Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.21.73 (urokinase-type plasminogen activator)
 10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In myeloid leukemia, immature leukemic cells are able to egress into peripheral blood to infiltrate extra-medullary organs. We therefore analyzed the migrating and invasive potential of human HL-60 and NB4 cell lines, representative of acute myelogenous leukemia, their ability to express matrix metalloproteases (MMPs), tissue inhibitors of metalloproteases (TIMPs) and urokinase plasminogen activator (uPA) in response to differentiating agents. Granulocytic differentiation by all-trans-retinoic acid (ATRA) and aclacinomycin (ACLA) strongly increased HL-60 and NB4 cell migration and invasion. At mRNA and protein levels, these cell lines produced significant amounts of MMP-9 (HL-60<NB4). Granulocytic differentiation by ACLA increased both pro and active forms of MMP-9 whereas ATRA decreased them and stimulated uPA mRNAs. TIMP-1, the physiological MMP inhibitor, increased during granulocytic differentiation whereas TIMP-2 did not significantly vary. Use of Batimastat and aprotinin suggests that ATRA was active by modulating the uPA system while ACLA interfered with MMP expression. In conclusion, our data demonstrate that HL-60 and NB4 cells express MMPs and uPA which are differentially regulated by the differentiating agents ATRA and ACLA and suggest the clinical usefulness of MMPs and serine protease inhibitors in the prophylaxis and treatment of the ATRA syndrome.
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PMID:Matrix and serine protease expression during leukemic cell differentiation induced by aclacinomycin and all-trans-retinoic acid. 1184 92

A lot of parallels have been described between invasion of malignant tumor cells and leukocyte movement during inflammatory responses. Concerning these similarities, we investigated the function of cytokine-suppressive anti-inflammatory drugs (CSAIDs), which act via inhibition of stress-activated MAP-kinases, in regulation of expression of proteolytic enzymes and in vitro invasion of malignant melanoma cells. The p38MAPK inhibitor SB203580 reduced matrigel invasion of MeWo cells by 60%, while the MEK-1 inhibitor PD98059 did not have any effect on invasion. Active p38MAPK was detected in MeWo cells by immunoblotting and confocal microscopy. Cells showed a constitutive expression of matrix-metalloproteinase (MMP)-2 as well as tissue inhibitor of metalloproteinases (TIMP)-1 and TIMP-2 mRNAs. Expression of MMP-1 or urokinase-type plasminogen activator (uPA) was not detected by Northern blot. Inhibition of p38MAPK by the specific inhibitor SB203580 resulted in downregulation of MMP-2 mRNA and protein levels as well as gelatinolytic activity, while expression levels of TIMP-1 and TIMP-2 mRNAs were not changed. The specific MEK-1 inhibitor PD98059 did not change expression of MMP-2 or TIMPs. Neither SB203580 nor PD98059 changed proliferation of cells. The results suggest that stress-activated protein kinases like p38MAPK are involved in regulation of expression of MMP-2 as well as in vitro invasion of malignant melanoma cells. Inhibitors of p38MAPK may be promising substances to interfere with a signaling cascade associated with invasion of malignant tumor cells.
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PMID:An inhibitor of stress-activated MAP-kinases reduces invasion and MMP-2 expression of malignant melanoma cells. 1191 86

