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)

The phosphatase and tensin homology deleted on chromosome 10 (PTEN) is a tumor suppressor gene with sequence homology to tyrosine phosphatases and the cytoskeletal proteins tensin and auxilin. PTEN has recently been shown to inhibit cell migration and the spreading and formation of focal adhesions. This study investigated the role of PTEN in carcinoma invasion in a lung-cancer cell line and examined the downstream genes regulated by PTEN. We have previously established a cell-line model in human lung adenocarcinoma with different invasive abilities and metastatic potentials. Examining PTEN gene expression in these cell lines, we found that a homozygous deletion in exon 5 is associated with high invasive ability. We then constructed stable constitutive and inducible wild-type PTEN-overexpressed transfectants in the highly invasive cell line CL(1-5). We found that an overexpression of PTEN can inhibit invasion in lung cancer cells. To further explore the downstream genes regulated by PTEN, a high-density complementary DNA (cDNA) microarray technique was used to profile gene changes after PTEN overexpression. Our results indicate a panel of genes that can be modulated by PTEN. PTEN overexpression downregulated genes, including integrin alpha(6), laminin beta(3), heparin-binding epidermal growth factor-like growth factor, urokinase-type plasminogen activator, myb protein B, Akt2, and some expressed sequence tag (EST) clones. In contrast, PTEN overexpression upregulated protein phosphatase 2A1B, ubiquitin protease (unph), secreted phosphoprotein 1, leukocyte elastase inhibitor, nuclear factor-kappaB, cyclic adenosine monophosphate response element binding protein, DNA ligase 1, heat shock protein 90, and some EST genes. Northern hybridization and flow cytometry analysis also confirmed that PTEN overexpression results in the reduced expression of the integrin alpha(6) subunit. The results of this study indicate that PTEN overexpression may inhibit lung cancer invasion by downregulation of a panel of genes including integrin alpha(6). The cDNA microarray technique may be an effective tool to study the downstream function of a tumor suppressor gene.
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PMID:Profiling the downstream genes of tumor suppressor PTEN in lung cancer cells by complementary DNA microarray. 1097 Aug 13

To understand the mechanism of invasion and metastasis of hepatocellular carcinoma (HCC), the expression of c-met and Ets-1, and the effect of HGF on these cell's motility and invasion ability were examined in four hepatoma cell lines. The analysis revealed that the overexpression of c-met and Ets-1 is closely connected with the motility and invasion ability of the HCC cell lines. Invasion activity of HepG2 and HLE cells were enhanced by the addition of HGF to medium. HGF regulated c-met transcription in HepG2 and Bel-7402 cells, HGF also induced Ets-1 transcription in Bel-7402 cell. Bel-7402 cells stably transduced with the human Ets-1 gene showed significantly increased invasion potentials compared to parental and mock-transfected cells. The expression level of c-met, MMP1, MMP9, and u-PA in Bel-7402 cells transfected with Ets-1 were markedly increased, and as a consequence of c-met expression increase. Bel-7402 cells transfected with Ets-1 were more responsive to exogenous HGF stimulation in invasiveness and motility ability. In addition, conditioned by antisense Ets-1 oligonucleotide-treat-Bel-7402 cells transfected with Ets-1 gene and HLE hepatoma cells showed markedly reduced invasion activity, and down-regulated the transcription of Ets-1, c-met, u-PA, MMP-1, and MMP-9. These results strongly suggest that Ets-1 has a crucial role in the invasive property in hepatoma cell lines, and there may exist a loop to enhance the invasive ability of hepatoma cell lines.
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PMID:Invasiveness of hepatocellular carcinoma cell lines: contribution of hepatocyte growth factor, c-met, and transcription factor Ets-1. 1152 16

