Multiple regulatory elements in the murine stromelysin-3 promoter - Evidence for direct control by CCAAT/enhancer-binding protein beta and thyroid and retinoid receptors
Mg. Ludwig et al., Multiple regulatory elements in the murine stromelysin-3 promoter - Evidence for direct control by CCAAT/enhancer-binding protein beta and thyroid and retinoid receptors, J BIOL CHEM, 275(51), 2000, pp. 39981-39990
Stromelysin-3 (ST3) belongs to the matrix metalloproteinase (MMPs) family,
a protease family involved in tissue remodeling. Although this family of en
zymes is regulated by nuclear receptors, few hormone-responsive elements ha
ve been demonstrated in MMP promoters. In order to identify regulatory elem
ents and/or factors that control the expression of the mouse st3 gene, we h
ave analyzed genomic sequences encompassing 5 kilobase pairs of the ST3 pro
moter. 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 de
monstrated for all elements. Consistent with previous reports, retinoid X r
eceptor is required for maximal binding to the ST3 RAREs and the TRE. The S
T3-C/EBP element was shown to mediate dose-dependent promoter activation by
C/EBP beta, Among the RAREs, the proximal DR1-RARE was shown to be suffici
ent 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 retinoi
c 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 assoc
iated with st3 expression. Our findings therefore assign to C/EBP, retinoid
s, and thyroid hormone important roles in the regulation of ST3 gene expres
sion.