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

Publication Type	Academic Article
Authors	Vincent T, Neve E, Johnson J, Kukalev A, Rojo F, Albanell J, Pietras K, Virtanen I, Philipson L, Leopold P, Crystal R, de Herreros A, Moustakas A, Pettersson R, Fuxe J
Journal	Nat Cell Biol
Volume	11
Issue	8
Pagination	943-50
Date Published	07/13/2009
ISSN	1476-4679
Keywords	Smad3 Protein, Smad4 Protein, Transcription Factors, Transforming Growth Factor beta
Abstract	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.
DOI	10.1038/ncb1905
PubMed ID	19597490
PubMed Central ID	PMC3769970