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:3.4.21.73 (urokinase-type plasminogen activator)
10,685 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Uninephrectomized rats with diet-induced hypercholesterolemia develop interstitial inflammation and fibrosis after 8 to 12 weeks. Fibrosis has been associated with the accumulation of lipid peroxidation products within the tubulointerstitium, along with increased renal mRNA levels for transforming growth factor beta-1 (TCF-beta 1), some matrix proteins, and the tissue inhibitor of metalloproteinases (TIMP-1). However, mRNA levels for urokinase-type plasminogen activator (uPA) have been found to be decreased. The purpose of the present study was to determine whether antioxidant therapy could attenuate interstitial fibrosis in hypercholesterolemic rats and to determine changes in the pattern of renal gene expression induced by antioxidant therapy. Three groups of uninephrectomized rats were studied after 12 weeks of feeding standard rat chow, an atherogenic diet (standard chow plus 4% cholesterol/1% cholic acid), or an atherogenic diet supplemented with high doses of the antioxidants probucol and vitamin E. Rats fed the atherogenic diet developed hypercholesterolemia and a 56% increase in total kidney collagen compared with rats fed standard chow. In comparison, the hypercholesterolemic rats treated with antioxidants had normal levels of renal lipid peroxidation products and a normal kidney collagen content. In contrast, there were no significant differences in urinary albumin excretion rates or the number of interstitial macrophages between the two hypercholesterolemic groups. Compared with the untreated hypercholesterolemic group, antioxidant therapy induced significant reductions in renal mRNA levels for procollagen III (to 60% of untreated levels), collagen IV (60%), and TIMP-1 (20%), while uPA levels were significantly increased (to 210%). Paradoxically, antioxidant therapy was associated with a significant increase in renal TGF-beta 1 mRNA levels (to 150%), although TGF-beta 1 protein expression shifted from interstitial to tubular epithelial cells in predominance. The results of the present study demonstrate the efficiency of antioxidant therapy in preventing renal interstitial fibrosis in hypercholesterolemic rats with a single kidney. Based on changes in renal gene expression at the mRNA level, impaired matrix protein synthesis and increased intrarenal activity of the metalloproteinases and uPA/plasmin may play a role in the attenuation of fibrosis.
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PMID:Interstitial fibrosis in hypercholesterolemic rats: role of oxidation, matrix synthesis, and proteolytic cascades. 957 32

Osteoarthritis is the most common joint disease in humans. It is characterized by a gradual loss of extracellular matrix components of articular cartilage such as collagen and proteoglycan. Presently, however, emphasis is placed on enzymes exerting a strong influence on cartilage degradation. These enzymes include matrix metalloproteinases (MMP), their specific inhibitors (TIMP) and the plasminogen activator/inhibitor system. We applied monoclonal antibodies against MMP-1, -2, -3, -9 and their inhibitors TIMP-1/-2, as well as against urokinase-plasminogen activator u-PA and its inhibitor PAI to investigate their influence on articular cartilage degradation in patients with varusgonarthritis. We examined the cartilage of the lateral and medial compartments of 20 tibia plateaus, which can present with slight and severe cartilage degradations at the same time. In doing so, we tried to show whether or not immunohistological detection of enzymes could serve as a parameter for chondral degradation. The strongest immunoreaction for all enzymes was noted in the superficial layer of articular cartilage both medially and laterally. Between medial and lateral compartments, however, there were striking differences in the immunoreaction intensity of chondrocytes for MMP-1 and -3 as well as for TIMP-1 and u-PA. We noted that in cartilage with more advanced degradation, the immunoreaction for these enzymes was significantly higher in medial than in lateral compartments (p < 0.05). At the immunohistological level, a direct correlation between the grade of cartilage degradation and immunoreaction intensity was found. Our results corroborate the assumption that the expression of certain matrix-degradating enzymes serves as a parameter for the grade of cartilage degradation.
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PMID:Immunohistochemical analysis of several proteolytic enzymes as parameters of cartilage degradation. 958 19

