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Melanocortin 1 receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation
Author(s) -
Kadekaro Ana Luisa,
Leachman Sancy,
Kavanagh Renny J.,
Swope Viki,
Cassidy Pamela,
Supp Dorothy,
Sartor Maureen,
Schwemberger Sandy,
Babcock George,
Wakamatsu Kazumasa,
Ito Shosuke,
Koshoffer Amy,
Boissy Raymond E.,
Manga Prashiela,
Sturm Richard A.,
AbdelMalek Zalfa A.
Publication year - 2010
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.10-158485
Subject(s) - melanocortin 1 receptor , melanocortin , genotype , ultraviolet radiation , chemistry , receptor , ultraviolet , ultraviolet b , biology , genetics , medicine , dermatology , physics , phenotype , gene , optoelectronics , radiochemistry
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 α‐melanocortin and ultraviolet radiation. We found that expression of 2 red hair variants abolished the response to α‐melanocortin and its photoprotective 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 . non‐functional receptor to α‐melanocortin and ultraviolet radiation, and identified DNA repair and antioxidant genes that are modulated by α‐melanocortin. Our findings highlight the molecular mechanisms by which the melanocortin 1 receptor genotype controls genomic stability of and the mutagenic effect of ultraviolet radiation on human melanocytes.—Kadekaro, A. L., Leachman, S., Kavanagh, R. J., Swope, V., Cassidy, P., Supp, D., Sartor, M., Schwemberger, S., Babcock, G., Wakamatsu, K., Ito, S., Koshoffer, A., Boissy, R. E., Manga, P., Sturm, R. A., Abdel‐Malek, Z. A. Melanocortin 1 receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation. FASEB J. 24, 3850–3860 (2010). www.fasebj.org