Inactivation of the retinoblastoma tumor suppressor induces apoptosis protease-activating factor-1 dependent and independent apoptotic pathways during embryogenesis.
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.
Guo
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Z
Division of Cell and Molecular Biology, Toronto General Research Institute-University Health Network, Department of Medicine, University of Toronto, Toronto, Ontario, Canada.
Yikang
S
S
Yoshida
H
H
Mak
T W
TW
Zacksenhaus
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E
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology*; D053477:Apoptotic Protease-Activating Factor 1; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D005314:Embryonic and Fetal Development / Q000235:genetics*; D005260:Female; D018507:Gene Expression Regulation, Developmental; D020868:Gene Silencing; D016161:Genes, Retinoblastoma / Q000235:genetics / Q000502:physiology*; D007908:Lens, Crystalline / Q000196:embryology / Q000378:metabolism; D008297:Male; D051379:Mice; D018482:Muscle, Skeletal / Q000196:embryology / Q000378:metabolism; D010911:Pituitary Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D011506:Proteins / Q000235:genetics / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000502:physiology
C506593:Apaf1 protein, mouse; D053477:Apoptotic Protease-Activating Factor 1; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D011506:Proteins; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53