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RESEARCH PAPER
1 Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montréal, Québec H3T 1E2, Canada; 2 Department of Nutrition, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA; 3 Departments of Radiation Oncology and Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA; 4 Radiobiology Division, National Cancer Center Research Institute, Tokyo 104-0045, Japan; 5 Medical Institute of Bioregulation, Kyushu University, Fukuoka 812-8582, Japan
The tumor suppressor p53, a sensor of multiple forms of cellular stress, is regulated by post-translational mechanisms to induce cell-cycle arrest, senescence, or apoptosis. We demonstrate that endoplasmic reticulum (ER) stress inhibits p53-mediated apoptosis. The mechanism of inhibition involves the increased cytoplasmic localization of p53 due to phosphorylation at serine 315 and serine 376, which is mediated by glycogen synthase kinase-3 
(GSK-3). ER stress induces GSK-3 binding to p53 in the nucleus and enhances the cytoplasmic localization of the tumor suppressor. Inhibition of apoptosis caused by ER stress requires GSK-3 and does not occur in cells expressing p53 with mutation(s) of serine 315 and/or serine 376 to alanine(s). As a result of the increased cytoplasmic localization, ER stress prevents p53 stabilization and p53-mediated apoptosis upon DNA damage. It is concluded that inactivation of p53 is a protective mechanism utilized by cells to adapt to ER stress.
[Keywords: Endoplasmic reticulum stress; p53; glycogen synthase kinase-3; protein phosphorylation; protein localization; apoptosis]
Received October 29, 2003; revised version accepted December 12, 2003.
Supplemental material is available at http://www.genesdev.org.
6 Corresponding author.
E-MAIL antonis.koromilas{at}mcgill.ca; FAX (514) 340-7576.
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