Back to Search
Start Over
The eIF2α Kinases PERK and PKR Activate Glycogen Synthase Kinase 3 to Promote the Proteasomal Degradation of p53
- Source :
- Journal of Biological Chemistry. 282:31675-31687
- Publication Year :
- 2007
- Publisher :
- Elsevier BV, 2007.
-
Abstract
- Phosphorylation of eukaryotic initiation factor 2alpha (eIF2alpha) is mediated by a family of kinases that respond to various forms of environmental stress. The eIF2alpha kinases are critical for mRNA translation, cell proliferation, and apoptosis. Activation of the tumor suppressor p53 results in cell cycle arrest and apoptosis in response to various types of stress. We previously showed that, unlike the majority of stress responses that stabilize and activate p53, induction of endoplasmic reticulum stress leads to p53 degradation through an Mdm2-dependent mechanism. Here, we demonstrate that the endoplasmic reticulum-resident eIF2alpha kinase PERK mediates the proteasomal degradation of p53 independently of translational control. This role is not specific for PERK, because the eIF2alpha kinase PKR also promotes p53 degradation in response to double-stranded RNA. We further establish that the eIF2alpha kinases induce glycogen synthase kinase 3 to promote the nuclear export and proteasomal degradation of p53. Our findings reveal a novel cross-talk between the eIF2alpha kinases and p53 with implications in cell proliferation and tumorigenesis.
- Subjects :
- Proteasome Endopeptidase Complex
Fibrosarcoma
Models, Biological
environment and public health
Biochemistry
MAP2K7
Glycogen Synthase Kinase 3
Mice
eIF-2 Kinase
GSK-3
Cell Line, Tumor
Animals
Humans
ASK1
RNA, Messenger
Molecular Biology
MAPK14
EIF-2 kinase
biology
Kinase
Cell Biology
Protein kinase R
Cell biology
Enzyme Activation
enzymes and coenzymes (carbohydrates)
Mitogen-activated protein kinase
NIH 3T3 Cells
biology.protein
Tumor Suppressor Protein p53
biological phenomena, cell phenomena, and immunity
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 282
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....3c5fafc005741521d03229bd0c59a9a3