The p53 activation and apoptosis induced by DNA damage are reversibly inhibited by salicylate.
Treatment of mouse (12)1/CA cells with adriamycin or irradiation with U.V.C. induces p53-dependent transcription of a beta-galactosidase reporter and the endogenous p21/Waf1/Cip1 gene. Despite the induction of Waf1, the cells arrest only transiently in G1 or G2, then resume growth and eventually undergo apoptosis. In situ analysis of beta-galactosidase activity in U.V.C.-irradiated cells revealed a much higher level of p53-dependent transcription in cells undergoing apoptosis compared to transiently arrested cells. Incubation of the treated cells with salicylate, which inhibits the activation of protein kinases and transcription factors involved in stress responses, inhibits both p53-dependent transcription and apoptosis. The inhibition of transcription is due mainly to impairment of the ability of p53 to bind to DNA. The treated cells resume their p53-dependent programs whenever the salicylate is removed, even after as long as 60 h after the DNA has been damaged. Therefore, the p53-activating signals generated by adriamycin or U.V.C. are very long lived. The resumption of p53-dependent transcription is not accompanied by additional accumulation of the p53 protein, indicating that the activation of p53 is regulated by a separate pathway.
Chernov
M V
MV
Department of Molecular Biology, Research Institute, The Cleveland Clinic Foundation, Ohio 44195, USA.
Stark
G R
GR
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D004249:DNA Damage; D004317:Doxorubicin / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005347:Fibroblasts / Q000187:drug effects; D005786:Gene Expression Regulation; D016158:Genes, p53; D051379:Mice; D047428:Protein Kinase Inhibitors; D012459:Salicylates / Q000494:pharmacology*; D020156:Salicylic Acid; D013997:Time Factors; D014157:Transcription Factors / Q000037:antagonists & inhibitors; D014466:Ultraviolet Rays
C493957:Cdkn1a protein, mouse; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D047428:Protein Kinase Inhibitors; D012459:Salicylates; D014157:Transcription Factors; D004317:Doxorubicin; D020156:Salicylic Acid