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Molecular and Cellular Biology, November 2005, p. 9392-9405, Vol. 25, No. 21
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.21.9392-9405.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Endoplasmic Reticulum Stress Accelerates p53 Degradation by the Cooperative Actions of Hdm2 and Glycogen Synthase Kinase 3ß

Olivier Pluquet, Li-Ke Qu, Dionissios Baltzis, and Antonis E. Koromilas*

Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote-Ste-Catherine St., Montreal, Quebec H3T 1E2, Canada

Received 16 February 2005/ Returned for modification 13 April 2005/ Accepted 26 July 2005

Inactivation of the tumor suppressor p53 by degradation is a mechanism utilized by cells to adapt to endoplasmic reticulum (ER) stress. However, the mechanisms of p53 destabilization by ER stress are not known. We demonstrate here that the E3 ubiquitin-ligase Hdm2 is essential for the nucleocytoplasmic transport and proteasome-dependent degradation of p53 in ER-stressed cells. We also demonstrate that p53 phosphorylation at S315 and S376 is required for its nuclear export and degradation by Hdm2 without interfering with the ubiquitylation process. Furthermore, we show that p53 destabilization in unstressed cells utilizes the cooperative action of Hdm2 and glycogen synthase kinase 3ß, a process that is enhanced in cells exposed to ER stress. In contrast to other stress pathways that stabilize p53, our findings further substantiate a negative role of ER stress in p53 activation with important implications for the function of the tumor suppressor in cells with a dysfunctional ER.

* Corresponding author. Mailing address: Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote-Ste-Catherine St. Montreal, Quebec H3T 1E2, Canada. Phone: (514) 340-8260, ext. 3697. Fax: (514) 340-7576. E-mail: antonis.koromilas{at}mcgill.ca.

Molecular and Cellular Biology, November 2005, p. 9392-9405, Vol. 25, No. 21
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.21.9392-9405.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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