The specialized interaction between embryonic and maternal tissue is unique to mammalian development. This interaction begins with the invasion of the uterus by the first differentiated embryonic cells, the trophoblasts, and culminates in formation of the placenta. Because of their highly specialized behavior invasive cells must attach to the extracellular matrix proteins, secrete proteinases, capable of degrading matrix, and migrate through the degraded matrix; invasion is partially dependent on the proteinase activity of the cells. The objective, therefore, was to study a vitro system to examine the mechanism(s) of trophoblast cell invasion and its relationship to proteinases. Since little is known about the actual mechanism(s) involved. The mouse trophoblast cell lines established from placentas of different gestational ages were chosen to study their invasive properties in vitro. To begin to understand the biochemical basis of this behavior, the chromogenic assay and the substrate gel technique was used to analyze the cell associated and secreted plasminogen activators. All lines secrete and synthesize both urokinase-type (uPA) and tissue-type (tPA) plasminogen activators. The most invasive line SM9-2, derived from mid-gestation (day 9) placenta showed the highest enzymatic activity in the conditioned medium (CM), whereas in cell extract (CE) SM-10 line derived from late gestation placenta had the highest PAs activity. Four forms of secreted PAs in CM were of 79, 72, 43 and 35 kDa molecular weights, whereas in CE only 79 kDa molecular weight form of PA was detected using substrate SDS-PAGE gels. Additional observations from cells cultured on Marrigel Invasion Chambers also showed secretion of PAs by noninvading and invading cells in a biphasic pattern suggest the involvement of these enzymes in the extracellular proteolysis. The expression of matrix metalloproteinase gelatinase B (MMP-9) and tissue inhibitor of metalloproteinase (TIMP-1) were examined by RT-PCR in all the lines, however MMP-9 and TIMP-1 signals were strongly expressed in SM9-2 and SM-10 lines respectively. CM and CE were characterized by gelatin zymography, and the proteinases secreted by these cells in CM were confirmed to be metalloproteinases with approximate molecular masses between 52 to 92 kDa. Proteinases secreted by noninvading and invading cells cultured on Matrigel Invasion Chambers were not identical suggesting that specialized, temporally regulated metallopro-teinases are involved in trophoblast invasion. Trophoblast cell invasion in Matrigel Invasion Chambers was significantly inhibited in all the lines by using 1, 10-phenanthroline, an inhibitor of metalloproteinases. The results indicated that mouse trophoblast cells have matrix--degrading capabilities through metalloproteinase activity. Similar metalloproteinase activity has been reported to be necessary for human trophoblast invasion, suggesting a similar mechanism of implantation. Trophoblast culture system described here should be useful in studying some of the early events in human placentation.
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PMID:Mouse trophoblastic cell lines: II--Relationship between invasive potential and proteases. 962 4

Knee laxity has been shown to increase during human pregnancy, and the laxity of the rabbit medial collateral ligament also increases during pregnancy. To determine whether the changes in tissue function could be related to alterations in the regulation of gene expression for a subset of relevant molecules in ligaments, RNA was isolated from the medial collateral(MCL) and anterior cruciate(ACL) ligaments of first time pregnant adolescent rabbits. Levels of mRNA for matrix molecules (collagen types I and III and the proteoglycans biglycan, decorin, versican and lumican), proteinases and inhibitors (collagenase, urokinase, PAI-1 and TIMP-1, -2 and -3), growth factors (bFGF, IGF-I, TGF-beta1 and ET-1), cytokines (IL-1beta and TNF) and enzymes responsible for important tissue mediators (COX-2 and iNOS) were assessed by semi-quantitative RT-PCR. In the MCL, levels of transcripts for all of the matrix molecules, growth factors and TIMPs 1 and 2 were significantly depressed at 29 days of pregnancy compared to age-matched non-pregnant controls. In contrast, transcripts for PAI-1 were elevated during pregnancy, while those for collagenase (MMP-1), urokinase, TIMP-3, IL-1beta, TNF, COX-2 and iNOS were not statistically altered. mRNA transcript levels rebounded by 7 days post-partum for most genes studied, indicating that the changes were rapidly reversible. For some molecules, transcript levels were again depressed at 18 days post-partum, indicating that regulatory mechanisms were still not stabilized. Analysis of mRNA from the ACL also revealed changes in the pattern of gene expression, with some similarities and differences from the MCL noted. These results indicate that pregnancy induces reversible changes in mRNA for matrix molecules in ligaments, but differences in responsiveness exist between different ligaments. The complexity of the changes observed indicates that there is probably no simple cause and effect relationship between laxity changes and the molecular alterations during pregnancy.
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PMID:Pregnancy induces complex changes in the the pattern of mRNA expression in knee ligaments of the adolescent rabbit. 962 50

