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Science 300 (5616): 135-139

Copyright © 2003 by the American Association for the Advancement of Science

BAX and BAK Regulation of Endoplasmic Reticulum Ca2+: A Control Point for Apoptosis

Luca Scorrano,12* Scott A. Oakes,1* Joseph T. Opferman,1 Emily H. Cheng,1 Mia D. Sorcinelli,1 Tullio Pozzan,23 Stanley J. Korsmeyer1dagger

BAX and BAK are "multidomain" proapoptotic proteins that initiate mitochondrial dysfunction but also localize to the endoplasmic reticulum (ER). Mouse embryonic fibroblasts deficient for BAX and BAK (DKO cells) were found to have a reduced resting concentration of calcium in the ER ([Ca2+]er) that results in decreased uptake of Ca2+ by mitochondria after Ca2+ release from the ER. Expression of SERCA (sarcoplasmic-endoplasmic reticulum Ca2+ adenosine triphosphatase) corrected [Ca2+]er and mitochondrial Ca2+ uptake in DKO cells, restoring apoptotic death in response to agents that release Ca2+ from intracellular stores (such as arachidonic acid, C2-ceramide, and oxidative stress). In contrast, targeting of BAX to mitochondria selectively restored apoptosis to "BH3-only" signals. A third set of stimuli, including many intrinsic signals, required both ER-released Ca2+ and the presence of mitochondrial BAX or BAK to fully restore apoptosis. Thus, BAX and BAK operate in both the ER and mitochondria as an essential gateway for selected apoptotic signals.

1 Howard Hughes Medical Institute, Dana-Farber Cancer Institute, Brigham and Women's Hospital, Department of Pathology and Medicine, Harvard Medical School, Boston, MA 02115, USA.
2 Venetian Institute for Molecular Medicine, 35121 Padova, Italy.
3 Department of Biomedical Sciences, University of Padova, 35121 Padova, Italy.
*   These authors contributed equally to this work.

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

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Granzyme K Directly Processes Bid to Release Cytochrome c and Endonuclease G Leading to Mitochondria-dependent Cell Death.
T. Zhao, H. Zhang, Y. Guo, and Z. Fan (2007)
J. Biol. Chem. 282, 12104-12111
   Abstract »    Full Text »    PDF »
GRP78/BiP Inhibits Endoplasmic Reticulum BIK and Protects Human Breast Cancer Cells against Estrogen Starvation-Induced Apoptosis.
Y. Fu, J. Li, and A. S. Lee (2007)
Cancer Res. 67, 3734-3740
   Abstract »    Full Text »    PDF »
Tumor prone phenotype of mice deficient in a novel apoptosis-inducing gene, drs.
Y. Tambe, A. Yoshioka-Yamashita, K.-i. Mukaisho, S. Haraguchi, T. Chano, T. Isono, T. Kawai, Y. Suzuki, R. Kushima, T. Hattori, et al. (2007)
Carcinogenesis 28, 777-784
   Abstract »    Full Text »    PDF »
Suppression of Endoplasmic Reticulum Stress-induced Caspase Activation and Cell Death by the Overexpression of Bcl-xL or Bcl-2.
Y. Murakami, E. Aizu-Yokota, Y. Sonoda, S. Ohta, and T. Kasahara (2007)
J. Biochem. 141, 401-410
   Abstract »    Full Text »    PDF »
Mice Lacking bi-1 Gene Show Accelerated Liver Regeneration.
B. Bailly-Maitre, E. Bard-Chapeau, F. Luciano, N. Droin, J.-M. Bruey, B. Faustin, C. Kress, J. M. Zapata, and J. C. Reed (2007)
Cancer Res. 67, 1442-1450
   Abstract »    Full Text »    PDF »
Key Note Lecture: Toward a Mechanistic Taxonomy for Cell Death Programs.
D. E. Bredesen (2007)
Stroke 38, 652-660
   Abstract »    Full Text »    PDF »
Ca2+ Signals and Neuronal Death in Brain Ischemia.
D. Bano and P. Nicotera (2007)
Stroke 38, 674-676
   Abstract »    Full Text »    PDF »
Cell Death Suppressor Arabidopsis Bax Inhibitor-1 Is Associated with Calmodulin Binding and Ion Homeostasis.
Y. Ihara-Ohori, M. Nagano, S. Muto, H. Uchimiya, and M. Kawai-Yamada (2007)
Plant Physiology 143, 650-660
   Abstract »    Full Text »    PDF »
Mitochondrial Membrane Permeabilization in Cell Death.
G. Kroemer, L. Galluzzi, and C. Brenner (2007)
Physiol Rev 87, 99-163
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Dual effect of thapsigargin on cell death in porcine aortic smooth muscle cells.
T.-Y. Chin, H.-C. Lin, J.-P. Kuo, and S.-H. Chueh (2007)
Am J Physiol Cell Physiol 292, C383-C395
   Abstract »    Full Text »    PDF »
Orchestration of lymphocyte chemotaxis by mitochondrial dynamics.
S. Campello, R. A. Lacalle, M. Bettella, S. Manes, L. Scorrano, and A. Viola (2006)
J. Exp. Med. 203, 2879-2886
   Abstract »    Full Text »    PDF »

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