Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.23 (MMP)
 4,246 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Human collagenase-3 (MMP13) is a recently identified member of the matrix metalloproteinase (MMP) family that is expressed in breast carcinomas and in articular cartilage from arthritic patients. In this work we have isolated and characterized genomic clones coding for human collagenase-3. This gene is composed of 10 exons and 9 introns and spans over 12.5 kb. The overall organization of the collagenase-3 gene is similar to that of other MMP genes clustered at chromosome 11q22, including fibroblast collagenase (MMP-1), matrilysin (MMP-7), and macrophage metalloelastase (MMP-12), but is more distantly related to genes coding for stromelysin-3 (MMP-11), gelatinase-A (MMP-2), and gelatinase-B (MMP-9), which map outside of this gene cluster. Nucleotide sequence analysis of about 1 kb of the 5'-flanking region of the collagenase-3 gene revealed the presence of a TATA box, an AP-1 motif, a PEA-3 consensus sequence, an osteoblast specific element (OSE-2), and a TGF-beta inhibitory element. Transient transfection experiments in HeLa and COS-1 cells with chloramphenicol acetyltransferase (CAT)-containing constructs showed that the AP-1 site is functional and responsible for the observed inducibility of the reporter gene by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). However, and in contrast to other MMP genes, no significative synergistic effect on CAT activity between the AP-1 and PEA-3 elements found in the collagenase-3 gene promoter was found. DNA binding analysis with nuclear extracts from HeLa cells revealed the formation of specific complexes between collagenase-3 promoter sequences containing the AP-1 site and nuclear proteins. The presence of this AP-1 functional site, which is able to confer responsiveness to a variety of tumor promoters and oncogene products, amy contribute to explaining the high-level expression of collagenase-3 in breast carcinomas and degenerative joint diseases.
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PMID:Structural analysis and promoter characterization of the human collagenase-3 gene (MMP13). 911 88

Many females develop bone diseases such as osteoporosis, and joint diseases such as osteoarthritis after menopause when estrogen levels decline. As estrogen receptors (ER) are present in such tissues, it is possible that the loss of estrogen at menopause influences the expression of enzymes such as members of the MMP family of proteinases to affect bone and connective tissue metabolism. The present study was undertaken to assess a possible relationship between ER-alpha and MMP-13 expression at the promoter level, and to determine how such a relationship could be modulated by ligands such as estrogen. Using a rabbit synovial cell line lacking endogenous ER, a transient transfection system with an ER-alpha construct, and a series of MMP-13 promoter-luciferase constructs of varying lengths and with specific mutations in transcription factor binding sites, it was found that ER-alpha can significantly enhance MMP-13 promoter activity via the AP-1 site, with modulatory influences by the Runx and PEA-3 sites on this ER-alpha dependent enhancement of the promoter activity. This enhancement by ER-alpha was significantly depressed in the presence of 17-ss-estradiol in a dose dependent manner. The influence of tamoxifen and raloxifen on the activity of the ER-alpha was consistent with their known agonist/antagonist activity. These findings indicate that loss of estrogen in vivo could potentially lead to enhanced expression of MMP-13, a proteinase that has been implicated in both osteoporosis and osteoarthritis, and thus contribute to the development and progression of these conditions.
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PMID:Estrogen receptor alpha regulates matrix metalloproteinase-13 promoter activity primarily through the AP-1 transcriptional regulatory site. 1691 24