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)

Although ulceration of the corneal stroma after alkali burns is known to be correlated with persistent epithelial defects, the relationship between a defect and the mediators thought to contribute to stromal destruction (plasminogen activator, plasmin, collagenase) has not been understood. This report demonstrates that fibrin and fibronectin appear on the stromal surface after an alkali burn, and that those substratum, matrix components disappear in correlation with the appearance of plasminogen activator on the stromal surface, re-surfacing by the epithelium and a persistent epithelial defect. The facts that epithelium releases plasminogen activator and that plasmin, generated from plasminogen by an activator, can degrade both fibrin and fibronectin, as well as the laminin component of the subepithelial basement membrane, would suggest that the plasminogen activator-plasmin system effect degradation of those macromolecules, thus initiating the events that lead to eventual, frank stromal ulceration. It is hypothesized that stromal ulceration is initiated by the chronic secretion from an epithelium with a persistent defect of a protease (plasminogen activator) involved in wound healing.
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PMID:Ulceration is correlated with degradation of fibrin and fibronectin at the corneal surface. 622 46

Plasminogen is present in the cornea andcan be activated to plasmin by plasminogen activator. Plasmin is able, in turn, to activate latent collagenase. This system could initiate and perpetuate the collagen degradation of corneal ulceration. This report details evidence for such a system in the cornea. Plasmin has been found to activate latent collagenase from organ cultures of ulcerating rabbit corneas and from fibroblast cultures derived from such corneas. As in the case of activation by trypsin, activation by plasmin results in the conversion of the 40,000 MW latent form to an active species of 23,000 MW. Explants of normal or alkali-burned, ulcerating corneas demonstrated plasminogen-dependent lysis of fibrin clots; frozen sections of such corneas demonstrated that lysis begins in the superficial stroma near the periphery of the cornea. Multiply freeze-thawed ulcerating corneas, but not normal corneas, showed initial lysis, not peripherally but at the ulcer region containing polymorphonuclear leukocytes. The fact that the peripheral lytic pattern existed in corneas that were obtained from eyes prefrozen in liquid nitrogen before excision of the corneas would suggest that plasminogen activator is normally contained in cells in vivo and is not made only in response to tissue injury. There was no correlation between the location of blood vessels or the presence of the corneal endothelium and the plasminogen-dependent lysis. Plasminogen activator from the ulcerating cornea and from fibroblasts was characterized by sodium dodecyl sulfate--gel electrophoresis of its cleavage products of plasminogen. The activator cleaves plasminogen into heavy- and light-chain fragments similar to those produced from plasminogen by urokinase. Plasminogen activator activity was quantitated by a new assay that restricts diffusion of the enzyme to one dimension into a narrow bore tube. The addition of plasminogen daily to cultures of ulcerating corneas resulted in earlier rises of plasminogen activator, collagenase, and collagen degradation fragments in the culture media. Although total plasminogen activator levels were not increased by the addition of plasminogen to culture, levels of both collagenase and solubilized collagen were approximately doubled. It is concluded that the plasminogen activator--plasmin system might play an important role in the destruction of stromal matrix in corneal ulceration.
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PMID:Evidence for a role of the plasminogen activator--plasmin system in corneal ulceration. 625 12

A spontaneous mammary adenocarcinoma (AC) from an inbred female rat was investigated with regard to secretion of neutral proteases. Cultures of neoplastic epithelial cells derived from the tumour secreted an enzyme that fulfilled the criteria for a specific collagenase. In contrast to cultures of non-neoplastic cells, tumour collagenase was present as an active enzyme, since treatment with trypsin or p-aminophenylmercuric acetate (APMA) did not increase activity. The neoplastic cells were also prolific producers of plasminogen activator (PA). Dexamethasone (Dex) (10(-6)M) markedly reduced the levels of both enzymes. Addition of tranexamic acid (TA), an inhibitor of plasmin and of plasminogen activation, did not affect collagenase activity, even at 10(-1)M TA, nor did latent collagenase accumulate. Latent collagenase was secreted in culture by normal fibroblasts from neonatal rat lungs. This latent enzyme was activated by the addition of tumour cell medium plus plasminogen, but this effect was inhibited by the addition of TA. These results demonstrate that the neoplastic cells themselves secrete collagenase as an active enzyme. PA is also secreted, is not involved with tumour collagenase, but is capable, in the presence of plasminogen, of activating latent collagenase produced by the non-neoplastic cells within the tumour or in the surrounding tissue. This tumour possesses potent collagenolytic ability in vitro which may be partly responsible for its rapid invasion in vivo.
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PMID:Rat mammary carcinoma cells secrete active collagenase and activate latent enzyme in the stroma via plasminogen activator. 627 36

