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Science 292 (5517): 727-730

Copyright © 2001 by the American Association for the Advancement of Science

Proapoptotic BAX and BAK: A Requisite Gateway to Mitochondrial Dysfunction and Death

Michael C. Wei,12* Wei-Xing Zong,3* Emily H.-Y. Cheng,1 Tullia Lindsten,3 Vily Panoutsakopoulou,1 Andrea J. Ross,4 Kevin A. Roth,5 Grant R. MacGregor,4 Craig B. Thompson,3dagger Stanley J. Korsmeyer1dagger

Multiple death signals influence mitochondria during apoptosis, yet the critical initiating event for mitochondrial dysfunction in vivo has been unclear. tBID, the caspase-activated form of a "BH3-domain-only" BCL-2 family member, triggers the homooligomerization of "multidomain" conserved proapoptotic family members BAK or BAX, resulting in the release of cytochrome c from mitochondria. We find that cells lacking both Bax and Bak, but not cells lacking only one of these components, are completely resistant to tBID-induced cytochrome c release and apoptosis. Moreover, doubly deficient cells are resistant to multiple apoptotic stimuli that act through disruption of mitochondrial function: staurosporine, ultraviolet radiation, growth factor deprivation, etoposide, and the endoplasmic reticulum stress stimuli thapsigargin and tunicamycin. Thus, activation of a "multidomain" proapoptotic member, BAX or BAK, appears to be an essential gateway to mitochondrial dysfunction required for 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.

dagger    To whom correspondence should be addressed. E-mail: craig{at}mail.med.upem.edu; stanley_korsmeyer{at}dfci.harvard.edu

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Am J Physiol Cell Physiol 300, C447-C455
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Bifunctional Apoptosis Regulator (BAR), an Endoplasmic Reticulum (ER)-associated E3 Ubiquitin Ligase, Modulates BI-1 Protein Stability and Function in ER Stress.
J. Rong, L. Chen, J. I. Toth, M. Tcherpakov, M. D. Petroski, and J. C. Reed (2011)
J. Biol. Chem. 286, 1453-1463
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BH3 Domains other than Bim and Bid Can Directly Activate Bax/Bak.
H. Du, J. Wolf, B. Schafer, T. Moldoveanu, J. E. Chipuk, and T. Kuwana (2011)
J. Biol. Chem. 286, 491-501
   Abstract »    Full Text »    PDF »
Integration of Apoptosis and Metabolism.
C. H. Yi, H. Vakifahmetoglu-Norberg, and J. Yuan (2011)
Cold Spring Harb Symp Quant Biol 76, 375-387
   Abstract »    Full Text »    PDF »
Reovirus Infection or Ectopic Expression of Outer Capsid Protein {micro}1 Induces Apoptosis Independently of the Cellular Proapoptotic Proteins Bax and Bak.
M. L. Wisniewski, B. G. Werner, L. G. Hom, L. J. Anguish, C. M. Coffey, and J. S. L. Parker (2011)
J. Virol. 85, 296-304
   Abstract »    Full Text »    PDF »
Heterodimerization of BAK and MCL-1 Activated by Detergent Micelles.
Q. Liu and K. Gehring (2010)
J. Biol. Chem. 285, 41202-41210
   Abstract »    Full Text »    PDF »
Distinct molecular mechanisms responsible for bortezomib-induced death of therapy-resistant versus -sensitive B-NHL cells.
S. H. Olejniczak, J. Blickwedehl, A. Belicha-Villanueva, N. Bangia, W. Riaz, C. Mavis, J. L. Clements, J. Gibbs, F. J. Hernandez-Ilizaliturri, and M. S. Czuczman (2010)
Blood 116, 5605-5614
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Neuronal Apoptosis Induced by Endoplasmic Reticulum Stress Is Regulated by ATF4-CHOP-Mediated Induction of the Bcl-2 Homology 3-Only Member PUMA.
Z. Galehdar, P. Swan, B. Fuerth, S. M. Callaghan, D. S. Park, and S. P. Cregan (2010)
J. Neurosci. 30, 16938-16948
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Oligomerization of the Mitochondrial Protein Voltage-Dependent Anion Channel Is Coupled to the Induction of Apoptosis.
N. Keinan, D. Tyomkin, and V. Shoshan-Barmatz (2010)
Mol. Cell. Biol. 30, 5698-5709
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A role for proapoptotic Bax and Bak in T-cell differentiation and transformation.
S. Biswas, Q. Shi, L. Matise, S. Cleveland, U. Dave, and S. Zinkel (2010)
Blood 116, 5237-5246
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BID, BIM, and PUMA Are Essential for Activation of the BAX- and BAK-Dependent Cell Death Program.
D. Ren, H.-C. Tu, H. Kim, G. X. Wang, G. R. Bean, O. Takeuchi, J. R. Jeffers, G. P. Zambetti, J. J.- D. Hsieh, and E. H.- Y. Cheng (2010)
Science 330, 1390-1393
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Quercetin Induces Tumor-Selective Apoptosis through Downregulation of Mcl-1 and Activation of Bax.
S. Cheng, N. Gao, Z. Zhang, G. Chen, A. Budhraja, Z. Ke, Y.-o. Son, X. Wang, J. Luo, and X. Shi (2010)
Clin. Cancer Res. 16, 5679-5691
   Abstract »    Full Text »    PDF »
Inhibition of Bak Activation by VDAC2 Is Dependent on the Bak Transmembrane Anchor.
M. Lazarou, D. Stojanovski, A. E. Frazier, A. Kotevski, G. Dewson, W. J. Craigen, R. M. Kluck, D. L. Vaux, and M. T. Ryan (2010)
J. Biol. Chem. 285, 36876-36883
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AMP-activated Protein Kinase Mediates Apoptosis in Response to Bioenergetic Stress through Activation of the Pro-apoptotic Bcl-2 Homology Domain-3-only Protein BMF.
S. M. Kilbride, A. M. Farrelly, C. Bonner, M. W. Ward, K. C. Nyhan, C. G. Concannon, C. B. Wollheim, M. M. Byrne, and J. H. M. Prehn (2010)
J. Biol. Chem. 285, 36199-36206
   Abstract »    Full Text »    PDF »

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