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-beta1 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-beta1-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-beta1-induced EMT.
Department of Neuroscience, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan.
Tsuyoshi
T
Morita
Taira
T
Mayanagi
Kenji
K
Sobue
D000199:Actins / Q000378:metabolism*; D000818:Animals; D003599:Cytoskeleton / Q000187:drug effects / Q000378:metabolism; D004285:Dogs; D004847:Epithelial Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008648:Mesoderm / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D011401:Promoter Regions, Genetic; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D021381:Protein Transport / Q000187:drug effects; D051900:Smad3 Protein / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D013347:Subcellular Fractions; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D020741:rho GTP-Binding Proteins / Q000378:metabolism
D000199:Actins; C000604407:SNAI1 protein, human; D051900:Smad3 Protein; C000604449:Snai2 protein, mouse; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; D020741:rho GTP-Binding Proteins