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J. Biol. Chem., Vol. 276, Issue 34, 32257-32263, August 24, 2001
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From the Departments of Apoptosis is a physiological counterbalance to
mitosis and plays important roles in tissue development and
homeostasis. Cytosolic Ca2+ has been implicated as a
proapoptotic second messenger involved in both triggering apoptosis and
regulating cell death-specific enzymes. A critical early event
in apoptosis is associated with the redistribution of Bax from cytosol
to mitochondria and endoplasmic reticulum (ER) membranes; however, the
molecular mechanism of Bax translocation and its relationship to
Ca2+ is largely unknown. Here we provide functional
evidence for a synergistic interaction between the movements of
intracellular Ca2+ and cytosolic Bax in the induction of
apoptosis. Overexpression of Bax in cultured cells causes a loss
of ER Ca2+ content. Depletion of ER Ca2+
through activation of the ryanodine receptor enhances the participation of Bax into the mitochondrial membrane. Neither Bax translocation nor
Bax-induced apoptosis is affected by buffering of cytosolic Ca2+ with
1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic
acid, suggesting that depletion of ER Ca2+ rather
than elevation of cytosolic Ca2+ is the signal for cell
apoptosis. This dynamic interplay of Ca2+ and Bax
movements may serve as an amplifying factor in the initial signaling
steps of apoptosis.
Synergistic Movements of Ca2+ and Bax
in Cells Undergoing Apoptosis*
§,§,
Physiology and Biophysics and
¶ Anatomy, Case Western Reserve University School of Medicine,
10900 Euclid Avenue, Cleveland, Ohio 44106
*
This work was supported by National Institutes of Health
Grants RO1-AG15556 and RO1-CA85834 (to J. M.) and RO1-NS39469 and S10-RR14690 (to A. L. N.).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.
To whom correspondence should be addressed: Dept. of
Physiology and Biophysics, University of Medicine and Dentistry of New Jersey/Robert Wood Johnson Medical School, 675 Hoes Lane, Piscataway, NJ 08854.Tel.: 732-235-4552; Fax: 732-235-5038; E-mail:
jxm63@po.cwru.edu.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
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