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 Crystal, Antonio Garcia de Herreros, Aristidis Moustakas, Ralf F. Pettersson, Jonas Fuxe

Research output: Contribution to journalArticle

393 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Epithelial-Mesenchymal Transition
Transforming Growth Factors
Cadherins
Occludin
Claudin-3
Breast Neoplasms
Tight Junction Proteins
Co-Repressor Proteins
Organogenesis
Small Interfering RNA
Genes
Breast
Epithelial Cells
Carcinoma

ASJC Scopus subject areas

  • Cell Biology

Cite this

Vincent, T., Neve, E. P. A., Johnson, J. R., Kukalev, A., Rojo, F., Albanell, J., ... 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

A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial-mesenchymal transition. / Vincent, Theresa; Neve, Etienne P.A.; Johnson, Jill R.; Kukalev, Alexander; Rojo, Federico; Albanell, Joan; Pietras, Kristian; Virtanen, Ismo; Philipson, Lennart; Leopold, Philip L.; Crystal, Ronald; de Herreros, Antonio Garcia; Moustakas, Aristidis; Pettersson, Ralf F.; Fuxe, Jonas.

In: Nature Cell Biology, Vol. 11, No. 8, 14.07.2009, p. 943-950.

Research output: Contribution to journalArticle

Vincent, T, Neve, EPA, Johnson, JR, Kukalev, A, Rojo, F, Albanell, J, Pietras, K, Virtanen, I, Philipson, L, Leopold, PL, Crystal, R, de Herreros, AG, Moustakas, A, Pettersson, RF & Fuxe, J 2009, 'A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial-mesenchymal transition', Nature Cell Biology, vol. 11, no. 8, pp. 943-950. https://doi.org/10.1038/ncb1905
Vincent, Theresa ; Neve, Etienne P.A. ; Johnson, Jill R. ; Kukalev, Alexander ; Rojo, Federico ; Albanell, Joan ; Pietras, Kristian ; Virtanen, Ismo ; Philipson, Lennart ; Leopold, Philip L. ; Crystal, Ronald ; de Herreros, Antonio Garcia ; Moustakas, Aristidis ; Pettersson, Ralf F. ; Fuxe, Jonas. / A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial-mesenchymal transition. In: Nature Cell Biology. 2009 ; Vol. 11, No. 8. pp. 943-950.
@article{f5419c7e726a4487994add3790e78b96,
title = "A SNAIL1-SMAD3/4 transcriptional repressor complex promotes TGF-β mediated epithelial-mesenchymal transition",
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.",
author = "Theresa Vincent and Neve, {Etienne P.A.} and Johnson, {Jill R.} and Alexander Kukalev and Federico Rojo and Joan Albanell and Kristian Pietras and Ismo Virtanen and Lennart Philipson and Leopold, {Philip L.} and Ronald Crystal and {de Herreros}, {Antonio Garcia} and Aristidis Moustakas and Pettersson, {Ralf F.} and Jonas Fuxe",
year = "2009",
month = "7",
day = "14",
doi = "10.1038/ncb1905",
language = "English",
volume = "11",
pages = "943--950",
journal = "Nature Cell Biology",
issn = "1465-7392",
publisher = "Nature Publishing Group",
number = "8",

}

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

AU - de Herreros, Antonio Garcia

AU - Moustakas, Aristidis

AU - Pettersson, Ralf F.

AU - Fuxe, Jonas

PY - 2009/7/14

Y1 - 2009/7/14

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 - http://www.scopus.com/inward/citedby.url?scp=68249092353&partnerID=8YFLogxK

U2 - 10.1038/ncb1905

DO - 10.1038/ncb1905

M3 - Article

C2 - 19597490

AN - SCOPUS:68249092353

VL - 11

SP - 943

EP - 950

JO - Nature Cell Biology

JF - Nature Cell Biology

SN - 1465-7392

IS - 8

ER -