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Proapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and Death
Michael C. Wei,12*Wei-Xing Zong,3*Emily H.-Y. Cheng,1Tullia Lindsten,3Vily Panoutsakopoulou,1Andrea J. Ross,4Kevin A. Roth,5Grant R. MacGregor,4Craig B. Thompson,3Stanley J. Korsmeyer1
Multiple death signals influence mitochondria during
apoptosis, yet the critical initiating event for mitochondrial
dysfunctionin vivo has been unclear. tBID, the caspase-activated
form ofa "BH3-domain-only" BCL-2 family member, triggers
the homooligomerizationof "multidomain" conserved proapoptotic
family members BAK orBAX, resulting in the release of cytochrome c
from mitochondria.We find that cells lacking both Bax and
Bak, but not cells lackingonly one of these components, are
completely resistant to tBID-inducedcytochrome c release and
apoptosis. Moreover, doubly deficientcells are resistant to multiple
apoptotic stimuli that act throughdisruption of mitochondrial
function: staurosporine, ultravioletradiation, growth factor
deprivation, etoposide, and the endoplasmicreticulum stress stimuli
thapsigargin and tunicamycin. Thus, activationof a "multidomain"
proapoptotic member, BAX or BAK, appears tobe an essential gateway to
mitochondrial dysfunction requiredfor cell death in response to
diverse stimuli.
1 Howard Hughes Medical Institute, Departments
of Pathology and Medicine, Harvard Medical School, Dana-Farber Cancer
Institute, Boston, MA 02115, USA.
2 Division of
Biology and Biomedical Sciences, Washington University School of
Medicine, St. Louis, MO 63110, USA.
3 Departments of
Medicine and Pathology and Laboratory Medicine, Abramson Family Cancer
Research Institute, University of Pennsylvania, Philadelphia, PA 19104, USA.
4 Center for Molecular Medicine, Emory
University School of Medicine, Atlanta, GA 30322, USA.
5 Department of Pathology, Washington University
School of Medicine, St. Louis, MO 63110, USA.
*
These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail:
craig{at}mail.med.upem.edu; stanley_korsmeyer{at}dfci.harvard.edu
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