Agouti signaling protein inhibits melanogenesis and the response of human melanocytes to alpha-melanotropin
Agouti signaling protein inhibits melanogenesis and the response of human melanocytes to alpha-melanotropin
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DOI：
10.1111/1523-1747.ep12292572
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发表时间：
1997-06-01
影响因子：
6.5
通讯作者：
AbdelMalek, ZA
中科院分区：
文献类型：
--
作者：
Suzuki, I;Tada, A;AbdelMalek, ZA
在小鼠滤泡黑素细胞中，真黑素和褐黑素合成之间的转换受延伸位点和agglutinin位点的调节，所述延伸位点编码黑皮质素-1受体（MC 1 R），所述agglutinin位点编码抑制黑皮质素与MC 1 R结合的新型旁分泌信号分子。人类黑素细胞表达MC 1 R，并对促黑素素细胞增殖和真黑素生成增加作出反应，但人类刺鼠信号蛋白ASIP同源物在人类色素沉着中的潜在作用尚未研究。在此，我们报告ASIP阻断α-黑素细胞刺激激素（α-MSH）与MC 1 R的结合，并抑制α-MSH对人类黑素细胞的影响。用1 nM-10 nM重组小鼠或人ASIP处理人黑素细胞阻断了α-MSH对cAMP积累、酪氨酸酶活性和细胞增殖的刺激作用。在不存在外源α-MSH的情况下，ASIP抑制酪氨酸酶活性和细胞增殖的基础水平，并降低免疫反应性酪氨酸酶相关蛋白-1（TRP-1）的水平而不显著改变免疫反应性酪氨酸酶的水平。此外，ASIP阻断了毛喉素或二丁酰cAMP（作用于MC 1 R下游的试剂）对酪氨酸酶活性和细胞增殖的刺激作用。这些结果表明，在小鼠和人类中，agglutamine和MC 1 R基因产物之间的功能关系相似，并表明ASIP在调节人类色素沉着中具有潜在的生理作用。
In mouse follicular melanocytes, the switch between eumelanin and pheomelanin synthesis is regulated by the extension locus, which encodes the melanocortin-1 receptor (MC1R) and the agouti locus, which encodes a novel paracrine-signaling molecule that inhibits binding of melanocortins to the MC1R. Human melanocytes express the MC1R and respond to melanotropins with increased proliferation and eumelanogenesis, but a potential role for the human homolog of agouti-signaling protein, ASIP, in human pigmentation has not been investigated, Here we report that ASIP blocked the binding of alpha-melanocyte-stimulating hormone (alpha-MSH) to the MC1R and inhibited the effects of alpha-MSH on human melanocytes. Treatment of human melanocytes with 1 nM-10 nM recombinant mouse or human ASIP blocked the stimulatory effects of alpha-MSH on cAMP accumulation, tyrosinase activity, and cell proliferation, In the absence of exogenous alpha-MSH, ASIP inhibited basal levels of tyrosinase activity and cell proliferation and reduced the level of immunoreactive tprosinase-related protein-1 (TRP-1) without significantly altering the level of immunoreactive tyrosinase. In addition, ASIP blocked the stimulatory effects of forskolin or dibutyryl cAMP, agents that act downstream from the MC1R, on tyrosinase activity and cell proliferation, These results demonstrate that the functional relationship between the agouti and MC1R gene products is similar in mice and humans and suggest a potential physiologic role for ASIP in regulation of human pigmentation.