Differential Role of Snail1 and Snail2 Zinc Fingers in E-cadherin Repression and Epithelial to Mesenchymal Transition
Differential Role of Snail1 and Snail2 Zinc Fingers in E-cadherin Repression and Epithelial to Mesenchymal Transition
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DOI：
10.1074/jbc.m113.528026
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发表时间：
2014-01-10
影响因子：
4.8
通讯作者：
Cano, Amparo
中科院分区：
文献类型：
--
作者：
Villarejo, Ana;Cortes-Cabrera, Alvaro;Cano, Amparo
Snail1 （Snail）和Snail2 （Slug）是两种具有相似DNA结合结构的转录因子，它们分别具有4个和5个C2H2锌指基序（ZF）。这两种因子特异性结合靶启动子（如e -钙粘蛋白启动子）中的E-box基序子集（E2-box: CAGGTG/CACCTG），是上皮细胞向间质转化（EMT）的关键介质。然而，Snail1和Snail2的生物学作用、与E-cadherin启动子的结合亲和力以及靶基因都存在差异，尽管分子基础目前尚不清楚。特别是，每个Snail1和Snail2 ZF在与e -box的结合和EMT诱导中的作用以前没有被探索过。我们通过模拟Snail1和Snail2蛋白- dna相互作用以及通过不同ZFs的突变和功能分析来解决这个问题。结果表明，Snail1有效抑制和结合人和小鼠E-cadherin启动子以及诱导emt的能力需要完整的ZF1和ZF2，而对于Snail2来说，ZF3或ZF4是这些功能所必需的。此外，e2 -box在小鼠和人E-cadherin启动子中的差异分布也有助于蜗牛因子活性的差异。这些数据表明Snail1和Snail2 ZFs在基因抑制中的作用不相等，有助于阐明这些重要EMT调控因子之间的分子差异。
Snail1 (Snail) and Snail2 (Slug) are transcription factors that share a similar DNA binding structure of four and five C2H2 zinc finger motifs (ZF), respectively. Both factors bind specifically to a subset of E-box motifs (E2-box: CAGGTG/CACCTG) in target promoters like the E-cadherin promoter and are key mediators of epithelial-to-mesenchymal transition (EMT). However, there are differences in the biological actions, in binding affinities to E-cadherin promoter, and in the target genes of Snail1 and Snail2, although the molecular bases are presently unknown. In particular, the role of each Snail1 and Snail2 ZF in the binding to E-boxes and in EMT induction has not been previously explored. We have approached this question by modeling Snail1 and Snail2 protein-DNA interactions and through mutational and functional assays of different ZFs. Results show that Snail1 efficient repression and binding to human and mouse E-cadherin promoter as well as EMT-inducing ability require intact ZF1 and ZF2, while for Snail2, either ZF3 or ZF4 is essential for those functions. Furthermore, the differential distribution of E2-boxes in mouse and human E-cadherin promoters also contributes to the differential Snail factor activity. These data indicate a non-equivalent role of Snail1 and Snail2 ZFs in gene repression, contributing to the elucidation of the molecular differences between these important EMT regulators.