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PMID: 16227590 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

Molecular and cellular biology ·Vol. 25 ·No. 21 ·2005-11-00 ·Pages 9392-405

Pluquet O, Qu LK, Baltzis D, Koromilas AE

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.

MeSH Terms
Animals Cell Line Cycloheximide/pharmacology Doxorubicin/pharmacology Endoplasmic Reticulum/drug effects,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,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
Chemicals
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
Authors & Affiliations
4 authors, click to expand affiliations / ORCID
Pluquet Olivier
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.
Qu Li-Ke
Baltzis Dionissios
Koromilas Antonis E
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Article Info
Journal
Molecular and cellular biology
Abbr.
Mol Cell Biol
ISSN
0270-7306
DOI
10.1128/MCB.25.21.9392-9405.2005
Published
2005-11-00
Pages
9392-405
Language
English
Region
United States
NLM ID
8109087
PMCID
PMC1265800
Subset
IM
External Links
PubMed source DOI: 10.1128/MCB.25.21.9392-9405.2005 PMC Full Text View journal details
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