Suzuki I, Tada A, Ollmann M M, Barsh G S, Im S, Lamoreux M L, Hearing V J, Nordlund J J, Abdel-Malek Z A
POLA Laboratories, Yokohama, Japan.
J Invest Dermatol. 1997 Jun;108(6):838-42. doi: 10.1111/1523-1747.ep12292572.
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 tyrosinase-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.
在小鼠毛囊黑素细胞中，真黑素与褐黑素合成之间的转换受延伸基因座调控，该基因座编码黑素皮质素-1受体（MC1R）；以及刺鼠基因座调控，该基因座编码一种新型旁分泌信号分子，可抑制黑素皮质素与MC1R的结合。人类黑素细胞表达MC1R，并对促黑素产生反应，表现为增殖增加和真黑素生成，但刺鼠信号蛋白（ASIP）的人类同源物在人类色素沉着中的潜在作用尚未得到研究。在此我们报告，ASIP可阻断α-黑素细胞刺激素（α-MSH）与MC1R的结合，并抑制α-MSH对人类黑素细胞的作用。用1 nM - 10 nM重组小鼠或人类ASIP处理人类黑素细胞，可阻断α-MSH对环磷酸腺苷（cAMP）积累、酪氨酸酶活性和细胞增殖的刺激作用。在没有外源性α-MSH的情况下，ASIP可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，而不会显著改变免疫反应性酪氨酸酶的水平。此外，ASIP可阻断毛喉素或二丁酰环磷腺苷（它们作用于MC1R的下游）对酪氨酸酶活性和细胞增殖的刺激作用。这些结果表明，刺鼠基因和MC1R基因产物之间的功能关系在小鼠和人类中相似，并提示ASIP在调节人类色素沉着中具有潜在的生理作用。
