Rouzaud Francois, Kadekaro Ana Luisa, Abdel-Malek Zalfa A, Hearing Vincent J
Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Building 37, Room 2132, Bethesda, MD 20892, USA.
Mutat Res. 2005 Apr 1;571(1-2):133-52. doi: 10.1016/j.mrfmmm.2004.09.014. Epub 2005 Jan 26.
The constitutive color of our skin plays a dramatic role in our photoprotection from solar ultraviolet radiation (UVR) that reaches the Earth and in minimizing DNA damage that gives rise to skin cancer. More than 120 genes have been identified and shown to regulate pigmentation, one of the key genes being melanocortin 1 receptor (MC1R) that encodes the melanocortin 1 receptor (MC1R), a seven-transmembrane G protein-coupled receptor expressed on the surface of melanocytes. Modulation of MC1R function regulates melanin synthesis by melanocytes qualitatively and quantitatively. The MC1R is regulated by the physiological agonists alpha-melanocyte-stimulating hormone (alphaMSH) and adrenocorticotropic hormone (ACTH), and antagonist agouti signaling protein (ASP). Activation of the MC1R by binding of an agonist stimulates the synthesis of eumelanin primarily via activation of adenylate cyclase. The significance of cutaneous pigmentation lies in the photoprotective effect of melanin, particularly eumelanin, against sun-induced carcinogenesis. Epidermal melanocytes and keratinocytes respond to UVR by increasing their expression of alphaMSH and ACTH, which up-regulate the expression of MC1R, and consequently enhance the response of melanocytes to melanocortins. Constitutive skin pigmentation dramatically affects the incidence of skin cancer. The pigmentary phenotype characterized by red hair, fair complexion, inability to tan and tendency to freckle is an independent risk factor for all skin cancers, including melanoma. The MC1R gene is highly polymorphic in human populations, and allelic variation at this locus accounts, to a large extent, for the variation in pigmentary phenotypes and skin phototypes (SPT) in humans. Several allelic variants of the MC1R gene are associated with the red hair and fair skin (RHC) phenotype, and carrying one of these variants is thought to diminish the ability of the epidermis to respond to DNA damage elicited by UVR. The MC1R gene is considered a melanoma susceptibility gene, and its significance in determining the risk for skin cancer is of tremendous interest.
我们皮肤的固有颜色在抵御到达地球的太阳紫外线辐射（UVR）的光保护作用以及将引发皮肤癌的DNA损伤降至最低方面起着重要作用。已鉴定出120多个基因并证明它们可调节色素沉着，其中一个关键基因是黑皮质素1受体（MC1R），它编码黑皮质素1受体（MC1R），这是一种在黑素细胞表面表达的七跨膜G蛋白偶联受体。MC1R功能的调节在定性和定量上调节黑素细胞的黑色素合成。MC1R受生理激动剂α-黑素细胞刺激素（αMSH）和促肾上腺皮质激素（ACTH）以及拮抗剂刺鼠信号蛋白（ASP）的调节。激动剂结合激活MC1R主要通过激活腺苷酸环化酶刺激真黑素的合成。皮肤色素沉着的意义在于黑色素，特别是真黑素对阳光诱导的致癌作用的光保护作用。表皮黑素细胞和角质形成细胞通过增加它们的αMSH和ACTH表达来响应UVR，这上调了MC1R的表达，从而增强了黑素细胞对黑皮质素的反应。固有皮肤色素沉着显著影响皮肤癌的发病率。以红头发、白皙肤色、不能晒黑和容易出现雀斑为特征的色素沉着表型是包括黑色素瘤在内的所有皮肤癌的独立危险因素。MC1R基因在人类群体中高度多态，该位点的等位基因变异在很大程度上解释了人类色素沉着表型和皮肤光型（SPT）的变异。MC1R基因的几个等位基因变体与红头发和白皙皮肤（RHC）表型相关，携带这些变体之一被认为会降低表皮对UVR引起的DNA损伤的反应能力。MC1R基因被认为是一种黑色素瘤易感基因，其在确定皮肤癌风险方面的意义备受关注。
