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Science 12 December 1997:
Vol. 278. no. 5345, pp. 1966 - 1968
DOI: 10.1126/science.278.5345.1966
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Reports

Conversion of Bcl-2 to a Bax-like Death Effector by Caspases

Emily H.-Y. Cheng, * David G. Kirsch, Rollie J. Clem, Rajani Ravi, Michael B. Kastan, Atul Bedi, Kazuyoshi Ueno, J. Marie Hardwick dagger

Caspases are a family of cysteine proteases implicated in the biochemical and morphological changes that occur during apoptosis (programmed cell death). The loop domain of Bcl-2 is cleaved at Asp34 by caspase-3 (CPP32) in vitro, in cells overexpressing caspase-3, and after induction of apoptosis by Fas ligation and interleukin-3 withdrawal. The carboxyl-terminal Bcl-2 cleavage product triggered cell death and accelerated Sindbis virus-induced apoptosis, which was dependent on the BH3 homology and transmembrane domains of Bcl-2. Inhibitor studies indicated that cleavage of Bcl-2 may further activate downstream caspases and contribute to amplification of the caspase cascade. Cleavage-resistant mutants of Bcl-2 had increased protection from interleukin-3 withdrawal and Sindbis virus-induced apoptosis. Thus, cleavage of Bcl-2 by caspases may ensure the inevitability of cell death.

E. H.-Y. Cheng, R. J. Clem, J. M. Hardwick, Department of Molecular Microbiology and Immunology, Johns Hopkins School of Public Health, Baltimore, MD 21205, USA.
D. G. Kirsch, R. Ravi, M. B. Kastan, A. Bedi, Oncology Center, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
K. Ueno, Center for Chronic Viral Diseases, Faculty of Medicine, Kagoshima University, Kagoshima 890, Japan.
*   Present address: Department of Pathology, Washington University School of Medicine, St. Louis, MO 63110, USA.

dagger    To whom correspondence should be addressed. E-mail: hardwick{at}welchlink.welch.jhu.edu

