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Science 9 April 1999:
Vol. 284. no. 5412, pp. 339 - 343
DOI: 10.1126/science.284.5412.339
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Reports

Ca2+-Induced Apoptosis Through Calcineurin Dephosphorylation of BAD

Hong-Gang Wang, 12* Nuzhat Pathan, 1* Iryna M. Ethell, 1 Stanislaw Krajewski, 1 Yu Yamaguchi, 1 Futoshi Shibasaki, 3 Frank McKeon, 3 Tanya Bobo, 4 Thomas F. Franke, 4 John C. Reed 1dagger

The Ca2+-activated protein phosphatase calcineurin induces apoptosis, but the mechanism is unknown. Calcineurin was found to dephosphorylate BAD, a pro-apoptotic member of the Bcl-2 family, thus enhancing BAD heterodimerization with Bcl-xL and promoting apoptosis. The Ca2+-induced dephosphorylation of BAD correlated with its dissociation from 14-3-3 in the cytosol and translocation to mitochondria where Bcl-xL resides. In hippocampal neurons, L-glutamate, an inducer of Ca2+ influx and calcineurin activation, triggered mitochondrial targeting of BAD and apoptosis, which were both suppressible by coexpression of a dominant-inhibitory mutant of calcineurin or pharmacological inhibitors of this phosphatase. Thus, a Ca2+-inducible mechanism for apoptosis induction operates by regulating BAD phosphorylation and localization in cells.

1 The Burnham Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
2 H. Lee Moffitt Cancer Center and Research Institute, Department of Pharmacology and Therapeutics, University of South Florida, Tampa, FL 33612, USA.
3 Department of Cell Biology, Harvard University, School of Medicine, Boston, MA 02115, USA.
4 Columbia University, Department of Pharmacology, 630 West 168 Street, New York, NY 10032, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed: E- mail: jreed{at}burnham-institute.org

