Melanocortin 1 receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation.
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. nonfunctional 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
Ana Luisa
AL
Department of Dermatology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0592, USA.
Leachman
Sancy
S
Kavanagh
Renny J
RJ
Swope
Viki
V
Cassidy
Pamela
P
Supp
Dorothy
D
Sartor
Maureen
M
Schwemberger
Sandy
S
Babcock
George
G
Wakamatsu
Kazumasa
K
Ito
Shosuke
S
Koshoffer
Amy
A
Boissy
Raymond E
RE
Manga
Prashiela
P
Sturm
Richard A
RA
Abdel-Malek
Zalfa A
ZA
D002478:Cells, Cultured; D005838:Genotype; D006801:Humans; D008544:Melanocytes / Q000528:radiation effects*; D044102:Receptor, Melanocortin, Type 1 / Q000235:genetics*; D014466:Ultraviolet Rays
D044102:Receptor, Melanocortin, Type 1