Back to Search
Start Over
A DR4:tBID axis drives the p53 apoptotic response by promoting oligomerization of poised BAX
- Source :
- The EMBO Journal. 31:1266-1278
- Publication Year :
- 2012
- Publisher :
- Wiley, 2012.
-
Abstract
- The cellular response to p53 activation varies greatly in a stimulus- and cell type-specific manner. Dissecting the molecular mechanisms defining these cell fate choices will assist the development of effective p53-based cancer therapies and also illuminate fundamental processes by which gene networks control cellular behaviour. Using an experimental system wherein stimulus-specific p53 responses are elicited by non-genotoxic versus genotoxic agents, we discovered a novel mechanism that determines whether cells undergo proliferation arrest or cell death. Strikingly, we observe that key mediators of cell-cycle arrest (p21, 14-3-3σ) and apoptosis (PUMA, BAX) are equally activated regardless of outcome. In fact, arresting cells display strong translocation of PUMA and BAX to the mitochondria, yet fail to release cytochrome C or activate caspases. Surprisingly, the key differential events in apoptotic cells are p53-dependent activation of the DR4 death receptor pathway, caspase 8-mediated cleavage of BID, and BID-dependent activation of poised BAX at the mitochondria. These results reveal a previously unappreciated role for DR4 and the extrinsic apoptotic pathway in cell fate choice following p53 activation.
- Subjects :
- 0303 health sciences
Programmed cell death
General Immunology and Microbiology
biology
Cell growth
General Neuroscience
Cytochrome c
Cell
Cell fate determination
biology.organism_classification
General Biochemistry, Genetics and Molecular Biology
Cell biology
03 medical and health sciences
0302 clinical medicine
medicine.anatomical_structure
Apoptosis
030220 oncology & carcinogenesis
Puma
medicine
biology.protein
Molecular Biology
Caspase
030304 developmental biology
Subjects
Details
- ISSN :
- 02614189
- Volume :
- 31
- Database :
- OpenAIRE
- Journal :
- The EMBO Journal
- Accession number :
- edsair.doi...........b11480dc4801707169d39bb1b3732cde