Endoplasmic reticulum stress accelerates p53 degradation by the cooperative actions of Hdm2 and glycogen synthase kinase 3beta

Olivier Pluquet; Li-Ke Qu; Dionissios Baltzis; Antonis E Koromilas

doi:10.1128/MCB.25.21.9392-9405.2005

Endoplasmic reticulum stress accelerates p53 degradation by the cooperative actions of Hdm2 and glycogen synthase kinase 3beta

Mol Cell Biol. 2005 Nov;25(21):9392-405. doi: 10.1128/MCB.25.21.9392-9405.2005.

Authors

Olivier Pluquet¹, Li-Ke Qu, Dionissios Baltzis, Antonis E Koromilas

Affiliation

¹ Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, 3755 Cote-Ste-Catherine Street, Montreal, Quebec H3T 1E2, Canada.

Abstract

Inactivation of the tumor suppressor p53 by degradation is a mechanism utilized by cells to adapt to endoplasmic reticulum (ER) stress. However, the mechanisms of p53 destabilization by ER stress are not known. We demonstrate here that the E3 ubiquitin-ligase Hdm2 is essential for the nucleocytoplasmic transport and proteasome-dependent degradation of p53 in ER-stressed cells. We also demonstrate that p53 phosphorylation at S315 and S376 is required for its nuclear export and degradation by Hdm2 without interfering with the ubiquitylation process. Furthermore, we show that p53 destabilization in unstressed cells utilizes the cooperative action of Hdm2 and glycogen synthase kinase 3beta, a process that is enhanced in cells exposed to ER stress. In contrast to other stress pathways that stabilize p53, our findings further substantiate a negative role of ER stress in p53 activation with important implications for the function of the tumor suppressor in cells with a dysfunctional ER.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cell Line
Cycloheximide / pharmacology
Doxorubicin / pharmacology
Endoplasmic Reticulum / drug effects
Endoplasmic Reticulum / metabolism*
Fatty Acids, Unsaturated / pharmacology
Glycogen Synthase Kinase 3 / metabolism*
Glycogen Synthase Kinase 3 beta
Humans
Leupeptins / pharmacology
Mice
Phosphorylation
Proteasome Endopeptidase Complex / drug effects
Proteasome Endopeptidase Complex / physiology
Protein Synthesis Inhibitors / pharmacology
Protein Transport
Serine / metabolism
Signal Transduction
Thapsigargin / pharmacology
Tumor Suppressor Protein p53 / physiology*
Tunicamycin / pharmacology
Ubiquitin / metabolism
Ubiquitin-Protein Ligases / metabolism*

Substances

Fatty Acids, Unsaturated
Leupeptins
Protein Synthesis Inhibitors
Tumor Suppressor Protein p53
Ubiquitin
Tunicamycin
Serine
Thapsigargin
Doxorubicin
Cycloheximide
Ubiquitin-Protein Ligases
GSK3B protein, human
Glycogen Synthase Kinase 3 beta
Gsk3b protein, mouse
Glycogen Synthase Kinase 3
Proteasome Endopeptidase Complex
benzyloxycarbonylleucyl-leucyl-leucine aldehyde
leptomycin B