Antagonistic regulation of EMT by TIF1γ and Smad4 in mammary epithelial cells.

ABSTRACT

TGF-ß is a potent inducer of epithelial-to-mesenchymal transition (EMT), a process involved in tumour invasion. TIF1γ participates in TGF-ß signalling. To understand the role of TIF1γ in TGF-ß signalling and its requirement for EMT, we analysed the TGF-ß1 response of human mammary epithelial cell lines. A strong EMT increase was observed in TIF1γ-silenced cells after TGF-ß1 treatment, whereas Smad4 inactivation completely blocked this process. Accordingly, the functions of several TIF1γ target genes can be linked to EMT, as shown by microarray analysis. As a negative regulator of Smad4, TIF1γ could be crucial for the regulation of TGF-ß signalling. Furthermore, TIF1γ binds to and represses the plasminogen activator inhibitor 1 promoter, demonstrating a direct role of TIF1γ in TGF-ß-dependent gene expression. This study shows the molecular relationship between TIF1γ and Smad4 in TGF-ß signalling and EMT.