Previous studies in the laboratory have shown that platelet-activating factor (PAF), a potent inflammatory mediator that accumulates rapidly in the cornea after an injury, stimulates the expression of urokinase (uPA) and matrix metalloproteinase-1 (MMP-1) and -9 (MMP-9). Tissue inhibitors of MMPs (TIMPs) and plasminogen activator inhibitor (PAI-1) are produced in conjunction with these enzymes and are important regulators of their activity. Here, the authors investigated how PAF affects the expression of PAI-1, TIMP-1 and -2 relative to that of uPA, MMP-1, and -9 in rabbit corneal epithelial cells. Rabbit corneas were incubated in MEM medium containing 100 nM cPAF. To block the effects of PAF in some studies, corneas were preincubated for 1 hr in the presence of the PAF antagonist BN50730 (10 microM). At several time intervals, mRNA was extracted from epithelial cells and the levels of gene expression for the enzymes and their inhibitors were determined by real-time PCR. All quantitations were normalized to the 18s rRNA values (endogenous control) and changes in gene expression were reported as fold increase relative to untreated controls. PAF produced a 20-fold increase in the gene expression of PAI-1 at 8 hr, while similar fold increases in uPA mRNA expression occurred at 2 hr. PAF treatment also stimulated the expression of TIMP-1 and -2 genes, with a six-fold increase in TIMP-1 expression occurring at 36 hr and a four-fold increase in TIMP-2 expression at 24 hr. Maximal induction of MMP-1 and -9 mRNA, on the other hand, occurred at 4 and 8 hr, respectively. Induction of MMP-1 gene expression was similar to that of its inhibitors TIMP-1 and -2, while MMP-9 mRNA induction exceeded that of these inhibitors by 100-fold. The PAF-induced expression of PAI-1, TIMP-1 and -2 mRNAs was abolished by pre-treatment with BN50730. These data indicate that PAF activates the gene expression of TIMP-1, -2, and PAI-1 in corneal epithelium by a receptor-mediated mechanism. Furthermore, PAF induced overexpression of MMP-9 mRNA relative to that of TIMP-1 and -2, suggesting an imbalance between the expression of this proteolytic enzyme and its inhibitors, which may contribute to changes in the wound-healing process and ultimately lead to corneal ulcer development.
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PMID:Platelet-activating factor induces the gene expression of TIMP-1, -2, and PAI-1: imbalance between the gene expression of MMP-9 and TIMP-1 and -2. 1201 20

Clinical complications of atherosclerosis are often triggered by the rupture of unstable plaques, while thinning of the atherosclerotic vessel wall owing to elastin and collagen degradation and media necrosis may result in aneurysm formation and bleeding. Proteolysis, mediated via the plasminogen/plasmin and/or matrix metalloproteinase (MMP) systems may contribute to neovascularization and rupture of plaques, or to ulceration and rupture of aneurysms. In an in vivo model of atherosclerosis, using mice that had a combined deficiency of apolipoprotein E (ApoE) and urokinase-type plasminogen activator (u-PA) and that were maintained on a cholesterol-rich diet, it was observed that u-PA deficiency protects against aneurysm formation. This was explained by the findings that plasmin, generated from plasminogen by u-PA, activates several macrophage-secreted proMMPs (e.g. proMMP-3, -9, -12 and -13), which in turn cause extracellular matrix degradation. A potential role for MMP-3 (stromelysin-1) was confirmed in a subsequent study using mice with a combined deficiency of ApoE and MMP-3, that were kept on a cholesterol-rich diet. The results suggest that MMP-3 contributes to plaque destabilization, possibly by degrading extracellular matrix components, but also promotes aneurysm formation by degrading the elastic lamina. These effects may be mediated by MMP-3 directly or by activation of other proMMPs or other (proteolytic) systems. A functional role of MMPs is further supported by the finding that deficiency in TIMP-1 (tissue inhibitor of MMPs type 1) reduces atherosclerotic plaque size but enhances aneurysm formation. Taken together, these results suggest that u-PA has an important role in the structural integrity of the atherosclerotic vessel wall, which is likely to involve triggering the activation of MMPs and, furthermore, they suggest that increased u-PA levels are a risk factor for aneurysm formation.
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PMID:Extracellular proteolysis in the development and progression of atherosclerosis. 1202 44

