Carcinogenesis, Vol 18, 2313-2318, Copyright © 1997 by Oxford University Press
QA Khan, KH Vousden and A Dipple
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.
ARTICLES
Cellular response to DNA damage from a potent carcinogen involves stabilization of p53 without induction of p21(waf1/cip1)
Chemistry of Carcinogenesis, ABL-Basic Research Program, NCI-Frederick Cancer Research and Development Center, MD 21702, USA.
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