The relationship of a basement membrane collagen degrading enzyme (BM collagenase) and plasminogen activator (PA) was studied in a number of non-malignant and malignant human and murine cell lines. Several non-malignant cell lines secreted significant amounts of PA but not detectable BM collagenase activity whereas the malignant cell lines, with one exception, secreted both enzymes. Therefore, the secretion of BM collagenase appears to be a characteristic of many malignant cells whereas PA is synthesized also by normal cells. The BM collagenase needed proteolytic activation for maximal activity indicating that it is secreted in a latent form. The addition of plasminogen to the culture medium of human fibrosarcoma cells (HT-1080) resulted in maximal activation of the enzyme. Plasmin, but not plasminogen, increased the activity of partially purified enzyme protein. Accordingly, the activation of latent BM collagenase in vivo may be facilitated by PA through the conversion of plasminogen to plasmin. It is suggested that the secretion of BM collagenase concomitantly with PA is a prerequisite for metastasis.
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PMID:Secretion of basement membrane collagen degrading enzyme and plasminogen activator by transformed cells--role in metastasis. 629 70

Independent studies have previously shown that mononuclear cell supernatants stimulate the release of plasminogen activator and latent collagenase from synovial cell monolayer cultures. Simultaneous secretion of these enzymes could be an important pathway for tissue destruction under inflammatory conditions, since plasminogen activator can cause activation of latent collagenase in the presence of plasminogen. We investigated the kinetics of release of the two enzymes from synovial cells in response to the addition of mononuclear cell supernatants and retinoic acid. Synovial cells derived from osteoarthritic and rheumatoid arthritic patients responded similarly. Plasminogen activator is released within a few hours of stimulation, and secretion usually stops when the stimulus is removed. In contrast, significant amounts of collagenase are secreted only after an initial lag period of 1--2 days, and secretion is sustained long after removal of mononuclear cell supernatant. Another difference in regulation of the secretion of these two neutral proteinases is that the addition of all-trans retinoic acid to the same synovial cell culture elevates plasminogen activator secretion while suppressing that of latent collagenase. Differential regulation of these enzymes under conditions of chronic inflammation may allow for continual accumulation of latent enzyme(s) which are activated during short periods of plasminogen activator release.
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PMID:Differential release of plasminogen activator and latent collagenase from mononuclear cell-stimulated synovial cells. 629 7

Interactions between cancer cells and host macrophages might have important regulatory roles in controlling the expression of the metastatic phenotype, particularly by regulating the production of proteases necessary for tissue invasion. To investigate that possibility, mouse macrophages and Lewis lung carcinoma (LLC) cells from four clonal subpopulations with either low or high metastatic ability were cultured on [14C]collagen (type l)-coated plates. They did not degrade collagen when they were cultured independently on that substrate, but they were induced to do so when macrophages and cancer cells were cultured together. An increased production of neutral collagenase and other neutral protease activities was observed simultaneously. The degree of stimulation of collagen degradation varied according to the cancer cell subpopulation present in the cocultures. For a given LLC cell subpopulation, similar degrees of stimulation of collagen degradation were achieved with either bone marrow-derived or resident peritoneal macrophages, either syngeneic (from C57BL/6 mice) or allogeneic; lower stimulations were obtained with thioglycolate-elicited peritoneal macrophages. Macrophage-conditioned culture media could be substituted for living macrophages to stimulate collagen degradation or collagenase secretion by LLC cells, but LLC cell-conditioned media did not stimulate collagen degradation by macrophages. This suggests that, in the cocultures, collagen degradation is achieved mainly by the cancer cells, not by the macrophages, and that it is induced by a soluble factor, a monokine, produced by the macrophages. That factor might be identical to a recently identified rabbit monokine that stimulates fibroblasts or synovial cells to degrade collagen and proteoglycan and to activate plasminogen, because rabbit macrophage-conditioned media containing that monokine also stimulated collagen degradation by LLC cells.
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PMID:Collagen degradation by metastatic variants of Lewis lung carcinoma: cooperation between tumor cells and macrophages. 635 18

A new hydrolase activity has been identified by its capability of cleaving t-boc-Ala-Ala-Pro-Ala-AMC, the released 7-amino-4-methylcoumarin (AMC) being quantified fluorometrically. The activity in the 28,000 X g supernatant fraction of homogenates of weanling mouse uterus was about one fifth that of the adult mouse. The administration of estradiol to the weanling mouse caused a prompt increase in uterine hydrolase, the response being biphasic with peaks at 2 and 6 h. Stimulation was dose responsive and effectively blocked by cycloheximide and puromycin. Estrogen stimulation of hydrolase activity was also observed in the kidney (one fourth that of in the uterus), but not in the heart or liver. Progesterone and testosterone were poor stimulators, but estriol was as effective as estradiol. According to its elution profile in gel filtration, a molecular weight for the hydrolase of about 60,000 is suggested. Inhibition studies in vitro with crude enzyme preparations indicate a serine protease with a SH group essential for maximal activity. The natural substrate for the hydrolase has not been elucidated. It does not solubilize [3H]elastin, and the properties seem to eliminate plasminogen or latent collagenase as possible substrates.
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PMID:A new hormone-response hydrolase activity in the mouse uterus. 700 May

