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Originally published In Press as doi:10.1074/jbc.M007529200 on September 18, 2000

J. Biol. Chem., Vol. 275, Issue 51, 39981-39990, December 22, 2000
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Multiple Regulatory Elements in the Murine Stromelysin-3 Promoter
EVIDENCE FOR DIRECT CONTROL BY CCAAT/ENHANCER-BINDING PROTEIN beta  AND THYROID AND RETINOID RECEPTORS*

Marie-Gabrielle LudwigDagger , Paul Bassetdagger , and Patrick Anglard§

From the Institut de Génétique et de Biologie Moléculaire et Cellulaire, INSERM, CNRS, Université Louis Pasteur, BP 163, 67404 Illkirch Cedex, C.U. de Strasbourg, France

Stromelysin-3 (ST3) belongs to the matrix metalloproteinase (MMPs) family, a protease family involved in tissue remodeling. Although this family of enzymes is regulated by nuclear receptors, few hormone-responsive elements have been demonstrated in MMP promoters. In order to identify regulatory elements and/or factors that control the expression of the mouse st3 gene, we have analyzed genomic sequences encompassing 5 kilobase pairs of the ST3 promoter. Analysis of these sequences revealed several CCAAT/enhancer-binding proteins (C/EBP) and retinoic acid-responsive elements (RAREs), as well as one thyroid-responsive element. However, in contrast to most MMP promoters, no AP-1-binding sites were identified. Specific binding activities were demonstrated for all elements. Consistent with previous reports, retinoid X receptor is required for maximal binding to the ST3 RAREs and the TRE. The ST3-C/EBP element was shown to mediate dose-dependent promoter activation by C/EBPbeta . Among the RAREs, the proximal DR1-RARE was shown to be sufficient for ST3 promoter activation by ligand-bound retinoid receptors, whereas the two distal DR2-RAREs appear to be involved more in the control of base-line promoter activity. Accordingly, ST3 expression was induced by retinoic acid and was reduced in cells where specific retinoic acid receptors had been inactivated. The involvement of these conserved regulatory elements is discussed in the context of physiological or pathological situations associated with st3 expression. Our findings therefore assign to C/EBP, retinoids, and thyroid hormone important roles in the regulation of ST3 gene expression.

* This work was supported by funds from INSERM, the CNRS, the Hôpital Universitaire de Strasbourg, the Bristol-Myers Squibb Pharmaceutical Research Institute, the Association pour la Recherche sur le Cancer Project 5421, the Ligue Nationale Française Contre le Cancer, and the Comité du Bas Rhin et du Haut-Rhin, and the Fondation pour la Recherche Médicale Française.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

This work is dedicated to the memory of Professor Paul Basset.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBankTM/EMBL Data Bank with accession number(s) AF297645.

dagger Deceased.

Dagger Supported by a fellowship from the Association pour la Recherche sur le Cancer.

§ To whom correspondence should be addressed: Institut de Génétique et de Biologie Moléculaire et Cellulaire, BP 163, 67404 Illkirch Cedex, France. Tel.: 33-388-65-3420; Fax: 33-388-65-3201; E-mail: anglard@igbmc.u-strasbg.fr.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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