In this study we determined the in vitro effects of polysulfated glycosaminoglycan (PSGAG) and the glucocorticoid triamcinolone acetonid (TA) on the IL-1 altered expression and activity of matrix metalloproteinases (MMP-1, MMP-3), tissue inhibitor of metalloproteinases-1, the plasminogen activators tPA and uPA and plasminogen activator inhibitor 1 by articular chondrocytes. Bovine chondrocytes were cultured in alginate gel beads. Cells were treated with interleukin-1alpha (IL-1alpha) in the presence of vehicle or drugs at various concentrations. After 48hr mRNA expression of MMP-1, MMP-3, TIMP-1, uPA, tPA and PAI-1 was analyzed by RT-PCR-ELISA. The protein synthesis of TIMP-1 and MMP-3 was determined by immunoprecipitation, PAI-1 protein was quantitated by ELISA. The activity of enzymes and inhibitors was measured by functional assays. Treating chondrocytes with IL-1 induced the expression of MMPs and downregulated TIMP-1 but stimulated both the expression of PAs and PAI-1. Both drugs significantly reduced collagenase and proteoglycanase activities which was accompanied by inhibition of the expression of MMP-1 and MMP-3. The IL-1 decreased expression of TIMP-1 was further reduced by TA, which resulted in a significant loss of TIMP activity. No effects on TIMP activity or TIMP-1 biosynthesis were observed after treatment of chondrocytes with PSGAG. Both drugs inhibited the IL-1-induced mRNA expression of tPA, whereas expression of uPA was only mildly reduced by PSGAG, which also induced PAI-1 above IL-1 stimulated levels. As inhibition of collagenase activities and tPA expression by PSGAG occurred at physiological concentrations it might be of clinical relevance, indicating that PSGAG could help reducing cartilage degradation and has a strong anti-fibrinolytic potential. Due to their co-regulation of MMPs and TIMP(s) glucocorticoids should be carefully studied for their overall effect on extracellular matrix proteolysis.
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PMID:Effects of polysulfated glycosaminoglycan and triamcinolone acetonid on the production of proteinases and their inhibitors by IL-1alpha treated articular chondrocytes. 1212 42

We have previously reported on the anti-invasive and angiosuppressive effects of SI-27, an anti-matrix metalloproteinase (MMP) agent. The molecular mechanism of its anti-MMP action, however, has not yet been determined. The purpose of this study was to investigate the effects of SI-27 on MMP- 1, -2, -3, -9, and TIMP-1, -2 secreted by human glioma cell lines (U87MG, U251MG, U373MG, and Y98G). When cells were exposed to non-cytotoxic concentrations of SI-27 (preliminarily determined by the MTT assay), expressions of mRNAs for the enzymes was not inhibited. For an MMP activity assay, we employed the fact that active MMPs could cleave modified pro-urokinase to form active urokinase, which then acted on S-2444 peptide to create a chromogenic product. Secretion of all pro-MMPs from glioma cells was not significantly reduced by SI-27. However, activation of pro-MMPs was significantly inhibited in a dose-dependent manner ((IC50 values for MMP-2; U87MG, 3.5 microg/ml; U25 IMG, 4.2 microg/ml; U373MG, 4.8 microg/ml; Y98G, 4.0 degreesg/ml); (IC50 values for MMP-9; 251MG, 7.2 microg/ml, U373MG, 2.8 microg/ml). In addition, active MMPs were not inhibited by SI-27. These findings were supported by zymographic analysis and by collagenolysis assay data. TIMP-1 and -2 were also not inactivated by SI-27. These findings suggest that SI-27 targets the activation process of pro-MMP. S-2444, a specific chromogenic peptide, was useful for quantitative analysis of the activity of MMP subtypes in this study.
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PMID:Suppression of matrix metalloproteinase activity by SI-27: detection by a new activity assay with S-2444, a specific chromogenic peptide. 1216 Jan 35

We examined the role of matrix metalloproteinases (MMPs), tissue inhibitors of MMP (TIMPs), and plasminogen activator (PA) in transmyocardial laser revascularization (TMLR)-induced angiogenesis. TMLR was accomplished with a carbon dioxide laser in seven dogs whose left anterior descending coronary artery (LAD) was ligated. Seven control dogs underwent only LAD ligation, and four dogs underwent a sham operation, consisting only of a left thoracotomy. Two weeks later, transmural myocardial samples were harvested from the distributions of the LAD and the left circumflex artery for substrate zymography, immunohistochemical staining, and in situ zymography. MMP-1, MMP-2, TIMP-1, TIMP-2, and urokinase-type PA levels in the distribution of the LAD were higher in the laser group than in the control or sham group. Counts of von Willebrand factor-positive microvessels and smooth muscle alpha-actin-positive arterioles demonstrated that the angiogenesis and ateriogenesis was promoted in the laser group and correlated directly with the number of MMP-stained microvessels. We conclude that TMLR induces the expression of MMPs, TIMPs, and urokinase-type PA and that these proteinases play an important role in angiogenesis after TMLR.
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PMID:Role of MMPs and plasminogen activators in angiogenesis after transmyocardial laser revascularization in dogs. 1238 87

