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)

Matrix metalloproteinase-1 (MMP-1) is one of three collagenases that can degrade the interstitial collagens, types I, II, and III at neutral pH. As these collagens are the most abundant proteins in the body, collagenase plays a critical role in modeling and remodeling the extracellular matrix. Therefore, it is not surprising that MMP-1 gene expression can be regulated at multiple points. Procollagenase can be activated by mechanisms that generate an active enzyme with differing specific activities, and the active enzyme can be inhibited by complexing with either the tissue inhibitor of metalloproteinases (TIMPs) or alpha 2 macroglobulin. The activator protein-1 (AP-1) site in the collagenase promoter plays a prominent role in the transcriptional control of the collagenase gene. It is essential for basal transcription, and contributes to induction by phorbol esters, although other sites in the proximal promoter are essential. In contrast, transactivation by cytokines such as Interleukin-1 depends on sequences in more distal regions of the promoter. Posttranscriptional mechanisms also regulate gene expression, and several cytokines and growth factors increase the stability of the collagenase transcript. Finally, glucocorticoid hormones repress transcription of the collagenase gene by the interaction of glucocorticoid receptors with the AP-1 proteins, Fos and Jun. Retinoids also suppress transcription by mechanisms that involve down-regulation of fos and jun mRNA, sequestration of Fos and Jun proteins, and the formation of complexes of retinoic acid receptors (RAR/RXR heterodimers) and AP-1 proteins on the DNA. These multiple points of regulation assure precise control of collagenolytic activity in a variety of physiologic and pathologic conditions.
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PMID:Regulating expression of the gene for matrix metalloproteinase-1 (collagenase): mechanisms that control enzyme activity, transcription, and mRNA stability. 895 74

Membrane type 1 matrix metalloproteinase (MT1-MMP) is expressed on cancer cell membranes and activates the zymogen of MMP-2 (gelatinase A). We have recently isolated MT1-MMP complexed with tissue inhibitor of metalloproteinases 2 (TIMP-2) and demonstrated that MT1-MMP exhibits gelatinolytic activity by gelatin zymography (Imai, K., Ohuchi, E., Aoki, T., Nomura, H., Fujii, Y., Sato, H., Seiki, M., and Okada, Y. (1996) Cancer Res. 56, 2707-2710). In the present study, we have further purified to homogeneity a deletion mutant of MT1-MMP lacking the transmembrane domain (DeltaMT1) and native MT1-MMP secreted from a human breast carcinoma cell line (MDA-MB-231 cells) and examined their substrate specificities. Both proteinases are active, without any treatment for activation, and digest type I (guinea pig), II (bovine), and III (human) collagens into characteristic 3/4 and 1/4 fragments. The cleavage sites of type I collagen are the Gly775-Ile776 bond for alpha1(I) chains and the Gly775-Leu776 and Gly781-Ile782 bonds for alpha2(I) chains. DeltaMT1 hydrolyzes type I collagen 6.5- or 4-fold more preferentially than type II or III collagen, whereas MMP-1 (tissue collagenase) digests type III collagen more efficiently than the other two collagens. Quantitative analyses of the activity of DeltaMT1 and MMP-1 indicate that DeltaMT1 is 5-7.1-fold less efficient at cleaving type I collagen. On the other hand, gelatinolytic activity of DeltaMT1 is 8-fold higher than that of MMP-1. DeltaMT1 also digests cartilage proteoglycan, fibronectin, vitronectin and laminin-1 as well as alpha1-proteinase inhibitor and alpha2-macroglobulin. The activity of DeltaMT1 on type I collagen is synergistically increased with co-incubation with MMP-2. These results indicate that MT1-MMP is an extracellular matrix-degrading enzyme sharing the substrate specificity with interstitial collagenases, and suggest that MT1-MMP plays a dual role in pathophysiological digestion of extracellular matrix through direct cleavage of the substrates and activation of proMMP-2.
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PMID:Membrane type 1 matrix metalloproteinase digests interstitial collagens and other extracellular matrix macromolecules. 899 57

The purpose of this study was to examine the appearance and activation of collagenase-1 (MMP-1) in the wound environment. We found that MMP-1 accumulates in the fluid phase of the burn wound environment within 2 d of injury and reaches maximal levels by day 4. Two forms of the enzyme were evident; one that corresponded to proMMP-1 and another that corresponded to a group of high molecular mass (approximately 200 kDa and >200 kDa doublet) MMP-1 containing complexes. ProMMP-1 and MMP-1 containing complexes also occurred in wound fluid from venous stasis ulcers, but neither was detected in mastectomy fluid or in plasma. Levels of the proteinase inhibitor alpha2-macroglobulin in burn fluid and chronic ulcer wound fluid were almost as high as in plasma, and the high molecular mass MMP-1 containing complexes in burn fluid appeared to result from binding between alpha2-macroglobulin and activated MMP-1. These observations provide direct evidence that active MMP-1 in the fluid phase of the wound environment becomes complexed to alpha2-macroglobulin.
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PMID:Collagenase-1 complexes with alpha2-macroglobulin in the acute and chronic wound environments. 957 44

