Dual roles of myocardin-related transcription factors in epithelial-mesenchymal transition via slug induction and actin remodeling

Epithelial - mesenchymal transition ( EMT) is a critical process occurring during embryonic development and in. fibrosis and tumor progression. Dissociation of cell - cell contacts and remodeling of the actin cytoskeleton are major events of the EMT. Here, we show that myocardin- related transcription factors ( MRTFs; also known as MAL and MKL) are critical mediators of transforming growth factor beta ( TGF- beta) 1 - induced EMT. In all epithelial cell lines examined here, TGF- beta 1 triggers the nuclear translocation of MRTFs. Ectopic expression of constitutive-active MRTF- A induces EMT, whereas dominant- negative MRTF- A or knockdown of MRTF- A and - B prevents the TGF- beta 1 - induced EMT. MRTFs form complexes with Smad3. Via Smad3, the MRTF - Smad3 complexes bind to a newly identified cis- element GCCG- like motif in the promoter region of Canis familiaris and the human slug gene, which activates slug transcription and thereby dissociation of cell - cell contacts. MRTFs also increase the expression levels of actin cytoskeletal proteins via serum response factor, thereby triggering reorganization of the actin cytoskeleton. Thus, MRTFs are important mediators of TGF- beta 1 induced EMT.