E-cadherin controls β-catenin and NF-κB transcriptional activity in mesenchymal gene expression
E-cadherin controls β-catenin and NF-κB transcriptional activity in mesenchymal gene expression
复制标题
DOI：
10.1242/jcs.021667
复制
发表时间：
2008-07-01
影响因子：
4
通讯作者：
Baulida, Josep
中科院分区：
文献类型：
--
作者：
Solanas, Guiomar;Porta-de-la-Riva, Montserrat;Baulida, Josep
E-钙粘附素及其转录抑制因子Snail1(Snai1)是控制上皮表型的两个因素。Snail1的表达促进了上皮细胞向间充质细胞的转化，并伴随着E-钙粘附素的下调和间质基因如纤维连接蛋白和LEF1的表达上调。我们研究了这些基因在间充质细胞中表达的分子机制。E-钙粘蛋白的强制表达强烈下调纤维连接蛋白和LEF1的RNA水平，表明E-钙粘素敏感因子参与了这些基因的转录。E-钙粘蛋白的过表达降低了纤维连接蛋白启动子的转录活性，并减少了β-连环蛋白和核因子-kappaB与该启动子的相互作用。与β-连环蛋白类似，通过免疫共沉淀和下拉实验发现，核因子-kappa B与E-钙粘蛋白和其他细胞黏附成分有关。当黏附连接被K-ras过表达或E-cad缺失干扰时，核转录因子-kappa B p65亚基与E-钙粘蛋白或β-连环素的相互作用减少。这些条件不影响p65与核因子-kappa B抑制物I kappa Bα的联系。这些结果的功能意义是由E-cadherin siRNA诱导的核因子-kappa B转录活性的刺激，既有基础的，也有肿瘤坏死因子-α刺激的。因此，这些结果表明，E-钙粘蛋白不仅控制β-连环蛋白的转录活性，而且还控制核因子-kappaB的转录活性。这些结果还表明，后者与贴壁连接复合体的结合阻止了间充质基因的转录。
E-cadherin and its transcriptional repressor Snail1 ( Snai1) are two factors that control epithelial phenotype. Expression of Snail1 promotes the conversion of epithelial cells to mesenchymal cells, and occurs concomitantly with the downregulation of E-cadherin and the upregulation of expression of mesenchymal genes such as those encoding fibronectin and LEF1. We studied the molecular mechanism controlling the expression of these genes in mesenchymal cells. Forced expression of E-cadherin strongly downregulated fibronectin and LEF1 RNA levels, indicating that E-cadherin-sensitive factors are involved in the transcription of these genes. E-cadherin overexpression decreased the transcriptional activity of the fibronectin promoter and reduced the interaction of beta-catenin and NF-kappa B with this promoter. Similar to beta-catenin, NF-kappa B was found, by co-immunoprecipitation and pull-down assays, to be associated with E-cadherin and other cell-adhesion components. Interaction of the NF-kappa B p65 subunit with E-cadherin or beta-catenin was reduced when adherens junctions were disrupted by K-ras overexpression or by E-cadherin depletion using siRNA. These conditions did not affect the association of p65 with the NF-kappa B inhibitor I kappa B alpha. The functional significance of these results was stressed by the stimulation of NF-kappa B transcriptional activity, both basal and TNF-alpha-stimulated, induced by an E-cadherin siRNA. Therefore, these results demonstrate that E-cadherin not only controls the transcriptional activity of beta-catenin but also that of NF-kappa B. They indicate too that binding of this latter factor to the adherens junctional complex prevents the transcription of mesenchymal genes.