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Nature:美学者揭示诱导色素预防小鼠黑色素瘤

摘要 : 2017年9月6日,国际学术权威刊物自然出版集团《Nature》杂志在线发表了美国波士顿大学医学院崔儒涛研究组的一篇研究论文,研究显示对一种参与色素沉着过程的蛋白进行修饰,可预防小鼠黑色素瘤,该方法有潜力成为未来人类预防黑色素瘤的临床对策。

2017年9月6日,国际学术权威刊物自然出版集团《Nature》杂志在线发表了美国波士顿大学医学院崔儒涛研究组的一篇研究论文,研究显示对一种参与色素沉着过程的蛋白进行修饰,可预防小鼠黑色素瘤,该方法有潜力成为未来人类预防黑色素瘤的临床对策。

黑色素瘤起源于一种能产生色素的皮肤细胞——黑色素细胞。黑色素瘤是最常见的、最致命的皮肤癌,恶性程度最高,容易出现转移,占所有皮肤癌死亡病例的75%,因此,开发出能预防和早期诊疗的方法尤为重要。

目前科学家们已经知道,黑素皮质素受体1(MC1R)蛋白在人类和小鼠的皮肤色素沉着中扮演重要角色。但携带一种名为MC1R RHC变体的个体,也就是表现为红头发、浅肤色、晒黑能力弱的人,由于诱导色素沉着的能力下降,患上黑色素瘤的风险更高,也就是说,皮肤色素基因对人患有皮肤癌的影响非常大。

此次,崔儒涛及同事通过筛选多种小分子,发现棕榈酸可以调节MC1R RHC变体的活性。研究团队利用培养细胞进行一系列实验后发现,MC1R的棕榈酰化(增加棕榈酸)对于激活MC1R信号传导至关重要,而激活MC1R信号传导,最终会引起色素沉着的增加。这项研究还表明,激活棕榈酰化可以弥补MC1R RHC变体的缺陷,增加色素沉着,从而预防MC1R RHC变异小鼠产生黑色素瘤。

英国爱丁堡大学的研究人员认为该成果通过调节棕榈酰转移酶ZDHHC13或抑制去棕榈酰化,从而促进MC1R棕榈酰化,这或许就是未来预防人类黑色素瘤的潜在临床对策。

原文链接:

Palmitoylation-dependent activation of MC1R prevents melanomagenesis

原文摘要:

The melanocortin-1 receptor (MC1R), a G-protein-coupled receptor, has a crucial role in human and mouse pigmentation. Activation of MC1R in melanocytes by α-melanocyte-stimulating hormone (α-MSH)9 stimulates cAMP signalling and melanin production and enhances DNA repair after ultraviolet irradiation10, 11, 12, 13, 14, 15, 16. Individuals carrying MC1R variants, especially those associated with red hair colour, fair skin and poor tanning ability (denoted as RHC variants), are associated with higher risk of melanoma5, 17, 18, 19, 20. However, how MC1R activity is modulated by ultraviolet irradiation, why individuals with red hair are more prone to developing melanoma, and whether the activity of RHC variants might be restored for therapeutic benefit are unknown. Here we demonstrate a potential MC1R-targeted intervention strategy in mice to rescue loss-of-function MC1R in MC1R RHC variants for therapeutic benefit by activating MC1R protein palmitoylation. MC1R palmitoylation, primarily mediated by the protein-acyl transferase ZDHHC13, is essential for activating MC1R signalling, which triggers increased pigmentation, ultraviolet-B-induced G1-like cell cycle arrest and control of senescence and melanomagenesis in vitro and in vivo. Using C57BL/6J-Mc1re/eJ mice, in which endogenous MC1R is prematurely terminated, expressing Mc1r RHC variants, we show that pharmacological activation of palmitoylation rescues the defects of Mc1r RHC variants and prevents melanomagenesis. The results highlight a central role for MC1R palmitoylation in pigmentation and protection against melanoma.

来源: Nature 浏览次数:0

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