6533b85dfe1ef96bd12bf0d3

RESEARCH PRODUCT

Molecular and Cellular Aspects of Chemical Carcinogenesis

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Different DNA-adducts produced by one given genotoxic agent can lead to different mutational preferences, as exemplified in this mini-review, by the cis-diamminedichloroplatinum(II)-induced d(GpG)-N7(1)-N7(2) adduct, giving rise predominantly to G→T transversions targeted to the 5′-modified G, the d(ApG)-N7(l)-N7(2) adduct to A→T transversions, while for the d(GpTpA)-N7(l)-N7(3) adduct no crosslink-specific mutations were observed. Expression of mutated Hras put under the control of cell-compartment specific promoters in different layers of the mouse skin showed that the consequent expression of the malignant phenotype depended on the degree of differentiation of the cell, progression to carcinomas occurring in the basal cells of the hair follicles, but not in the suprabasal layer of the epidermis. The novel Ca2+-independent protein kinase C η is expressed in differentiating and differentiated epithelial cells of the skin and was activated by cholesterol sulfate whereby tumor promotion was inhibited. Finally, the hypothesis was tested whether hypomethylation of DNA is a nongenotoxic mechanism underlying the aberrant expression of protooncogenes involved in carcinogenesis. The 5-methyleytosine content of the mouse liver tumorigenesis-relevant Hras and raf oncogenes was lower in the liver of the liver tumor-prone B6C3F1 and C3H/He mice than in the relatively resistant C57BL/6 mice, indicating that differences in DNA methylation, at least in part, account for the different susceptibilities to nongenotoxic liver carcinogens.