TY - JOUR
T1 - A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial-mesenchymal transition
AU - Vincent, Theresa
AU - Neve, Etienne P.A.
AU - Johnson, Jill R.
AU - Kukalev, Alexander
AU - Rojo, Federico
AU - Albanell, Joan
AU - Pietras, Kristian
AU - Virtanen, Ismo
AU - Philipson, Lennart
AU - Leopold, Philip L.
AU - Crystal, Ronald G.
AU - de Herreros, Antonio Garcia
AU - Moustakas, Aristidis
AU - Pettersson, Ralf F.
AU - Fuxe, Jonas
PY - 2009/7/13
Y1 - 2009/7/13
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=68249092353&partnerID=8YFLogxK
UR - https://www.nature.com/articles/ncb1905
U2 - 10.1038/ncb1905
DO - 10.1038/ncb1905
M3 - Article
C2 - 19597490
AN - SCOPUS:68249092353
SN - 1465-7392
VL - 11
SP - 943
EP - 950
JO - Nature Cell Biology
JF - Nature Cell Biology
IS - 8
ER -