Cleavage of E2F-1-regulating proteins and activation of E2F-1 during CD95-induced death of thymocytes.
The CD95 death receptor activates caspases that cleave a variety of intracellular substrates, including cell cycle control proteins. However, the significance of this cleavage for the induction of apoptosis is unclear. In this study, CD95-induced cleavage of the G1/S checkpoint regulator proteins, retinoblastoma protein (pRb) and murine-double-minute-2 (mdm-2), was associated with an increased protein concentration of a key transcription factor, E2F-1, which is regulated by both of them. Furthermore, DNA-binding activity to E2F sites is increased. In thymocytes, CD95-induced apoptosis was associated with increased E2F-1 DNA-binding activity, while thymocytes that lacked E2F-1 were less susceptible to CD95-induced apoptosis. We conclude that the G1/S checkpoint is an important target of CD95 signalling. CD95-activated caspases cleave regulator proteins to increase E2F-1 activity, and inappropriate activation of E2F-1 is part of the mechanism of CD95-induced apoptosis.
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Section of Immunobiology, Yale University School of Medicine, New Haven, CT, USA.
Littlewood
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Crispe
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D000818:Animals; D017209:Apoptosis / Q000276:immunology; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002453:Cell Cycle / Q000276:immunology; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D051379:Mice; D008815:Mice, Inbred Strains; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051736:Proto-Oncogene Proteins c-mdm2; D016160:Retinoblastoma Protein / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D019014:fas Receptor / Q000276:immunology* / Q000378:metabolism
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016160:Retinoblastoma Protein; D014157:Transcription Factors; D019014:fas Receptor; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2