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J. Biol. Chem., Vol. 282, Issue 43, 31675-31687, October 26, 2007

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The eIF2 Kinases PERK and PKR Activate Glycogen Synthase Kinase 3 to Promote the Proteasomal Degradation of p53^*

From the Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec H3T 1E2,Canada

Phosphorylation of eukaryotic initiation factor 2 (eIF2) is mediated by a family of kinases that respond to various forms of environmental stress. The eIF2 kinases are critical for mRNA translation, cell proliferation, and apoptosis. Activation of the tumor suppressor p53 results in cell cycle arrest and apoptosis in response to various types of stress. We previously showed that, unlike the majority of stress responses that stabilize and activate p53, induction of endoplasmic reticulum stress leads to p53 degradation through an Mdm2-dependent mechanism. Here, we demonstrate that the endoplasmic reticulum-resident eIF2 kinase PERK mediates the proteasomal degradation of p53 independently of translational control. This role is not specific for PERK, because the eIF2 kinase PKR also promotes p53 degradation in response to double-stranded RNA. We further establish that the eIF2 kinases induce glycogen synthase kinase 3 to promote the nuclear export and proteasomal degradation of p53. Our findings reveal a novel cross-talk between the eIF2 kinases and p53 with implications in cell proliferation and tumorigenesis.

Received for publication, May 31, 2007 , and in revised form, August 14, 2007.

^* This work was supported by a grant from the National Cancer Institute of Canada (to A. E. K.) and fellowships and studentships from the Terry Fox Foundation through the National Cancer Institute of Canada (NCIC) (to D. B., O. P., and S. K.). A.I.P. is the recipient of the McGill Cancer Centre Canderel Studentship. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Both authors contributed equally.

² Current address: INSERM, U889-Université de Bordeaux 2, 33076 Bordeaux, Cedex, France.

³ Current address: Abramson Family Cancer Research Institute and Department of Cancer Biology, University of Pennsylvania School of Medicine, Philadelphia, PA.

⁴ To whom correspondence should be addressed: 3755 Cote-Ste-Catherine St., Montreal, Quebec H3T 1E2, Canada. Tel.: 514-340-8260 (ext. 3697); Fax: 514-340-7576; E-mail: antonis.koromilas{at}mcgill.ca.

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