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Originally published in Science Express on 6 March 2003
Science 4 April 2003:
Vol. 300. no. 5616, pp. 135 - 139
DOI: 10.1126/science.1081208
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Reports

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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Tipifarnib and Bortezomib Are Synergistic and Overcome Cell Adhesion-Mediated Drug Resistance in Multiple Myeloma and Acute Myeloid Leukemia.
N. Yanamandra, N. M. Colaco, N. A. Parquet, R. W. Buzzeo, D. Boulware, G. Wright, L. E. Perez, W. S. Dalton, and D. M. Beaupre (2006)
Clin. Cancer Res. 12, 591-599
   Abstract »    Full Text »    PDF »
Microdomains of Intracellular Ca2+: Molecular Determinants and Functional Consequences.
R. Rizzuto and T. Pozzan (2006)
Physiol Rev 86, 369-408
   Abstract »    Full Text »    PDF »
Role of calreticulin in the sensitivity of myocardiac H9c2 cells to oxidative stress caused by hydrogen peroxide.
Y. Ihara, Y. Urata, S. Goto, and T. Kondo (2006)
Am J Physiol Cell Physiol 290, C208-C221
   Abstract »    Full Text »    PDF »
Subplasmalemmal Mitochondria Modulate the Activity of Plasma Membrane Ca2+-ATPases.
M. Frieden, S. Arnaudeau, C. Castelbou, and N. Demaurex (2005)
J. Biol. Chem. 280, 43198-43208
   Abstract »    Full Text »    PDF »
Ca2+ signals and death programmes in neurons.
L. Berliocchi, D. Bano, and P. Nicotera (2005)
Phil Trans R Soc B 360, 2255-2258
   Abstract »    Full Text »    PDF »
Accumulation of Mutant {alpha}1-Antitrypsin Z in the Endoplasmic Reticulum Activates Caspases-4 and -12, NF{kappa}B, and BAP31 but Not the Unfolded Protein Response.
T. Hidvegi, B. Z. Schmidt, P. Hale, and D. H. Perlmutter (2005)
J. Biol. Chem. 280, 39002-39015
   Abstract »    Full Text »    PDF »
Ca2+ Dysregulation Induces Mitochondrial Depolarization and Apoptosis: ROLE OF Na+/Ca2+ EXCHANGER AND AKT.
S. Miyamoto, A. L. Howes, J. W. Adams, G. W. Dorn II, and J. H. Brown (2005)
J. Biol. Chem. 280, 38505-38512
   Abstract »    Full Text »    PDF »
SphK1 and SphK2, Sphingosine Kinase Isoenzymes with Opposing Functions in Sphingolipid Metabolism.
M. Maceyka, H. Sankala, N. C. Hait, H. Le Stunff, H. Liu, R. Toman, C. Collier, M. Zhang, L. S. Satin, A. H. Merrill Jr., et al. (2005)
J. Biol. Chem. 280, 37118-37129
   Abstract »    Full Text »    PDF »
Loss of Bif-1 Suppresses Bax/Bak Conformational Change and Mitochondrial Apoptosis.
Y. Takahashi, M. Karbowski, H. Yamaguchi, A. Kazi, J. Wu, S. M. Sebti, R. J. Youle, and H.-G. Wang (2005)
Mol. Cell. Biol. 25, 9369-9382
   Abstract »    Full Text »    PDF »
The Anti-apoptotic Protein Mcl-1 Inhibits Mitochondrial Ca2+ Signals.
N. Minagawa, E. A. Kruglov, J. A. Dranoff, M. E. Robert, G. J. Gores, and M. H. Nathanson (2005)
J. Biol. Chem. 280, 33637-33644
   Abstract »    Full Text »    PDF »
Slit or pore? A mutation of the ion channel TRPC6 causes FSGS.
G. Walz (2005)
Nephrol. Dial. Transplant. 20, 1777-1779
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Cyclophilin D is a component of mitochondrial permeability transition and mediates neuronal cell death after focal cerebral ischemia.
A. C. Schinzel, O. Takeuchi, Z. Huang, J. K. Fisher, Z. Zhou, J. Rubens, C. Hetz, N. N. Danial, M. A. Moskowitz, and S. J. Korsmeyer (2005)
PNAS 102, 12005-12010
   Abstract »    Full Text »    PDF »
Caspase-12 and Caspase-4 Are Not Required for Caspase-dependent Endoplasmic Reticulum Stress-induced Apoptosis.
E. A. Obeng and L. H. Boise (2005)
J. Biol. Chem. 280, 29578-29587
   Abstract »    Full Text »    PDF »
Mechanisms of Group B Streptococcal-Induced Apoptosis of Murine Macrophages.
G. C. Ulett, K. H. Maclean, S. Nekkalapu, J. L. Cleveland, and E. E. Adderson (2005)
J. Immunol. 175, 2555-2562
   Abstract »    Full Text »    PDF »


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