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The comparative role of activator protein 1 and Smad factors in the regulation of Timp-1 and MMP-1 gene expression by transforming growth factor-β1

Lookup NU author(s): Professor David YoungORCiD, Emeritus Professor Drew Rowan

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Abstract

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.

Publication metadata

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

Year: 2003

Volume: 278

Issue: 12

Pages: 10304-10313

ISSN (print): 0021-9258

ISSN (electronic): 1083-351X

Publisher: American Society for Biochemistry and Molecular Biology, Inc.

URL: http://dx.doi.org/10.1074/jbc.M212334200

DOI: 10.1074/jbc.M212334200

PubMed id: 12525489

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