Essential role for caspase-8 in transcription-independent apoptosis triggered by p53

p53's dual regulation of arrest versus apoptosis may underlie tumor-selecti ve effects of anti-cancer therapy. p53's apoptotic effect has been suggeste d to involve both transcription-dependent and -independent mechanisms. It i s shown here that caspase-8 is activated early in cells undergoing p53-medi ated apoptosis and in S100 cell-free extracts that recapitulate transcripti on-independent apoptosis, Depletion or inactivation of caspase-8 either in cells or cell-free extracts completely prevents this transcription-independ ent apoptosis and significantly attenuates overall death induced by wildtyp e p53. Importantly, caspase-8 activation appears to be independent of FADD, and caspase-8 is found in a novel 600-kDa complex following p53 activation . These findings highlight the roles of both transcription-dependent and -i ndependent apoptosis by p53 and identify an essential role for caspase-8 in the transcription-independent pathway.