Snail and Slug Promote Epithelial-Mesenchymal Transition through β-Catenin-T-Cell Factor-4-dependent Expression of Transforming Growth Factor-β3
Snail and Slug Promote Epithelial-Mesenchymal Transition through β-Catenin-T-Cell Factor-4-dependent Expression of Transforming Growth Factor-β3
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DOI：
10.1091/mbc.e08-05-0506
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发表时间：
2008-11-01
影响因子：
3.3
通讯作者：
Olsen, Bjorn R.
中科院分区：
文献类型：
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作者：
Medici, Damian;Hay, Elizabeth D.;Olsen, Bjorn R.
蜗牛转录因子家族的成员已被证明可诱导上皮-间质转化（EMT），这是胚胎发生和进行性疾病的基本机制。在这里，我们发现蜗牛和蛞蝓促进β -连环蛋白- t细胞因子(TCF)-4转录复合物的形成，该复合物与tgf - β 3基因的启动子结合以增加其转录。随后的转化生长因子(TGF)- β 3信号传导增加了LEF-1基因表达，导致β -连环蛋白-淋巴细胞增强因子(LEF)-1复合物的形成，从而引发EMT。tgf - β 1或tgf - β 2通过上调蜗牛和蛞蝓的合成来刺激这种信号机制。发现tgf - β 1-和tgf - β 2诱导的EMT依赖于tgf - β 3，建立了多种tgf - β亚型的重要作用。最后，我们确定β -catenin- lef -1复合物可以在没有上游信号通路的情况下促进EMT。这些发现为统一的信号机制提供了证据，该机制由多个tgf - β和TCF信号分子的聚合驱动，从而导致细胞-细胞粘附丧失和间充质表型的获得。
Members of the Snail family of transcription factors have been shown to induce epithelial-mesenchymal transition (EMT), a fundamental mechanism of embryogenesis and progressive disease. Here, we show that Snail and Slug promote formation of beta-catenin-T-cell factor (TCF)-4 transcription complexes that bind to the promoter of the TGF-beta 3 gene to increase its transcription. Subsequent transforming growth factor (TGF)-beta 3 signaling increases LEF-1 gene expression causing formation of beta-catenin-lymphoid enhancer factor (LEF)-1 complexes that initiate EMT. TGF-beta 1 or TGF-beta 2 stimulates this signaling mechanism by up-regulating synthesis of Snail and Slug. TGF-beta 1- and TGF-beta 2-induced EMT were found to be TGF-beta 3 dependent, establishing essential roles for multiple TGF-beta isoforms. Finally, we determined that beta-catenin-LEF-1 complexes can promote EMT without upstream signaling pathways. These findings provide evidence for a unified signaling mechanism driven by convergence of multiple TGF-beta and TCF signaling molecules that confers loss of cell-cell adhesion and acquisition of the mesenchymal phenotype.