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MBC in Press, published online ahead of print July 5, 2007
Mol. Biol. Cell 10.1091/mbc.E07-03-0249

A more recent version of this article appeared on September 1, 2007
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Submitted on March 16, 2007
Revised on June 18, 2007
Accepted on June 25, 2007

Differential Regulation of Epithelial and Mesenchymal Markers by {delta}EF1 Proteins in Epithelial-Mesenchymal Transition Induced by TGF-{beta}

Takuya Shirakihara, Masao Saitoh, and Kohei Miyazono

Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan

Monitoring Editor: Carl-Henrik Heldin

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 knock-down of SIP1 and {delta}EF1. TGF-{beta} induced the expression of Ets1, which in turn activated {delta}EF1 promoter activity. Moreover, upregulation of SIP1 and {delta}EF1 expression by TGF-{beta} was suppressed by knock-down of Ets1 expression. In addition, Id2 suppressed the TGF-{beta}- and Ets1-induced upregulation 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.

Address correspondence to: Kohei Miyazono (miyazono-ind{at}umin.ac.jp)




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