Gli1 acts through Snail and E-cadherin to promote nuclear signaling by β-catenin
Gli1 acts through Snail and E-cadherin to promote nuclear signaling by β-catenin
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DOI：
10.1038/sj.onc.1210241
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发表时间：
2007-07-01
期刊：
影响因子：
8
通讯作者：
Ruppert, J. M.
中科院分区：
文献类型：
--
作者：
Li, X.;Deng, W.;Ruppert, J. M.
Hedgehog途径转录因子Gli 1通过诱导Snail（一种E-钙粘蛋白（E-cad）的阻遏物）诱导上皮细胞转化。E-cad通常在细胞膜上与β-连环蛋白复合。在发育上皮-间充质转化过程中E-cad的丢失可以将β-连环蛋白从其在粘附连接中的作用转变为其在核转录中的作用。在肿瘤发生过程中，尚不清楚哪些途径触发了这种开关。在目前的研究中，获得和丧失功能的方法确定E-cad作为Gli 1转化的选择性抑制剂，并通过下调E-cad来挽救Snail敲除。Gli 1诱导β-连环蛋白从细胞膜到细胞核的重新定位。野生型或突变体等位基因的E-cad的能力，以调节转化Gli 1与他们的能力，以调节定位的β-连环蛋白。显性负性Tcf 4抑制Wnt-β-catenin信号传导选择性阻断Gli 1体外转化。在Gli 1转基因小鼠中，浸润性皮肤肿瘤细胞表达活性的非磷酸化β-连环蛋白。我们的研究确定E-cad作为Gli 1转化的选择性抑制因子，并指出Sonic Hedgehog-Gli 1通路是上皮细胞和癌症中β-连环蛋白开关的关键调节因子。
The Hedgehog pathway transcription factor Gli1 induces transformation of epithelial cells via induction of Snail, a repressor of E-cadherin (E-cad). E-cad is normally complexed with beta-catenin at the cell membrane. Loss of E-cad during developmental epithelial-mesenchymal transitions can switch beta-catenin from its role at adherens junctions to its role in nuclear transcription. During tumorigenesis it is unclear which pathways trigger this switch. In the current study, gain- and loss-of-function approaches identified E-cad as a selective inhibitor of transformation by Gli1, and Snail knockdown was rescued by downregulation of E-cad. Gli1 induced relocalization of beta-catenin from the cell membrane to the nucleus. The ability of wild-type or mutant alleles of E-cad to modulate transformation by Gli1 correlated with their ability to regulate localization of beta-catenin. Inhibition of Wnt-beta-catenin signaling by dominant negative Tcf4 selectively blocked in vitro transformation by Gli1. In Gli1-transgenic mice, infiltrating skin tumor cells expressed active, unphosphorylated beta-catenin. Our studies identify E-cad as a selective suppressor of transformation by Gli1 and point to the Sonic Hedgehog-Gli1 pathway as a key regulator of the beta-catenin switch in epithelial cells and cancers.