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 |