Browse by author
Lookup NU author(s): Professor David YoungORCiD,
Emeritus Professor Drew Rowan
Full text for this publication is not currently held within this repository. Alternative links are provided below where available.
The balance between matrix metalloproteinases (MMPs) and their inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), is pivotal in the remodeling of extracellular matrix. TGF-β has profound effects on extracellular matrix homeostasis, in part via its ability to alter this balance at the level of gene expression. The intracellular signaling pathways by which TGF-β mediates its actions include the Smad pathway, specific to the TGF-β superfamily, but also, for example, mitogen-activated protein kinase pathways; furthermore, crosstalk between the Smads and other signaling pathways modifies the TGF-β response. The reciprocal effect of TGF-β on the expression of Timp-1 and MMP-1 supports its role in matrix anabolism, yet the mechanisms by which TGF-β induces Timp-1 and represses induced MMP-1 have remained opaque. Here, we (i) investigate the mechanism(s) by which TGF-β1 induces expression of the Timp-1 gene and (ii) compare this with TGF-β1 repression of phorbol ester-induced MMP-1 expression. We report that the promoter-proximal activator protein 1 (AP1) site is essential for the response of both Timp-1 and MMP-1 to TGF-β (induction and repression, respectively). c-Fos, JunD, and c-Jun are essential for the induction of Timp-1 gene expression by TGF-β1, but these AP1 factors transactivate equally well from both Timp-1 and MMP-1 AP1 sites. Smad-containing complexes do not interact with the Timp-1 AP1 site, and overexpression of Smads does not substitute or potentiate the induction of the gene by TGF-β1; furthermore, Timp-1 is still induced by TGF-β1 in Smad knockout cell lines, although to varying extents. In contrast, Smads do interact with the MMP-1 AP1 site and mediate repression of induced MMP-1 gene expression by TGF-β1.
Author(s): Hall M-C, Young DA, Waters JG, Rowan AD, Chantry A, Edwards DR, Clark IM
Publication type: Article
Publication status: Published
Journal: Journal of Biological Chemistry
ISSN (print): 0021-9258
ISSN (electronic): 1083-351X
Publisher: American Society for Biochemistry and Molecular Biology, Inc.
PubMed id: 12525489
Altmetrics provided by Altmetric