Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.24.3 (collagenase)
 18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A clone containing genomic sequences of part of the murine collagenase type 1 (MMP-1) gene was isolated. It contains exons 1-6 encoding all the domains required for collagenase function and 9 kb of 5'-flanking sequences. The gene organization and exon/intron borders are highly similar to the already described human and rabbit MMP-1 genes. However, neither the intron sequences, nor the promoter region up to position -660 exhibit significant sequence homologies with rabbit and human MMP-1, except for an AP-1-binding site and two PEA-3 consensus sequences. Binding studies in vitro revealed that the AP-1-binding site is recognized by Fos/Jun heterodimers with very high affinity. By in situ hybridization the mouse MMP-1 gene was located to the A1-A2 region of chromosome 9 in proximity to the curly whiskers (cw) locus. Based on the lack of sequence homologies of the promoter and intron regions, and since the chromosomal localization of the mouse and human MMP-1 genes may not be syntenic, these data strongly support previous suggestions that the MMP-1 genes from mouse, compared with rabbit and human, have evolved from different ancestral genes. The presence of the AP-1- and PEA-3- binding sites in all mammalian MMP-1 genes isolated so far, may, however, suggest evolutionary selection for common regulatory mechanisms of MMP-1 transcription.
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PMID:Structural organization and chromosomal localization of the mouse collagenase type I gene. 775 67

To investigate the regulation of promoters containing classical phorbol ester response sequences (PEA-3/12-O-tetradecanoylphorbol-13-acetate response element motifs) by protein kinase C (PKC) isozymes, co-transfections were performed in human dermal fibroblasts with a plasmid containing either the human collagenase promoter or the porcine urokinase plasminogen activator (uPA) promoter linked to the chloramphenicol acetyltransferase gene and a plasmid expressing an individual PKC isozyme. Using this experimental design, seven PKC isozymes were analyzed for their ability to trans-activate the collagenase and uPA promoters. Our results demonstrate that only PKC delta, epsilon, and eta trans-activated the collagenase promoter and that binding of Ap-1 family members to the collagenase 12-O-tetradecanoylphorbol-13-acetate response element (TRE) was not responsible for the isozyme-specific trans-activation. In contrast, the uPA promoter was stimulated by all of the PKC isozymes examined (PKC alpha, betaII, gamma, delta, epsilon, zeta, and eta). These results indicate that PKC isozymes differentially regulate promoters containing PEA-3/TRE motifs and suggest that individual isozymes play unique roles within the cell.
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PMID:Protein kinase C isozymes differentially regulate promoters containing PEA-3/12-O-tetradecanoylphorbol-13-acetate response element motifs. 870 56

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

Estradiol (E) primes human endometrial stromal cells (HESCs) for the decidualizing effects of progesterone in vivo and in vitro. Matrix metalloproteinase (MMP) expression was evaluated in confluent HESCs incubated in control medium, and in medium supplemented with either E, or the synthetic progestin medroxyprogesterone acetate (P), or E + P. Measurements with a specific ELISA indicated that basal pro-MMP-1 output was unaffected by E, whereas E + P, which induces the expression of several decidualization-related markers, produced a time-dependent inhibition in HESC-secreted levels of pro-MMP-1. Consistent with progestin inhibition of MMP-1 protein expression in the HESCs, P but not E, reduced steady state levels of MMP-1 messenger RNA (mRNA) as determined by Northern analysis. By contrast, mRNA levels for MMP-2 and the MMP inhibitor TIMP-1 were not altered by either P or E. Steroid withdrawal studies indicated that after MMP-1 expression was suppressed by incubation of the HESCs with E + P, 4 days of exposure to the antiprogestin RU 486 (mifepristone) significantly up-regulated MMP-1 levels in the conditioned medium by severalfold compared with cultures maintained in E + P. The change to steroid-free control medium required a more prolonged period of withdrawal to attain up regulatory effects that were comparable with those evoked by RU 486. The ELISA measurements were validated by immunoblot analysis with a specific MMP-1 antibody, which showed corresponding changes in a band at the expected mobility of about 50 kDa. Moreover, Northern analysis revealed parallel changes in MMP-1 mRNA levels, whereas neither MMP-2 nor TIMP-1 mRNA levels were modulated by adding or withdrawing steroids. The contrast between regulated MMP-1 expression and constitutive MMP-2 expression observed in the cultured HESCs is consistent with the demonstrated presence on the MMP-1 promoter of regulatory elements such as AP-1 and PEA-3 that are absent from the MMP-2 promoter. Extrapolation of these in vitro changes in HESCs to in vivo endometrial events suggests that: 1) inhibition of MMP-1 expression by E and progesterone would stabilize the perivascular endometrial ECM to prevent local hemorrhage during endovascular invasion by the implanting trophoblast; 2) enhanced expression of MMP-1 evoked by steroid withdrawal would mediate endometrial ECM degradation leading to sloughing of the functional layer during menstruation.
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PMID:Matrix metalloproteinase and matrix metalloproteinase inhibitor expression in endometrial stromal cells during progestin-initiated decidualization and menstruation-related progestin withdrawal. 979 72

