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Cell. 2005 May 20;121(4):579-591. doi: 10.1016/j.cell.2005.03.016.

Specific ablation of the apoptotic functions of cytochrome C reveals a differential requirement for cytochrome C and Apaf-1 in apoptosis.

Author information

1
The Campbell Family Institute for Breast Cancer Research, University Health Network, University of Toronto, Toronto, Ontario M5G 2C1, Canada; Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario M5G 2C1, Canada; Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada. Electronic address: zyhao@uhnres.utoronto.ca.
2
The Campbell Family Institute for Breast Cancer Research, University Health Network, University of Toronto, Toronto, Ontario M5G 2C1, Canada; Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario M5G 2C1, Canada; Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada.
3
Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.
4
The Campbell Family Institute for Breast Cancer Research, University Health Network, University of Toronto, Toronto, Ontario M5G 2C1, Canada; Ontario Cancer Institute, University Health Network, University of Toronto, Toronto, Ontario M5G 2C1, Canada; Departments of Immunology and Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada. Electronic address: tmak@uhnres.utoronto.ca.

Abstract

As components of the apoptosome, a caspase-activating complex, cytochrome c (Cyt c) and Apaf-1 are thought to play critical roles during apoptosis. Due to the obligate function of Cyt c in electron transport, its requirement for apoptosis in animals has been difficult to establish. We generated "knockin" mice expressing a mutant Cyt c (KA allele), which retains normal electron transfer function but fails to activate Apaf-1. Most KA/KA mice displayed embryonic or perinatal lethality caused by defects in the central nervous system, and surviving mice exhibited impaired lymphocyte homeostasis. Although fibroblasts from the KA/KA mice were resistant to apoptosis, their thymocytes were markedly more sensitive to death stimuli than Apaf-1(-/-) thymocytes. Upon treatment with gamma irradiation, procaspases were efficiently activated in apoptotic KA/KA thymocytes, but Apaf-1 oligomerization was not observed. These studies indicate the existence of a Cyt c- and apoptosome-independent but Apaf-1-dependent mechanism(s) for caspase activation.

PMID:
15907471
DOI:
10.1016/j.cell.2005.03.016
[Indexed for MEDLINE]
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