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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227 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
Externally publishedYes

Bibliographical note

Funding Information:
We thank M. Capecchi for the ACN cassette, S. Asa for advice on the endocrine-gland work, G. Oleg and K. Tatsuya for help with the O 2 consumption measurements, N.J. Chen for help with the graphics, A.F. Parlow for the GH and related antibodies, various Mak lab members for helpful discussions, and M. Saunders for scientific editing. This work was supported by the Terry Fox Cancer Foundation and National Cancer Institute of Canada (T.W.M.) and NIH grant GMRO1-57158 (M.F. and X.W.).

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