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Qu, L, Huang, S, Baltzis, D, Rivas-Estilla, AM, Pluquet, O, Hatzoglou, M, Koumenis, C, Taya, Y, Yoshimura, A and Koromilas, AE (2004) Endoplasmic reticulum stress induces p53 cytoplasmic localization and prevents p53-dependent apoptosis by a pathway involving glycogen synthase kinase-3beta. Genes Dev. 18:261-77
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.
Apoptosis; Cell Cycle; Cells, Cultured; Cytoplasm/metabolism; DNA Damage; Endoplasmic Reticulum/metabolism; Genes, p53; Glycogen Synthase Kinase 3/metabolism; Glycogen Synthase Kinases; Mutation; Phosphorylation; Signal Transduction
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