J. Cell Biol., Volume 144, Number 2, January 25, 1999 281-292

Ordering the Cytochrome c-initiated Caspase Cascade: Hierarchical Activation of Caspases-2, -3, -6, -7, -8, and -10 in a Caspase-9-dependent Manner

Elizabeth A. Slee,^* Mary T. Harte,^* Ruth M. Kluck, Beni B. Wolf, Carlos A. Casiano,^§ Donald D. Newmeyer, Hong-Gang Wang, John C. Reed, Donald W. Nicholson,^¶ Emad S. Alnemri,^** Douglas R. Green, and Seamus J. Martin^*

^* Molecular Cell Biology Laboratory, Department of Biology, National University of Ireland, Maynooth, Co. Kildare, Ireland;  Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, San Diego, California 92121; ^§ Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, California 92037;   The Burnham Institute, La Jolla, California 92037; ^¶ Departments of Biochemistry and Molecular Biology, Merck Frosst Centre for Therapeutic Research, Pointe Claire-Dorval, Quebec, H9R 4P8, Canada; and ^** Center for Apoptosis Research and The Kimmel Cancer Institute, Jefferson Medical College, Philadelphia, Pennsylvania 19107

Exit of cytochrome c from mitochondria into the cytosol has been implicated as an important step in apoptosis. In the cytosol, cytochrome c binds to the CED-4 homologue, Apaf-1, thereby triggering Apaf-1-mediated activation of caspase-9. Caspase-9 is thought to propagate the death signal by triggering other caspase activation events, the details of which remain obscure. Here, we report that six additional caspases (caspases-2, -3, -6, -7, -8, and -10) are processed in cell-free extracts in response to cytochrome c, and that three others (caspases-1, -4, and -5) failed to be activated under the same conditions. In vitro association assays confirmed that caspase-9 selectively bound to Apaf-1, whereas caspases-1, -2, -3, -6, -7, -8, and -10 did not. Depletion of caspase-9 from cell extracts abrogated cytochrome c-inducible activation of caspases-2, -3, -6, -7, -8, and -10, suggesting that caspase-9 is required for all of these downstream caspase activation events. Immunodepletion of caspases-3, -6, and -7 from cell extracts enabled us to order the sequence of caspase activation events downstream of caspase-9 and reveal the presence of a branched caspase cascade. Caspase-3 is required for the activation of four other caspases (-2, -6, -8, and -10) in this pathway and also participates in a feedback amplification loop involving caspase-9.