The purified metalloprotease and the partially purified cysteine protease from pathogenic Cryptobia salmositica were characterized. Using haemoglobin gel electrophoresis, we detected five enzymatic bands in crude parasite lysate; one protease (200 kDa) yielded a metalloprotease band and other four, cysteine protease bands (97, 70, 66 and 49 kDa). Both the metalloprotease and the cysteine protease had high levels of proteolytic activity against azocasein, haemoglobin and fibrinogen. The metalloprotease had high levels of activity against azocoll and gelatin but a low degree of activity against albumin. In contrast, the cysteine protease had extensive activity against albumin but low levels of activity against azocoll and gelatin. The metallo- and cysteine proteases had no activity against Pz-peptide, a specific substrate for bacterial collagenase. The optimal pH for the metalloprotease and the cysteine protease was 7.0 and 5.0, respectively. The metalloprotease was inhibited by metal-chelating agents and excess of zinc ions but was activated by calcium ions. The cysteine protease was inhibited by thiol-blocking agents. The natural antiprotease alpha2-macroglobulin, but not alpha1-protease inhibitor, inhibited the activity of both proteases from C. salmositica. The optimal in vitro temperature for the purified metalloprotease was 30 degrees C.
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PMID:Characterization of purified metallo- and cysteine proteases from the pathogenic haemoflagellate Cryptobia salmositica Katz 1951. 966 Jan 40

1. Hepatic stellate cells are key mediators of hepatic fibrosis. We have studied hepatic stellate cell expression of the collagenase and general protease inhibitor alpha2-macroglobulin after activation in tissue culture and in response to certain cytokines. 2. Hepatic stellate cells isolated by Pronase-collagenase digestion were activated by culture on uncoated plastic. By Northern analysis hepatic stellate cells undergoing activation (5 days) expressed alpha2-macroglobulin mRNA and alpha2-macroglobulin could be immunolocalized to hepatic stellate cells from 5 to 15 days of culture. 3. By ELISA of cell culture supernatants hepatic stellate cell secretion of alpha2-macroglobulin was found to increase from 2. 78+/-1.13 ng x ml-1 x microgram-1 DNA per 24 h at 5 days of culture (n=8) to 13.55+/-4.64 ng x ml-1 x microgram-1 DNA per 24 h at 15 days of culture (n=7). Stimulation of hepatic stellate cells with interleukin-6 at 5 days caused a significant increase in alpha2-macroglobulin expression as did exposure to Kupffer-cell conditioned medium. However, exposure of hepatic stellate cells to interleukin-1, transforming growth factor-beta1 and tumour necrosis factor-alpha had no significant effect. 4. During profibrotic liver injury plasma alpha2-macroglobulin levels were found to increase to between 850% and 250% of the control value (100%) after bile duct ligation (72 h to 13 days respectively), and to 1166% and 1106% of the control value during progressive CCl4-induced fibrosis (24 h to 4 weeks respectively). 5. These data suggest that hepatic stellate cells are a potential source of the potent protease inhibitor alpha2-macroglobulin, expression of which may inhibit matrix remodelling during progressive fibrosis.
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PMID:Rat hepatic stellate cell expression of alpha2-macroglobulin is a feature of cellular activation: implications for matrix remodelling in hepatic fibrosis. 968 May

The plasma fibrinolytic/proteolytic balance was assessed in 60 stable angina patients who underwent control coronary catheterization and the results were correlated with angiographic findings and control samples (n = 20). The concentrations of t-PA, PAI-1, collagenase (MMP-1), tissue inhibitor of MMP (TIMP-1), plasmin-antiplasmin (PAP) complexes and alpha2-macroglobulin (alpha2-M) were measured in plasma samples. The results showed a significant increase of PAP (p <0.001) and a reduction of alpha2-M (p <0.001) in the group of patients when compared to controls, indicating a degree of fibrinolysis/proteolysis activation. There was no correlation between the different parameters analyzed and the extent of angiographically proven atherosclerosis (one or more stenotic vessels), while the t-PA levels were significantly elevated (p <0.03) in patients with coronary stenosis > or =75% or occlusion. We conclude that there is a disturbance of the plasma fibrinolysis/proteolysis in patients with stable angina not related to the extent of atherosclerosis. The t-PA levels may be a good marker for coronary occlusion in these patients.
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PMID:Fibrinolysis/proteolysis balance in stable angina pectoris in relation to angiographic findings. 1152 15

