / Q000235:genetics / Q000528:radiation effects; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D016159:Tumor Suppressor Protein p53; C517690:Eef2k protein, mouse; D054736:Elongation Factor 2 Kinase
keywords: apoptosis; cell cycle; cell death; eukaryotic elongation factor-2 kinase (eEF2K); mitotic catastrophe; radiation biology; stem cells