丧失人类肾上腺受体基因的变异在黑色素瘤细胞受体功能的定义结构的决定因素。
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桑切斯Mas J,集中政策桑切斯C,加尼姆克,干草堆J, Lozano前线是的,Garcia-Borron JC, Jimenez-Cervantes C
丧失人类肾上腺受体基因的变异在黑色素瘤细胞受体功能的定义结构的决定因素。
12月。2002欧元;269 (24):6133 - 41。
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12473109 (在PubMed]
- 文摘
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alpha-melanocyte-stimulating激素(alphaMSH)受体(受体)是哺乳动物的皮肤和头发色素的主要决定因素。绑定alphaMSH受体在人黑色素细胞刺激的光保护真黑素细胞增殖和合成色素。某些受体等位基因与黑素瘤的风险增加相关。这可以从理论上考虑两个理由。首先,功能突变可能刺激细胞增殖,促进发育异常的病变。其次,相反,丧失突变可能真黑素含量降低,并损害预防紫外线的致癌效应,从而诱发皮肤癌。为了测试这些可能性,我们从七个人类黑色素瘤细胞黑素皮质素受体基因测序(HMC)线和三巨头先天性痣细胞(GCNC)文化。四个HMC线和两个GCNC文化包含MC1R等位变异。这些都是已知的功能丧失Arg142His Arg151Cys等位基因和一个新的变种,Leu93Arg。此外,不良反应superpotent alphaMSH模拟演示了细胞系携带Leu93Arg等位基因和野生型受体的HMC线纯合子。 Functional analysis in heterologous cells stably or transiently expressing this variant demonstrated that Leu93Arg is a loss-of-function mutation abolishing agonist binding. These results, together with site-directed mutagenesis of the vicinal Glu94, demonstrate that the MC1R second transmembrane fragment is critical for agonist binding and maintenance of a resting conformation, whereas the second intracellular loop is essential for coupling to the cAMP system. Therefore, loss-of-function, but not activating MC1R mutations are common in HMC. Their study provides important clues to understand MC1R structure-function relationships.