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 G 2 /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.

Heterozygous variants in GATA2 contribute to DCML deficiency in mice by disrupting tandem protein binding

“…9c ). In addition, we chose the Eef2k gene as a tandem GATA motif-containing gene from the ENCODE dataset since Eef2k is known to regulate HSC apoptosis 44 and found changes in expression in G2 R398W/+ mice (Fig. 9d ).…”

Elongation factor-2 kinase is a critical determinant of the fate and antitumor immunity of CD8 + T cells

“…Recently, others have also reported that maintaining the equilibrium of the Akt-mTOR signaling pathway is critical for promoting T cell quiescence, longevity, and homeostasis (32). In addition, elevations of HSP90 and the phospho-Akt proteins have been reported in other types of cells deficient in eEF-2K, including the intestinal stem cells, epithelial cells (33), human tumor cells, and mouse embryonic fibroblasts (21). Similarly, we found that the up-regulations of this signaling also occur in CD8 + T cells subjected to eEF-2K ablation (Fig.…”

Insights Into the Pathologic Roles and Regulation of Eukaryotic Elongation Factor-2 Kinase

“…Interestingly, eEF2K shows opposing functions in stem cells. One study showed that eEF2K knock-out mice were protected from hematopoietic syndrome yet hypersensitive to gastrointestinal syndrome ( Liao et al, 2016 ). eEF2K also functions to maintain germline quality via regulating apoptosis by controlling translation of the anti-apoptotic proteins XIAP and c-FLIPL in oocytes from C. elegans ( Chu et al, 2014 ).…”