A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial-mesenchymal transition

Theresa Vincent, Etienne P.A. Neve, Jill R. Johnson, Alexander Kukalev, Federico Rojo, Joan Albanell, Kristian Pietras, Ismo Virtanen, Lennart Philipson, Philip L. Leopold, Ronald G. Crystal, Antonio Garcia de Herreros, Aristidis Moustakas, Ralf F. Pettersson, Jonas Fuxe

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Abstract

Epithelial-mesenchymal transition (EMT) is essential for organogenesis and is triggered during carcinoma progression to an invasive state. Transforming growth factor-β (TGF-β) cooperates with signalling pathways, such as Ras and Wnt, to induce EMT, but the molecular mechanisms are not clear. Here, we report that SMAD3 and SMAD4 interact and form a complex with SNAIL1, a transcriptional repressor and promoter of EMT. The SNAIL1-SMAD3/4 complex was targeted to the gene promoters of CAR, a tight-junction protein, and E-cadherin during TGF-β-driven EMT in breast epithelial cells. SNAIL1 and SMAD3/4 acted as co-repressors of CAR, occludin, claudin-3 and E-cadherin promoters in transfected cells. Conversely, co-silencing of SNAIL1 and SMAD4 by siRNA inhibited repression of CAR and occludin during EMT. Moreover, loss of CAR and E-cadherin correlated with nuclear co-expression of SNAIL1 and SMAD3/4 in a mouse model of breast carcinoma and at the invasive fronts of human breast cancer. We propose that activation of a SNAIL1-SMAD3/4 transcriptional complex represents a mechanism of gene repression during EMT.

Original languageEnglish
Pages (from-to)943-950
Number of pages8
JournalNature Cell Biology
Volume11
Issue number8
DOIs
Publication statusPublished - 14 Jul 2009

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ASJC Scopus subject areas

  • Cell Biology

Cite this

Vincent, T., Neve, E. P. A., Johnson, J. R., Kukalev, A., Rojo, F., Albanell, J., Pietras, K., Virtanen, I., Philipson, L., Leopold, P. L., Crystal, R. G., de Herreros, A. G., Moustakas, A., Pettersson, R. F., & Fuxe, J. (2009). A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial-mesenchymal transition. Nature Cell Biology, 11(8), 943-950. https://doi.org/10.1038/ncb1905