View the Current Issue

Article

  • The EMBO Journal (2006) 25, 1114 - 1125
  • doi:10.1038/sj.emboj.7600998

Published online: 9 February 2006

Gene expression during acute and prolonged hypoxia is regulated by distinct mechanisms of translational control

Marianne Koritzinsky1, Michaël G Magagnin1,a, Twan van den Beucken1,a, Renaud Seigneuric1, Kim Savelkouls1, Josée Dostie2, Stéphane Pyronnet2, Randal J Kaufman3, Sherry A Weppler1, Jan Willem Voncken4, Philippe Lambin1, Constantinos Koumenis5, Nahum Sonenberg2 and Bradly G Wouters1

  1. Department of Radiation Oncology (Maastro), GROW Research Institute, University of Maastricht, The Netherlands
  2. Department of Biochemistry, McGill Cancer Centre, McGill University, Canada
  3. Howard Hughes Medical Institute, University of Michigan Medical Center, USA
  4. Department of Molecular Genetics, University of Maastricht, The Netherlands
  5. Departments of Radiation Oncology and Cancer Biology, Wake Forest University School of Medicine, USA

Correspondence to:

Bradly G Wouters, Department of Radiation Oncology (Maastro), GROW Research Institute, University of Maastricht, UNS50/23 Postbus 616, 6200 MD Maastricht, The Netherlands. Tel.: +31 43 388 2912; Fax: +31 43 388 4540; E-mail: brad.wouters@maastro.unimaas.nl

aThese authors contributed equally to this work

Received 26 September 2005; Accepted 18 January 2006

Hypoxia has recently been shown to activate the endoplasmic reticulum kinase PERK, leading to phosphorylation of eIF2alpha 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 eIF2alpha. Continued hypoxic exposure activates a second, eIF2alpha-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 eIF2alpha. Together, our data indicate that acute and prolonged hypoxia regulates mRNA translation through distinct mechanisms, each with important contributions to hypoxic gene expression.

  • Keywords:

    • eIF2alpha,
    • eIF4F,
    • hypoxia,
    • mRNA translation