Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.4.24.3 (collagenase)
18,340 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Recent studies show that the p53 tumor suppressor protein is overexpressed in rheumatoid arthritis (RA) synovium and that somatic mutations previously identified in human tumors are present in RA synovium (Firestein, G. S., Echeverri, F., Yeo, M., Zvaifler, N. J., and Green, D. R. (1997) Proc. Natl. Acad. Sci. U. S. A. 94, 10895-10900; Firestein, G. S., Nguyen, K., Aupperle, K. R., Yeo, M., Boyle, D. L., and Zvaifler, N. J. (1996) Am. J. Pathol. 149, 2143-2151; Reme, T., Travaglio, A., Gueydon, E., Adla, L., Jorgensen, C., and Sany, J. (1998) Clin. Exp. Immunol. 111, 353-3581). We hypothesize that the abnormality of p53 seen in RA synovium may contribute to joint degeneration through the regulation of human matrix metalloproteinase-1 (hMMP-1, collagenase-1) gene expression. Transcription assays were performed with luciferase reporters driven by the promoter of the hMMP-1 gene or by a minimal promoter containing tandem repeats of the consensus binding sequence for activator protein-1, cotransfected with p53-expressing plasmids. The results revealed that (i) wild-type (wt) p53 down-regulated the promoter activity of hMMP-1 in a dose-dependent fashion; (ii) four of six p53 mutants (commonly found in human cancers) lost this repression activity; and (iii) this p53 repression activity was mediated at least in part by the activator protein-1 sites found in the hMMP-1 promoter. These findings were further confirmed by Northern analysis. The down-regulation of hMMP-1 gene expression by endogenous wt-p53 was shown by treatment of U2-OS cells, a wt-p53-containing osteogenic sarcoma line, and Saos-2 cells, a p53-negative osteogenic sarcoma line, with etoposide, a potent inducer of p53 expression. p53, activated by etoposide, appears to block hMMP-1 promoter activity induced by etoposide in U2-OS cells. In summary, we have shown for the first time that the hMMP-1 gene is a p53 target gene, subject to p53 repression. Because MMP-1 is principally responsible for the irreversible destruction of collagen in articular tissue in RA, abnormality of p53 may contribute to joint degeneration through the regulation of MMP-1 expression.
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PMID:p53 down-regulates human matrix metalloproteinase-1 (Collagenase-1) gene expression. 1020 59

Activator protein-1 (AP-1) is a transcription factor that consists of either a Jun-Jun homodimer or a Jun-Fos heterodimer. Transactivation of AP-1 is required for tumor promoter-induced transformation in mouse epidermal JB6 cells and for progression in mouse and human keratinocytes. Until now, the question of whether AP-1 transactivation is required for carcinogenesis in vivo has remained unanswered, as has the issue of functionally significant target genes. To address these issues we have generated a transgenic mouse in which transactivation mutant c-jun (TAM67), under the control of the human keratin-14 promoter, is expressed specifically in the basal cells of the epidermis where tumor induction is initiated. The keratin-14-TAM67 transgene was expressed in the epidermis, tongue, and cervix, with no apparent abnormalities in any tissue or organ. TAM67 expression blocked 12-O-tetradecanoylphorbol 13-acetate (TPA, phorbol 12-tetradecanoate 13-acetate) induction of the AP-1-regulated luciferase in AP-1 luciferase/TAM67 mice, but did not inhibit induction of candidate AP-1 target genes, collagenase-1 or stromelysin-3. More interestingly, TAM67 expression did not inhibit TPA-induced hyperproliferation. In two-stage skin carcinogenesis experiments, the transgenic animals showed a dramatic inhibition of papilloma induction. We conclude that transactivation of a subset of AP-1-dependent genes is required for tumor promotion and may be targeted for cancer prevention.
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PMID:Transgenic mice demonstrate AP-1 (activator protein-1) transactivation is required for tumor promotion. 1044 79