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Myocyte contractile activity modulates norepinephrine cytotoxicity and survival effects of neuregulin-1{beta}.
Y. Kuramochi, C. C. Lim, X. Guo, W. S. Colucci, R. Liao, and D. B. Sawyer (2004)
Am J Physiol Cell Physiol 286, C222-C229
   Abstract »    Full Text »
AKT/Protein Kinase B Regulation of BCL Family Members during Oxysterol-induced Apoptosis.
A. E. Rusinol, D. Thewke, J. Liu, N. Freeman, S. R. Panini, and M. S. Sinensky (2004)
J. Biol. Chem. 279, 1392-1399
   Abstract »    Full Text »    PDF »
Calcineurin A{beta} Gene Targeting Predisposes the Myocardium to Acute Ischemia-Induced Apoptosis and Dysfunction.
O. F. Bueno, D. J. Lips, R. A. Kaiser, B. J. Wilkins, Y.-S. Dai, B. J. Glascock, R. Klevitsky, T. E. Hewett, T. R. Kimball, B. J. Aronow, et al. (2004)
Circ. Res. 94, 91-99
   Abstract »    Full Text »    PDF »
Rapid Ca2+-dependent decrease of protein ubiquitination at synapses.
H. Chen, S. Polo, P. P. Di Fiore, and P. V. De Camilli (2003)
PNAS 100, 14908-14913
   Abstract »    Full Text »    PDF »
Enhancement of Bik Antitumor Effect by Bik Mutants.
Y. M. Li, Y. Wen, B. P. Zhou, H.-P. Kuo, Q. Ding, and M.-C. Hung (2003)
Cancer Res. 63, 7630-7633
   Abstract »    Full Text »    PDF »
Bcl-2 on the endoplasmic reticulum: protecting the mitochondria from a distance.
M. J. Thomenius and C. W. Distelhorst (2003)
J. Cell Sci. 116, 4493-4499
   Abstract »    Full Text »    PDF »
Neuroprotection by Nicotine in Mouse Primary Cortical Cultures Involves Activation of Calcineurin and L-Type Calcium Channel Inactivation.
T. R. Stevens, S. R. Krueger, R. M. Fitzsimonds, and M. R. Picciotto (2003)
J. Neurosci. 23, 10093-10099
   Abstract »    Full Text »    PDF »
Signal Transduction and Genes-to-Behaviors Pathways in Psychiatric Diseases.
H. K. Manji, I. I. Gottesman, and T. D. Gould (2003)
Sci. STKE 2003, pe49
   Abstract »    Full Text »    PDF »
The Combination of Calmodulin Antagonists and Interferon-{gamma} Induces Apoptosis through Caspase-Dependent and -Independent Pathways in Cholangiocarcinoma Cells.
E.-Y. Ahn, G. Pan, J. H. Oh, E. M. Tytler, and J. M. McDonald (2003)
Am. J. Pathol. 163, 2053-2063
   Abstract »    Full Text »    PDF »
Control of Cardiac Growth and Function by Calcineurin Signaling.
R. B. Vega, R. Bassel-Duby, and E. N. Olson (2003)
J. Biol. Chem. 278, 36981-36984
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Protein Phosphatase 2A Dephosphorylation of Phosphoserine 112 Plays the Gatekeeper Role for BAD-Mediated Apoptosis.
C.-W. Chiang, C. Kanies, K. W. Kim, W. B. Fang, C. Parkhurst, M. Xie, T. Henry, and E. Yang (2003)
Mol. Cell. Biol. 23, 6350-6362
   Abstract »    Full Text »    PDF »
Fluorescent Indicators for Akt/Protein Kinase B and Dynamics of Akt Activity Visualized in Living Cells.
K. Sasaki, M. Sato, and Y. Umezawa (2003)
J. Biol. Chem. 278, 30945-30951
   Abstract »    Full Text »    PDF »
TNF-{alpha}-induced cell death in ethanol-exposed cells depends on p38 MAPK signaling but is independent of Bid and caspase-8.
J. G. Pastorino, N. Shulga, and J. B. Hoek (2003)
Am J Physiol Gastrointest Liver Physiol 285, G503-G516
   Abstract »    Full Text »    PDF »
Prostate-Specific Antigen-Activated Thapsigargin Prodrug as Targeted Therapy for Prostate Cancer.
S. R. Denmeade, C. M. Jakobsen, S. Janssen, S. R. Khan, E. S. Garrett, H. Lilja, S. B. Christensen, and J. T. Isaacs (2003)
J Natl Cancer Inst 95, 990-1000
   Abstract »    Full Text »    PDF »
Molecular Switches Deciding the Death of Injured Neurons.
P. Nicotera (2003)
Toxicol. Sci. 74, 4-9
   Abstract »    Full Text »    PDF »
The Herpes Simplex Virus 1 US3 Protein Kinase Blocks Caspase-Dependent Double Cleavage and Activation of the Proapoptotic Protein BAD.
L. Benetti, J. Munger, and B. Roizman (2003)
J. Virol. 77, 6567-6573
   Abstract »    Full Text »    PDF »
Cleavage of 14-3-3 Protein by Caspase-3 Facilitates Bad Interaction with Bcl-x(L) during Apoptosis.
J. Won, D. Y. Kim, M. La, D. Kim, G. G. Meadows, and C. O. Joe (2003)
J. Biol. Chem. 278, 19347-19351
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Mitochondria to nucleus stress signaling: a distinctive mechanism of NF{kappa}B/Rel activation through calcineurin-mediated inactivation of I{kappa}B{beta}.
G. Biswas, H. K. Anandatheerthavarada, M. Zaidi, and N. G. Avadhani (2003)
J. Cell Biol. 161, 507-519
   Abstract »    Full Text »    PDF »
Zinc Finger Protein Prz1 Regulates Ca2+ but Not Cl- Homeostasis in Fission Yeast. IDENTIFICATION OF DISTINCT BRANCHES OF CALCINEURIN SIGNALING PATHWAY IN FISSION YEAST.
S. Hirayama, R. Sugiura, Y. Lu, T. Maeda, K. Kawagishi, M. Yokoyama, H. Tohda, Y. Giga-Hama, H. Shuntoh, and T. Kuno (2003)
J. Biol. Chem. 278, 18078-18084
   Abstract »    Full Text »    PDF »
NFAT Transcription Factors Are Critical Survival Factors That Inhibit Cardiomyocyte Apoptosis During Phenylephrine Stimulation In Vitro.
W. T. Pu, Q. Ma, and S. Izumo (2003)
Circ. Res. 92, 725-731
   Abstract »    Full Text »    PDF »


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