An experimental paradigm was devised to remove the retinal basal lamina for defined periods of development: the basal lamina was dissolved by injecting collagenase into the vitreous of embryonic chick eyes, and its regeneration was induced by a chase with mouse laminin-1 and alpha2-macroglobulin. The laminin-1 was essential in reconstituting a new basal lamina and could not be replaced by laminin-2 or collagen IV, whereas the macroglobulin served as a collagenase inhibitor that did not directly contribute to basal lamina regeneration. The regeneration occurred within 6 h after the laminin-1 chase by forming a morphologically complete basal lamina that included all known basal lamina proteins from chick embryos, such as laminin-1, nidogen-1, collagens IV and XVIII, perlecan, and agrin. The temporary absence of the basal lamina had dramatic effects on retinal histogenesis, such as an irreversible retraction of the endfeet of the neuroepithelial cells from the vitreal surface of the retina, the formation of a disorganized ganglion cell layer with an increase in ganglion cells by 30%, and the appearance of multiple retinal ectopias. Finally, basal lamina regeneration was associated with aberrant axons failing to correctly enter the optic nerve. The present data demonstrate that a transient disruption of the basal lamina leads to dramatic and probably irreversible aberrations in the histogenesis in the developing central nervous system.
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PMID:Temporary disruption of the retinal basal lamina and its effect on retinal histogenesis. 1178 95

Oxidation of proteins occurs both as a side-effect of aerobic energy metabolism and as an effect of specific metabolism of phagocytic polymorphonuclear granulocytes producing O2- and H2O2. In contrast to other cells, which control their H2O2 level by degrading it to O2 and H2O, polymorphonuclear neutrophilic leukocytes (PMN) use H2O2 as a substrate for oxidizing chloride ions to HOCl which rapidly react with all neighboring thiol, disulfide and amino residues. Chloramines, which are the most abundant HOCl reaction products, react with proteins, modifying only certain exposed methionine and cysteine residues. This may account for selective inactivation of a number of enzymes, carrier proteins and peptide mediators, including the alpha1-proteinase inhibitor, alpha2-macroglobulin and plasminogen activator inhibitor. Inactivaton of plasma proteinase inhibitors protects PMN elastase, collagenase, cathepsin G and other serine proteases in the inflammatory foci. This promotes proteolytic degradation of damaged tissue, removal of bacterial debris and wound healing, as well as tissue remodeling related to the inflammatory processes. Oxidative control of protease-anti-protease balance affects the development of the inflammatory processes. Moreover, inactivation of plasma proteinase inhibitors facilitates primary antigen processing, upregulates lymphocyte proliferative response and activates the local immune response. Oxidation produces a specific protein tagging which attracts and stimulates immune active cells. Therefore, humoral response against oxidatively modified proteins occurs more effectively than that of the native proteins. The effect is dose-dependent with respect to the amount of oxidant employed. Glycol aldehyde, which is the serine chloramine spontaneous decay product, in mice immunized with glycol aldehyde-modified egg-white albumin, yields specific IgG production manifold higher than that in mice immunized with native albumin. Immunopotentiation is produced by proliferation expansion of the same immunocompetent clones. Oxidative tagging of proteins may also affect the autoimmune-type reaction. Thus, a growing body of data suggest that the specific role of protein oxidation by activated PMN is oxidative protein tagging facilitating further development of the immune reaction.
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PMID:Myeloperoxidase-mediated protein oxidation: its possible biological functions. 1211 89

Excess proteolysis of the extracellular matrix (ECM) of articular cartilage is a key characteristic of arthritis. The main enzymes involved belong to the metalloproteinase family, specifically the matrix metalloproteinases (MMPs) and a group of proteinases with a disintegrin and metalloproteinase domain with thrombospondin motifs (ADAMTS). Chondrocytes are the only cell type embedded in the cartilage ECM, and cell-matrix interactions can influence gene expression and cell behaviour. Thus, although the use of monolayer cultures can be informative, it is essential to study chondrocytes encapsulated within their native environment, cartilage, to fully assess cellular responses. The aim of this study was to profile the temporal gene expression of metalloproteinases and their endogenous inhibitors, the tissue inhibitors of metalloproteinases (TIMPs), reversion-inducing cysteine-rich protein with Kazal motifs (RECK), and alpha2-macroglobulin (alpha2M), in actively resorbing cartilage. The addition of the pro-inflammatory cytokine combination of interleukin-1 (IL-1) + oncostatin M (OSM) to bovine nasal cartilage induces the synthesis and subsequent activation of pro-metalloproteinases, leading to cartilage resorption. We show that IL-1+OSM upregulated the expression of MMP-1, -2, -3, -9, 12, -13, -14, TIMP-1, and ADAMTS-4, -5, and -9. Differences in basal expression and the magnitude of induction were observed, whilst there was no significant modulation of TIMP-2, -3, RECK, or ADAMTS-15 gene expression. IL-1+OSM downregulated MMP-16,TIMP-4, and alpha2M expression. All IL-1+OSM-induced metalloproteinases showed marked upregulation early in the culture period, whilst inhibitor expression was reduced throughout the stimulation period such that metalloproteinase production would be in excess of inhibitors. Moreover, although pro-collagenases were upregulated and synthesized early (by day 5), collagenolysis became apparent later with the presence of active collagenases (day 10) when inhibitor levels were low. These findings indicate that the activation cascades for pro-collagenases are delayed relative to collagenase expression, further confirm the coordinated regulation of metalloproteinases in actively resorbing cartilage, and support the use of bovine nasal cartilage as a model system to study the mechanisms that promote cartilage degradation.
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PMID:Metalloproteinase and inhibitor expression profiling of resorbing cartilage reveals pro-collagenase activation as a critical step for collagenolysis. 1691 64


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