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J. Biol. Chem., Vol. 283, Issue 6, 3097-3108, February 8, 2008

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PKR and PKR-like Endoplasmic Reticulum Kinase Induce the Proteasome-dependent Degradation of Cyclin D1 via a Mechanism Requiring Eukaryotic Initiation Factor 2 Phosphorylation^*

Jennifer F. Raven¹, Dionissios Baltzis², Shuo Wang³, Zineb Mounir³⁴, Andreas I. Papadakis⁵, Hong Qing Gao, and Antonis E. Koromilas⁶

From the Department of Oncology, Faculty of Medicine, McGill University, Montreal, Quebec H2W 1S6, Canada and Lady Davis Institute for Medical Research, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec H3T 1E2, Canada

Cyclin D1 plays a critical role in controlling the G₁/S transition via the regulation of cyclin-dependent kinase activity. Several studies have indicated that cyclin D1 translation is decreased upon activation of the eukaryotic initiation factor 2 (eIF2) kinases. We examined the effect of activation of the eIF2 kinases PKR and PKR-like endoplasmic reticulum kinase (PERK) on cyclin D1 protein levels and translation and determined that cyclin D1 protein levels decrease upon the induction of PKR and PERK catalytic activity but that this decrease is not due to translation. Inhibition of the 26 S proteasome with MG132 rescued cyclin D1 protein levels, indicating that rather than inhibiting translation, PKR and PERK act to increase cyclin D1 degradation. Interestingly, this effect still requires eIF2 phosphorylation at serine 51, as cyclin D1 remains unaffected in cells containing a non-phosphorylatable form of the protein. This proteasome-dependent degradation of cyclin D1 requires an intact ubiquitination pathway, although the ubiquitination of cyclin D1 is not itself affected. Furthermore, this degradation is independent of phosphorylation of cyclin D1 at threonine 286, which is mediated by the glycogen synthase kinase 3β and mitogen-activated protein kinase pathways as described in previous studies. Our study reveals a novel functional cross-talk between eIF2 phosphorylation and the proteasomal degradation of cyclin D1 and that this degradation is dependent upon eIF2 phosphorylation during short, but not prolonged, periods of stress.

Received for publication, November 27, 2007

^* This work was supported in part by grants from the National Cancer Institute of Canada and the Canadian Institute of Health Research (to A. E. K.). 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. 1 and 2.

¹ Recipient of a United States Army Predoctoral Traineeship Award.

² Recipient of the Terry Fox Research Studentship from the National Cancer Institute of Canada.

³ These authors contributed equally to this work.

⁴ Recipient of a Canadian Institute of Health Research Canada Graduate Student Award.

⁵ Recipient of the Canderel Studentship Award from the McGill Cancer Centre.

⁶ To whom correspondence should be addressed: Lady Davis Institute for Medical Research, Rm. 508, Sir Mortimer B. Davis Jewish General Hospital, 3999 Ch. de la Côte-Ste.-Catherine, Montréal, Québec H3T 1E2, Canada. Tel.: 514-340-8222 (ext. 3697); Fax: 514-340-7576; E-mail: antonis.koromilas{at}mcgill.ca.

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