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• Svingen, P. A., Loegering, D., Rodriquez, J., Meng, X. W., Mesner, P. W. Jr., Holbeck, S., Monks, A., Krajewski, S., Scudiero, D. A., Sausville, E. A., Reed, J. C., Lazebnik, Y. A., Kaufmann, S. H. (2004). Components of the Cell Death Machine and Drug Sensitivity of the National Cancer Institute Cell Line Panel. Clin. Cancer Res. 10: 6807-6820 [Abstract] [Full Text]  
• Starenki, D. V., Namba, H., Saenko, V. A., Ohtsuru, A., Maeda, S., Umezawa, K., Yamashita, S. (2004). Induction of Thyroid Cancer Cell Apoptosis by a Novel Nuclear Factor {kappa}B Inhibitor, Dehydroxymethylepoxyquinomicin. Clin. Cancer Res. 10: 6821-6829 [Abstract] [Full Text]  
• Daniel, S., Arvelo, M. B., Patel, V. I., Longo, C. R., Shrikhande, G., Shukri, T., Mahiou, J., Sun, D. W., Mottley, C., Grey, S. T., Ferran, C. (2004). A20 protects endothelial cells from TNF-, Fas-, and NK-mediated cell death by inhibiting caspase 8 activation. Blood 104: 2376-2384 [Abstract] [Full Text]  
• Essmann, F., Engels, I. H., Totzke, G., Schulze-Osthoff, K., Janicke, R. U. (2004). Apoptosis Resistance of MCF-7 Breast Carcinoma Cells to Ionizing Radiation Is Independent of p53 and Cell Cycle Control but Caused by the Lack of Caspase-3 and a Caffeine-Inhibitable Event. Cancer Res. 64: 7065-7072 [Abstract] [Full Text]  
• Rashmi, R., Kumar, S., Karunagaran, D. (2004). Ectopic expression of Bcl-XL or Ku70 protects human colon cancer cells (SW480) against curcumin-induced apoptosis while their down-regulation potentiates it. Carcinogenesis 25: 1867-1877 [Abstract] [Full Text]  
• Sanvicens, N., Gomez-Vicente, V., Masip, I., Messeguer, A., Cotter, T. G. (2004). Oxidative Stress-induced Apoptosis in Retinal Photoreceptor Cells Is Mediated by Calpains and Caspases and Blocked by the Oxygen Radical Scavenger CR-6. J. Biol. Chem. 279: 39268-39278 [Abstract] [Full Text]  
• Eissing, T., Conzelmann, H., Gilles, E. D., Allgower, F., Bullinger, E., Scheurich, P. (2004). Bistability Analyses of a Caspase Activation Model for Receptor-induced Apoptosis. J. Biol. Chem. 279: 36892-36897 [Abstract] [Full Text]  
• Murphy, B. M., Creagh, E. M., Martin, S. J. (2004). Interchain Proteolysis, in the Absence of a Dimerization Stimulus, Can Initiate Apoptosis-associated Caspase-8 Activation. J. Biol. Chem. 279: 36916-36922 [Abstract] [Full Text]  
• Adrain, C., Creagh, E. M., Cullen, S. P., Martin, S. J. (2004). Caspase-dependent Inactivation of Proteasome Function during Programmed Cell Death in Drosophila and Man. J. Biol. Chem. 279: 36923-36930 [Abstract] [Full Text]  
• Wilkinson, J. C., Cepero, E., Boise, L. H., Duckett, C. S. (2004). Upstream Regulatory Role for XIAP in Receptor-Mediated Apoptosis. Mol. Cell. Biol. 24: 7003-7014 [Abstract] [Full Text]  
• Chandra, D., Choy, G., Deng, X., Bhatia, B., Daniel, P., Tang, D. G. (2004). Association of Active Caspase 8 with the Mitochondrial Membrane during Apoptosis: Potential Roles in Cleaving BAP31 and Caspase 3 and Mediating Mitochondrion-Endoplasmic Reticulum Cross Talk in Etoposide-Induced Cell Death. Mol. Cell. Biol. 24: 6592-6607 [Abstract] [Full Text]  
• Gaddy, V. T., Barrett, J. T., Delk, J. N., Kallab, A. M., Porter, A. G., Schoenlein, P. V. (2004). Mifepristone Induces Growth Arrest, Caspase Activation, and Apoptosis of Estrogen Receptor-Expressing, Antiestrogen-Resistant Breast Cancer Cells. Clin. Cancer Res. 10: 5215-5225 [Abstract] [Full Text]  
• Yakovlev, A. G., Di Giovanni, S., Wang, G., Liu, W., Stoica, B., Faden, A. I. (2004). BOK and NOXA Are Essential Mediators of p53-dependent Apoptosis. J. Biol. Chem. 279: 28367-28374 [Abstract] [Full Text]  
• Ginzberg, H. H., Shannon, P. T., Suzuki, T., Hong, O., Vachon, E., Moraes, T., Abreu, M. T. H., Cherepanov, V., Wang, X., Chow, C.-W., Downey, G. P. (2004). Leukocyte elastase induces epithelial apoptosis: role of mitochondial permeability changes and Akt. Am. J. Physiol. Gastrointest. Liver Physiol. 287: G286-G298 [Abstract] [Full Text]  
• Kang, P. M., Yue, P., Liu, Z., Tarnavski, O., Bodyak, N., Izumo, S. (2004). Alterations in apoptosis regulatory factors during hypertrophy and heart failure. Am. J. Physiol. Heart Circ. Physiol. 287: H72-H80 [Abstract] [Full Text]  
• Creagh, E. M., Murphy, B. M., Duriez, P. J., Duckett, C. S., Martin, S. J. (2004). Smac/Diablo Antagonizes Ubiquitin Ligase Activity of Inhibitor of Apoptosis Proteins. J. Biol. Chem. 279: 26906-26914 [Abstract] [Full Text]  

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