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Molecular and Cellular Biology, November 2002, p. 7405-7416, Vol. 22, No. 21
0270-7306/02/$04.00+0     DOI: 10.1128/MCB.22.21.7405-7416.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Regulation of Protein Synthesis by Hypoxia via Activation of the Endoplasmic Reticulum Kinase PERK and Phosphorylation of the Translation Initiation Factor eIF2{alpha}

Constantinos Koumenis,1* Christine Naczki,1 Marianne Koritzinsky,2 Sally Rastani,1 Alan Diehl,3 Nahum Sonenberg,4 Antonis Koromilas,5 and Bradly G. Wouters2

Departments of Radiation Oncology and Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157,1 Laboratory of Experimental Radiation Oncology, Department of Radiotherapy, University of Maastricht, 6200MD, Maastricht, The Netherlands,2 Abramson Family Cancer Research Institute, University of Pennsylvania Cancer Center, Philadelphia, Pennsylvania 19104,3 Department of Biochemistry, McGill University,4 Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada5

Received 17 April 2002/ Returned for modification 29 May 2002/ Accepted 23 July 2002

Hypoxia profoundly influences tumor development and response to therapy. While progress has been made in identifying individual gene products whose synthesis is altered under hypoxia, little is known about the mechanism by which hypoxia induces a global downregulation of protein synthesis. A critical step in the regulation of protein synthesis in response to stress is the phosphorylation of translation initiation factor eIF2{alpha} on Ser51, which leads to inhibition of new protein synthesis. Here we report that exposure of human diploid fibroblasts and transformed cells to hypoxia led to phosphorylation of eIF2{alpha}, a modification that was readily reversed upon reoxygenation. Expression of a transdominant, nonphosphorylatable mutant allele of eIF2{alpha} attenuated the repression of protein synthesis under hypoxia. The endoplasmic reticulum (ER)-resident eIF2{alpha} kinase PERK was hyperphosphorylated upon hypoxic stress, and overexpression of wild-type PERK increased the levels of hypoxia-induced phosphorylation of eIF2{alpha}. Cells stably expressing a dominant-negative PERK allele and mouse embryonic fibroblasts with a homozygous deletion of PERK exhibited attenuated phosphorylation of eIF2{alpha} and reduced inhibition of protein synthesis in response to hypoxia. PERK-/- mouse embryo fibroblasts failed to phosphorylate eIF2{alpha} and exhibited lower survival after prolonged exposure to hypoxia than did wild-type fibroblasts. These results indicate that adaptation of cells to hypoxic stress requires activation of PERK and phosphorylation of eIF2{alpha} and suggest that the mechanism of hypoxia-induced translational attenuation may be linked to ER stress and the unfolded-protein response.

* Corresponding author. Mailing address: Departments of Radiation Oncology and Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157. Phone: (336) 713-7637. Fax: (336) 713-7639. E-mail: ckoumeni{at}wfubmc.edu.

Molecular and Cellular Biology, November 2002, p. 7405-7416, Vol. 22, No. 21
0022-538X/02/$04.00+0     DOI: 10.1128/MCB.22.21.7405-7416.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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