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Epidemiologic investigations demonstrated that arsenite exposure increases the risk of various human cancers, including skin, lung, bladder, and kidney cancers. However, oral administration of arsenite alone has failed to induce tumors in animal models, suggesting that arsenic may act to enhance mutagenicity induced by other carcinogens. Arsenite may function as a co-carcinogen, acting by inhibiting repair of carcinogen-induced DNA damage mediated by the p53 tumor suppressor protein and p21, a p53 target gene. To elucidate the interaction between arsenite and p53, we studied the effect of arsenite on ultraviolet B (UVB)-induced p53 phosphorylation, p53 DNA binding activity and p53-induced target gene transactivation in the mouse epidermal JB6 Cl41 skin cell model. Our results indicated that arsenite suppressed UVB-induced p53 phosphorylation and p53 DNA binding activity. Arsenite also inhibited casein kinase 2 (CK2) activity and decreased p53-regulated p21 protein expression. These data suggest that the direct inhibition of p53 functional activation is one of the mechanisms through which arsenite interferes with p53 function, and thus may be a significant mechanism for the co-carcinogenic effects of arsenite.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]