title: Endoplasmic reticulum stress induces p53 cytoplasmic localization and prevents p53-dependent apoptosis by a pathway involving glycogen synthase kinase-3beta.
abstract: 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.
authors.affiliation: Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B Davis-Jewish General Hospital, Montréal, Québec H3T 1E2, Canada.
authors.forename: LiKe
authors.initials: L
authors.lastname: Qu
authors.forename: Shirley
authors.initials: S
authors.lastname: Huang
authors.forename: Dionissios
authors.initials: D
authors.lastname: Baltzis
authors.forename: Ana-Maria
authors.initials: AM
authors.lastname: Rivas-Estilla
authors.forename: Olivier
authors.initials: O
authors.lastname: Pluquet
authors.forename: Maria
authors.initials: M
authors.lastname: Hatzoglou
authors.forename: Costas
authors.initials: C
authors.lastname: Koumenis
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Taya
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Antonis E
authors.initials: AE
authors.lastname: Koromilas
mesh_terms: 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
chemical_list: D038341:Glycogen Synthase Kinases; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3