Department of Biochemistry, Chung-Ang University College of Medicine, Seoul, Korea.
Exp Dermatol. 2011 Mar;20(3):237-41. doi: 10.1111/j.1600-0625.2010.01148.x. Epub 2010 Dec 17.
We previously reported that sphingosine-1-phosphate (S1P) decreases melanin synthesis via extracellular signal-regulated protein kinase (ERK) activation and microphthalmia-associated transcription factor (MITF) degradation. Although FTY720 is an S1P structural analogue, the effects of FTY720 on melanogenesis are not completely understood. Thus, we investigated the influence of FTY720 on melanin synthesis in a spontaneously immortalized mouse melanocyte cell line (Mel-Ab). FTY720 inhibited melanin synthesis in a concentration-dependent manner. Further, FTY720 has a different signal transduction mechanism to regulate melanogenesis from the S1P-induced signalling pathway. Our results showed that FTY720 down-regulated MITF and tyrosinase expression without ERK activation. MITF, the master regulator of pigmentation, is a target for the Wnt signalling pathway, including glycogen synthase kinase 3β (GSK3β) and β-catenin. Thus, the influence of FTY720 on GSK3β and β-catenin was further investigated. Decreased MITF and tyrosinase were associated with a reduction of β-catenin protein and mRNA levels. Decreased β-catenin expression by FTY720 may down-regulate expression of MITF, which finally reduces melanin synthesis.
我们之前报道过，鞘氨醇-1-磷酸（S1P）通过细胞外信号调节蛋白激酶（ERK）的激活和小眼畸形相关转录因子（MITF）的降解来减少黑色素的合成。虽然 FTY720 是 S1P 的结构类似物，但 FTY720 对黑色素生成的影响尚不完全清楚。因此，我们研究了 FTY720 对自发永生化小鼠黑素细胞系（Mel-Ab）中黑色素合成的影响。FTY720 呈浓度依赖性地抑制黑色素合成。此外，FTY720 具有不同于 S1P 诱导的信号通路调节黑色素生成的信号转导机制。我们的结果表明，FTY720 在不激活 ERK 的情况下下调 MITF 和酪氨酸酶的表达。MITF 是色素沉着的主要调节因子，是包括糖原合酶激酶 3β（GSK3β）和 β-连环蛋白在内的 Wnt 信号通路的靶标。因此，进一步研究了 FTY720 对 GSK3β 和 β-连环蛋白的影响。MITF 和酪氨酸酶表达的降低与 β-连环蛋白蛋白和 mRNA 水平的降低有关。FTY720 下调 β-连环蛋白表达可能下调 MITF 的表达，最终减少黑色素合成。
