A DR4:tBID axis drives the p53 apoptotic response by promoting oligomerization of poised BAX

RYAN E, HENRY; ZDENEK, ANDRYSIK; RAMIRO, PARÍS; MATTHEW D GALBRAITH; JOAQUIN M, ESPINOSA

EMBO JOURNAL

NATURE PUBLISHING GROUP

Lugar: Londres; Año: 2012 vol. 31 p. 1266 - 1278

0261-4189

The cellular response to p53 activation varies greatly in astimulus- and cell type-specific manner. Dissecting themolecular mechanisms defining these cell fate choices willassist the development of effective p53-based cancer thera-pies and also illuminate fundamental processes by whichgene networks control cellular behaviour. Using an experi-mental system wherein stimulus-specific p53 responses areelicited by non-genotoxic versus genotoxic agents, we dis-covered a novel mechanism that determines whether cellsundergo proliferation arrest or cell death. Strikingly, weobserve that key mediators of cell-cycle arrest (p21, 14-3-3r) and apoptosis (PUMA, BAX) are equally activated regard-less of outcome. In fact, arresting cells display strong trans-location of PUMA and BAX to the mitochondria, yet fail torelease cytochrome C or activate caspases. Surprisingly, thekey differential events in apoptotic cells are p53-dependentactivation of the DR4 death receptor pathway, caspase 8-mediated cleavage of BID, and BID-dependent activation ofpoised BAX at the mitochondria. These results reveal apreviously unappreciated role for DR4 and the extrinsicapoptotic pathway in cell fate choice following p53 activation.