Carcinogenesis, Vol 19, 1117-1125, Copyright © 1998 by Oxford University Press
J Yang and P Duerksen-Hughes
The tumor suppressor gene p53 encodes a nuclear phosphoprotein which is
critical for cell cycle control and prevention of uncontrolled cell
proliferation that can lead to cancer. Previous studies have shown that
cells respond to DNA damage by increasing their levels of p53, which then
acts to prevent replication of damaged DNA. This study examined the effects
on p53 protein levels of several different categories of chemical
carcinogens. N-Methyl-N'-nitro-nitrosoguanidine and N-ethyl-N- nitrosourea,
two direct-acting genotoxic (DNA-reactive) carcinogens, caused p53
induction as early as 2 h following treatment, with peak increases within
4-12 h. Aflatoxin B1 and 2-acetylaminofluorene, indirect-acting genotoxic
carcinogens, caused a later induction of p53, with the peak increase
appearing between 16 and 24 h following treatment. These observations
demonstrate a correlation between p53 induction pattern and DNA damaging
mechanism of genotoxins. Phenol, diethylstilbestrol and ethylacrylate also
induced increases in cellular p53. The half-life of p53 protein was
increased in cells treated with genotoxic agents. On the other hand, the
epigenetic (non-DNA-reactive) carcinogens azathioprine and saccharin, as
well as two substances generally considered to be non-carcinogens,
dimethylsulfoxide and benzethonium chloride, had no effect on p53 protein
levels of treated cells. Measurement of the cytotoxic effects of each of
these chemicals led to the conclusion that p53 protein induction is not a
general, non- specific consequence of the cytotoxic effect of these
genotoxins. These results suggest that measurement of p53 protein induction
may be an effective tool to identify environmental genotoxins.
ARTICLES
A new approach to identifying genotoxic carcinogens: p53 induction as an indicator of genotoxic damage
Department of Biology, Georgia State University, Atlanta 30303, USA.
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