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Human melanocortin 1 receptor variants, receptor function and melanocyte response to UV radiation

¹ Department of Dermatology, University of Cincinnati College of Medicine, PO Box 670592, Cincinnati, Ohio 45267-0592, USA
² Fujita Health University School of Health Sciences, Toyoake, Aichi 470-1192, Japan
³ Department of Dermatology, Nara Medical University, Kashihara, Nara 634-8522, Japan
⁴ Department of Molecular Genetics, Biochemistry and Microbiology, University of Cincinnati College of Medicine, PO Box 670524, Cincinnati, Ohio 45267-0524, USA
⁵ POLA Laboratories, 560 Kashio-cho, Totsuka-ku, Yokohama 244-0812, Japan
⁶ Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA

^* Author for correspondence (e-mail: abdelmza{at}email.uc.edu )

Accepted 6 March 2002

Cutaneous pigmentation is determined by the amounts of eumelanin and pheomelanin synthesized by epidermal melanocytes and is known to protect against sun-induced DNA damage. The synthesis of eumelanin is stimulated by the binding of -melanotropin (-melanocyte-stimulating hormone) to the functional melanocortin 1 receptor (MC1R) expressed on melanocytes. The human MC1R gene is highly polymorphic and certain allelic variants of the gene are associated with red hair phenotype, melanoma and non-melanoma skin cancer. The importance of the MC1R gene in determining skin cancer risk led us to examine the impact of specific polymorphisms in this gene on the responses of human melanocytes to -melanotropin and UV radiation. We compared the ability of human melanocyte cultures, each derived from a single donor, to respond to -melanotropin with dose-dependent stimulation of cAMP formation, tyrosinase activity and proliferation. In each of those cultures the MC1R gene was sequenced, and the eumelanin and pheomelanin contents were determined. Human melanocytes homozygous for Arg160Trp, heterozygous for Arg160Trp and Asp294His, or for Arg151Cys and Asp294His substitutions, but not melanocytes homozygous for Val92Met substitution, in the MC1R demonstrated a significantly reduced response to -melanotropin. Additionally, melanocytes with a non-functional MC1R demonstrated a pronounced increase in their sensitivity to the cytotoxic effect of UV radiation compared with melanocytes expressing functional MC1R. We conclude that loss-of-function mutations in the MC1R gene sensitize human melanocytes to the DNA damaging effects of UV radiation, which may increase skin cancer risk.

Key words: Melanocortin 1 receptor, Human melanocytes, MC1R variants

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