Analysis of the mechanism of ultraviolet irradiation-mediated induction skin malignant melanoma

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We previously established three lines of RET oncogene-transgenic mice. In all of these three lines of transgenic mice skin melanosis developed soon after birth. Melanocytic tumors developed in lines 304 and 192 but not in line 242 during ageing. Malignant skin melanoma also developed in line 304 which had been crossed repeatedly with C57BL (line 304/B6), but not in line 192. Using these transgenic mouse lines, we analyzed the mechanism of ultraviolet irradiation-mediated induction of skin malignant melanoma. When line 192 of transgenic mice were irradiated repeatedly with ultraviolet light for 7 months skin, malignant melanoma developed. Ultraviolet irradiation of line 242 of transgenic mice, however, did not induce the development of melanocytic tumors. These results suggested that ultraviolet irradiation affects the step of tumor promotion from benign to malignant but not the step of the initial development of tumor. We then showed that ultraviolet irradiation of either RET-transgenic mice or NIH3T3 cells that carried RET oncogene induced activation of RET kinase. The mechanism of activation of RET kinase by ultraviolet irradiation was then examined. Mutant RETs in which each of the conserved cysteine residues in the kinase domain was replaced with alanine were prepared, and the levels of catalytic activity and reactivity to ultraviolet irradiation required for augmention of the activity of these mutant RETs were measured. We found in this study that structural modification through oxidation of a conserved cysteine residue (Cys-987 of c-RET) causes dimerization or polymerization of RET antigens, which accompanies an increase in catalytic activity of RET. It was speculated from these results that ultraviolet irradiation, which is long known to injure DNA and membrane lipid, also affects proteins for modification of structure and function and this mechanism plays a role in the promotion of benign melanocytictumors to malignant melanoma.