Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail
Regulation of tight junctions during the epithelium-mesenchyme transition: direct repression of the gene expression of claudins/occludin by Snail
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DOI：
10.1242/jcs.00389
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发表时间：
2003-05-15
影响因子：
4
通讯作者：
Tsukita, S
中科院分区：
文献类型：
--
作者：
Ikenouchi, J;Matsuda, M;Tsukita, S
Snail是一种转录抑制因子，在上皮-间充质转化（EMT）中起核心作用，上皮细胞通过EMT失去极性。Claudius和occludin是位于紧密连接处的完整膜蛋白，其负责建立和维持上皮细胞极性。我们研究了Snail与claudin和occludin启动子活性之间的关系。当Snail在培养的小鼠上皮细胞中过表达时，EMT诱导伴随着不仅在蛋白质而且在mRNA水平上对claudins和occludin的表达的抑制。然后，我们分离了编码claudins和occludin的基因的启动子，其中鉴定了多个E盒。用各种启动子构建体的转染实验以及电泳迁移率测定显示，蜗牛直接结合到紧密连接蛋白/闭合蛋白基因的启动子的E盒，导致其启动子活性的完全抑制。由于E-cadherin编码基因也被Snail抑制，我们得出结论，EMT与E-cadherin和claudins/occludin编码基因的同时抑制有关（即分别表达粘附分子和紧密连接粘附分子）。
Snail is a transcription repressor that plays a central role in the epithelium-mesenchyme transition (EMT), by which epithelial cells lose their polarity. Claudius and occludin are integral membrane proteins localized at tight junctions, which are responsible for establishing and maintaining epithelial cell polarity. We examined the relationship between Snail and the promoter activity of claudins and occludin. When Snail was overexpressed in cultured mouse epithelial cells, EMT was induced with concomitant repression of the expression of claudins and occludin not only at the protein but also at the mRNA level. We then isolated the promoters of genes encoding claudins and occludin, in which multiple E-boxes were identified. Transfection experiments with various promoter constructs as well as electrophoretic mobility assays revealed that Snail binds directly to the E-boxes of the promoters of claudin/occludin genes, resulting in complete repression of their promoter activity. Because the gene encoding E-cadherin was also reported to be repressed by Snail, we concluded that EMT was associated with the simultaneous repression of the genes encoding E-cadherin and claudins/occludin (i.e. the expression of adherens and tight junction adhesion molecules, respectively).