Endoplasmic reticulum stress induces p53 cytoplasmic localization and prevents p53-dependent apoptosis by a pathway involving glycogen synthase kinase-3β

Li Ke Qu, Shirley Huang, Dionissios Baltzis, Ana Maria Rivas-Estilla, Olivier Pluquet, Maria Hatzoglou, Costas Koumenis, Yoichi Taya, Akihiko Yoshimura, Antonis E. Koromilas

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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 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.

Original languageEnglish
Pages (from-to)261-277
Number of pages17
JournalGenes and Development
Volume18
Issue number3
DOIs
Publication statusPublished - 2004 Feb 1
Externally publishedYes

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Keywords

  • Apoptosis
  • Endoplasmic reticulum stress
  • Glycogen synthase kinase-3β
  • Protein localization
  • Protein phosphorylation
  • p53

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Qu, L. K., Huang, S., Baltzis, D., Rivas-Estilla, A. M., Pluquet, O., Hatzoglou, M., Koumenis, C., Taya, Y., Yoshimura, A., & Koromilas, A. E. (2004). Endoplasmic reticulum stress induces p53 cytoplasmic localization and prevents p53-dependent apoptosis by a pathway involving glycogen synthase kinase-3β. Genes and Development, 18(3), 261-277. https://doi.org/10.1101/gad.1165804