title: Elongation factor 2 diphthamide is critical for translation of two IRES-dependent protein targets, XIAP and FGF2, under oxidative stress conditions.
abstract: Elongation factor-2 (eEF2) catalyzes the movement of the ribosome along the mRNA. A single histidine residue in eEF2 (H715) is modified to form diphthamide. A role for eEF2 in the cellular stress response is highlighted by the fact that eEF2 is sensitive to oxidative stress and that it must be active to drive the synthesis of proteins that help cells to mitigate the adverse effects of oxidative stress. Many of these proteins are encoded by mRNAs containing a sequence called an "internal ribosomal entry site" (IRES). Under high oxidative stress conditions diphthamide-deficient cells were significantly more sensitive to cell death. These results suggest that diphthamide may play a role in protection against the degradation of eEF2. This protection is especially important in those situations in which eEF2 is necessary for the reprogramming of translation from global to IRES synthesis. Indeed, we found that the expression of X-linked inhibitor of apoptosis (XIAP) and fibroblast growth factor 2 (FGF2), two proteins synthesized from mRNAs with IRESs that promote cell survival, is deregulated in diphthamide-deficient cells. Our findings therefore suggest that eEF2 diphthamide controls the selective translation of IRES-dependent protein targets XIAP and FGF2, critical for cell survival under conditions of oxidative stress.
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, Baltimore, MD 21224, USA; Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain.
authors.forename: Sandro
authors.initials: S
authors.lastname: Argüelles
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, Baltimore, MD 21224, USA.
authors.forename: Simonetta
authors.initials: S
authors.lastname: Camandola
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, Baltimore, MD 21224, USA.
authors.forename: Roy G
authors.initials: RG
authors.lastname: Cutler
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, University of Seville, 41012 Seville, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Ayala
authors.affiliation: Laboratory of Neurosciences, National Institute on Aging, Intramural Research Program, Baltimore, MD 21224, USA; Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA. Electronic address: mattsonm@grc.nia.nih.gov.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
mesh_terms: D000818:Animals; D001555:Benzene Derivatives / Q000494:pharmacology; D016466:CHO Cells; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D003412:Cricetulus; D016222:Fibroblast Growth Factor 2 / Q000235:genetics* / Q000378:metabolism; D005786:Gene Expression Regulation; D006639:Histidine / Q000031:analogs & derivatives* / Q000378:metabolism; D018384:Oxidative Stress; D020652:Peptide Elongation Factor 2 / Q000235:genetics* / Q000378:metabolism; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012270:Ribosomes / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D001555:Benzene Derivatives; D020652:Peptide Elongation Factor 2; D012333:RNA, Messenger; D051636:X-Linked Inhibitor of Apoptosis Protein; D016222:Fibroblast Growth Factor 2; D006639:Histidine; C027527:diphthamide; C007164:cumene hydroperoxide
keywords: Diphthamide; Eukaryotic elongation factor-2; FGF-2; Free radicals; Internal ribosomal entry site; Lipid peroxidation; XIAP