Basic fibroblast growth factor (bFGF) stimulates collagenase-3 synthesis in fetal rat osteoblast-enriched (Ob) cells. In this study we examined the mechanism of collagenase-3 regulation in Ob cells. bFGF at 0.6 nM or more increased the transcriptional rate of collagenase-3 by 3- to 7-fold. bFGF at 0.6 nM increased the activity of collagenase-3 promoter-luciferase reporter deletion constructs from -721 to -53 nucleotides transiently transfected into Ob cells by 3- to 5-fold. The minimal bFGF response was retained within the -53 to +28 sequence. Mutational analysis revealed that the bFGF effect was mediated through an activator protein-1 (AP-1)-binding site located at -48 to -42 nucleotides in the promoter. bFGF stimulated the binding of nuclear factors to the collagenase AP-1 site by 3- to 4-fold, as determined by electrophoretic mobility shift assays. Supershift analysis of nuclear extracts revealed that bFGF stimulates the occupancy of AP-1 site by c-Jun, JunB, JunD, c-Fos, FosB, and Fra2. In conclusion, bFGF increases collagenase-3 gene transcription, an effect mediated through an AP-1 site, due to the induction or activation of Jun and Fos family transcription factors. The stimulation of collagenase-3 synthesis by bFGF may be critical in mediating the actions of this growth factor in bone remodeling.
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PMID:Basic fibroblast growth factor stimulates collagenase-3 promoter activity in osteoblasts through an activator protein-1-binding site. 1083 Mar 7

The effects of p38 mitogen-activated protein kinases on ultraviolet (UV) B irradiation-induced activator protein 1 (AP-1) activation were studied in a human keratinocyte cell line, HaCaT. The HaCaT cells were stably transfected with a plasmid containing a promoter fragment of human collagenase 1 driving a luciferase reporter gene. There is an AP-1-binding site within this fragment, without any other known transcription factor-binding sites. As we reported previously, UVB significantly induces activation of AP-1 and p38 in HaCaT cells. SB202190, a p38-specific inhibitor, inhibits UVB-induced p38 activation and c-fos gene expression. In the present study, we further examined the role of p38 in UVB-induced AP-1 activation. We observed that SB202190 strongly inhibited UVB-induced AP-1 transactivation at different time points and UVB doses in transfected HaCaT cells. Furthermore, SB202190 markedly inhibited UVB-induced AP-1 DNA binding as determined by mobility shift analyses. These results suggested, for the first time, that activation of p38 is required for UVB-induced AP-1 activation in human keratinocytes. In addition, a potential mechanism of UVB-induced AP-1 activation through p38 is to enhance AP-1 complex binding to its target DNA. Because c-fos gene expression plays a critical role in UVB-induced AP-1 activation and p38 is required for UVB-induced c-fos gene expression in HaCaT cells, as reported previously, a potential UVB signaling cascade for AP-1 activation in human keratinocytes has been determined. This cascade involves UVB, p38 activation, c-fos gene expression, and AP-1 activation.
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PMID:Role of p38 mitogen-activated protein kinases in ultraviolet-B irradiation-induced activator protein 1 activation in human keratinocytes. 1097 89

beta-catenin was shown to be a major oncoprotein in colon cancer development. Its oncogenic function as a transcriptional activator is upregulated by mutations in the APC tumor suppressor gene, leading to a constitutive activation of the proliferation-associated genes c-myc and cyclin D. The aim of this study was to demonstrate a role of APC-mutations and dysregulated beta-catenin also for the progression of colorectal cancer, by identifying new target genes of beta-catenin associated with tumor invasion and metastasis. Potential invasion genes regulated by beta-catenin and its DNA binding partner TCF4 were identified by a computer search for the consensus DNA binding sequence in relevant promoter regions. Specific DNA binding was confirmed by gel shift assays. Functional importance of beta-catenin for the activation of identified genes was determined by luciferase reporter assays. The significance was demonstrated by coexpression of nuclear beta-catenin and the identified target genes by immunohistochemistry. Among other invasion genes, we identified the matrix metallo proteinases MMP-7 and MMP-1 activated by beta-catenin in the tumor cells. MMP-7 is an important factor for invasion and metastasis and overexpressed in 75% of colon carcinomas. The significance for human colon cancer development was demonstrated by a correlated overexpression of beta-catenin and the MMPs, beginning in large, severely dysplastic adenomas. Our results explain the high percentage of MMP-7 overexpression in colorectal tumors and the resulting activation of invasive growth. Moreover by identifying dysregulated beta-catenin as a transcriptional activator of MMPs and other invasion factors, we demonstrated an important role of mutated APC not only for early steps but also for the progression of colorectal carcinogenesis.
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PMID:[beta-Catenin induces invasive growth by activating matrix metalloproteinases in colorectal carcinoma]. 1121 38

