Significance of the Melanocortin 1 and Endothelin B Receptors in Melanocyte Homeostasis and Prevention of Sun-Induced Genotoxicity.
Significance of the Melanocortin 1 and Endothelin B Receptors in Melanocyte Homeostasis and Prevention of Sun-Induced Genotoxicity.
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DOI：
10.3389/fgene.2016.00146
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发表时间：
2016
影响因子：
3.7
通讯作者：
Abdel-Malek ZA
中科院分区：
文献类型：
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作者：
Swope VB;Abdel-Malek ZA
膜结合黑色素皮质素1受体（MC1R）和内皮素B受体（ENDBR）是两个g蛋白偶联受体，在黑色素细胞的组成调节及其对紫外线辐射（UVR）的反应中起重要作用，紫外线辐射是黑色素瘤的主要病因。人MC1R是一种Gs蛋白偶联受体，可被其激动剂α-促黑素细胞激素（α-melanocortin, α-MSH）和促肾上腺皮质激素（ACTH）激活。ENDBR是一种Gq偶联受体，在胚胎发育期间被内皮素(ET)-3激活，出生后被ET-1激活。色素沉着和DNA修复能力是决定患黑色素瘤风险的两个主要因素。MC1R的激动剂激活会刺激真黑素的合成，这是一种深棕色的光防护色素。体外研究表明，α-MSH和ET-1在碱性成纤维细胞生长因子存在下协同作用，促进人黑素细胞增殖和黑色素形成，抑制uvr诱导的细胞凋亡。MC1R的一个重要功能是减少氧化应激和激活DNA修复途径。人类MC1R是高度多态性的，MC1R变异，特别是那些导致表达受体功能丧失的MC1R变异，与黑色素瘤风险增加相关，与色素沉着无关。这些变异损害了人类黑素细胞的DNA修复和抗氧化能力。最近，ET-1激活ENDBR可以减少uvr诱导的DNA光产物的诱导并增强其修复。我们得出结论，α-MSH和ET-1及其同源受体MC1R和ENDBR通过调节太阳紫外线对DNA损伤的反应，维持黑色素细胞的基因组稳定性，从而降低黑色素瘤的风险。阐明黑素细胞对紫外线辐射的反应有助于提高我们对黑色素瘤形成过程的理解，并有助于有效的黑色素瘤化学预防和治疗策略。
The membrane bound melanocortin 1 receptor (MC1R), and the endothelin B receptor (ENDBR) are two G-protein coupled receptors that play important roles in constitutive regulation of melanocytes and their response to ultraviolet radiation (UVR), the main etiological factor for melanoma. The human MC1R is a Gs protein-coupled receptor, which is activated by its agonists α-melanocyte stimulating hormone (α-melanocortin; α-MSH) and adrenocorticotropic hormone (ACTH). The ENDBR is a Gq coupled-receptor, which is activated by Endothelin (ET)-3 during embryonic development, and ET-1 postnatally. Pigmentation and the DNA repair capacity are two major factors that determine the risk for melanoma. Activation of the MC1R by its agonists stimulates the synthesis of eumelanin, the dark brown photoprotective pigment. In vitro studies showed that α-MSH and ET-1 interact synergistically in the presence of basic fibroblast growth factor to stimulate human melanocyte proliferation and melanogenesis, and to inhibit UVR-induced apoptosis. An important function of the MC1R is reduction of oxidative stress and activation of DNA repair pathways. The human MC1R is highly polymorphic, and MC1R variants, particularly those that cause loss of function of the expressed receptor, are associated with increased melanoma risk independently of pigmentation. These variants compromise the DNA repair and antioxidant capacities of human melanocytes. Recently, activation of ENDBR by ET-1 was reported to reduce the induction and enhance the repair of UVR-induced DNA photoproducts. We conclude that α-MSH and ET-1 and their cognate receptors MC1R and ENDBR reduce the risk for melanoma by maintaining genomic stability of melanocytes via modulating the DNA damage response to solar UVR. Elucidating the response of melanocytes to UVR should improve our understanding of the process of melanomagenesis, and lead to effective melanoma chemoprevention, as well as therapeutic strategies.