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J. Virol. 76, 2469-2479
   Abstract »    Full Text »    PDF »
The Cyclin-dependent Kinase Inhibitor Flavopiridol Disrupts Sodium Butyrate-induced p21WAF1/CIP1 Expression and Maturation while Reciprocally Potentiating Apoptosis in Human Leukemia Cells.
R. R. Rosato, J. A. Almenara, L. Cartee, V. Betts, S. P. Chellappan, and S. Grant (2002)
Mol. Cancer Ther. 1, 253-266
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Pharmacologic Mitogen-activated Protein/Extracellular Signal-regulated Kinase Kinase/Mitogen-activated Protein Kinase Inhibitors Interact Synergistically with STI571 to Induce Apoptosis in Bcr/Abl-expressing Human Leukemia Cells.
C. Yu, G. Krystal, L. Varticovksi, R. McKinstry, M. Rahmani, P. Dent, and S. Grant (2002)
Cancer Res. 62, 188-199
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Novel triterpenoid CDDO-Me is a potent inducer of apoptosis and differentiation in acute myelogenous leukemia.
M. Konopleva, T. Tsao, P. Ruvolo, I. Stiouf, Z. Estrov, C. E. Leysath, S. Zhao, D. Harris, S. Chang, C. E. Jackson, et al. (2002)
Blood 99, 326-335
   Abstract »    Full Text »    PDF »
IL-7 Enhances the Survival and Maintains the Size of Naive T Cells.
J. C. Rathmell, E. A. Farkash, W. Gao, and C. B. Thompson (2001)
J. Immunol. 167, 6869-6876
   Abstract »    Full Text »    PDF »
Receptor- and mitochondrial-mediated apoptosis in acute leukemia: a translational view.
A. D. Schimmer, D. W. Hedley, L. Z. Penn, and M. D. Minden (2001)
Blood 98, 3541-3553
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Arsenic trioxide induces apoptosis in human T-cell leukemia virus type 1- and type 2-infected cells by a caspase-3-dependent mechanism involving Bcl-2 cleavage.
R. Mahieux, C. Pise-Masison, A. Gessain, John. N. Brady, R. Olivier, E. Perret, T. Misteli, and C. Nicot (2001)
Blood 98, 3762-3769
   Abstract »    Full Text »    PDF »
Characterization of Fortilin, a Novel Antiapoptotic Protein.
F. Li, D. Zhang, and K. Fujise (2001)
J. Biol. Chem. 276, 47542-47549
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Prion Protein Fragment PrP-(106-126) Induces Apoptosis via Mitochondrial Disruption in Human Neuronal SH-SY5Y Cells.
C. N. O'Donovan, D. Tobin, and T. G. Cotter (2001)
J. Biol. Chem. 276, 43516-43523
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Transient Expression of Wild-type or Mitochondrially Targeted Bcl-2 Induces Apoptosis, whereas Transient Expression of Endoplasmic Reticulum-targeted Bcl-2 Is Protective against Bax-induced Cell Death.
N. S. Wang, M. T. Unkila, E. Z. Reineks, and C. W. Distelhorst (2001)
J. Biol. Chem. 276, 44117-44128
   Abstract »    Full Text »    PDF »
The expanding role of mitochondria in apoptosis.
X. Wang (2001)
Genes & Dev. 15, 2922-2933
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Enhanced Acetaminophen Hepatotoxicity in Transgenic Mice Overexpressing BCL-2.
M. L. Adams, R. H. Pierce, M. E. Vail, C. C. White, R. P. Tonge, T. J. Kavanagh, N. Fausto, S. D. Nelson, and S. A. Bruschi (2001)
Mol. Pharmacol. 60, 907-915
   Abstract »    Full Text »    PDF »
Nerve Growth Factor Inhibits Apoptosis in Memory B Lymphocytes via Inactivation of p38 MAPK, Prevention of Bcl-2 Phosphorylation, and Cytochrome c Release.
M. Torcia, G. De Chiara, L. Nencioni, S. Ammendola, D. Labardi, M. Lucibello, P. Rosini, L. N. J. L. Marlier, P. Bonini, P. D. Sbarba, et al. (2001)
J. Biol. Chem. 276, 39027-39036
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Bcl2-L-10, a novel anti-apoptotic member of the Bcl-2 family, blocks apoptosis in the mitochondria death pathway but not in the death receptor pathway.
H. Zhang, W. Holzgreve, and C. De Geyter (2001)
Hum. Mol. Genet. 10, 2329-2339
   Abstract »    Full Text »    PDF »
Morphine modulates lymph node-derived T lymphocyte function: role of caspase-3, -8, and nitric oxide.
J. Wang, R. Charboneau, S. Balasubramanian, R. A. Barke, H. H. Loh, and S. Roy (2001)
J. Leukoc. Biol. 70, 527-536
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Apo2L/TRAIL and Bcl-2-related proteins regulate type I interferon-induced apoptosis in multiple myeloma.
Q. Chen, B. Gong, A. S. Mahmoud-Ahmed, A. Zhou, E. D. Hsi, M. Hussein, and A. Almasan (2001)
Blood 98, 2183-2192
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Light induced apoptosis is accelerated in transgenic retina overexpressing human EAT/mcl-1, an anti-apoptotic bcl-2 related gene.
K. Shinoda, Y. Nakamura, K. Matsushita, K. Shimoda, H. Okita, M. Fukuma, T. Yamada, H. Ohde, Y. Oguchi, J.-i. Hata, et al. (2001)
Br J Ophthalmol 85, 1237-1243
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Cocaine-Mediated Apoptosis in Bovine Coronary Artery Endothelial Cells: Role of Nitric Oxide.
J. He, Y. Xiao, and L. Zhang (2001)
J. Pharmacol. Exp. Ther. 298, 180-187
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Caspase Cleavage Enhances the Apoptosis-Inducing Effects of BAD.
F. Condorelli, P. Salomoni, S. Cotteret, V. Cesi, S. M. Srinivasula, E. S. Alnemri, and B. Calabretta (2001)
Mol. Cell. Biol. 21, 3025-3036
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Apoptosis in sepsis: a new target for therapeutic exploration.
C. OBERHOLZER, A. OBERHOLZER, M. CLARE-SALZLER, and L. L. MOLDAWER (2001)
FASEB J 15, 879-892
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Glycoprotein 130 Regulates Cardiac Myocyte Survival in Doxorubicin-Induced Apoptosis Through Phosphatidylinositol 3-Kinase/Akt Phosphorylation and Bcl-xL/Caspase-3 Interaction.
S. Negoro, H. Oh, E. Tone, K. Kunisada, Y. Fujio, K. Walsh, T. Kishimoto, and K. Yamauchi-Takihara (2001)
Circulation 103, 555-561
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Cleavage of Mitogen-Activated Protein Kinases in Human Neutrophils Undergoing Apoptosis: Role in Decreased Responsiveness to Inflammatory Cytokines.
K. Suzuki, T. Hasegawa, C. Sakamoto, Y.-M. Zhou, F. Hato, M. Hino, N. Tatsumi, and S. Kitagawa (2001)
J. Immunol. 166, 1185-1192
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Apoptosis of ventricular and atrial myocytes from pacing-induced canine heart failure.
M. Y Heinke, M. Yao, D. Chang, R. Einstein, and C. G dos Remedios (2001)
Cardiovasc Res 49, 127-134
   Abstract »    Full Text »    PDF »


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