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Inactivation of the Retinoblastoma Tumor Suppressor Induces Apoptosis Protease-activating Factor-1 Dependent and Independent Apoptotic Pathways during Embryogenesis¹

Division of Cell and Molecular Biology, Toronto General Research Institute-University Health Network, Departments of Medicine, Laboratory Medicine, and Pathobiology and Medical Biophysics, University of Toronto, Toronto, Ontario, M5G 2M1 [Z. G., S. Y., E. Z.], and The Amgen Institute, Ontario Cancer Institute, and the Department of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, M5G 2C1 [H. Y., T. W. M.] Canada

Inactivation of the retinoblastoma (Rb) tumor suppressor in the mouse induces mid-gestational death accompanied by massive apoptosis in certain tissues. Herein, we analyzed the role of the apoptosis protease-activating factor Apaf-1, an essential component of the apoptosome, in mediating apoptosis in Rb-deficient mice. Analysis of compound mutant embryos lacking Rb and Apaf-1 revealed that Apaf-1 was absolutely required for apoptosis in the central nervous system and lens. In contrast, apoptosis in the peripheral nervous system and skeletal muscles only partly depended on Apaf-1 function. The dependency on Apaf-1 coincided with the requirement documented previously for E2F1 and p53 in the respective tissues. Loss of Apaf-1 specifically suppressed apoptosis but not the proliferation and differentiation defects in Rb-mutant embryos. We also show that the Apaf1+ but not the Rb+ allele is retained in pituitary tumors arising in Rb+/-:Apaf1+/- double heterozygous mice. Our results indicate that Apaf-1 plays a critical role in apoptosis in a subset of tissues and that both E2F1:p53:Apaf-1-dependent and -independent apoptotic pathways operate downstream of Rb.

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