MMP-2, MMP-9, and uPA have been previously described as important to the invasive and metastatic potential of human tumors, including breast, lung, glioblastoma, and prostate. We examined the activity of these proteases and the levels of their inhibitors (TIMP-1 and TIMP-2) in a series of human meningioma tissue samples. Normal brain tissue did not show elevated levels of uPA, MMP-2 or MMP-9 activity. Meningiomas showed a mild, to moderate to significantly high level of uPA, MMP-2, and MMP-9. However, no increase in TIMP-1 or TIMP-2 levels was detected. Immunohistochemistry confirmed the assay findings and localized these molecules to the cell surface. The findings provide evidence for elevated levels of uPA and MMPs in meningiomas and suggest a therapeutic target for minimizing the malignant propensity of meningiomas using protease inhibitors.
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PMID:Expression of matrix metalloproteinases, their inhibitors, and urokinase plasminogen activator in human meningiomas. 1252 24

The aim of this study was to determine the expression of proteinases and inhibitors from the matrix metalloproteinase (MMP) (MMPs 1, 2, 3, 9, tissue inhibitors of metalloproteinases (TIMPs) 1, 2) and plasminogen activator ((PA) urokinase (uPA), tissue type (tPA), uPAR, plasminogen activator inhibitors (PAIs) 1, 2) systems in colorectal cancer pathology by gelatin zymography, enzyme-linked immunosorbent assays (ELISAs) and quenched fluorescent substrate hydrolysis. The levels of all studied MMPs, uPA, uPAR, TIMP-1 and PAIs were significantly greater in tumour tissues than normal tissues. However, tPA and TIMP-2 were greater in normal colon (P<0.05, Mann-Whitney) e.g. PAI-1: tumour, median 14.9 (range 0.2-80.2) ng/mg total protein; normal, 2.1 (0.1-65.0). Tumour levels of several factors, in particular MMP-1 and PAI-1, correlated with pathology, i.e. Dukes' stage, differentiation, lymphatic or vascular invasion and tumour depth. The interactions between proteinase systems in colorectal cancer are complex and the balance between active proteinases and their inhibitors is important for extracellular matrix (ECM) degradation/remodelling at each stage of the metastatic cascade.
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PMID:The plasminogen activator and matrix metalloproteinase systems in colorectal cancer: relationship to tumour pathology. 1270 68

Flavonoids have been proposed to act as chemopreventive agents in numerous epidemiological studies and have been shown to inhibit angiogenesis and proliferation of tumor cells and endothelial cells in vitro. Angiogenesis requires tightly controlled extracellular matrix degradation mediated by extracellular proteolytic enzymes including matrix metalloproteinases (MMPs) and serine proteases, in particular, the urokinase-type plasminogen activator (uPA)-plasmin system. In this study, we have investigated the antiangiogenic mechanism of the flavonoids, genistein, apigenin, and 3-hydroxyflavone in a human umbilical vein endothelial cell (HUVEC) model. The stimulation of serum-starved HUVECs with vascular endothelial growth factor/basic fibroblast growth factor (VEGF/bFGF) caused marked increase in MMP-1 production and induced the pro-MMP-2 activation accompanied by the increase in MT1-MMP expression. However, pretreatment with flavonoids before VEGF/bFGF stimulation completely abolished the VEGF/bFGF-stimulated increase in MMP-1 and MT1-MMP expression and pro-MMP-2 activation. Genistein blocked VEGF/bFGF-stimulated increase in TIMP-1 expression and decrease in TIMP-2 expression. Apigenin and 3-hydroxyflavone further decreased TIMP-1 expression below basal level and completely abolished TIMP-2 expression. VEGF and bFGF stimulation also significantly induced uPA expression, most strikingly the level of 33 kDa uPA, and increased the expression of PA inhibitor (PAI)-1. Genistein, apigenin, and 3-hydroxyflavone effectively blocked the generation of 33 kDa uPA, and further decreased the activity of the 55 kDa uPA and the expression of PAI-1 below the basal level. In conclusion, these data suggest that genistein, apigenin, and 3-hydroxyflavone inhibit in vitro angiogenesis, in part via preventing VEGF/bFGF-induced MMP-1 and uPA expression and the activation of pro-MMP-2, and via modulating their inhibitors, TIMP-1 and -2, and PAI-1.
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PMID:Flavonoids inhibit VEGF/bFGF-induced angiogenesis in vitro by inhibiting the matrix-degrading proteases. 1276 86


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