Differential regulation of epithelial and mesenchymal markers by δEF1 proteins in epithelial-mesenchymal transition induced by TGF-β
Differential regulation of epithelial and mesenchymal markers by δEF1 proteins in epithelial-mesenchymal transition induced by TGF-β
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DOI：
10.1091/mbc.e07-03-0249
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发表时间：
2007-09-01
影响因子：
3.3
通讯作者：
Miyazono, Kohei
中科院分区：
文献类型：
--
作者：
Shirakihara, Takuya;Saitoh, Masao;Miyazono, Kohei
上皮-间质转化（EMT）是癌症进展和胚胎发育中的关键事件，由小鼠乳腺NMuMG上皮细胞中的转化生长因子（TGF）-β诱导。Id蛋白先前已报道抑制TGF-β诱导的EMT的主要特征。在这项研究中，我们表明，表达的delta EF 1家族蛋白，delta EF 1（ZEB 1）和SIP 1，是逐渐增加的TGF-β与表达的档案倒数E-钙粘蛋白。SIP 1和delta EF 1均通过直接结合E-钙粘蛋白启动子显着下调NMuMG细胞中E-钙粘蛋白的转录。SIP 1和Δ EF 1的表达沉默，但不是单独沉默，完全消除了TGF-β诱导的E-钙粘蛋白抑制。然而，表达间充质标记物，包括纤连蛋白，N-钙粘蛋白，波形蛋白，不受SIP 1和Δ EF 1敲低。TGF-β诱导Ets 1的表达，Ets 1反过来激活Δ EF 1启动子活性。此外，SIP 1和Δ EF 1表达的上调由TGF-β抑制敲低Ets 1表达。此外，Id 2抑制TGF-β和Ets 1诱导的Δ EF 1上调。综上所述，这些发现表明Δ EF 1家族蛋白SIP 1和Δ EF 1对于TGF-β诱导的EMT是必需的，但不是充分的，并且TGF-β诱导的Ets 1可能作为SIP 1和Δ EF 1的上游转录调节因子起作用。
Epithelial-mesenchymal transition (EMT), a crucial event in cancer progression and embryonic development, is induced by transforming growth factor (TGF)-beta in mouse mammary NMuMG epithelial cells. Id proteins have previously been reported to inhibit major features of TGF-beta-induced EMT. In this study, we show that expression of the delta EF1 family proteins, delta EF1 (ZEB1) and SIP1, is gradually increased by TGF-beta with expression profiles reciprocal to that of E-cadherin. SIP1 and delta EF1 each dramatically down-regulated the transcription of E-cadherin in NMuMG cells through direct binding to the E-cadherin promoter. Silencing of the expression of both SIP1 and delta EF1, but not either alone, completely abolished TGF-beta-induced E-cadherin repression. However, expression of mesenchymal markers, including fibronectin, N-cadherin, and vimentin, was not affected by knockdown of SIP1 and delta EF1. TGF-beta-induced the expression of Ets1, which in turn activated delta EF1 promoter activity. Moreover, up-regulation of SIP1 and delta EF1 expression by TGF-beta was suppressed by knockdown of Ets1 expression. In addition, Id2 suppressed the TGF-beta- and Ets1-induced up-regulation of delta EF1. Taken together, these findings suggest that the delta EF1 family proteins, SIP1 and delta EF1, are necessary, but not sufficient, for TGF-beta-induced EMT and that Ets1 induced by TGF-beta; may function as an upstream transcriptional regulator of SIP1 and delta EF1.