Lack of p53-mediated G1 arrest in response to an environmental carcinogen.
The environmental carcinogen, 5-methylchrysene, is a component of cigarette smoke. Its reactive metabolite, anti-5-methylchrysene-1, 2-dihydrodiol-3,4-epoxide (5-MeCDE) mainly reacts with the N(2)-position of guanine residues in the DNA molecule. In this study, we demonstrate that the tumor suppressor protein p53 is stabilized in response to DNA damage by 5-MeCDE but fails to induce the cells' protective mechanism of G1 arrest in the human breast carcinoma cell line, MCF-7. In contrast, actinomycin D treatment of these cells did lead to G1 arrest. Western analyses revealed that, though both actinomycin D and 5-MeCDE treatment stabilized p53, only trace levels of p21(waf1/cip1) were seen in the latter case. This lack of p21(waf1/cip1) expression in 5-MeCDE-treated cells is attributed to a stealth characteristic of this environmental carcinogen that allows it to damage DNA and still escape the p53-mediated cellular defense mechanism of G1 arrest.
Khan
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Chemistry of Carcinogenesis Laboratory, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, Frederick, Md., USA. Khanq@ncifcrf.gov
Vousden
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Dipple
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D015153:Blotting, Western; D001943:Breast Neoplasms / Q000139:chemically induced* / Q000235:genetics / Q000378:metabolism*; D002273:Carcinogens / Q000009:adverse effects*; D002911:Chrysenes / Q000009:adverse effects*; D004249:DNA Damage; D004273:DNA, Neoplasm / Q000187:drug effects; D005434:Flow Cytometry; D016193:G1 Phase / Q000187:drug effects*; D006801:Humans; D012907:Smoking / Q000009:adverse effects; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
D002273:Carcinogens; D002911:Chrysenes; D004273:DNA, Neoplasm; D016159:Tumor Suppressor Protein p53; C037783:1,2-dihydroxy-epoxy-1,2,3,4-tetrahydro-5-methylchrysene; C008422:5-methylchrysene