Interleukin-1 has been shown to contribute to infection-induced inflammatory processes during pregnancy. Prior work from this laboratory has demonstrated that serotonin-induced IL-1alpha also is required for the in-vitro production of collagenase in uterine smooth muscle cells, a normal, non-inflammatory process that occurs in-vivo during post-partum uterine involution. To understand the molecular mechanisms that regulate transcription of the IL-1alpha gene in these cells, we isolated and characterized 1.6 kilobases of the 5'-flanking region of the rat IL-1alpha gene. Sequencing and primer extension identified a single transcription start site and multiple potential regulatory elements, including a TATA box at - 30 bp, a CAAT box at - 74 bp, and a conserved AP-1 site at - 9 bp. This 5'-flanking DNA exhibited low basal promoter activity that was inducible by serotonin. Serotonin-induced promoter activity was unaffected or induced by either medroxyprogesterone or IL-1 receptor antagonist. This occurred despite the ability of both of these hormones to markedly decrease IL-1alpha mRNA. Deletional analysis revealed a strong repressor in the region between - 147 and - 98 bp; removal of this sequence resulted in a fivefold higher basal promoter activity that was still serotonin responsive. Constitutive promoter activity appeared to reside between - 97 and - 22 bp. Deletion of this promoter region, which contained the TATA and CAAT boxes and an NF-IL-6/PEA-3 site, resulted in decreased basal transcriptional activity to the low level seen in larger constructs. Mutational analysis showed that serotonin-inducible transcriptional activity was mediated, at least in part, by the conserved AP-1 site at - 9 bp. This site is located within a larger extended palindromic region: 5'-AAGCCTGACTCAGACTT-3', that together effects both the basal and serotonin-inducible expression of the IL-1alpha gene.
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PMID:Serotonin-inducible transcription of interleukin-1alpha in uterine smooth muscle cells requires an AP-1 site: cloning and partial characterization of the rat IL-1alpha promoter. 1043 20

In 1994, a new human matrix metalloproteinase (MMP) was identified and cloned. This enzyme displayed the structural characteristics of a collagenase and was named collagenase-3, or MMP-13 according to MMP nomenclature. This review describes the research advances in the understanding of the function/production of the human MMP-13 at the tissular, cellular, biochemical, and molecular levels. In contrast to many human MMPs, the MMP-13 distribution pattern is restrictive in normal tissues and selective in pathological conditions. This enzyme plays a premier role in tissue remodeling as well as in some pathological processes such as cancer and arthritis. MMP-13 demonstrates versatility in its substrate utilization. In addition to being highly active on type II collagen, MMP-13 cleaves other substrates, mostly macromolecules of the extracellular matrix, but also molecules such as connective tissue (CTGF) and fibrinogen. MMP-13 is controlled at multiple levels: i.e., the expression/synthesis, activation, and inhibition of the active enzyme. Unlike other MMPs, the human MMP-13 gene is transcribed into several transcripts which could yield proteins with activities and functions different from those of the original MMP-13. Activation of MMP-13 involves a proteolytic cascade including MMP-14 (MT1-MMP) and MMP-2. Transcription is regulated by numer-ous agents, mostly by growth factors, proinflammatory cytokines and mechanical stimuli. Cloning of the MMP-13 promoter revealed the presence of a number of binding sites implicated in transcriptional regulation: TATA box, AP-1, PEA-3, OSE-2, and the newly identified negative regulator, AGRE. MMP-13 constitutes a more complex system than was originally thought. Although our knowledge of MMP-13 biochemistry and regulation has greatly increased over the years, there is still much to discover.
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PMID:Ten years in the life of an enzyme: the story of the human MMP-13 (collagenase-3). 1714 75

OBJECTIVES - Relaxin induces the matrix metalloproteinase MMP-1 (collagenase-1) in TMJ fibrocartilaginous cells, and this response is potentiated by beta-estradiol. We identified the MMP-1 promoter sites and transcription factors that are induced by relaxin with or without beta-estradiol in fibrocartilaginous cells. MATERIAL AND METHODS - Early passage cells were transiently transfected with the pBLCAT2 plasmid containing specific segments of the human MMP-1 promoter regulating the chloramphenicol acyl transferase (CAT) gene and co-transfected with a plasmid containing the beta-galactosidase gene. The cells were cultured in serum-free medium alone or medium containing 0.1 ng/ml relaxin, or 20 ng/ml beta-estradiol or both hormones, and lysates assayed for CAT and beta-galactosidase activity. RESULTS - Cells transfected with the -1200/-42 or -139/-42 bp MMP-1 promoter-reporter constructs showed 1.5-fold and 3-fold induction of CAT by relaxin in the absence or presence of beta-estradiol, respectively. Relaxin failed to induce CAT in the absence of the -137/-69 region of the MMP-1 promoter, which contains the AP-1-and PEA3-binding sites. Using wild type or mutated minimal AP-1 and PEA-3 promoters we found that both these promoter sites are essential for the induction of MMP-1 by relaxin. The mRNAs for transcription factors c-fos and c-jun, which together form the AP-1 heterodimer, and Ets-1 that modulates the PEA-3 site, were upregulated by relaxin or beta-estradiol plus relaxin. CONCLUSION - These studies show that both the AP-1 and PEA-3 promoter sites are necessary for the induction of MMP-1 by relaxin in fibrocartilaginous cells.
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PMID:Induction of MMP-1 (collagenase-1) by relaxin in fibrocartilaginous cells requires both the AP-1 and PEA-3 promoter sites. 1962 19