Specific ablation of the apoptotic functions of cytochrome …

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.

MeSH Terms

Animals Apoptosis/physiology,radiation effects Apoptotic Protease-Activating Factor 1 Caspase 1 Caspases/metabolism,radiation effects Cytochromes c/genetics Electron Transport/physiology,radiation effects Enzyme Activation/physiology,radiation effects Enzyme Precursors/metabolism,radiation effects Gamma Rays Lymphocyte Activation/genetics Mice Mice, Knockout Mice, Mutant Strains Mice, Transgenic Nervous System Malformations/genetics,metabolism Proteins/metabolism T-Lymphocytes/metabolism

Chemicals

Apaf1 protein, mouse Apoptotic Protease-Activating Factor 1 Enzyme Precursors Proteins Cytochromes c Caspases Caspase 1

Authors & Affiliations

14 authors, click to expand affiliations / ORCID

Hao Zhenyue

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: [email protected].

Duncan Gordon S

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.

Chang Chia-Che

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.

Elia Andrew

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.

Fang Min

Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.

Wakeham Andrew

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.

Okada Hitoshi

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.

Calzascia Thomas

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.

Jang YingJu

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.

You-Ten Annick

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.

Yeh Wen-Chen

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.

Ohashi Pamela

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.

Wang Xiaodong

Howard Hughes Medical Institute and Department of Biochemistry, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 75390.

Mak Tak W

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: [email protected].

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

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