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Prolyl hydroxylase-dependent modulation of eukaryotic elongation factor 2 activity and protein translation in acute hypoxia

AuthorsRomero-Ruiz, Antonio; Bautista, Lucía; Navarro, Virginia; Heras-Garvin, Antonio ; March Díaz, Rosana ; Castellano, Antonio; Gómez-Díaz, Raquel; Castro, María J.; Berra, Edurne; López-Barneo, José ; Pascual Bravo, Alberto
KeywordsAMP Kinase
Translation Elongation Factors
Issue Date3-Feb-2012
PublisherAmerican Society for Biochemistry and Molecular Biology
CitationJournal of Biological Chemistry 287(12): 9651-9658 (2012)
AbstractEarly adaptive responses to hypoxia are essential for cell survival, but their nature and underlying mechanisms are poorly known. We have studied the post-transcriptional changes in the proteome of mammalian cells elicited by acute hypoxia and found that phosphorylation of eukaryotic elongation factor 2 (eEF2), a ribosomal translocase whose phosphorylation inhibits protein synthesis, is under the precise and reversible control of O2 tension. Upon exposure to hypoxia, phosphorylation of eEF2 at Thr56 occurred rapidly (<15 min) and resulted in modest translational arrest, a fundamental homeostatic response to hypoxia that spares ATP and thus facilitates cell survival. Acute inhibitory eEF2 phosphorylation occurred without ATP depletion or AMP kinase activation. Furthermore, eEF2 phosphorylation was mimicked by prolyl hydroxylase (PHD) inhibition with dimethyloxalylglycine or by selective PHD2 siRNA silencing but was independent of hypoxia-inducible factor α stabilization. Moreover, overexpression of PHD2 blocked hypoxic accumulation of phosphorylated eEF2. Therefore, our findings suggest that eEF2 phosphorylation status (and, as a consequence, translation rate) is controlled by PHD2 activity. They unravel a novel pathway for cell adaptation to hypoxia that could have pathophysiologic relevance in tissue ischemia and cancer.
Description24 páginas, 8 figuras, 2 tablas.
Publisher version (URL)http://dx.doi.org/10.1074/jbc.M111.299180
Appears in Collections:(IBIS) Artículos
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