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Science 297 (5585): 1352-1354

Copyright © 2002 by the American Association for the Advancement of Science

Requirement for Caspase-2 in Stress-Induced Apoptosis Before Mitochondrial Permeabilization

Patrice Lassus, Ximena Opitz-Araya, Yuri Lazebnik*

A current view is that cytotoxic stress, such as DNA damage, induces apoptosis by regulating the permeability of mitochondria. Mitochondria sequester several proteins that, if released, kill by activating caspases, the proteases that disassemble the cell. Cytokines activate caspases in a different way, by assembling receptor complexes that activate caspases directly; in this case, the subsequent mitochondrial permeabilization accelerates cell disassembly by amplifying caspase activity. We found that cytotoxic stress causes activation of caspase-2, and that this caspase is required for the permeabilization of mitochondria. Therefore, we argue that cytokine-induced and stress-induced apoptosis act through conceptually similar pathways in which mitochondria are amplifiers of caspase activity rather than initiators of caspase activation.

Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.
*   To whom correspondence should be addressed. E-mail: lazebnik{at}cshl.org



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   Abstract »    Full Text »    PDF »
Down-regulation of apoptosis mediators by RNAi inhibits axotomy-induced retinal ganglion cell death in vivo.
P. Lingor, P. Koeberle, S. Kugler, and M. Bahr (2005)
Brain 128, 550-558
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Caspases. Regulating Death Since the Origin of Life.
M. Sanmartin, L. Jaroszewski, N. V. Raikhel, and E. Rojo (2005)
Plant Physiology 137, 841-847
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Functional Role of Caspases in Heat-Induced Testicular Germ Cell Apoptosis.
Y. Vera, S. Rodriguez, M. Castanares, Y. Lue, V. Atienza, C. Wang, R. S. Swerdloff, and A. P. Sinha Hikim (2005)
Biol Reprod 72, 516-522
   Abstract »    Full Text »    PDF »
A Novel Caspase-2 Complex Containing TRAF2 and RIP1.
M. Lamkanfi, K. D'hondt, L. Vande Walle, M. van Gurp, G. Denecker, J. Demeulemeester, M. Kalai, W. Declercq, X. Saelens, and P. Vandenabeele (2005)
J. Biol. Chem. 280, 6923-6932
   Abstract »    Full Text »    PDF »
Inhibition of Macroautophagy Triggers Apoptosis.
P. Boya, R.-A. Gonzalez-Polo, N. Casares, J.-L. Perfettini, P. Dessen, N. Larochette, D. Metivier, D. Meley, S. Souquere, T. Yoshimori, et al. (2005)
Mol. Cell. Biol. 25, 1025-1040
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Caspase-Dependent and -Independent Neuronal Death: Two Distinct Pathways to Neuronal Injury.
L. Stefanis (2005)
Neuroscientist 11, 50-62
   Abstract »    PDF »
Newcomers in the process of mitochondrial permeabilization.
S. Lucken-Ardjomande and J.-C. Martinou (2005)
J. Cell Sci. 118, 473-483
   Abstract »    Full Text »    PDF »
The Birc6 (Bruce) gene regulates p53 and the mitochondrial pathway of apoptosis and is essential for mouse embryonic development.
J. Ren, M. Shi, R. Liu, Q.-H. Yang, T. Johnson, W. C. Skarnes, and C. Du (2005)
PNAS 102, 565-570
   Abstract »    Full Text »    PDF »
Filtering of Ineffective siRNAs and Improved siRNA Design Tool.
S. M. Yiu, P. W. H. Wong, T.W. Lam, Y.C. Mui, H. F. Kung, M. Lin, and Y. T. Cheung (2005)
Bioinformatics 21, 144-151
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A Death Receptor-associated Anti-apoptotic Protein, BRE, Inhibits Mitochondrial Apoptotic Pathway.
Q. Li, A. K.-K. Ching, B. C.-L. Chan, S. K.-Y. Chow, P.-L. Lim, T. C.-Y. Ho, W.-K. Ip, C.-K. Wong, C. W.-K. Lam, K. K.-H. Lee, et al. (2004)
J. Biol. Chem. 279, 52106-52116
   Abstract »    Full Text »    PDF »
Hsp72 Inhibits Apoptosis Upstream of the Mitochondria and Not through Interactions with Apaf-1.
R. Steel, J. P. Doherty, K. Buzzard, N. Clemons, C. J. Hawkins, and R. L. Anderson (2004)
J. Biol. Chem. 279, 51490-51499
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Caspase-2 Permeabilizes the Outer Mitochondrial Membrane and Disrupts the Binding of Cytochrome c to Anionic Phospholipids.
M. Enoksson, J. D. Robertson, V. Gogvadze, P. Bu, A. Kropotov, B. Zhivotovsky, and S. Orrenius (2004)
J. Biol. Chem. 279, 49575-49578
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Proteasome Inhibitor PS-341 Induces Apoptosis through Induction of Endoplasmic Reticulum Stress-Reactive Oxygen Species in Head and Neck Squamous Cell Carcinoma Cells.
A. Fribley, Q. Zeng, and C.-Y. Wang (2004)
Mol. Cell. Biol. 24, 9695-9704
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The Mitochondrial Death Pathway and Cardiac Myocyte Apoptosis.
M. T. Crow, K. Mani, Y.-J. Nam, and R. N. Kitsis (2004)
Circ. Res. 95, 957-970
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Apoptosis Protease Activator Protein-1 Expression Is Dispensable for Response of Human Melanoma Cells to Distinct Proapoptotic Agents.
M. Zanon, A. Piris, I. Bersani, C. Vegetti, A. Molla, A. Scarito, and A. Anichini (2004)
Cancer Res. 64, 7386-7394
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Components of the Cell Death Machine and Drug Sensitivity of the National Cancer Institute Cell Line Panel.
P. A. Svingen, D. Loegering, J. Rodriquez, X. W. Meng, P. W. Mesner Jr., S. Holbeck, A. Monks, S. Krajewski, D. A. Scudiero, E. A. Sausville, et al. (2004)
Clin. Cancer Res. 10, 6807-6820
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A20 protects endothelial cells from TNF-, Fas-, and NK-mediated cell death by inhibiting caspase 8 activation.
S. Daniel, M. B. Arvelo, V. I. Patel, C. R. Longo, G. Shrikhande, T. Shukri, J. Mahiou, D. W. Sun, C. Mottley, S. T. Grey, et al. (2004)
Blood 104, 2376-2384
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