Polymorphonuclear leucocytes (PMN) are important in the resolution of human thrombi, with u-PA as a key player. We have shown that the u-PA activity of PMN depends on the presence of plasma; the study presented here provides an explanation for that requirement. Here we show that PMN degraded scu-PA and also tcu-PA, t-PA and plasmin, resulting in loss of fibrinolytic activity. Plasma protected against this degradation; alpha1-antitrypsin was identified as a protective factor. Purified human neutrophil elastase mirrored the effects of PMN, again neutralized by plasma inhibitors. These findings illustrate the dual role of PMN in the breakdown of thrombi, in that they contribute both u-PA, which lyses fibrin, and other proteases, including elastase, which can cleave fibrin and plasminogen activators/plasmin. Similarly, plasma can potentiate fibrinolysis by neutralization of PMN elastase, in addition to direct inhibition of fibrinolytic proteases. Our previous studies show that PMN in thrombi are mostly pro-fibrinolytic; the anti-fibrinolytic role defined here may be important in other pathologies where fibrin persists.
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PMID:Polymorphonuclear leucocytes have two opposing roles in fibrinolysis. 1208 79

The response of the fibrinolytic system to inflammatory mediators in empyema and complicated parapneumonic pleural effusions is still uncertain. We prospectively analysed 100 patients with pleural effusion: 25 with empyema or complicated parapneumonic effusion, 22 with tuberculous effusion, 28 with malignant effusion and 25 with transudate effusion. Inflammatory mediators, tumour necrosis factor-alpha (TNF-alpha), interleukin-8 (IL-8) and polymorphonuclear elastase, were measured in serum and pleural fluid. Fibrinolytic system parameters, plasminogen, tissue-type plasminogen activator (t-PA) and urokinase PA, PA inhibitor type 1 (PAI 1) and PAI type 2 concentrations and PAI 1 activity, were quantified in plasma and pleural fluid. The Wilcoxon signed-rank test was used to compare plasma and pleural values and to compare pleural values according to the aetiology of the effusion. The Pearson correlation coefficient was used to assess the relationship between fibrinolytic and inflammatory markers in pleural fluid. Significant differences were found between pleural and plasma fibrinolytic system levels. Pleural fluid exudates had higher fibrinolytic levels than transudates. Among exudates, tuberculous, empyema and complicated parapneumonic effusions demonstrated higher pleural PAI levels than malignant effusions, whereas t-PA was lowest in empyema and complicated parapneumonic pleural effusions. PAI concentrations correlated with TNF-alpha, IL-8 and polymorphonuclear elastase when all exudative effusions were analysed, but the association was not maintained in empyema and complicated parapneumonic effusions. A negative association found between t-PA and both IL-8 and polymorphonuclear elastase in exudative effusions was strongest in empyema and complicated parapneumonic effusions. Blockage of fibrin clearance in empyema and complicated parapneumonic effusions was associated with both enhanced levels of PAIs and decreased levels of t-PA.
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PMID:Association between inflammatory mediators and the fibrinolysis system in infectious pleural effusions. 1286 57

Earthworm fibrinolytic enzyme II (EFE-II) from Eisenia fetida has a broad hydrolytic specificity for peptide bonds. Our experiments show that EFE-II can hydrolyze the specific chromogenic substrates of thrombin (Chromozym TH), trypsin (Chromozym TRY) and elastase (Chromozym ELA). The Michaelis-Menten constant (K(m)) for Chromozym ELA (approximately 245 microM) is much higher than those for the thrombin (approximately 90 microM) and trypsin (approximately 60 microM) substrates. On the other hand, EFE-II is inhibited most strongly by soybean trypsin inhibitor (SBTI), and weakly inhibited by elastinal, suggesting that EFE-II has a trypsin-like activity. Degradation of plasminogen (PLg) and fibrinogen by EFE-II was investigated after EFE-II had been immobilized onto 1,1'-carboryl-diimidazole (CDI)-activated Sepharose CL-6B. The immobilized EFE-II has 55-60% activity of the native enzyme with a higher thermal and pH resistance. EFE-II cleaves PLg at four hydrolytic sites: Lys(77)-Arg(78), Arg(342)-Met(343), Ala(444)-Ala(445) and Arg(557)-Ile(558). The site Arg(557)-Ile(558) is also recognized and cleaved by tissue plasminogen activator (t-PA) and urokinase (UK), producing active plasmin. Cleaving Ala(444)-Ala(445) released mini-plasmin with secondary activity to hydrolyze fibrin. Immobilized EFE-II degrades not only the Aalpha chain of fibrinogen in the C-terminal region (like human neutrophil elastase, HNE), but also in the N-terminal region at the Val(21)-Glu(22) site.
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PMID:Hydrolysis of fibrinogen and plasminogen by immobilized earthworm fibrinolytic enzyme II from Eisenia fetida. 1295 13

