Journal
PLOS ONE
Volume 8, Issue 2, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0057474
Keywords
-
Categories
Funding
- Academy of Finland [137687]
- Finnish Cancer Research Foundation
- Sigrid Juselius Foundation
- Turku University Hospital [13336]
- European Union [LSHC-CT-2003-503297]
- Biotechnology and Biological Sciences Research Council
- Big C Appeal
- Cancer Foundation Finland sr [110087, 120097] Funding Source: researchfish
- Academy of Finland (AKA) [120097, 110087, 120097, 110087] Funding Source: Academy of Finland (AKA)
Ask authors/readers for more resources
Transforming growth factor-beta (TGF-beta) 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-beta-induced expression of TIMP-3. Basal and TGF-beta-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-beta-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-beta-induced TIMP-3 expression, indicating that ERK1/2 and p38 MAPK mediate the effect of TGF-beta on TIMP-3 expression. Specific activation of p38 alpha 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-beta 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, p38 alpha, 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.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available