Dose-dependent effects of DNA-damaging agents on p53-mediated cell cycle arrest.
We examined the dose-dependent effects of DNA-damaging agents on G1 arrest in isogenic human cell lines differing in their p53 status. As expected, 5 or 20 Gy of ionizing radiation induced a p53-dependent G1 arrest. In contrast, UV light or actinomycin D induced a modest G1 arrest that was p53-dependent only at lower doses. At higher doses, cells were arrested in G1 in a p53-independent manner coinciding with inhibition of RNA synthesis and abolished cyclin E expression. Interestingly, expression of cyclin E was enhanced after exposure to moderate doses of UV light and actinomycin D, and this enhancement was suppressed by wild-type p53. We propose that agents inducing transcription-blocking DNA lesions will at higher doses inhibit the progression of cells into S phase by a p53-independent mechanism involving the attenuation of E2F-mediated transcription of genes, such as cyclin E.
Chang
D
D
Department of Radiation Oncology, University of Michigan Comprehensive Cancer Center, Ann Arbor 48109-0582, USA.
Chen
F
F
Zhang
F
F
McKay
B C
BC
Ljungman
M
M
D015153:Blotting, Western; D001973:Bromodeoxyuridine / Q000378:metabolism; D002453:Cell Cycle / Q000502:physiology*; D003110:Colonic Neoplasms / Q000378:metabolism; D019927:Cyclin E / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology*; D003609:Dactinomycin / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D005434:Flow Cytometry; D016193:G1 Phase / Q000502:physiology; D006801:Humans; D007259:Infrared Rays; D008954:Models, Biological; D009856:Oncogene Proteins, Viral / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins; D013997:Time Factors; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D014466:Ultraviolet Rays
D019927:Cyclin E; C068651:E6 protein, Human papillomavirus type 16; D009856:Oncogene Proteins, Viral; D012333:RNA, Messenger; D012097:Repressor Proteins; D016159:Tumor Suppressor Protein p53; D003609:Dactinomycin; D001973:Bromodeoxyuridine