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Science 21 February 1997:
Vol. 275. no. 5303, pp. 1132 - 1136
DOI: 10.1126/science.275.5303.1132
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Reports

The Release of Cytochrome c from Mitochondria: A Primary Site for Bcl-2 Regulation of Apoptosis

Ruth M. Kluck, Ella Bossy-Wetzel, Douglas R. Green, * Donald D. Newmeyer *dagger

In a cell-free apoptosis system, mitochondria spontaneously released cytochrome c, which activated DEVD-specific caspases, leading to fodrin cleavage and apoptotic nuclear morphology. Bcl-2 acted in situ on mitochondria to prevent the release of cytochrome c and thus caspase activation. During apoptosis in intact cells, cytochrome c translocation was similarly blocked by Bcl-2 but not by a caspase inhibitor, zVAD-fmk. In vitro, exogenous cytochrome c bypassed the inhibitory effect of Bcl-2. Cytochrome c release was unaccompanied by changes in mitochondrial membrane potential. Thus, Bcl-2 acts to inhibit cytochrome c translocation, thereby blocking caspase activation and the apoptotic process.

Division of Cellular Immunology, La Jolla Institute for Allergy and Immunology, 10355 Science Park Drive, San Diego, CA 92121, USA.
*   These authors contributed equally to this work.

dagger    To whom correspondence should be addressed.

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Activation of Bak and Bax through c-Abl-Protein Kinase C{delta}-p38 MAPK Signaling in Response to Ionizing Radiation in Human Non-small Cell Lung Cancer Cells.
S.-Y. Choi, M.-J. Kim, C.-M. Kang, S. Bae, C.-K. Cho, J.-W. Soh, J.-H. Kim, S. Kang, H. Y. Chung, Y.-S. Lee, et al. (2006)
J. Biol. Chem. 281, 7049-7059
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Age-dependent susceptibility of the retinal ganglion cell layer to cell death..
D. P. McKernan, C. Caplis, M. Donovan, C. J. O'Brien, and T. G. Cotter (2006)
Invest. Ophthalmol. Vis. Sci. 47, 807-814
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Resistance of Cancers to Immunologic Cytotoxicity and Adoptive Immunotherapy via X-Linked Inhibitor of Apoptosis Protein Expression and Coexisting Defects in Mitochondrial Death Signaling.
R. Ravi, E. J. Fuchs, A. Jain, V. Pham, K. Yoshimura, T. Prouser, S. Jalla, X. Zhou, E. Garrett-Mayer, S. H. Kaufmann, et al. (2006)
Cancer Res. 66, 1730-1739
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Berberine, a natural product, induces G1-phase cell cycle arrest and caspase-3-dependent apoptosis in human prostate carcinoma cells..
S. K. Mantena, S. D. Sharma, and S. K. Katiyar (2006)
Mol. Cancer Ther. 5, 296-308
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Changes in intracellular electrolyte concentrations during apoptosis induced by UV irradiation of human myeloblastic cells.
F. Arrebola, E. Fernandez-Segura, A. Campos, P. V. Crespo, J. N. Skepper, and A. Warley (2006)
Am J Physiol Cell Physiol 290, C638-C649
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The expression of 70 apoptosis genes in relation to lineage, genetic subtype, cellular drug resistance, and outcome in childhood acute lymphoblastic leukemia.
A. Holleman, M. L. den Boer, R. X. de Menezes, M. H. Cheok, C. Cheng, K. M. Kazemier, G. E. Janka-Schaub, U. Gobel, U. B. Graubner, W. E. Evans, et al. (2006)
Blood 107, 769-776
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Restoration of p53 function for selective Fas-mediated apoptosis in human and rat glioma cells in vitro and in vivo by a p53 COOH-terminal peptide.
P. B. Senatus, Y. Li, C. Mandigo, G. Nichols, G. Moise, Y. Mao, M. D. Brown, R. C. Anderson, A. T. Parsa, P. W. Brandt-Rauf, et al. (2006)
Mol. Cancer Ther. 5, 20-28
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Prognostic and Predictive Effects of Immunohistochemical Factors in High-Risk Primary Breast Cancer Patients.
N. Kroger, K. Milde-Langosch, S. Riethdorf, C. Schmoor, M. Schumacher, A. R. Zander, and T. Loning (2006)
Clin. Cancer Res. 12, 159-168
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Reduced Apaf-1 levels in cardiomyocytes engage strict regulation of apoptosis by endogenous XIAP.
M. B. Potts, A. E. Vaughn, H. McDonough, C. Patterson, and M. Deshmukh (2005)
J. Cell Biol. 171, 925-930
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Hydrogen Peroxide Induces Apoptotic-Like Cell Death in Coelomocytes of Themiste petricola (Sipuncula).
G. A. Blanco, J. Bustamante, M. Garcia, and S. E. Hajos (2005)
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