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)

We have characterized a transcriptional enhancer of the human urokinase-type plasminogen activator (uPA) gene and found a regulatory element required for co-operation between a PEA3--AP-1 element and an AP-1 site in the enhancer. We designated this regulatory element co-operation mediator (COM). Both the PEA3--AP-1 element, the AP-1 site and the COM are required for efficient phorbol ester induction of transcription from the uPA promoter in the HepG2 hepatoma cell line. We show that the COM is also required for co-operation between the PEA3--AP-1 element and a glucocorticoid response element, both in the presence or absence of TPA, indicating that the COM is generally capable of mediating synergism between inducible enhancer elements. The COM contains multiple overlapping binding sites for nuclear proteins, designated uPA enhancer factors 1-4 (UEF-1-4). We have identified putative binding sites for UEF-1, -2 and -3. The UEF-1 and -3 sites in the uPA enhancer are highly conserved between species. We demonstrate the binding of UEF-3 to the NIP element, a previously characterized regulatory element in the human interleukin-3 and stromelysin promoters, suggesting that this factor plays a role in regulation of a variety of genes.
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PMID:A regulatory element that mediates co-operation between a PEA3-AP-1 element and an AP-1 site is required for phorbol ester induction of urokinase enhancer activity in HepG2 hepatoma cells. 133 May 39

1. Extracts with physiological saline solution were obtained from about 20 species of invertebrates and seaweed. Tosyl-L-Arg-MeOH hydrolysing and fibrin plate lytic activity were detected in the invertebrates Stichopus japonicus, Crassost gigas, Tapes japonica, and Kintai-gai as well as the seaweed Codiales codium. 2. These activities were all labile against heat (at 65 degrees C for 1 hr). Except for the extract from Stichopus japonicus, lytic activities against fibrin plates with and without plasminogen were similar. 3. The extract from S. japonicus showed plasminogen activating potency as well as the existence of urokinase (UK) activity enhancing factor. 4. On the other hand, the extract of the seaweed Hizikia fusiformis showed a strong UK inhibiting activity. 5. A fraction of fibrinolytic enzyme was obtained from the extract of S. japonicus by absorption to the celite affinity chromatography. It was orally administered to rabbits at a dosage of 40 mg/kg/day. 6. Fibrinolytic activity was determined periodically on the eugloblin fraction of plasma samples collected from these animals. 7. As compared with the pretreatment value, the activity increased about 2 times (P less than 0.01) and 3 times (P less than 0.005) after 4 and 8 weeks, respectively, of the treatment. 8. After 8 weeks of treatment, the kidney of treated rabbits was extracted with 2 M KCl. The activity of tissue plasminogen activator (free-type TPA) was revealed to be enhanced significantly (P less than 0.001) in the extracts. 9. The fibrinolytic enzyme increased in the blood was recognized by zymography to be mainly the UK type plasminogen activator with mol. wt of 53,000.
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PMID:Fibrinolysis relating substances in marine creatures. 152 24

The signal transduction pathways of urokinase (u-PA) in A431 cells, a human epidermoid carcinoma cell line, were studied using the inducers EGF and TPA. Based on the following observations, we conclude that the two pathways are different: (1) The effects are additive; (2) EGF induction of u-PA was not compromised either by down-regulation of PKC or selective inhibition of the same by H7; (3) 8-Br-cAMP has no effect by itself; however, it inhibits the EGF effect and doubles the TPA induction of u-PA; (4) after EGF-induced tyrosine phosphorylations are completed, addition of TPA can still induce u-PA, an effect that can be blocked by the addition of the tyrosine phosphorylation inhibitor, genistein, indicating that the two agents induce different tyrosine phosphorylation; (5) in 2-dimensional electrophoresis of 32P-labeled cell lysates, inducer-specific differences in the intensity of spots can be observed. Some of the spots weakened by genistein (tyrosine phosphorylations) are different, depending on the inducer used.
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PMID:Epidermal growth factor and 12-tetradecanoyl phorbol 13-acetate induction of urokinase in A431 cells. 179 95