Hyperforin (Hyp), the major lipophilic constituent of St. John's wort, was assayed as a stable dicyclohexylammonium salt (Hyp-DCHA) for cytotoxicity and inhibition of matrix proteinases, tumor invasion, and metastasis. Hyp-DCHA triggered apoptosis-associated cytotoxic effect in both murine (C-26, B16-LU8, and TRAMP-C1) and human (HT-1080 and SK-N-BE) tumor cells; its effect varied, with B16-LU8, HT-1080, and C-26 the most sensitive (IC50 = 5 to 8 micromol/L). At these concentrations, a marked and progressive decline of growth was observed in HT-1080 cells, whereas untransformed endothelial cells were only marginally affected. Hyp-DCHA inhibited in a dose-dependent and noncompetitive manner various proteinases instrumental to extracellular matrix degradation; the activity of leukocyte elastase was inhibited the most (IC50 = 3 micromol/L), followed by cathepsin G and urokinase-type plasminogen activator, whereas that of the matrix metalloproteinases (MMPs) 2 and 9 showed an IC50 > 100 micromol/L. Nevertheless, inhibition of extracellular signal-regulated kinase 1/2 constitutive activity and reduction of MMP-2 and MMP-9 secretion was triggered by 0.5 micromol/L Hyp-DCHA to various degrees in different cell lines, the most in C-26. Inhibition of C-26 and HT-1080 cell chemoinvasion (80 and 54%, respectively) through reconstituted basement membrane was observed at these doses. Finally, in mice that received i.v. injections of C-26 or B16-LU8 cells, daily i.p. administration of Hyp-DCHA-without reaching tumor-cytotoxic blood levels-remarkably reduced inflammatory infiltration, neovascularization, lung weight (-48%), and size of experimental metastases with C-26 (-38%) and number of lung metastases with B16-LU8 (-22%), with preservation of apparently healthy and active behavior. These observations qualify Hyp-DCHA as an interesting lead compound to prevent and contrast cancer spread and metastatic growth.
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PMID:Hyperforin inhibits cancer invasion and metastasis. 1534 8

Plasma levels of granulocyte-derived elastase (GE-XDP), D-dimer and soluble fibrin (SF) were examined in 53 patients with deep vein thrombosis (DVT) and in 100 healthy volunteers. The mean plasma level of D-dimer was 0.92+/-0.81 microg/ml (+/-S.D.) in healthy volunteers and the mean+2 S.D. value (cutoff value for DVT) was 2.53 microg/ml, which was higher than that used in Europe and North America. Plasma levels of GE-XDP, D-dimer and SF were significantly higher in patients with DVT than in healthy volunteers, and diminished after 1 week of treatment with heparin, urokinase or tissue type plasminogen activator, though were still higher than those of the control subjects. The sensitivity of GE-XDP, D-dimer and SF for DVT was 81.1%, 75.5% and 79.2%, respectively. GE-XDP levels correlated with those of D-dimer and SF. Our results indicate that GE-XDP is a potentially useful marker for the diagnosis of DVT, suggesting that granulocytes are activated in patients with DVT. In our system, the cutoff value of D-dimer for the diagnosis of DVT is higher than in western countries, probably due to the use of different analytical assays.
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PMID:Elevated plasma levels of fibrin degradation products by granulocyte-derived elastase in patients with deep vein thrombosis. 1556 53