We show that osteopontin (OPN), bone sialoprotein (BSP) and GRGDSP peptides, in solution, induce activation of metalloproteinase-2 (MMP-2) secreted by human GCT23 giant cell tumour cells. Activation of MMP-2 is RGD sequence dependent, possibly involves anti-alphaVbeta3 integrins, is preceded by a change from spread to rounded cell morphology and is mimicked by the actin depolymerising agent cytochalasin B. Cells that had spread on OPN, BSP and GRGDSP substrata failed to activate MMP-2, but subsequent addition of soluble GRGDSP induced rounding and MMP-2 activation. Activation induced by GRGDSP and cytochalasin B was cell mediated, inhibited by EDTA, tissue inhibitor of metalloproteinase-2 (TIMP-2) and carboxyl terminal MMP-2 consistent with a role for membrane type (MT)-MMP but did not involve urokinase, plasmin or thrombin activity. Activation induced by GRGDSP and cytochalasin B, but not cell rounding, was inhibited by herbimycin A, cycloheximide and actinomycin D, suggesting a role for tyrosine kinases, protein and RNA synthesis, but was not associated with changes in mRNA for MT-MMP-1, MMP-1, MMP-2, TIMP-1 or TIMP-2. GRGDSP and cytochalasin B enhanced levels of membrane-associated pro- and active form MMP-1 and MMP-2 but not MT-MMP-1, stimulated cell surface MMP-1 staining and induced that of MT-MMP-1, MMP-2 and TIMP-2. This was consistent with the possible relocation of constitutive MT-MMP-1 to the cell surface as a prerequisite for subsequent cell surface MMP-2/TIMP-2/MT-MMP-1 complex formation and to the potential induction of conditions favourable for reciprocal cell surface MMP-1/MMP-2 activation. Our data provide a novel insight into interactions between RGD containing bone matrices, GCT cells and MMPs of potential relevance to GCT pathology.
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PMID:Activation of MMP-2 by human GCT23 giant cell tumour cells induced by osteopontin, bone sialoprotein and GRGDSP peptides is RGD and cell shape change dependent. 963 98

Membrane binding of urokinase type plasminogen activator (u-PA) is thought to play a pivotal role in connective tissue remodeling and invasive processes. We compare the ability of different matrix-metalloproteinases involved in connective tissue turnover to cleave pro-urokinase type plasminogen activator between the catalytic domain and the receptor binding part to investigate a potential role for matrix-metalloproteinases in the regulation of membrane-associated proteolytic activity. We employed several forms of human stromelysin-1 (full length, C-truncated, and recombinant catalytic domain), rabbit C-truncated stromelysin-1, the human gelatinases A and B and the human catalytic domain of neutrophil collagenase. The gelatinases and the collagenase did not separate the receptor binding domain of pro-urokinase type plasminogen activator from the catalytic domain, whereas all stromelysin-1 forms cleaved the glutamic acid 143-leucine 144 bond of pro-urokinase type plasminogen activator. This reaction could be inhibited by specific inhibitors of matrix metalloproteinases and was not affected by inhibitors of serine proteinases. The M(r) 31000 cleavage product with leucine 144 as N-terminus displayed no proteolytic activity towards the pro-urokinase type plasminogen activator substrate pyroGlu-Gly-Arg-pNA-HCI (S2444), but it could be activated by an additional treatment with plasmin. Comparison between full length stromelysin-1 and its C-truncated forms, showed that both exhibited the same cleavage properties towards pro-urokinase type plasminogen activator. Thus, the cleavage of pro-urokinase type plasminogen activator by stromelysin-1 is not influenced by the presence or absence of the C-terminal domain. The recombinant catalytic domain of MMP-3 generated pro-urokinase type plasminogen activator, whereas incubation of pro-urokinase type plasminogen activator with the native forms of human or rabbit stromelysin-1 led to a moderate activation of pro-uPA due to an additional cleavage that is catalyzed by a serine proteinase.
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PMID:The cleavage of pro-urokinase type plasminogen activator by stromelysin-1. 980 93

Wound healing in ligaments is a complex process which leads to functionally impaired scar tissue, even after extended time postinjury. To investigate the potential role of proteinases and inhibitors, as well as potential regulators of their expression, mRNA levels for collagenase, stromelysin, urokinase, PAI-1, and TIMPs 1 to 4 have been assessed by semiquantitative RT-PCR in RNA isolated from rabbit ligaments 3, 6, and 14 weeks postinjury. In addition, mRNA levels for IL-1, TNF, COX-2, and iNOS, potential regulators of proteinase/inhibitor expression, have been assessed. mRNA levels for the proteinases TIMP-1, -2, and -3 and PAI-1 were elevated early in scar tissue, but TIMP-4 mRNA levels exhibited a different pattern. In contrast, mRNA levels for the cytokines iNOS and COX-2 were either unchanged or depressed early after injury. The results indicate that alterations in mRNA levels for proteinases and inhibitors occurring early after injury are likely being influenced by factors other than IL-1, TNF, or products of COX-2 or iNOS.
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PMID:Temporal alterations in mRNA levels for proteinases and inhibitors and their potential regulators in the healing medial collateral ligament. 983 80