The expression of collagenase (matrix metalloproteinase 1) in human fibroblasts increases during aging both in vivo and in vitro. This age-associated increase in collagenase expression has been postulated to contribute to the age related decline in tissue function by increasing proteolysis of matrix components, but little is known regarding the regulation of collagenase expression. We examined the role that the serine/threonine kinase Akt plays in collagenase expression during in vitro senescence of WI-38 normal human lung fibroblast cells. Our results indicate that Akt-mediated signals, acting through the forkhead transcription factor FKHRL1, can regulate collagenase expression in WI-38 fibroblasts. Dominant negative forms of Akt increase collagenase promoter activity in early passage WI-38 fibroblasts, whereas an active form of Akt suppresses steady state levels of collagenase mRNA in senescent WI-38 fibroblasts. In addition, the activity of a synthetic promoter containing forkhead-specific binding sites, as measured by luciferase activity, is much higher in senescent cells compared with early passage WI-38 fibroblasts. These results indicate that members of the forkhead family of transcription factors play a role in the regulation of the collagenase promoter and that increased activity of forkhead transcription factors may underlie the increase in collagenase expression observed during replicative senescence.
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PMID:Regulation of collagenase expression during replicative senescence in human fibroblasts by Akt-forkhead signaling. 1175 76

A fragment of the 5' untranslated region corresponding to the canine matrix metalloproteinase-13 (MMP-13), collagenase-3 gene promoter has been isolated and characterized in rat cardiocytes to investigate the role of MMP-13 in cardiac disease. The promoter fragment (1.5 kb) demonstrated regions of sequence homology with the collagenase gene promoter sequences already determined for other species. Conserved regions were identified and shown to correlate with DNA binding motifs including AP-1 sites, a nuclear factor (NF) B-like binding domain, GATA and Nkx2.5 sites. A consensus TATA box was identified and shown to direct transcription initiation approximately 27 bp upstream of the translation start site. The canine MMP-13 promoter fragment was sufficient to drive basal expression of a luciferase reporter gene in both Madin Darby canine kidney cells (MDCK) and primary rat cardiocytes. The activity of the promoter fragment could be significantly increased by the treatment of transfected primary rat cardiocytes with interleukin-1 (IL-1) and basic fibroblastic growth factor (bFGF), with some induction also observed with tumour necrosis factor (TNF). The canine MMP-13 promoter activity has also been compared to the basal and induced activity of the canine MMP-9, gelatinase B promoter in these cell types.
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PMID:The cloning and functional analysis of canine matrix metalloproteinase-13 gene promoter. 1194 78

Immediately before parturition the cervix undergoes striking changes in structure (ripening) that facilitate dilatation and effacement. Cervical ripening shares many features in common with inflammation-associated tissue remodeling, making it a valuable process to explore with respect to the biochemical events in extracellular matrix restructuring. Cervical ripening can be pharmacologically induced with prostaglandin E(2) (PGE(2)). Among the biochemical changes in the cervix at parturition is a marked increase in the hyaluronic acid (HA) content. HA and HA-binding proteins have been implicated in tissue hydration, release of collagenase, and leukocyte migration, but their roles in cervical ripening have not been explored. In the present study we examined the ability of PGE(2) to induce expression of the HA-binding protein, tumor necrosis factor-stimulated gene (TSG)-6, in human cervical smooth muscle cells (hCSMCs) and compared the PGE(2) response to that of tumor necrosis factor-alpha (TNF-alpha), an established inducer of TSG-6. TNF-alpha stimulated TSG-6 mRNA accumulation in a dose- and time-dependent manner, with the maximal response observed at 10 ng/ml after 6 hours of incubation. PGE(2) stimulated TSG-6 mRNA expression, but the magnitude of response was substantially less than that produced by TNF-alpha, and it was maximal only after 24 hours of incubation. Quantitative real-time polymerase chain reaction was performed to assess the induction of TSG-6 mRNA and nascent transcripts at 24 hours of treatment. Induction of TSG-6 mRNA and nascent transcripts in response to 10 micromol/L of PGE(2) was 5.7-fold and 6.3-fold greater than control values, respectively, whereas TNF-alpha (10 ng/ml) induced TSG-6 mRNA and nascent transcripts by 80-fold and 134-fold, respectively. TNF-alpha and PGE(2) stimulated secretion of TSG-6 into the culture medium as detected by Western blotting. The effects of PGE(2) on secretion of TSG-6 were delayed compared to TNF-alpha. A 1.3-kb fragment of the human TSG-6 proximal promoter drove luciferase expression in transfected hCSMCs. PGE(2) increased TSG-6 promoter activity 1.75-fold. Paradoxically, TNF-alpha reduced TSG-6 promoter activity by 50%. We conclude that hCSMCs express the hyaladherin TSG-6; that TSG-6 expression in these cells is regulated by PGE(2) as well as proinflammatory cytokines; responses of hCSMCs to TNF-alpha and PGE(2) are distinct in terms of magnitude and the time course; and PGE(2) and TNF-alpha exert different effects on the TSG-6 proximal promoter.
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PMID:Induction of the hyaluronic acid-binding protein, tumor necrosis factor-stimulated gene-6, in cervical smooth muscle cells by tumor necrosis factor-alpha and prostaglandin E(2). 1194 33

