Melanocortin 1 receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation
2010
Abstract
The melanocortin 1 receptor gene is a main determinant of human pigmentation, and a melanoma susceptibility gene, because its variants that are strongly associated with red hair color increase melanoma risk. To test experimentally the association between melanocortin 1 receptor genotype and melanoma susceptibility, we compared the responses of primary human melanocyte cultures naturally expressing different melanocortin 1 receptor variants to ?-melanocortin and ultraviolet radiation. We found that expression of 2 red hair variants abolished the response to ?-melanocortin and its photo-protective effects, evidenced by lack of functional coupling of the receptor, and absence of reduction in ultraviolet radiation-induced hydrogen peroxide generation or enhancement of repair of DNA photoproducts, respectively. These variants had different heterozygous effects on receptor function. Microarray data confirmed the observed differences in responses of melanocytes with functional vs. nonfunctional receptor to ?-melanocortin and ultraviolet radiation, and identified DNA repair and antioxidant genes that are modulated by ?-melanocortin. Our findings highlight the molecular mechanisms by which the melanocortin-1 receptor genotype controls genomic stability of and the mutated effects of ultraviolet radiation with regard to specialized skin cells, melanocytes.
Alleles associated with red hair/fair skin phenotype underlined; mutations which alter melanocyte stimulating hormone ability to bind and/or activate adenylyl cyclase are bold & underlined. Variations of MC1R gene that have been assoc w/ increased melanoma risk shown in bold.
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