Systemic lysis may protect against the platelet activation and ongoing thrombosis associated with coronary thrombolysis. To address this hypothesis, we compared urokinase and tissue-type plasminogen activator (t-PA) given intravenously in a chronic, canine model of coronary thrombosis. T-PA 10 micrograms/kg per min induced reperfusion in 55 +/- 7 min but complete reocclusion occurred in 9/10 animals. Reocclusion was prevented by combining t-PA with 7E3, an antibody to the platelet glycoprotein IIb/IIIa which abolished ex vivo platelet aggregation. A similar time to reperfusion was seen with urokinase 750-1,000 U/kg per min. In contrast to t-PA, complete reocclusion occurred in only 1/20 cases (P less than 0.001 vs. t-PA), despite evidence of continued platelet activation in vivo and platelet aggregation ex vivo. Furthermore, this did not reflect a difference in the clearance of the two plasminogen activators. However, plasma fibrinogen was undetectable after urokinase in contrast with t-PA. Furthermore, in animals treated with prourokinase 20 micrograms/kg per min, reocclusion (4/7) correlated with the degree of systemic lysis. To determine whether platelet activation modified the response to urokinase, it was combined with 7E3. 7E3 0.8 mg/kg reduced the time to reperfusion with t-PA (30 +/- 5, n = 6; P = 0.025), but not with urokinase (56 +/- 8 vs. 62 +/- 6, P = ns). Systemic lysis protects against the propensity of continued thrombosis during coronary thrombolysis to delay reperfusion and induce reocclusion. This may modify the requirement for adjunctive antiplatelet therapy.
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PMID:Systemic lysis protects against the effects of platelet activation during coronary thrombolysis. 193 47

Tissue-type plasminogen activator (t-PA) is thought to be a promising fibrinolytic agent because of its high affinity to fibrin without evidence of significant systemic fibrinolysis. The feasibility of t-PA and urokinase (UK) in local fibrinolytic therapy was investigated in a canine common carotid artery thrombus model. After the screening of coagulation-fibrinolytic activities, autologous blood clot was injected into the segment of intimal injured common carotid artery. The fibrinolytic agent was locally applied from the origin of the common carotid artery under temporary flow arrest with a double lumen balloon catheter. T-PA used in this study was produced by the cell culture technique of normal human cells. Its activity was-expressed by AK units (AKU), namely, the fibrinolytic area of the fibrin-agar plate induced by 10 AKU/ml of t-PA solution corresponds to that of 10 IU/ml of UK solution. The doses of t-PA required to produce angiographical recanalization were 600-1,200 AKU/kg (approximately 0.015-0.03 mg/kg) of t-PA, while 24,000 IU/kg was necessary for UK. In these doses, t-PA evoked no adverse effects on the plasma coagulation-fibrinolytic system, while UK produced significant decrease in plasma fibrinogen and alpha-2 plasmin inhibitor levels. Thus, t-PA may be considered to have higher fibrinolytic ability and lower adverse effect on the plasma coagulation-fibrinolytic system than UK. Local fibrinolytic therapy for acute cerebral infarction using t-PA is considered to be a promising intravascular therapeutic procedure with less systemic fibrinolytic complications such as hemorrhagic infarction.
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PMID:[An experimental study of local fibrinolysis using tissue plasminogen activator and urokinase in a canine common carotid artery thrombus model]. 211 1

The lipoprotein Lp(a) is a cholesterol-rich plasma lipoprotein from the density fraction 1.06-1.21 g/ml. Numerous clinical and epidemiological studies have revealed a strong correlation between high plasma Lp(a) concentrations and the incidence of coronary heart disease. Furthermore, the Lp(a)-specific protein apo(a) has been detected in atherosclerotic lesions. Lp(a) is essentially an LDL-like lipoprotein particle to which the glycoprotein apo(a) is attached through a disulfide bridge with apo B-100. The elucidation of the amino acid sequence of apo(a) revealed a high homology to specific regions of human plasminogen. The latter consists of five tandemly arranged kringle domains followed by a C-terminal trypsin-like protease region. Apo(a) is composed of a large number of kringle domains, all highly homologous to kringle IV of plasminogen, followed by a kringle V-like protease-domain. The lipoprotein Lp(a), therefore, combines structural elements of both the lipoprotein and coagulation systems. In contrast to plasminogen, Lp(a) cannot be activated by TPA, streptokinase or urokinase to give proteolytic activity. However, in vitro studies have shown that Lp(a) can both inhibit endothelial cell induced fibrinolysis and can also bind to plasmin modified fibrin. These findings provide a pathobiochemical basis for the involvement of Lp(a) in atherosclerotic and thrombotic processes. The function of this lipoprotein is, however, still unclear.
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PMID:[Lipoprotein(a): characteristics of a special lipoprotein and its potential clinical significance]. 214 32

