title: Small contribution of G1 checkpoint control manipulation to modulation of p53-mediated apoptosis.
abstract: Deregulation of the S-phase promoting E2F-1 transcription factor has been shown to cooperate with p53 to induce apoptosis. BaF3 cells undergo rapid, p53-dependent apoptosis when irradiated in the absence of IL-3. Rapid apoptosis induced by ionizing radiation (IR) coincides with attenuated p21(WAF1/Cip1) induction. Failure to adequately induce p21 could result in inappropriate release of E2F from Rb which may then cooperate with p53 to induce apoptosis in cells deprived of growth factor. We engineered BaF3 cells to express exogenous p21 and tested whether overexpressing p21 in cells irradiated in the absence of IL-3 protects from IR-induced apoptosis. Enforced p21 expression resulted in a consistent, but partial, protection of cells from undergoing IR-induced apoptosis. However, deregulating E2F activity through expression of HPV E7 failed to sensitize cells to IR-induced apoptosis in the presence of IL-3. Together, these data strongly suggest that the IL-3-responsive factors which modulate p53-mediated apoptosis in BaF3 cells are largely independent of G1 cell cycle checkpoint control mediated by p21.
authors.affiliation: Johns Hopkins Oncology Center, Baltimore, Maryland 21205, USA.
authors.forename: C E
authors.initials: CE
authors.lastname: Canman
authors.forename: M B
authors.initials: MB
authors.lastname: Kastan
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002352:Carrier Proteins; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000502:physiology; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; D016193:G1 Phase / Q000502:physiology*; D016158:Genes, p53; D007377:Interleukin-3 / Q000494:pharmacology; D051379:Mice; D056465:Retinoblastoma-Binding Protein 1; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D050680:Transcription Factor DP1; D014157:Transcription Factors / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000502:physiology*
chemical_list: C533431:Arid4a protein, mouse; D002352:Carrier Proteins; C493957:Cdkn1a protein, mouse; D018797:Cell Cycle Proteins; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D050687:E2F1 Transcription Factor; C493754:E2f1 protein, mouse; D007377:Interleukin-3; D056465:Retinoblastoma-Binding Protein 1; D050680:Transcription Factor DP1; D014157:Transcription Factors; D016159:Tumor Suppressor Protein p53