The 92-kDa type IV collagenase (MMP-9) contributes to tumor invasion and metastases and strategies to down-regulate its expression could ultimately be of clinical utility. Although the expression of this collagenase is regulated by numerous growth factors, the signaling pathways that transduce these signals are fewer in number and therefore represent pharmacological targets. In this regard, we previously reported that MMP-9 expression was regulated by the c-jun amino terminal kinase (JNK) signaling cascade. Therefore, we undertook a study to determine the efficacy of a novel compound (SP600125), which binds to the ATP binding site of all known JNKs, in repressing MMP-9 expression. In OVCAR-3 cells, SP600125 inhibited the PMA-dependent secretion of MMP-9 in a time-dependent manner and over a dose range that blocked c-Jun phosphorylation and AP-1 binding. SP600125 repressed the activity of a PMA-stimulated MMP-9 promoter-driven luciferase reporter, suggesting that diminished secretion of this collagenase reflected reduced transcription. Further, the activity of a GAL4-driven reporter in PMA-treated cells, co-transfected with an expression construct encoding the trans-activation domain of c-Jun fused to the DNA binding domain of GAL4, was repressed by SP600125. These findings indicate the efficacy of SP600125 in inhibiting c-Jun activation, DNA-binding and the PMA-dependent induction of MMP-9 expression.
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PMID:An inhibitor of c-jun aminoterminal kinase (SP600125) represses c-Jun activation, DNA-binding and PMA-inducible 92-kDa type IV collagenase expression. 1203 98

Expression of 12 matrix metalloproteinases (MMPs) after exposure of human melanoma cell lines C32TG and Mewo to nitric oxide (NO) was investigated by the reverse transcription-polymerase chain reaction. Expression of the mRNA of MMP-1, -3, -10 and -13 in C32TG cells was transcriptionally enhanced in a dose-dependent manner by exposure to an NO donor, S-nitroso-N-acetyl-DL-penicillamine (SNAP) and mRNA expression of MMP-1 and -10 was similarly enhanced in Mewo cells. Exposure of C32TG cells to NO increased the MMP-1 protein concentration in the culture medium. Testing with the luciferase gene fused to the 1.5 Kbp 5'-flanking region of the human MMP-1 gene showed that exposure to NO upregulated MMP-1 promoter activity in C32TG cells. Endogenous NO production after introduction of inducible NO synthase cDNA also enhanced MMP-1 promoter activity in C32TG cells. Deletion and mutational analysis identified a critical AP-1 binding site required for NO regulation of MMP-1. A neighboring Ets motif from the AP-1 site in the promoter region acted as an accessory to enhance MMP-1 expression. Electromobility shift analysis using the AP-1 binding site showed that NO enhanced the AP-1 binding ability of nuclear factors in C32TG cells. PD98059, a selective MEK inhibitor and SB202190, a p38 MAPK inhibitor, attenuated the MMP-1 mRNA expression enhanced by NO. Thus, MMP-1 was transcriptionally enhanced by NO via MAPK (ERK and p38) pathways. The results of our study suggest that the increased expression of MMPs in response to NO may be associated with tumor progression under inflammation.
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PMID:Induction of matrix metalloproteinase gene transcription by nitric oxide and mechanisms of MMP-1 gene induction in human melanoma cell lines. 1245 29


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