Endoplasmic reticulum stress induces p53 cytoplasmic localization and prevents p53-dependent apoptosis by a pathway involving glycogen synthase kinase-3beta.
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 beta (GSK-3beta). ER stress induces GSK-3beta binding to p53 in the nucleus and enhances the cytoplasmic localization of the tumor suppressor. Inhibition of apoptosis caused by ER stress requires GSK-3beta 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.
Qu
LiKe
L
Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B Davis-Jewish General Hospital, Montréal, Québec H3T 1E2, Canada.
Huang
Shirley
S
Baltzis
Dionissios
D
Rivas-Estilla
Ana-Maria
AM
Pluquet
Olivier
O
Hatzoglou
Maria
M
Koumenis
Costas
C
Taya
Yoichi
Y
Yoshimura
Akihiko
A
Koromilas
Antonis E
AE
D017209:Apoptosis; D002453:Cell Cycle; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D004249:DNA Damage; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D016158:Genes, p53; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D038341:Glycogen Synthase Kinases; D009154:Mutation; D010766:Phosphorylation; D015398:Signal Transduction
D038341:Glycogen Synthase Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3