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PMID: 20123992 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Fate-determining mechanisms in epithelial-myofibroblast transition: major inhibitory role for Smad3.

The Journal of cell biology ·Vol. 188 ·No. 3 ·2010-02-08 ·Pages 383-99

Masszi A, Speight P, Charbonney E, Lodyga M, Nakano H, Szászi K, Kapus A

Abstract

Epithelial-myofibroblast (MF) transition (EMyT) is a critical process in organ fibrosis, leading to alpha-smooth muscle actin (SMA) expression in the epithelium. The mechanism underlying the activation of this myogenic program is unknown. We have shown previously that both injury to intercellular contacts and transforming growth factor beta (TGF-beta) are indispensable for SMA expression (two-hit model) and that contact disruption induces nuclear translocation of myocardin-related transcription factor (MRTF). Because the SMA promoter harbors both MRTF-responsive CC(A/T)-rich GG element (CArG) boxes and TGF-beta-responsive Smad-binding elements, we hypothesized that the myogenic program is mobilized by a synergy between MRTF and Smad3. In this study, we show that the synergy between injury and TGF-beta exclusively requires CArG elements. Surprisingly, Smad3 inhibits MRTF-driven activation of the SMA promoter, and Smad3 silencing renders injury sufficient to induce SMA expression. Furthermore, Smad3 is degraded under two-hit conditions, thereby liberating the myogenic program. Thus, Smad3 is a critical timer/delayer of MF commitment in the epithelium, and EMyT can be dissected into Smad3-promoted (mesenchymal) and Smad3-inhibited (myogenic) phases.

MeSH Terms
Actins/biosynthesis,genetics Active Transport, Cell Nucleus/genetics Animals Cell Nucleus/genetics,immunology,metabolism Epithelial Cells/metabolism,pathology Fibroblasts/metabolism,pathology Fibrosis Models, Biological Myoblasts/metabolism,pathology Rats Response Elements/genetics Smad3 Protein/genetics,metabolism Swine Transforming Growth Factor beta/genetics,metabolism
Chemicals
Actins Smad3 Protein Transforming Growth Factor beta
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Masszi András
Keenan Research Centre, Li Ka Shing Knowledge Institute, University of Toronto, Toronto, Ontario M5B 1W8, Canada.
Speight Pam
Charbonney Emmanuel
Lodyga Monika
Nakano Hiroyasu
Szászi Katalin
Kapus András
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Article Info
Journal
The Journal of cell biology
Abbr.
J Cell Biol
ISSN
1540-8140
DOI
10.1083/jcb.200906155
Published
2010-02-08
Epub
2010-00-01
Pages
383-99
Language
English
Region
United States
NLM ID
0375356
PMCID
PMC2819691
Subset
IM
Grants
Canadian Institutes of Health Research · MOP-86535 · Canada
Corrections
CommentIn
PMID: 20519950
External Links
PubMed source DOI: 10.1083/jcb.200906155 PMC Full Text View journal details
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