Structure and Regulation of the Human Collagenase3 Gene

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The gene encoding human collagenase-3 has been recently characterized using genomic clones obtained from a DNA library prepared in EMBL3 phage.30 The gene spans more than

Fig. 3.3. Structure of the promoter region of the human collagenase-3 gene. Sequences relevant for the transcriptional activity of the gene, including TATA box, and AP-1, PEA3, and OSE-2 motifs are indicated.

12.5 kb, and is composed of 10 exons and 9 introns. Its overall organization in terms of size of exons and distribution of intron-exon junctions is similar to other human MMP genes like collagenase-131 and macrophage metalloelastase,32 but more distantly related to genes coding for gelatinases33,34 and stromelysin-3.35 In addition, the collagenase-3 gene has the unique features, of an extremely short first intron (92 bp) and an unusually large last exon (1371 bp), the largest among all the equivalent exons from MMP genes.30 The increased length of this exon derives mainly from the presence of a large 3'-untranslated region that could be important in posttranscriptional regulatory events. In fact, this region contains three potential polyadenylation sites that are used to generate at least three different colla-genase-3 mRNAs, differing in size and relative abundance.1 The human collagenase-3 gene is located on chromosome 11q22.3,36,37 clustered to at least seven other members of the MMP gene family: collagenases-1 (MMP-1), and -2 (MMP-8); stromelysins-1 (MMP-3) and -2 (MMP-10), matrilysin (MMP-7), macrophage metalloelastase (MMP-12), and enamelysin (MMP-20).38 Fine physical mapping of this region of the human genome using pulsed-field gel electrophoresis has shown that MMP-13 is localized to the telomeric side of the MMP cluster, the relative order of the loci being centromere/MMP-8/MMP-10/MMP-1/MMP-3/ MMP-12/MMP-7/MMP-20/MMP-13 /telomere.35-38 On this basis, MMP-13 would be located close to the ataxia telangiectasia gene, a human disease characterized by its association to an increased likelihood of developing diverse human carcinomas.39

The promoter region of the human collagenase-3 gene has been analyzed both structurally and functionally,30,40 looking for regulatory motifs that could affect its transcription (Fig. 3.3). Like most MMP genes, the human collagenase-3 gene contains at equivalent positions a TATA box sequence (TATAAA), an AP-1 motif (TGACTCA), and a PEA3 site (TAGGAAGT). The presence of adjacent AP-1 and PEA3 motifs is of special interest in relation to the high-level expression of collagenase-3 in human carcinomas, since a combination of these two elements appears to confer responsiveness to growth factors, oncogene products and tumor promoters.41 Functional characterization of these elements has revealed that the AP-1 site is indeed functional, recognized by members of the Fos and Jun family of transcription factors, and responsible, at least in part, for the observed inducibility of this gene by TPA, TGF-p and IL-1p in human fibroblasts.8,30,42 The involvement of AP-1 binding factors in mediating collagenase-3 expression in murine fibroblasts has been confirmed by using cells derived from c-fos deficient mice generated through gene knockout techniques. In fact, collagenase-3 cannot be induced by growth factors or tumor promoters in 3T3-type cell lines derived from c-fos-' mice embryonic fibroblasts.43 However, unlike collagenase-1, in which a cooperative effect between AP-1 and PEA3 is required, the PEA3 site does not appear to play a significant role in the transcriptional regulation of the human collagenase-3 gene.30 Nevertheless, the presence of a functional AP-1 site that may contribute to the induction of this gene by oncogenic proteins, tumor promoters, or inflammatory mediators is a clear indication at the molecular level that collagenase-3 expression may be linked to oncogenic transformation or destructive joint diseases like rheumatoid arthritis. A final point of interest is that the promoter of the human collagenase-3 gene contains an OSE-2 element (CAAACCACA), proposed to be essential for the osteoblastic-specific expression of the mouse osteocalcin gene.44 The presence of this sequence in the human collagenase-3 gene, as well as in their murine homologues,45,46 could provide an explanation for recent results indicating that this gene is expressed in osteoblasts during fetal ossification as well as in postnatal bone remodeling processes.15,47

In summary, the mechanisms controlling expression of human collagenase-3 present both similarities and differences with those operating in other MMP genes. Of special relevance are the differences between collagenase-3 and collagenase-1, which belong to the same subfamily of MMPs and display similar substrate specificity on fibrillar collagens. These differences could provide a molecular basis for the different expression pattern of both enzymes, collagenase-1 being widely distributed and collagenase-3 highly restricted.

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