Endoplasmic Reticulum Stress Accelerates p53 Degradation by the Cooperative Actions of Hdm2 and Glycogen Synthase Kinase 3β
| Autor: | Li-Ke Qu, Dionissios Baltzis, Antonis E. Koromilas, Olivier Pluquet |
|---|---|
| Rok vydání: | 2005 |
| Předmět: |
Proteasome Endopeptidase Complex
Thapsigargin Leupeptins Ubiquitin-Protein Ligases Biology Endoplasmic Reticulum Cell Line Glycogen Synthase Kinase 3 Mice chemistry.chemical_compound GSK-3 Serine Animals Humans Cycloheximide Phosphorylation Nuclear export signal Molecular Biology GSK3B Protein Synthesis Inhibitors Glycogen Synthase Kinase 3 beta Ubiquitin Intracellular Trafficking Tunicamycin Endoplasmic reticulum Cell Biology Cell biology Protein Transport chemistry Doxorubicin Fatty Acids Unsaturated Unfolded protein response Tumor Suppressor Protein p53 Signal transduction Signal Transduction |
| Zdroj: | Molecular and Cellular Biology. 25:9392-9405 |
| ISSN: | 1098-5549 |
| DOI: | 10.1128/mcb.25.21.9392-9405.2005 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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