Department of Dermatology, University of Cincinnati College of Medicine, 231 Albert Sabin Way, Cincinnati, OH 45267-0592, USA.
FASEB J. 2010 Oct;24(10):3850-60. doi: 10.1096/fj.10-158485. Epub 2010 Jun 2.
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.
黑素皮质素 1 受体基因是人类肤色的主要决定因素，也是一个黑色素瘤易感性基因，因为其与红发强烈相关的变体增加了黑色素瘤的风险。为了实验测试黑素皮质素 1 受体基因型与黑色素瘤易感性之间的关联，我们比较了天然表达不同黑素皮质素 1 受体变体的原代人黑素细胞培养物对 α-黑素皮质素和紫外线辐射的反应。我们发现，2 种红发变体的表达消除了对 α-黑素皮质素及其光保护作用的反应，证据是受体缺乏功能性偶联，并且分别没有减少紫外线辐射诱导的过氧化氢生成或增强 DNA 光产物的修复。这些变体对受体功能具有不同的杂合效应。微阵列数据证实了对具有功能性和非功能性受体的黑素细胞对 α-黑素皮质素和紫外线辐射的反应差异，并鉴定了由 α-黑素皮质素调节的 DNA 修复和抗氧化基因。我们的研究结果强调了黑素皮质素 1 受体基因型控制人类黑素细胞基因组稳定性和紫外线辐射致突变作用的分子机制。
