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TGF-β-induced differentiation into myofibroblasts involves specific regulation of two MKL1 isoforms

Scharenberg, Matthias A. and Pippenger, Benjamin E. and Sack, Ragna and Zingg, Dominik and Ferralli, Jacqueline and Schenk, Susanne and Martin, Ivan and Chiquet-Ehrismann, Ruth. (2014) TGF-β-induced differentiation into myofibroblasts involves specific regulation of two MKL1 isoforms. Journal of Cell Science, 127 (Pt 5). pp. 1079-1091.

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Official URL: https://edoc.unibas.ch/62054/

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Abstract

Cellular transformation into myofibroblasts is a central physiological process enabling tissue repair. Its deregulation promotes fibrosis and carcinogenesis. TGF-β is the main inducer of the contractile gene program that drives myofibroblast differentiation from various precursor cell types. Crucial regulators of this transcriptional program are serum response factor (SRF) and its cofactor MKL1 (also known as MRTF-A). However, the exact mechanism of the crosstalk between TGF-β signaling and MKL1 remains unclear. Here, we report the discovery of a novel MKL1 variant/isoform, MKL1_S, transcribed from an alternative promoter and uncover a novel translation start for the published human isoform, MKL1_L. Using a human adipose-derived mesenchymal stem cell differentiation model, we show that TGF-β specifically upregulates MKL1_S during the initial phase of myofibroblast differentiation. We identified a functional N-terminal motif in MKL1_S that allows specific induction of a group of genes including the extracellular matrix (ECM) modifiers MMP16 and SPOCK3/testican-3. We propose that TGF-β-mediated induction of MKL1_S initiates progression to later stages of differentiation towards a stationary myofibroblast.
Faculties and Departments:03 Faculty of Medicine > Bereich Operative Fächer (Klinik) > Querschnittsbereich Forschung > Tissue Engineering (Martin)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Operative Fächer (Klinik) > Querschnittsbereich Forschung > Tissue Engineering (Martin)
03 Faculty of Medicine > Departement Biomedizin > Department of Biomedicine, University Hospital Basel > Tissue Engineering (Martin)
UniBasel Contributors:Martin, Ivan
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Company of Biologists
ISSN:0021-9533
e-ISSN:1477-9137
Note:Publication type according to Uni Basel Research Database: Journal article
Identification Number:
Last Modified:31 May 2020 09:29
Deposited On:31 May 2020 09:29

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