Cultured human endothelial cells synthesize and secrete two types of plasminogen activator, tissue plasminogen activator (t-PA) and urokinase (u-PA). Previous work from this laboratory (Hajjar, K.A., Hamel, N. M., Harpel, P. C., and Nachman, R. L. (1987) J. Clin. Invest. 80, 1712-1719) has demonstrated dose-dependent, saturable, and high affinity binding of t-PA to two sites associated with cultural endothelial cell monolayers. We now report that an isolated plasma membrane-enriched endothelial cell fraction specifically binds 125I-t-PA at a single saturable site (Kd 9.1 nM; Bmax 3.1 pmol/mg membrane protein). Ligand blotting experiments demonstrated that both single and double-chain t-PA specifically bound to a Mr 40,000 membrane protein present in detergent extracts of isolated membranes, while high molecular weight, low molecular weight, and single-chain u-PA associated with a Mr 48,000 protein. Both binding interactions were reversible and cell-specific and were inhibitable by pretreatment of intact cells with nanomolar concentrations of trypsin. The relevant binding proteins were not found in subendothelial cell matrix, failed to react with antibodies to plasminogen activator inhibitor type 1 and interacted with their respective ligands in an active site-independent manner. The isolated t-PA binding site was resistant to reduction and preserved the capacity for plasmin generation. In contrast, the isolated u-PA binding protein was sensitive to reduction, and did not maintain the catalytic activity of the ligand on the blot. The results suggest that in addition to sharing a matrix-associated binding site (plasminogen activator inhibitor type 1), both t-PA and u-PA have unique membrane binding sites which may regulate their function. The results also provide further support for the hypothesis that plasminogen and t-PA can assemble on the endothelial cell surface in a manner which enhances cell surface generation of plasmin.
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PMID:Identification and characterization of human endothelial cell membrane binding sites for tissue plasminogen activator and urokinase. 215 65

The effects of exogenously added urokinase type plasminogen activator, tissue type plasminogen activator, plasmin and thrombin on the proliferation of primary cultures of cells derived from prostatic hyperplasia or prostatic carcinomas were investigated by measuring the incorporation of 3H-thymidine into the cultures. Addition of urokinase type plasminogen activator (1.35 x 10(-9) M) or thrombin (10(-7) M) to the culture medium caused a two-fold increase of 3H-thymidine incorporation, regardless of the origin of the prostatic cells. Tissue type plasminogen activator did not alter the rate of 3H-thymidine incorporation, whereas plasmin caused a 25% decrease of 3H-thymidine incorporation in all cultures.
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PMID:Effect of urokinase on the proliferation of primary cultures of human prostatic cells. 244 91

Effects of tissue-type plasminogen activator (t-PA), urokinase (u-PA) and their combinations on plasminogen activation rate (PAR) in plasma, in vitro were investigated. T-PA and u-PA over concentrations range of 10 U/ml to 50 U/ml induced a linear, concentration dependent increase in PAR. Combinations of t-PA and u-PA in ratios of 3/1, 1/1 and 1/3 induced additive but not synergistic effect in the activation of plasminogen. We conclude, therefore, that t-PA and u-PA do not act synergistically in the activation of plasminogen in plasma in vitro.
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PMID:Absence of synergism between tissue-type plasminogen activator and urokinase on plasminogen activation rate in plasma. 249 46

Thrombospondin (TSP) is a multifunctional platelet alpha-granule and extracellular matrix glycoprotein that binds specifically to plasminogen (Plg) via that protein's lysine-binding site and modulates activation by tissue activator (TPA). In this study we report that the plasminogen activators, TPA and urokinase, greatly influence the binding of Plg to TSP. Using an enzyme-linked immunosorbent assay and a TSP-Sepharose affinity bead-binding assay we have found that Plg-TSP complex formation was markedly enhanced (up to 5-fold) when catalytic concentrations of Plg activators were included in the reaction mixtures. The enhancement was dependent upon the generation of small amounts of active plasmin and was duplicated by pretreatment of the immobilized TSP with plasmin prior to addition of the Plg. The enhancement effect was associated with selective proteolysis of the immobilized TSP. Purified Lys-Plg (the plasmin modified form of native Glu-Plg) bound to TSP to a greater extent than Glu-Plg, and binding of both forms was augmented by Plg activators. The apparent KD values of complex formation were unchanged in the presence of Plg activators suggesting that the enhancement effect was due to the generation of additional binding sites. The increased amount of bound Plg was demonstrated to result in a similar increase in the amount of plasmin generated from the complexes by TPA. Plg activators did not influence binding of Plg to histidine-rich glycoprotein or of histidine-rich glycoprotein to TSP, demonstrating specificity. In addition when TSP was treated with other proteases (human thrombin or human leukocyte elastase) no augmentation of Plg binding was seen. Thus, the initial production of small amounts of plasmin from Plg immobilized on TSP in fibrin-free microenvironments could generate a positive feedback loop by enzymatically modifying both TSP and Plg, resulting in an increase in TSP-Plg complex formation leading to the localized production of substantially more plasmin.
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PMID:Tissue plasminogen activator and urokinase enhance the binding of plasminogen to thrombospondin. 294 36


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