Molecular Ordering of the Cell Death Pathway
Bcl-2 AND Bcl-x
FUNCTION UPSTREAM OF THE CED-3-LIKE APOPTOTIC PROTEASES (*)
- Arul M. Chinnaiyan(§),
- Kim Orth,
- Karen O'Rourke,
- Hangjun Duan,
- Guy G. Poirier(1) and
- Vishva M. Dixit(¶)
- From the Department of Pathology, University of Michigan Medical School, Ann Arbor, Michigan 48109
- Poly(ADP-Ribose) Metabolism Group, Laboratory of Molecular Endocrinology, Centre Hospitalier de I'Université Laval Research Center and Laval University Sainte-Foy, Quebec G1V 4G2, Canada
- ¶Established Investigator of the American Heart Association. To whom correspondence should be addressed: The University of Michigan Medical School, Dept. of Pathology, 1301 Catherine St., Box 0602, Ann Arbor, MI 48109. Tel.: 313-747-2921; Fax: 313-764-4308; :vmdixit{at}umich.edu.
Abstract
Genetic analyses of Caenorhabditis elegans has identified three genes that function in the regulation of nematode cell death. Mammalian homologs of two of these genes,
ced-9 and ced-3, have been identified and comprise proteins belonging to the Bcl-2 and ICE families, respectively. To date, it is unclear
where the negative regulators, ced-9 and bcl-2, function relative to the death effectors, ced-3 and the mammalian ced-3 homologs, respectively. Here, the molecular order of the cell death pathway is defined. Our results establish that Bcl-2
and Bcl-x
function upstream of two members of the ICE/CED-3 family of cysteine proteases, Yama (CPP32/apopain) and ICE-LAP3 (Mch3).
Footnotes
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↵§ Fellow of the Medical Scientist Training Program, supported by the Experimental Immunopathology Training Grant.
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↵* This work was supported in part by National Institutes of Health Grant CA64803 and Grant CA68769 (to K. Orth). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore by hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵1 The abbreviations used are:
- ICE
-
interleukin-1β converting enzyme
- IL
-
interleukin
- PARP
-
poly(ADP-ribose) polymerase
- PAGE
-
polyacrylamide gel electrophoresis.
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- Received January 4, 1996.
- © 1996 by The American Society for Biochemistry and Molecular Biology, Inc.
