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

Epithelial-mesenchymal transition (EMT) is essential for organogenesis and is triggered during carcinoma progression to an invasive state. Transforming growth factor-beta (TGF-beta) cooperates with signalling pathways, such as Ras and Wnt, to induce EMT, but the molecular mechanisms are not clear. H...

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Detalles Bibliográficos
Autores: Vincent, Theresa, Neve, Etienne P.A., Johnson, Jill R., Kukalev, Alexander, Rojo, Federico, Albanell Mestres, Joan, Pietras, Kristian, Virtanen, Ismo, Philipson, Lennart, Leopold, Philip L., Crystal, Ronald G., García de Herreros, Antonio, Moustakas, Aristidis, Petterson, Ralf F., Fuxe, Jonas
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2009
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:10230/36611
Acceso en línea:http://hdl.handle.net/10230/36611
http://dx.doi.org/10.1038/ncb1905
Access Level:acceso abierto
Palabra clave:Smad3 -- Metabolisme
Smad4 -- Metabolisme
Factors de transcripció
Factor de creixement transformant beta
Descripción
Sumario:Epithelial-mesenchymal transition (EMT) is essential for organogenesis and is triggered during carcinoma progression to an invasive state. Transforming growth factor-beta (TGF-beta) 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-beta-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.

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