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

被引：615

作者：

Vincent, Theresa ^{[2
,8
]}

Neve, Etienne P. A. ^{[2
,9
]}

Johnson, Jill R. ^{[1
,12
]}

Kukalev, Alexander ^{[1
]}

Rojo, Federico ^{[3
,10
]}

Albanell, Joan ^{[3
,11
]}

Pietras, Kristian ^{[12
]}

Virtanen, Ismo ^{[4
]}

Philipson, Lennart ^{[1
]}

Leopold, Philip L. ^{[5
]}

Crystal, Ronald G. ^{[6
]}

Garcia de Herreros, Antonio ^{[3
]}

Moustakas, Aristidis ^{[7
]}

Pettersson, Ralf F. ^{[2
]}

Fuxe, Jonas ^{[1
,12
]}

机构：

[1] Karolinska Inst, Dept Cell & Mol Biol, S-17177 Stockholm, Sweden

[2] Ludwig Inst Canc Res, Stockholm Branch, S-17177 Stockholm, Sweden

[3] IMIM Hosp Mar, Programa Recerca Canc, Dept Oncol, Barcelona 08003, Spain

[4] Univ Helsinki, Inst Biomed Anat, FI-00014 Helsinki, Finland

[5] Stevens Inst Technol, Dept Chem Chem Biol & Biomed Engn, Hoboken, NJ 07030 USA

[6] Cornell Univ, Weill Med Coll, Dept Med Genet, New York, NY 10065 USA

[7] Ludwig Inst Canc Res, Uppsala Branch, SE-75124 Uppsala, Sweden

[8] Cornell Univ, Weill Med Coll, Dept Cell & Dev Biol, New York, NY 10065 USA

[9] Karolinska Inst, Dept Physiol & Pharmacol, Pharmacogenet Sect, S-17177 Stockholm, Sweden

[10] Fdn Jimenez Diaz, Serv Anat Patol, E-28040 Madrid, Spain

[11] Hosp del Mar, Serv Oncol Patol, Barcelona, Spain

[12] Karolinska Inst, Matrix Div, Dept Biochem & Biophys, S-17177 Stockholm, Sweden

来源：

NATURE CELL BIOLOGY | 2009年 / 11卷 / 08期

基金：

美国国家卫生研究院; 瑞典研究理事会;

关键词：

GROWTH-FACTOR-BETA; CADHERIN GENE-EXPRESSION; ADENOVIRUS-RECEPTOR; FACTOR SNAIL; TUMOR-CELLS; CARCINOMA-CELLS; TIGHT JUNCTIONS; BREAST-CANCER; COXSACKIE; METASTASIS;

D O I：

10.1038/ncb1905

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

Epithelial-mesenchymal transition (EMT) is essential for organogenesis and is triggered during carcinoma progression to an invasive state(1). Transforming growth factor-beta (TGF-beta) cooperates with signalling pathways, such as Ras and Wnt, to induce EMT2-5, 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 EMT6,7. 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.

引用

页码：943 / U84

页数：18

共 38 条

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Anders M, 2003, CANCER RES, V63, P2088

[2]

Glycogen synthase kinase-3 is an endogenous inhibitor of snail transcription: implications for the epithelial-mesenchymal transition [J].