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

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

Research output: Contribution to journalArticle

202 Citations (Scopus)

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

Fingerprint

Glycogen Synthase Kinase 3
Endoplasmic Reticulum Stress
Serine
Apoptosis
Cell Cycle Checkpoints
Alanine
DNA Damage
Neoplasms
Phosphorylation
Mutation

Keywords

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

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

Endoplasmic reticulum stress induces p53 cytoplasmic localization and prevents p53-dependent apoptosis by a pathway involving glycogen synthase kinase-3β. / Qu, LiKe; Huang, Shirley; Baltzis, Dionissios; Rivas-Estilla, Ana Maria; Pluquet, Olivier; Hatzoglou, Maria; Koumenis, Costas; Taya, Yoichi; Yoshimura, Akihiko; Koromilas, Antonis E.

In: Genes and Development, Vol. 18, No. 3, 01.02.2004, p. 261-277.

Research output: Contribution to journalArticle

Qu, L, Huang, S, Baltzis, D, Rivas-Estilla, AM, Pluquet, O, Hatzoglou, M, Koumenis, C, Taya, Y, Yoshimura, A & Koromilas, AE 2004, 'Endoplasmic reticulum stress induces p53 cytoplasmic localization and prevents p53-dependent apoptosis by a pathway involving glycogen synthase kinase-3β', Genes and Development, vol. 18, no. 3, pp. 261-277. https://doi.org/10.1101/gad.1165804
Qu, LiKe ; Huang, Shirley ; Baltzis, Dionissios ; Rivas-Estilla, Ana Maria ; Pluquet, Olivier ; Hatzoglou, Maria ; Koumenis, Costas ; Taya, Yoichi ; Yoshimura, Akihiko ; Koromilas, Antonis E. / Endoplasmic reticulum stress induces p53 cytoplasmic localization and prevents p53-dependent apoptosis by a pathway involving glycogen synthase kinase-3β. In: Genes and Development. 2004 ; Vol. 18, No. 3. pp. 261-277.
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