Cellular response to DNA damage from a potent carcinogen involves stabilization of p53 without induction of p21(waf1/cip1).
The effect of a potent mammary carcinogen, anti benzo[g]chrysene 11,12-dihydrodiol 13,14-epoxide, on the progress of human mammary carcinoma MCF-7 cells through the cell cycle was investigated. While these cells, which express wild-type p53, were arrested in G1 after treatment with actinomycin D (a positive control), treatment with the mammary carcinogen did not cause G1 arrest but instead delayed the cells in the DNA synthesis phase. In concert with the absence of a G1 arrest, it was found that though both chemical treatments led to increased levels of p53, only the p53 induced by actinomycin D was transcriptionally active and increased the levels of the cyclin dependent kinase inhibitor, p21(waf1/cip1). Since treatment of the cells with the mammary carcinogen did not abrogate the G1 arrest induced by actinomycin D, the lack of p21(waf1/cip1) and of G1 arrest, resulting from treatment with the mammary carcinogen alone, was not due to some general inhibition of transcription or translation. An analogous difference between these two chemicals was demonstrated also in other human cell systems. The stealth-like property of the mammary carcinogen that allows it to damage DNA without turning on the cells' 'guardian of the genome' defense mechanism presumably increases the likelihood of malignant change because DNA replication continues on a damaged template. It is suggested that this stealth characteristic may be a major contributor to the high carcinogenic potency of this mammary carcinogen and possibly to that of other highly potent carcinogens.
Khan
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QA
Chemistry of Carcinogenesis, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, MD 21702, USA.
Vousden
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KH
Dipple
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A
D002273:Carcinogens / Q000494:pharmacology*; D002453:Cell Cycle / Q000187:drug effects*; D002911:Chrysenes / Q000494:pharmacology*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism*; D004249:DNA Damage; D003609:Dactinomycin / Q000494:pharmacology; D005260:Female; D006801:Humans; D014158:Transcription, Genetic / Q000187:drug effects; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
C493956:CDKN1A protein, human; D002273:Carcinogens; D002911:Chrysenes; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D016159:Tumor Suppressor Protein p53; C089231:benzo(g)chrysene-11,12-dihydrodiol-13,14-epoxide; D003609:Dactinomycin