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J. Biol. Chem., Vol. 277, Issue 52, 50842-50854, December 27, 2002
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From the Department of Carcinogenesis, University of Texas M. D. Anderson Cancer Center, Science Park Research Division,
Smithville, Texas 78957
Apoptosis induced by many stimuli requires the
mitochondrial respiratory chain (MRC) function. While studying the
molecular mechanisms underlying this MRC-dependent apoptotic
pathway, we find that apoptosis in multiple cell types induced by
a variety of stimuli is preceded by an early induction of MRC proteins
such as cytochrome c (which is encoded by a nuclear gene)
and cytochrome c oxidase subunit II (COX II) (which is
encoded by the mitochondrial genome). Several non-MRC proteins
localized in the mitochondria, e.g. Smac, Bim, Bak, and
Bcl-2, are also rapidly up-regulated. The up-regulation of many of
these proteins (e.g. cytochrome c, COX II, and
Bim) results from transcriptional activation of the respective genes.
The up-regulated cytosolic cytochrome c rapidly translocates to the mitochondria, resulting in an accumulation of
holocytochrome c in the mitochondria accompanied by
increasing holocytochrome c release into the cytosol. The
increased cytochrome c transport from cytosol to the
mitochondria does not depend on the mitochondrial protein synthesis or
MRC per se. In contrast, cytochrome c release
from the mitochondria involves dynamic changes in Bcl-2 family proteins
(e.g. up-regulation of Bak, Bcl-2, and Bcl-xL),
opening of permeability transition pore, and loss of mitochondrial
membrane potential. Overexpression of cytochrome c enhances
caspase activation and promotes cell death in response to apoptotic
stimulation, but simple up-regulation of cytochrome c using
an ecdysone-inducible system is, by itself, insufficient to induce
apoptosis. Taken together, these results suggest that apoptosis induced
by many stimuli involves an early mitochondrial activation, which may
be responsible for the subsequent disruption of MRC functions, loss of
Early Mitochondrial Activation and Cytochrome c
Up-regulation during Apoptosis*,
,
m, cytochrome c release, and ultimately cell death.
*
This work was supported in part by the National Institutes
of Health NCI Grant CA 90297 and NIEHS Center Grant ES07784, and the
University of Texas MD Anderson Cancer Center institutional grants.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.
The on-line version of this article (available at
http://www.jbc.org) contains Figs.
1S
3S.
Supported by a Department of Defense Postdoctoral Traineeship
Award DAMD17-02-1-0083.
§
To whom correspondence should be addressed: Dept. of
Carcinogenesis, University of Texas M. D. Anderson Cancer Center,
Science Park Research Division, Park Rd. 1C, Smithville, TX 78957. Tel.: 512-237-9575; Fax: 512-237-2475; E-mail:
dtang@sprd1.mdacc.tmc.edu.
Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.
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