TY - JOUR
T1 - Endoplasmic reticulum stress induces p53 cytoplasmic localization and prevents p53-dependent apoptosis by a pathway involving glycogen synthase kinase-3β
AU - Qu, Li Ke
AU - Huang, Shirley
AU - Baltzis, Dionissios
AU - Rivas-Estilla, Ana Maria
AU - Pluquet, Olivier
AU - Hatzoglou, Maria
AU - Koumenis, Costas
AU - Taya, Yoichi
AU - Yoshimura, Akihiko
AU - Koromilas, Antonis E.
PY - 2004/2/1
Y1 - 2004/2/1
N2 - 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 β (GSK-3β). ER stress induces GSK-3β binding to p53 in the nucleus and enhances the cytoplasmic localization of the tumor suppressor. Inhibition of apoptosis caused by ER stress requires GSK-3β 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.
AB - 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 β (GSK-3β). ER stress induces GSK-3β binding to p53 in the nucleus and enhances the cytoplasmic localization of the tumor suppressor. Inhibition of apoptosis caused by ER stress requires GSK-3β 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.
KW - Apoptosis
KW - Endoplasmic reticulum stress
KW - Glycogen synthase kinase-3β
KW - Protein localization
KW - Protein phosphorylation
KW - p53
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U2 - 10.1101/gad.1165804
DO - 10.1101/gad.1165804
M3 - Article
C2 - 14744935
AN - SCOPUS:10744232627
SN - 0890-9369
VL - 18
SP - 261
EP - 277
JO - Genes and Development
JF - Genes and Development
IS - 3
ER -