A large body of experimental evidence supports the participation of two groups of extracellular proteases, matrix metalloproteinases (MMPs), and plasminogen activators/plasmin, in tissue remodeling in physiological and pathological invasion. In the late mouse placenta, several tissue remodeling and cell invasion processes take place. Spongiotrophoblast migration into maternal decidua, as well as decidual extracellular matrix remodeling require the coordinated action of extracellular proteolytic enzymes. Via Northern and in situ hybridization, we have analyzed the spatio-temporal expression patterns of members of the MMP family (stromelysin-3, gelatinases A and B), as well as their inhibitors TIMP-1, -2 and -3 in late murine placenta (days 10.5 to 18.5 of gestation). Gelatinase activity in placental extracts was assessed by substrate zymography. Gelatinase A and stromelysin-3 were found to be prominently expressed in decidual tissue; shortly after midpregnancy, the decidual expression patterns of gelatinase A and stromelysin-3 became overlapping with each other, as well as with the expression domain of TIMP-2. On the other hand, gelatinase B transcripts were expressed only by trophoblast giant cells at day 10.5, and were downregulated at later stages. TIMP-1 and TIMP-3 transcripts were detected in decidual periphery at day 10.5, while later the expression was restricted to the endometrial stroma and spongiotrophoblasts, respectively. The areas of stromelysin-3 expression were the same (giant trophoblasts) or adjacent (decidua) to those where urokinase (uPA) transcripts were detected, suggesting a possible cooperation between these proteinases in placental remodeling. We generated mice doubly deficient for stromelysin-3 and uPA, and report here that these mice are viable and fertile. Furthermore, these animals do not manifest obvious placental abnormalities, thereby suggesting the existence of compensatory/redundant mechanisms involving other proteolytic enzymes. Our findings document the participation of MMPs and their inhibitors in the process of late murine placenta maturation, and warrant the characterization of other members of the MMP family, like membrane type-MMPs, in this process.
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PMID:Expression of matrix metalloproteinases during murine chorioallantoic placenta maturation. 1009 Jan 51

Cardiac rupture is a fatal complication of acute myocardial infarction lacking treatment. Here, acute myocardial infarction resulted in rupture in wild-type mice and in mice lacking tissue-type plasminogen activator, urokinase receptor, matrix metalloproteinase stromelysin-1 or metalloelastase. Instead, deficiency of urokinase-type plasminogen activator (u-PA-/-) completely protected against rupture, whereas lack of gelatinase-B partially protected against rupture. However, u-PA-/- mice showed impaired scar formation and infarct revascularization, even after treatment with vascular endothelial growth factor, and died of cardiac failure due to depressed contractility, arrhythmias and ischemia. Temporary administration of PA inhibitor-1 or the matrix metalloproteinase-inhibitor TIMP-1 completely protected wild-type mice against rupture but did not abort infarct healing, thus constituting a new approach to prevent cardiac rupture after acute myocardial infarction.
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PMID:Inhibition of plasminogen activators or matrix metalloproteinases prevents cardiac rupture but impairs therapeutic angiogenesis and causes cardiac failure. 1050 7

Local invasiveness is an important prognostic factor in endometrial carcinoma. To study the role of two groups of secreted proteinases (serine proteinases and matrix metalloproteinases) in this process, we examined three endometrial cancer cell lines (Ishikawa HEC 1A, AN3CA) for their invasiveness in vitro. Additionally, we considered the secretion of urokinase type plasminogen activator (uPA), plasminogen activator inhibitor 1 and 2 (PAI-1 and PAI-2), as well as matrix metalloproteinases (MMP) 1, 2, 3, and 9, and their inhibitors TIMP-1 and TIMP-2. Compared to the highly invasive fibrosarcoma cell line HT 1080, Ishikawa displayed low and AN3CA moderate invasiveness, while HEC 1A cells were almost as invasive as HT 1080 cells. Ishikawa cells secreted the highest amounts of proteinases. Cytokine and steroid treatments upregulated MMP-1 in all cell lines while the effects were heterogeneous regarding other proteinases and inhibitors. No effect of these treatments on invasiveness could be detected. Both basal secretion and regulation of the proteinases tested in this set of experiments seem to be markers of differentiation rather than of invasiveness.
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PMID:Invasiveness corresponds to differentiation rather than to proteinase secretion in endometrial cancer cell lines. 1060 96


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