Center for Bioscience Research and Education, Utsunomiya University, Tochigi, Japan.
School of Bioscience and Biotechnology, Tokyo University of Technology, Tokyo, Japan.
Arch Dermatol Res. 2018 Apr;310(3):187-196. doi: 10.1007/s00403-018-1816-x. Epub 2018 Jan 23.
We recently found that treatment of normal human melanocytes (NHMs) with the antioxidant astaxanthin (AX) suppresses the stem cell factor (SCF)-stimulated protein expression levels of microphthalmia-associated transcription factor (MITF) at 1.5 h and of tyrosinase and endothelin B receptor at 96 h post-treatment. Analysis of the signaling cascade(s) involved revealed that although the major SCF-activated signaling cascade that leads to CREB activation (the c-KIT/Shc/Raf-1/ERK/RSK/CREB axis) is not interrupted, the increased phosphorylation of CREB is significantly abrogated by AX. We show for the first time that treatment of NHMs with SCF activates the p38/mitogen and stress-activated kinase (MSK1) axis in a c-KIT dependent fashion. Interestingly, whereas AX does not abrogate the SCF-induced activation of p38, it does affect the increased phosphorylation of its downstream target, MSK1. The lineage connection of p38/MSK1 activation with CREB activation and its associated MITF expression is supported by our finding that while silencing MSK1 abolishes the activation of CREB and the subsequent increase in total MITF proteins at 15 min and at 1.5 h, respectively, post-stimulation with SCF, inhibitors of p38 and of MSK1 abrogate the SCF-induced increase in total MITF proteins at 1.5 h post-stimulation. These findings suggest that SCF-stimulated melanogenesis can be abrogated by interrupting MSK1 phosphorylation, providing evidence for involvement of the p38/MSK1/CREB/MITF axis, providing new evidence for the ROS depletion independent interruption by antioxidants of SCF-triggered signaling.
我们最近发现，用抗氧化剂虾青素（AX）处理正常人黑素细胞（NHMs）可在 1.5 小时时抑制干细胞因子（SCF）刺激的小眼相关转录因子（MITF）和酪氨酸酶和内皮素 B 受体的蛋白表达水平，并在治疗后 96 小时时抑制。对涉及的信号级联反应的分析表明，尽管导致 CREB 激活的主要 SCF 激活信号级联反应（c-KIT/Shc/Raf-1/ERK/RSK/CREB 轴）没有中断，但 AX 显著抑制了 CREB 的磷酸化增加。我们首次表明，SCF 处理 NHMs 以 c-KIT 依赖的方式激活 p38/丝裂原和应激激活激酶（MSK1）轴。有趣的是，尽管 AX 没有阻断 SCF 诱导的 p38 激活，但它确实影响了其下游靶标 MSK1 的磷酸化增加。p38/MSK1 激活与 CREB 激活及其相关的 MITF 表达的谱系联系得到了我们的发现的支持，即虽然沉默 MSK1 可消除 CREB 的激活以及随后在 15 分钟和 1.5 小时分别在 SCF 刺激后总 MITF 蛋白的增加，但 p38 和 MSK1 的抑制剂可阻断 SCF 诱导的在刺激后 1.5 小时总 MITF 蛋白的增加。这些发现表明，通过中断 MSK1 磷酸化可以阻断 SCF 刺激的黑素生成，为 p38/MSK1/CREB/MITF 轴的参与提供了证据，为抗氧化剂对 SCF 触发的信号的 ROS 耗竭独立性中断提供了新的证据。
