Abstract
In the present study, we have isolated the human stromelysin-3 (ST3) gene which encodes a matrix metalloproteinase (MMP) expressed in fibroblastic cells of tissues associated with intense remodeling. The gene was found to span 11.5 kilobases (kb) including 8 exons and 7 introns. The genomic organization of ST3 gene exons is well conserved compared to other members of the MMP family, except for the 3 last exons corresponding to the hemopexin-like domain and to a long 3'-untranslated region. The transcription initiation site was located 31 nucleotides downstream of a TATA box. Analysis of 1.4 kb of 5'-flanking DNA sequence in the ST3 gene promoter revealed the presence of putative regulatory elements, but no consensus sequence for AP1-binding site in contrast to other MMP promoters. However, a specific cis-acting retinoic acid responsive element of the DR1 type was identified in the proximal region (-385) of the ST3 gene promoter. Transient transfection experiments demonstrated that a minimal promotor activity could be modulated by various sequences within the 3.4 kb of 5'-flanking region, and that the ST3 promoter was transactivated by retinoic acid receptors in the presence of retinoic acid. These findings indicate that the human ST3 gene promoter is characterized by structural and functional features which differ from those previously described in other MMP promoters, and further supports the possibility that ST3 gene expression is controlled by specific factors during tissue remodeling.
Highlights
In the present study, we have isolated the human stromelysin-3 (ST3) gene which encodes a matrix metalloproteinase (MMP) expressed in fibroblastic cells of tissues associated with intense remodeling
These findings indicate that the human ST3 gene promoter is characterized by structural and functional features which differ from those previously described in other MMP promoters, and further supports the possibility that ST3 gene expression is controlled by specific factors during tissue remodeling
We show in the present study that the ST3 gene promoter markedly differs from previously described MMP promoters by the absence of a consensus API-binding site and the presence of a functional retinoic acid responsive element (RARE) which can be transactivated by retinoic acid receptors in the presence of retinoic acid (RA)
Summary
We have isolated the human stromelysin-3 (ST3) gene which encodes a matrix metalloproteinase (MMP) expressed in fibroblastic cells of tissues associated with intense remodeling. Transient transfection experiments demonstrated that a minimal promoter activity could be modulated by various sequences within the 3.4 kb of 5'-flanking region, and that the ST3 promoter was transactivated by retinoic acid receptors in the presence of retinoic acid These findings indicate that the human ST3 gene promoter is characterized by structural and functional features which differ from those previously described in other MMP promoters, and further supports the possibility that ST3 gene expression is controlled by specific factors during tissue remodeling. Most MMP promoters including those of the interstitial collagenase (14, 15), stromelysin-l and -2 (16), matrilysin (17), and gelatinase B (18) genes are characterized by the presence of an API-binding site, called TRE (for TPA responsive element), which has been identified in a very conserved location within the first 80 bp upstream of the transcription start. Since this API motif has been shown to confer responsiveness to various stimuli including oncogenes (19), growth factors (20, 21), and cytokines (22-24), it has been proposed to playa major role in the induction (or repression) of transcription from various MMP gene promoters (9, 10, 25)
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