Ordering the Cytochrome c–initiated Caspase Cascade: Hierarchical Activation of Caspases-2, -3, -6, -7, -8, and -10 in a Caspase-9–dependent Manner
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- Elizabeth A. Slee
- *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
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- Mary T. Harte
- *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
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- Ruth M. Kluck
- *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
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- Beni B. Wolf
- *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
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- Carlos A. Casiano
- *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
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- Donald D. Newmeyer
- *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
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- Hong-Gang Wang
- *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
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- John C. Reed
- *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
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- Donald W. Nicholson
- *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
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- Emad S. Alnemri
- *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
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- Douglas R. Green
- *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
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- 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
抄録
<jats:p>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.</jats:p>
収録刊行物
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- The Journal of Cell Biology
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The Journal of Cell Biology 144 (2), 281-292, 1999-01-25
Rockefeller University Press
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詳細情報 詳細情報について
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- CRID
- 1364233269116969088
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- NII論文ID
- 80010918487
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- ISSN
- 15408140
- 00219525
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- データソース種別
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