Multiple regulatory elements in the murine stromelysin-3 promoter. Evidence for direct control by CCAAT/enhancer-binding protein beta and thyroid and retinoid receptors

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.