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Phosphorylation of eIF2α at Serine 51 Is an Important Determinant of Cell Survival and Adaptation to Glucose Deficiency

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      Abstract

      Glucose deficiency leads to the induction of eIF2α phosphorylation at serine 51, which results in a global inhibition of protein synthesis. Phosphorylation of eIF2α is an adaptive process that establishes a cytoprotective state in glucose-deficient cells, with possible implications in biological responses that interfere with glucose metabolism.

      Abstract

      Various forms of stress induce pathways that converge on the phosphorylation of the alpha (α) subunit of eukaryotic translation initiation factor eIF2 at serine 51 (S51), a modification that results in a global inhibition of protein synthesis. In many cases eIF2α phosphorylation is a biological response that facilitates cells to cope with stressful environments. Glucose deficiency, an important form of stress, is associated with an induction of apoptosis. Herein, we demonstrate that eIF2α phosphorylation is a key step in maintaining a balance between the life and death of a glucose-deficient cell. That is, eIF2α phosphorylation acts as a molecular switch that shifts cells from a proapoptotic to a cytoprotective state in response to prolonged glucose deficiency. This adaptation process is associated with the timely expression of proteins and activation of pathways with significant contributions to cell survival and adaptation including the X-linked inhibitor of apoptosis protein ( XIAP). We also show that among the eIF2α kinases GCN2 plays a proapoptotic role whereas PERK and PKR play a cytoprotective one in response to glucose deficiency. Our data demonstrate that eIF2α phosphorylation is a significant determinant of survival and adaptation of glucose-deficient cells with possible important implications in biological processes that interfere with glucose metabolism.

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      Most cited references 59

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      Regulation of translation initiation in eukaryotes: mechanisms and biological targets.

      Translational control in eukaryotic cells is critical for gene regulation during nutrient deprivation and stress, development and differentiation, nervous system function, aging, and disease. We describe recent advances in our understanding of the molecular structures and biochemical functions of the translation initiation machinery and summarize key strategies that mediate general or gene-specific translational control, particularly in mammalian systems.
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        Regulated translation initiation controls stress-induced gene expression in mammalian cells.

         H Zeng,  R Wek,  Isabel Novoa (2000)
        Protein kinases that phosphorylate the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha) are activated in stressed cells and negatively regulate protein synthesis. Phenotypic analysis of targeted mutations in murine cells reveals a novel role for eIF2alpha kinases in regulating gene expression in the unfolded protein response (UPR) and in amino acid starved cells. When activated by their cognate upstream stress signals, the mammalian eIF2 kinases PERK and GCN2 repress translation of most mRNAs but selectively increase translation of Activating Transcription Factor 4 (ATF4), resulting in the induction of the downstream gene CHOP (GADD153). This is the first example of a mammalian signaling pathway homologous to the well studied yeast general control response in which eIF2alpha phosphorylation activates genes involved in amino acid biosynthesis. Mammalian cells thus utilize an ancient pathway to regulate gene expression in response to diverse stress signals.
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          Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase.

          Protein synthesis and the folding of the newly synthesized proteins into the correct three-dimensional structure are coupled in cellular compartments of the exocytosis pathway by a process that modulates the phosphorylation level of eukaryotic initiation factor-2alpha (eIF2alpha) in response to a stress signal from the endoplasmic reticulum (ER). Activation of this process leads to reduced rates of initiation of protein translation during ER stress. Here we describe the cloning of perk, a gene encoding a type I transmembrane ER-resident protein. PERK has a lumenal domain that is similar to the ER-stress-sensing lumenal domain of the ER-resident kinase Ire1, and a cytoplasmic portion that contains a protein-kinase domain most similar to that of the known eIF2alpha kinases, PKR and HRI. ER stress increases PERK's protein-kinase activity and PERK phosphorylates eIF2alpha on serine residue 51, inhibiting translation of messenger RNA into protein. These properties implicate PERK in a signalling pathway that attenuates protein translation in response to ER stress.
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            Author and article information

            Affiliations
            *Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, QC, H3T 1E2, Canada;
            Division of Experimental Medicine, Faculty of Medicine, McGill University, Montreal, QC H3A 1A3, Canada;
            Departments of Nutrition, School of Medicine, Case Western University, Cleveland, OH 44106-4954;
            Apoptosis Research Centre, Children's Hospital of Eastern Ontario, Ottawa, ON K1H 8L1, Canada;
            Internal Medicine and the Howard Hughes Medical Institute, University of Michigan Medical Center, Ann Arbor, MI 48109; and
            #Department of Oncology, Faculty of Medicine, McGill University, Montreal, QC H2W 1S6, Canada
            Author notes
            Address correspondence to: Antonis E. Koromilas ( antonis.koromilas@ 123456mcgill.ca ).

            § These authors contributed equally to this work.

            Contributors
            Role: Monitoring Editor
            Journal
            Mol Biol Cell
            mbc
            mbc
            Mol. Bio. Cell
            Molecular Biology of the Cell
            The American Society for Cell Biology
            1059-1524
            1939-4586
            15 September 2010
            : 21
            : 18
            : 3220-3231
            20660158
            2938387
            3625694
            10.1091/mbc.E10-01-0023
            (Monitoring Editor)
            © 2010 by The American Society for Cell Biology

            This article is distributed by The American Society for Cell Biology under license from the author(s). Two months after publication it is available to the public under an Attribution–Noncommercial–Share Alike 3.0 Unported Creative Commons License ( http://creativecommons.org/licenses/by-nc-sa/3.0).

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