Serine proteases are attractive targets for the design of enzyme inhibitors since they are involved in the etiology of several diseases. Within the class of serine proteases, HLE is one of the most destructive enzymes in the body. It is implicated in the promotion or exacerbation of a number of diseases including pancreatitis, acute respiratory syndrome, rheumatoid arthritis, atherosclerosis, pulmonary emphysema, and cystic fibrosis. Thrombin, a trypsin-like serine protease, plays a dual role in thrombogenesis, including fibrin formation and platelet activation. As a result, thrombin constitutes one of the most widely studied targets for antithrombotic strategy. Numerous inhibitors of serine proteases have been reported during the past three decades. Among them, coumarin-type molecules displayed a high inhibitory potency towards various serine proteases. At that time, halomethyl dihydrocoumarins have been shown to behave as the first general suicide inhibitors of serine protease. These molecules inhibit several proteases such as human leucocyte elastase, porcine pancreatic elastase, thrombin, urokinase and human plasmin. Isocoumarins are very effective as mechanism-based inhibitors of serine proteases. Pharmacomodulation on the 3-alkoxy-4-chloroisocoumarins and the 3-alkoxy-7-amino-4-chloroisocoumarins led to strong inhibitors of numerous serine proteases such as HLE, human factor XIa and XIIa, thrombin, urokinase and kallikrein. Recently, a series of coumarins characterised by an alkyl, aryl ester, amide, thioester or ketone in the position 3 and an electrophilic chloromethyl moiety in the position 6 have been developed. These compounds were found to be high inhibitors of alpha-chymotrypin, HLE and human thrombin.
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PMID:Coumarin and isocoumarin as serine protease inhibitors. 1557 71

The aim of this study was to assess the expression of several metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) in exudative pleural effusions, and their relationship with inflammatory and fibrinolytic mediators in parapneumonic effusions. The study included 51 parapneumonic effusions (30 empyema or complicated parapneumonic, 21 noncomplicated parapneumonic), 28 tuberculous, 30 malignant and 30 transudates. Inflammatory markers (tumour necrosis factor-alpha, interleukin-8, polymorphonuclear elastase), fibrinolytic system variables (tissue plasminogen activator (PA), urokinase PA (u-PA), plasminogen activation inhibitor (PAI)-1, PAI-2), and several MMPs (MMP-1, MMP-2, MMP-8, MMP-9) and TIMPs (TIMP-1, TIMP-2) were determined by ELISA in plasma and pleural fluid. Elevated MMP-2 and TIMP-1 concentrations were observed in all the pleural fluid samples studied. The group of empyema or complicated parapneumonic effusions showed higher MMP-1, MMP-8 and MMP-9 concentrations than the remaining exudates. There was no correlation between MMP and TIMP levels in plasma and pleural fluid in this group of effusions. In parapneumonic effusions, MMP-1, MMP-8 and MMP-9 showed a positive correlation with the inflammatory markers and with u-PA and PAI-1. Moreover, there was a relationship between MMP-8 concentration in pleural fluid and pleural thickening at the end of treatment. In conclusion, elevated metalloproteinase-1, -8 and -9 expression was found in parapneumonic pleural effusions. These metalloproteinases could be implicated in the local inflammatory response existing in this group of effusions.
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PMID:Metalloproteinases and tissue inhibitors of metalloproteinases in exudative pleural effusions. 1564 Mar 30

The role of matrix-degrading enzymes, particularly plasminogen activators and matrix metalloproteinases, in the acute wound healing response has been the focus of many scientific studies. Only recently have these classes of endogenously produced proteinases been studied with regard to their involvement in the chronic wound environment. Using both in situ histologic zymography and immunohistochemical techniques, we examined the distribution of plasminogen activators and matrix metalloproteinase in the granulation tissue of pressure ulcers. Using in situ histologic zymography, urokinase was found to be the predominant plasminogen activator activity in the chronic wound granulation tissue, with little or no tissue-type plasminogen activator activity. These results were confirmed with the use of immunohistochemical techniques. In contrast, tissue-type plasminogen activator was found to be constitutively expressed in normal skin. Levels of matrix metalloproteinases were also found to be elevated in the granulation tissue of pressure ulcers. Immunohistochemical localization of leukocyte-associated proteinases (PMN elastase and cathepsin G) suggested a highly inflamed environment within the pressure ulcer granulation tissue. These results suggest a highly proteolytic environment within the chronic wound.
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PMID:Involvement of proteolytic enzymes--plasminogen activators and matrix metalloproteinases--in the pathophysiology of pressure ulcers. 1717 53


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