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Gene expression during acute and prolonged hypoxia is regulated by distinct mechanisms of translational control
Author(s) -
Koritzinsky Marianne,
Magagnin Michaël G,
van den Beucken Twan,
Seigneuric Renaud,
Savelkouls Kim,
Dostie Josée,
Pyronnet Stéphane,
Kaufman Randal J,
Weppler Sherry A,
Voncken Jan Willem,
Lambin Philippe,
Koumenis Constantinos,
Sonenberg Nahum,
Wouters Bradly G
Publication year - 2006
Publication title -
the embo journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 7.484
H-Index - 392
eISSN - 1460-2075
pISSN - 0261-4189
DOI - 10.1038/sj.emboj.7600998
Subject(s) - biology , eif4e , phosphorylation , translation (biology) , gene expression , protein biosynthesis , messenger rna , microbiology and biotechnology , translational regulation , hypoxia (environmental) , dephosphorylation , eukaryotic translation , gene , genetics , phosphatase , chemistry , organic chemistry , oxygen
Hypoxia has recently been shown to activate the endoplasmic reticulum kinase PERK, leading to phosphorylation of eIF2α and inhibition of mRNA translation initiation. Using a quantitative assay, we show that this inhibition exhibits a biphasic response mediated through two distinct pathways. The first occurs rapidly, reaching a maximum at 1–2 h and is due to phosphorylation of eIF2α. Continued hypoxic exposure activates a second, eIF2α‐independent pathway that maintains repression of translation. This phase is characterized by disruption of eIF4F and sequestration of eIF4E by its inhibitor 4E‐BP1 and transporter 4E‐T. Quantitative RT–PCR analysis of polysomal RNA indicates that the translation efficiency of individual genes varies widely during hypoxia. Furthermore, the translation efficiency of individual genes is dynamic, changing dramatically during hypoxic exposure due to the initial phosphorylation and subsequent dephosphorylation of eIF2α. Together, our data indicate that acute and prolonged hypoxia regulates mRNA translation through distinct mechanisms, each with important contributions to hypoxic gene expression.