A SNAIL1–SMAD3/4 transcriptional repressor complex promotes TGF‑β mediated epithelial–mesenchymal transition
2009 (English)In: Nature Cell Biology, ISSN 1465-7392, Vol. 11, no 8, 943-950 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2009. Vol. 11, no 8, 943-950 p.
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-108560DOI: 10.1038/ncb1905ISI: 000268593200007PubMedID: 19597490OAI: oai:DiVA.org:uu-108560DiVA: diva2:236349