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Published online
doi:10.1083/jcb.200708174
The Journal of Cell Biology, Vol. 179, No. 5, 1027-1042
The Rockefeller University Press, 0021-9525 $30.00
© Morita et al.
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Article

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



Tsuyoshi Morita1, Taira Mayanagi2, and Kenji Sobue1,2

1 Department of Neuroscience and 2 The Research Center for Child Mental Development, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan

Correspondence to Kenji Sobue: sobue{at}nbiochem.med.osaka-u.ac.jp

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 β (TGF-β) 1–induced EMT. In all epithelial cell lines examined here, TGF-β1 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-β1–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-β1–induced EMT.

Abbreviations used in this paper: {alpha}-SMA, {alpha}–smooth muscle actin; CA, constitutive active; ChIP, chromatin immunoprecipitation; DN, dominant negative; EMT, epithelial–mesenchymal transition; HMGA2, high mobility group A2; LMB, leptomycin B; MRTF, myocardin-related transcription factor; SBE, Smad-binding element; SRF, serum response factor.


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