Research Institute for Biological Functions, Chubu University, Aichi, Japan.
Center for Bioscience Research & Education, Utsunomiya University, Tochigi, Japan.
Photochem Photobiol. 2018 May;94(3):421-431. doi: 10.1111/php.12848. Epub 2018 Mar 8.
A single exposure of normal human melanocytes (NHMs) to ultraviolet B (UVB) radiation induces a distinct increase in the expression of c-KIT and endothelin B receptor (EDNRB) and upregulates the expression of microphthalmia-associated transcription factor (MITF). In this review, we clarify the signaling mechanisms by which UVB stimulates the expression of MITF in NHMs, thus leading to upregulation of those two important melanogenic receptors. The increased expression of MITF in UVB-exposed NHMs is accompanied by a markedly stimulated and prolonged phosphorylation of p38/CREB. The UVB-stimulated expression of c-KIT and EDNRB could be completely abolished by a p38 inhibitor concomitant with a reduced phosphorylation of CREB and a downregulation of MITF expression. The UVB exposure of NHMs stimulates the phosphorylation of p38 and c-jun N-terminal kinase, but not ERK, followed by the increased phosphorylation of MSK1 and subsequently CREB. Postirradiation treatment with the MSK1 inhibitor H89 significantly downregulates the increased mRNA and protein expression of MITF, EDNRB and c-KIT in UVB-exposed NHMs. Our findings indicate for the first time that the increased expression of MITF that leads to the upregulation of melanocyte-specific proteins in UVB-exposed NHMs is mediated via activation of the p38/MSK1/CREB axis but not the ERK/RSK/CREB axis.
正常人类黑素细胞（NHMs）单次暴露于中波紫外线（UVB）辐射会显著增加 c-KIT 和内皮素 B 受体（EDNRB）的表达，并上调小眼畸形相关转录因子（MITF）的表达。在这篇综述中，我们阐明了 UVB 刺激 NHMs 中 MITF 表达的信号机制，从而导致这两个重要的黑色素生成受体的上调。UVB 暴露后的 NHMs 中 MITF 的表达增加伴随着 p38/CREB 的明显激活和延长的磷酸化。p38 抑制剂可完全消除 UVB 刺激的 c-KIT 和 EDNRB 表达，同时降低 CREB 的磷酸化和 MITF 的表达下调。NHMs 的 UVB 暴露刺激 p38 和 c-jun N 端激酶的磷酸化，但不刺激 ERK 的磷酸化，随后 MSK1 和随后的 CREB 磷酸化增加。MSK1 抑制剂 H89 处理后，UVB 暴露的 NHMs 中 MITF、EDNRB 和 c-KIT 的 mRNA 和蛋白表达增加显著下调。我们的研究结果首次表明，UVB 暴露后导致黑素细胞特异性蛋白表达上调的 MITF 表达增加是通过激活 p38/MSK1/CREB 轴而不是 ERK/RSK/CREB 轴介导的。
