Department of Dermatology, University of Michigan, Ann Arbor, MI 48109-5609, USA.
J Dermatol Sci. 2010 Nov;60(2):105-13. doi: 10.1016/j.jdermsci.2010.08.003. Epub 2010 Aug 26.
Ultraviolet (UV) irradiation from the sun is the major cause of keratinocyte skin cancer. Transcription factor Snail plays an important role in epithelial-to-mesenchymal transition and epithelial tumor formation.
The aims of this study are to determine the regulation of Snail expression of ultraviolet (UV) irradiation on Snail expression in human skin in vivo, and the mechanisms by which UV irradiation induces Snail expression, in human keratinocytes.
Real-time RT-PCR was employed to measure Snail expression in human skin in vivo and cultured human keratinocytes. Luciferase assay and electrophoretic mobility shift assay (EMSA) were employed to investigate transcriptional regulation of the in Snail gene promoter.
Ultraviolet (UV) irradiation transiently induces Snail expression in human skin in vivo and cultured human keratinocytes. Snail induction is significantly reduced by specific inhibitors of ERK, p38 or JNK, indicating each of the three major mitogen-activated protein kinase (MAPK) pathways participate in Snail regulation. AP-1 transcription factor complex, a downstream target of MAPK signaling, is required for Snail induction. Inhibition of AP-1 activity by over-expression of dominant-negative c-Jun substantially reduces Snail induction. Analyses of the Snail promoter, revealed the presence of an AP-1 binding site. EMSA assay demonstrated that UV irradiation specifically induced c-Jun binding to this AP-1 site. Mutation of the AP-1-binding site completely blocked protein binding and inhibited UV irradiation-induced Snail promoter activity.
UV irradiation induces Snail gene expression in human skin keratinocytes. This induction is mediated by MAPK-AP-1 dependent signaling pathway. Elevated expression of Snail in response to chronic UV irradiation in human skin may contribute to UV irradiation-induced skin tumor development.
太阳紫外线（UV）辐射是角质细胞皮肤癌的主要原因。转录因子 SNAI1 在上皮-间充质转化和上皮肿瘤形成中发挥重要作用。
本研究旨在确定紫外线（UV）照射对体内人皮肤中 SNAI1 表达的调节作用，以及 UV 照射诱导人角质细胞中 SNAI1 表达的机制。
采用实时 RT-PCR 检测体内人皮肤和培养的人角质细胞中 SNAI1 的表达。采用荧光素酶报告基因检测和电泳迁移率变动分析（EMSA）检测 SNAI1 基因启动子的转录调控。
UV 照射可瞬时诱导体内人皮肤和培养的人角质细胞中 SNAI1 的表达。ERK、p38 或 JNK 的特异性抑制剂显著降低 SNAI1 的诱导，表明三种主要的丝裂原活化蛋白激酶（MAPK）途径中的每一种都参与 SNAI1 的调节。AP-1 转录因子复合物是 MAPK 信号的下游靶标，是 SNAI1 诱导所必需的。通过过表达显性失活的 c-Jun 抑制 AP-1 活性可显著降低 SNAI1 的诱导。对 SNAI1 启动子的分析表明存在一个 AP-1 结合位点。EMSA 实验表明，UV 照射特异性诱导 c-Jun 与该 AP-1 位点结合。AP-1 结合位点的突变完全阻断了蛋白结合，并抑制了 UV 照射诱导的 SNAI1 启动子活性。
UV 照射诱导人皮肤角质细胞中 SNAI1 基因的表达。这种诱导是通过 MAPK-AP-1 依赖的信号通路介导的。在人皮肤中，慢性 UV 照射导致 SNAI1 表达升高，可能有助于 UV 照射诱导的皮肤肿瘤发生。
Zotero 插件