We have investigated the ability of neutral and lysosomal enzymes of mouse macrophages to degrade the insoluble extracellular matrices secreted by smooth muscle cells, endothelial cells, and fibroblasts. Matrices produced by smooth muscle cells contained glycoproteins, elastin, and collagens, but matrices of endothelial cells and fibroblasts contained no elastin. Sequential enzyme digestion of residual matrix revealed that plasmin, a product of macrophage plasminogen activation, degraded 50-70% of the glycoprotein in the matrices but did not degrade the elastin or the collagens. Purified macrophage elastase degraded glycoprotein and elastin components but had no effect on the collagens. The rate of elastin degradation by macrophage elastase was decreased in the presence of the glycoproteins. In contrast, human granulocyte elastase effectively degraded the matrix glycoproteins, elastin, and, to a lesser extent, collagens, Mammalian collagenase degraded only collagens. Conditioned medium from resident and inflammatory macrophages, containing mixtures of the secreted proteinases, degraded the glycoprotein and elastin components of the matrices. However, conditioned medium was less effective in degrading matrix than comparable amounts of purified macrophage elastase because > 90% of the elastase in the medium was in a latent form. Inclusion of plasminogen in the assays accelerated degradation. In the presence of plasminogen, glycoproteins were degraded readily by medium from P388D1, pyran copolymer-, thioglycollate-, and periodate-elicited macrophages and, to a lesser extent, by medium from endotoxin-elicited and resident macrophages; medium from P388D1, thioglycollate-, and periodate-elicited macrophages was most effective in elastin degradation, and resident, endotoxin-elicited and pyran copolymer-elicited macrophages degraded almost no elastin. The macrophage cathepsins D and B degraded all the matrix components at an optimum pH of 5.5 and acted with the secreted neutral proteinases to degrade the connective tissue macromolecules to amino acids and oligopeptides. These data indicate that macrophages at inflammatory sites contain and secrete proteolytic enzymes that could degrade the extracellular matrix.
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PMID:Degradation of connective tissue matrices by macrophages. I. Proteolysis of elastin, glycoproteins, and collagen by proteinases isolated from macrophages. 700 Sep 66

Regression of the rat ventral prostate occurs when the level of 5 alpha-dihydrotestosterone, the trophic hormone, drops below the threshold required to suppress apoptosis. The induction of apoptosis in the ventral prostate is accompanied by the increase in the steady-state level of a number of mRNAs coding for proteins that are involved in the latter stages of apoptosis and thus represent secondary thanatogens. These include proteases (cathepsins, plasminogen activators, and collagenase), clusterin, poly(ADP)ribose polymerase, tenascin, and several unidentified genes, as well as several RNases and the classical Ca2+,Mg(2+)-dependent endonuclease. In addition, insulin-like growth-factor-binding protein 5 (IGFBP-5) is induced de novo. We propose that IGFBP-5 may serve to trigger the apoptotic process through the attenuation of the insulin-like growth factor signalling system (which is necessary for cell survival), and as such, represents a primary thanatogen in the prostate.
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PMID:The role of growth factors in the suppression of active cell death in the prostate: an hypothesis. 754 88

The present study was undertaken to determine the role of the metalloproteinase MMP-9 in the invasive phenotype of squamous-cell carcinoma of the oral cavity and the regulation of its expression. Zymographic analysis of conditioned medium from 2 highly invasive squamous-cell-carcinoma cell lines indicated large amounts of an enzyme which was indistinguishable, in size (92 kDa) from the MMP-9 pro-enzyme. Conversion of the 92-kDa gelatinase into a lower-molecular-weight species (84 kDa), identical in size to the activated gelatinase, was evident when both cell lines, which are avid secretors of urokinase, were cultured in the presence of plasminogen. Penetration of an extracellular-matrix-coated filter was dramatically reduced in the presence of the collagenase inhibitor, tissue inhibitor of metalloproteinase-2, suggesting a critical role for MMP-9 in the invasive process. Immunohistochemical studies demonstrating the presence of MMP-9 in tumor cells of resected squamous-cell cancers suggested that secretion of this collagenase by cells in vitro was reflective of the in vivo setting. Since several phorbol-ester response elements are present in the MMP-9 promoter, we determined the role of protein-kinase-C pathways in the regulation of MMP-9 expression in cultured SCC. Treatment of cells with PMA resulted in a more-than-20-fold increase in the level of protein and mRNA. Conversely, culturing of cells in the presence of the protein-kinase-C inhibitor, calphostin-C, led to a dose-dependent decrease in the amount of MMP-9 mRNA and protein, suggesting that the constitutive expression of this collagenase reflects activation of this signal transduction pathway. In summary, our data suggest that, for a sub-population of squamous-cell carcinomas, secreted MMP-9 is an important determinant of the invasive phenotype, and that the expression of this metalloproteinase is regulated by protein-kinase-C pathways.
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PMID:Role and regulation of expression of 92-kDa type-IV collagenase (MMP-9) in 2 invasive squamous-cell-carcinoma cell lines of the oral cavity. 768 50


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