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

Zhenyue Hao, Gordon S. Duncan, Chia Che Chang, Andrew Elia, Min Fang, Andrew Wakeham, Hitoshi Okada, Thomas Calzascia, Yingju Jang, Annick You-Ten, Wen Chen Yeh, Pamela Ohashi, Xiaodong Wang, Tak W. Mak

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209 Scopus citations

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 γ 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.

Original languageEnglish (US)
Pages (from-to)579-591
Number of pages13
JournalCell
Volume121
Issue number4
DOIs
StatePublished - May 20 2005

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    Hao, Z., Duncan, G. S., Chang, C. C., Elia, A., Fang, M., Wakeham, A., Okada, H., Calzascia, T., Jang, Y., You-Ten, A., Yeh, W. C., Ohashi, P., Wang, X., & Mak, T. W. (2005). Specific ablation of the apoptotic functions of cytochrome c reveals a differential requirement for cytochrome c and Apaf-1 in apoptosis. Cell, 121(4), 579-591. https://doi.org/10.1016/j.cell.2005.03.016