Differential regulation of epithelial and mesenchymal markers by deltaEF1 proteins in epithelial mesenchymal transition induced by TGF-beta.
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 deltaEF1 family proteins, deltaEF1 (ZEB1) and SIP1, is gradually increased by TGF-beta with expression profiles reciprocal to that of E-cadherin. SIP1 and deltaEF1 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 deltaEF1, 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 deltaEF1. TGF-beta-induced the expression of Ets1, which in turn activated deltaEF1 promoter activity. Moreover, up-regulation of SIP1 and deltaEF1 expression by TGF-beta was suppressed by knockdown of Ets1 expression. In addition, Id2 suppressed the TGF-beta- and Ets1-induced up-regulation of deltaEF1. Taken together, these findings suggest that the deltaEF1 family proteins, SIP1 and deltaEF1, 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 deltaEF1.
Shirakihara
Takuya
T
Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
Saitoh
Masao
M
Miyazono
Kohei
K
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015820:Cadherins / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D004285:Dogs; D024721:E-Box Elements; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008648:Mesoderm / Q000166:cytology* / Q000187:drug effects*; D051379:Mice; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D014176:Protein Biosynthesis / Q000187:drug effects; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D051785:Smad Proteins / Q000096:biosynthesis; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects; D000071799:Zinc Finger E-box-Binding Homeobox 1
D015415:Biomarkers; D015820:Cadherins; D018398:Homeodomain Proteins; D009419:Nerve Tissue Proteins; D050784:Proto-Oncogene Protein c-ets-1; D012097:Repressor Proteins; D051785:Smad Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D000071799:Zinc Finger E-box-Binding Homeobox 1; C494042:Ets1 protein, mouse; C491561:Sip1 protein, mouse; C486307:ZEB1 protein, human; C519422:ZEB1 protein, mouse