Skip to main navigation Skip to search Skip to main content

TGF-β-elicited induction of tissue inhibitor of metalloproteinases (TIMP)-3 expression in fibroblasts involves complex interplay between Smad3, p38α, and ERK1/2

  • Suvi-Katri Leivonen
  • , Konstantinos Lazaridis
  • , Julie Decock
  • , Andrew Chantry
  • , Dylan R. Edwards
  • , Veli-Matti Kähäri

Research output: Contribution to journal › Article › peer-review

81 Citations (Scopus)

Abstract

Transforming growth factor-β (TGF-β) promotes extracellular matrix deposition by down-regulating the expression of matrix degrading proteinases and upregulating their inhibitors. Tissue inhibitor of metalloproteinases (TIMP)-3 is an ECM-associated specific inhibitor of matrix degrading metalloproteinases. Here, we have characterized the signaling pathways mediating TGF-β-induced expression of TIMP-3. Basal and TGF-β-induced TIMP-3 mRNA expression was abolished in Smad4-deficient mouse embryonic fibroblasts and restoring Smad4 expression rescued the response. Inhibition of Smad signaling by expression of Smad7 and dominant negative Smad3 completely abolished TGF-β-elicited expression of TIMP-3 in human fibroblasts, whereas overexpression of Smad3 enhanced it. Inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activation with PD98059 and p38 mitogen-activated protein kinase activity by SB203580 resulted in suppression of TGF-β-induced TIMP-3 expression, indicating that ERK1/2 and p38 MAPK mediate the effect of TGF-β on TIMP-3 expression. Specific activation of p38α and ERK1/2 by constitutively active mutants of MKK3b or MEK1, respectively, and simultaneous co-expression of Smad3 resulted in induction of TIMP-3 expression in the absence of TGF-β indicating that Smad3 co-operates with p38 and ERK1/2 in the induction of TIMP-3 expression. These results demonstrate the complex interplay between Smad3, p38α, and ERK1/2 signaling in the regulation of TIMP-3 gene expression in fibroblasts, which may play a role in inflammation, tissue repair, and fibrosis.
Original languageEnglish
Article numbere57474
JournalPLoS One
Volume8
Issue number2
DOIs
Publication statusPublished - 28 Feb 2013

Access to Document

  • CANCERDEGRADOME: "Extracellular Proteases and the Cances Degradome: Innovative Diagnostic Markers, Therapeutic Targets and Tumour Imaging Agents"

    Edwards, D. (Principal Investigator), Andreasen (Aarhus), P. (Co-Investigator), Baker (Glasgow), A. (Co-Investigator), Bierau (Oncomethylome), K. (Co-Investigator), Binder (Vienna), B. (Co-Investigator), Bode (Max-Planck Institute), W. (Co-Investigator), Brand (Humboldt), K. (Co-Investigator), Brandstetter (Proteros), H. (Co-Investigator), Caschetto (IFOM), C. (Co-Investigator), Dano (Finsen Laboratory), K. (Co-Investigator), Dive (CEA), V. (Co-Investigator), Foidart (Liege), J.-M. (Co-Investigator), Gomis-Rüth (IBMB), F. X. (Co-Investigator), Kahari (Turku), V.-M. (Co-Investigator), Kos (KRKA), J. (Co-Investigator), Krüger (Munich), A. (Co-Investigator), Lah Turnsek (NIB), T. (Co-Investigator), Leonard (Uni of London), G. (Co-Investigator), Levy (Genoptics), Y. (Co-Investigator), Lopez-Otin (Oviedo), C. (Co-Investigator), Mueller (DKFZ), M. (Co-Investigator), Murphy (Cambridge), G. (Co-Investigator), Paridaens (Leuven), R. (Co-Investigator), Peters (Freiburg), C. (Co-Investigator), Ragno (Unina), P. (Co-Investigator), Rio (GIE), M.-C. (Co-Investigator), Sauter (Basel), G. (Co-Investigator), Slegers (Gent), G. (Co-Investigator), Stopelli (IIGB), M. P. (Co-Investigator), Taraboletti (Mario Negri), G. (Co-Investigator), Terenius (Stockholm), L. (Co-Investigator), Tryggvason (Karolinska), K. (Co-Investigator) & Yiotakis (Athens), A. (Co-Investigator)

    CEC (Framework 6)

    1/01/04 → 30/06/08

    Project: Research

Cite this