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J. Biol. Chem. 275 (49): 38905-38911

© 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

Essential Role for Caspase-8 in Transcription-independent Apoptosis Triggered by p53*

Han-Fei DingDagger §, Yi-Ling LinDagger , Gaël McGillDagger , Peter Juo||, Hong Zhu||, John Blenis||, Junying Yuan||, and David E. FisherDagger **

From the Dagger  Department of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute and Children's Hospital, Boston, Massachusetts 02115 and || Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115

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.


* This work was supported in part by Grant CA69531from the National Institutes of Health (to D.E.F.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ Supported by the Howard Temin Award from NCI, National Institutes of Health, and a Special Fellowship from the Leukemia and Lymphoma Society.

Recipient of a Howard Hughes Medical Institute predoctoral fellowship.

** Nirenberg Fellow at the Dana-Farber Cancer Institute. To whom correspondence should be addressed: D630, Division of Pediatric Hematology/Oncology, Dana-Farber Cancer Institute and Children's Hospital, 44 Binney St., Boston, MA 02115. Tel.: 617-632-4916; Fax: 617-632-2085; E-mail: david_fisher@dfci.harvard.edu.


Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.

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