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Vol. 18, Issue 9, 3533-3544, September 2007

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Differential Regulation of Epithelial and Mesenchymal Markers by EF1 Proteins in Epithelial–Mesenchymal Transition Induced by TGF-

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

Submitted March 16, 2007; Revised June 18, 2007; Accepted June 25, 2007
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)- in mouse mammary NMuMG epithelial cells. Id proteins have previously been reported to inhibit major features of TGF-–induced EMT. In this study, we show that expression of the EF1 family proteins, EF1 (ZEB1) and SIP1, is gradually increased by TGF- with expression profiles reciprocal to that of E-cadherin. SIP1 and 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 EF1, but not either alone, completely abolished TGF-–induced E-cadherin repression. However, expression of mesenchymal markers, including fibronectin, N-cadherin, and vimentin, was not affected by knockdown of SIP1 and EF1. TGF-–induced the expression of Ets1, which in turn activated EF1 promoter activity. Moreover, up-regulation of SIP1 and EF1 expression by TGF- was suppressed by knockdown of Ets1 expression. In addition, Id2 suppressed the TGF-– and Ets1-induced up-regulation of EF1. Taken together, these findings suggest that the EF1 family proteins, SIP1 and EF1, are necessary, but not sufficient, for TGF-–induced EMT and that Ets1 induced by TGF- may function as an upstream transcriptional regulator of SIP1 and EF1.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

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

Abbreviations used: TGF-, transforming growth factor-; HLH, helix-loop-helix; EMT, epithelial-mesenchymal transition; SIP1, Smad-interacting protein1; EF1 (ZEB1), delta-crystallin/E2-box factor 1.

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