Essential role for caspase-8 in transcription-independent apoptosis triggered by p53.
p53's dual regulation of arrest versus apoptosis may underlie tumor-selective effects of anti-cancer therapy. p53's apoptotic effect has been suggested to involve both transcription-dependent and -independent mechanisms. It is shown here that caspase-8 is activated early in cells undergoing p53-mediated apoptosis and in S100 cell-free extracts that recapitulate transcription-independent apoptosis. Depletion or inactivation of caspase-8 either in cells or cell-free extracts completely prevents this transcription-independent apoptosis and significantly attenuates overall death induced by wild-type 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 -independent apoptosis by p53 and identify an essential role for caspase-8 in the transcription-independent pathway.
Ding
H F
HF
Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute and Children's Hospital, Boston, Massachusetts 02115, USA.
Lin
Y L
YL
McGill
G
G
Juo
P
P
Zhu
H
H
Blenis
J
J
Yuan
J
J
Fisher
D E
DE
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002352:Carrier Proteins / Q000378:metabolism; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism*; D002474:Cell-Free System; D002478:Cells, Cultured; D053200:Fas-Associated Death Domain Protein; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D016158:Genes, p53; D051379:Mice; D014158:Transcription, Genetic / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C505534:Fadd protein, mouse; D053200:Fas-Associated Death Domain Protein; D016159:Tumor Suppressor Protein p53; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases