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 expression of certain proteolytic enzymes involved in cell migration (collagenase, urokinase) can be enhanced by the disruption of cellular cytoskeletal organization, suggesting an association between cell shape and gene expression. We have examined the effect of cytoskeleton-disrupting agents on the production and secretion of another proteolytic enzyme, tissue plasminogen activator (tPA), and its inhibitor, plasminogen activator inhibitor-1 (PAI-1), in human endothelial cells. Addition of 1 x 10(-6) M colchicine, 5 x 10(-6) M cytochalasin B, 10(-6) M nocodazole, or 10(-6) M tubulazole had no effect on the constitutive rate of release of tPA. However, the three microtubule-disrupting agents--colchicine, nocodazole, and tubulazole--depressed the stimulation of tPA secretion by phorbol myristate acetate (PMA) by 50- to 65%. Disruption of microfilament structure by cytochalasin B had no effect. In contrast, microtubule disruption in the absence or presence of PMA stimulated PAI-1 secretion by 2.5 and 2 times, respectively. The depression of tPA secretion was not due to inhibition of the secretory function since tPA did not accumulate intracellularly during colchicine treatment. Nor did colchicine affect the PMA activation of protein kinase C-alpha, upon which stimulation of tPA is dependent; neither translocation of the kinase nor phosphorylation of the protein kinase C substrate protein, P80, was inhibited. Measurement of tPA mRNA levels demonstrated that the increase which precedes PMA-enhanced tPA secretion was also inhibited by colchicine by 50%. However, tPA gene transcriptional activity was only reduced 13%, suggesting that a post-transcriptional event was affected by microtubule disruption. PAI-1 mRNA levels and transcription rates were elevated 3.5 times. This study suggests that the changes that occur in endothelial cells during PMA-induced signal transmission leading to enhanced tPA mRNA levels and tPA antigen production can be partly blocked by agents that disrupt microtubule organization.
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PMID:Disruption of microtubules inhibits the stimulation of tissue plasminogen activator expression and promotes plasminogen activator inhibitor type 1 expression in human endothelial cells. 163 33

A 33-year-old previously completely healthy man developed severe, at first colicky then persisting, pain in the left flank. The blood pressure was 190/110 mm Hg and he had pain over the left kidney on percussion. There was a mild leucocytosis (10,300/microliters), serum creatinine of 1.5 mg/dl and a rise in lactate dehydrogenase level to 395 U/l, while the urine was unremarkable. The pyelogram demonstrated on the left the upper calyceal system only and this very weakly. Colour Doppler ultrasound showed a massively reduced blood flow in the left renal vein while the artery was not visible. Digital subtraction angiography demonstrated eccentric narrowing of the left renal artery by an intravascular thrombus, providing the diagnosis of spontaneous renal artery dissection with thrombosis. Complete recanalization occurred after local thrombolysis with 500,000 IU urokinase over 7 hours, and subsequent administration of four times 40 mg tissue plasminogen activator over 4 hours. But the scintigram still demonstrated impaired renal function with decrease in clearance to 10% of total. The patient was still symptom-free on re-examination 16 months later, serum creatinine concentration was stable at 1.3 mg/dl and the blood pressure was normal.
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PMID:[The local lysis therapy of spontaneous renal artery dissection with arterial thrombosis]. 142 91

Human endothelial cells (EC) assemble plasmin-generating proteins on their surface. We have previously identified an EC membrane protein (Mr approximately 40,000) which specifically binds tissue plasminogen activator (t-PA) but not urokinase (Hajjar, K.A., and Hamel, N. M. (1990) J. Biol. Chem. 265, 2908-2916). In the present study, t-PA receptor protein (t-PA-R) was purified to apparent homogeneity from a detergent extract of human placental tissue by diisopropyl fluorophosphate-t-PA affinity chromatography and preparative gel electrophoresis. In a solid phase binding assay wells coated with t-PA-R bound both 125I-t-PA and 125I-Lys-plasminogen (PLG), but not 125I-urokinase in a specific, reversible, and noncompetitive fashion. Binding of 125I-Lys-PLG, but not 125I-t-PA, to t-PA-R was 80% inhibited by a 20-100-fold molar excess of the PLG-like lipoprotein(a), or by the lysine analog, epsilon-aminocaproic acid (50 mM). A polyclonal anti-t-PA-R antibody inhibited 66 and 79% of the specific 125I-t-PA and 125I-Lys-PLG binding, respectively, to EC monolayers. Biosynthetically labeled 40-kDa protein coprecipitated with t-PA- or Lys-PLG-Sepharose beads, but not with unconjugated Sepharose. In a functional assay, t-PA associated with immobilized t-PA-R generated 6.4 times more plasmin than an equivalent amount of t-PA in the fluid phase. These results suggest that t-PA-R can bind both t-PA and Lys-PLG in a manner that mimics the EC surface. This protein may play a role in modulating plasmin generation on cell surfaces.
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PMID:The endothelial cell tissue plasminogen activator receptor. Specific interaction with plasminogen. 165 83

To improve the efficacy of plasminogen activators, we produced a monoclonal antibody (RWR) that inhibits human alpha 2-antiplasmin (alpha 2AP). In addition to inhibiting alpha 2AP in plasma, RWR binds to and inhibits fibrin cross-linked alpha 2AP and reproduces the "spontaneous" clot lysis that is the hallmark of human alpha 2AP deficiency. By inhibiting the inactivation of plasmin by alpha 2AP, RWR interacts synergistically with plasminogen activators to increase the potency (for 50% clot lysis) of urokinase by 80-fold, tissue plasminogen activator by 27-fold, and streptokinase by 20-fold. Yet, for a given amount of fibrinolysis, the combination of RWR and lower doses of plasminogen activator leads to less fibrinogen consumption than is obtained with higher, equipotent doses of plasminogen activator alone. These results suggest a strategy for increasing the efficacy of plasminogen activators. More generally, this approach to amplifying enzymatic activity by immunoneutralizing an inhibitor may be useful in other biologic processes that are rigidly governed by inhibitors.
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PMID:Synergistic fibrinolysis: combined effects of plasminogen activators and an antibody that inhibits alpha 2-antiplasmin. 168 60

Immunohistochemical techniques applied to fresh frozen sections of metastatic malignant melanoma tissue revealed abundant fibrinogen (or fibrin I) in perivascular areas throughout the tumor connective tissue stroma. Fibrin was readily detected in a focal distribution in the connective tissue around nodules of viable tumor. Staining for D-dimer of cross-linked fibrin (using an antibody that cross-reacted with fragment D of fibrinogen) coincided with staining for fibrin. Diffuse staining of tumor cell bodies was observed for Factor X, and Factor XIII ("a" subunit) was detected in scattered areas of connective tissue throughout the tumors. Factor VII was not detected, and only rare tumor cells stained for tissue factor. These results support the concept that a tumor cell-associated, thrombin-generating pathway exists in situ in malignant melanoma tissue that includes Factor X but neither tissue factor nor Factor VII. By contrast, tumor cell staining was observed rarely for urokinase and to a variable extent for tissue plasminogen activator.
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PMID:Malignant melanoma. Interaction with coagulation and fibrinolysis pathways in situ. 169 Sep 50

A functional assay for equine plasminogen was established, using urokinase as the activator, a synthetic chromogenic substrate, a computer-assisted centrifugal analyzer, and acidified/neutralized plasma. One documented effect of plasma acidification appears to be inactivation of alpha-2-antiplasmin. Intra- and interassay precision testing yielded coefficients of variation of 4.1% (n = 10) and 5.6% (n = 26), respectively. Plasminogen was stable in equine plasma stored up to 1 week at 4 C and up to 5 months at -70 C. Plasminogen in nonacidified equine plasma was not activated by urokinase, streptokinase, tissue plasminogen activator, or tissue plasminogen activator plus soluble fibrin. Streptokinase also failed to activate plasminogen in acidified/neutralized equine plasma.
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PMID:Chromogenic assay for equine plasminogen. 169 46

Plasminogen activator inhibitor-1 (PAI-1) inhibits the tissue plasminogen activator (tPA) and urokinase activation of plasminogen to plasmin, a protease of trypsin-like specificity which is involved in a number of processes, including fibrinolysis, matrix degradation and angiogenesis. Both phorbol esters and cAMP elevating compounds have been shown to modulate PAI-1 and tPA expression in endothelial cell culture. HBGF-1 (previously designated endothelial cell growth factor) stimulates endothelial cell growth in vitro and is angiogenic in vivo. We have reported that removal of HBGF-1 from human umbilical vein endothelial cell (HUVEC) media results in an approximately 5-fold increase in PAI-1 mRNA levels and in PAI-1 protein secreted into the media by 20 h. Here we report the effects of HBGF-1 on the phorbol ester and cAMP modulation of HUVEC PAI-1 expression. The phorbol ester PMA induced an approximate 5-fold increase in PAI-1 mRNA levels at 4 h, which returned to base line by 20 h, with or without HBGF-1 present in the media. This increase in PAI-1 mRNA levels was mediated by an increase in PAI-1 gene transcription and was abated in the presence of cycloheximide. Treatment of cells with the adenylate cyclase activator forskolin or the phosphodiesterase inhibitor HL 725, in the presence of HBGF-1 or immediately after its withdrawal, decreased PAI-1 mRNA levels and protein secreted into the conditioned media by 20 h. However, forskolin or HL 725 addition had little or no effect on PAI-1 mRNA when added 20 h after HBGF-1 withdrawal. Both the PMA and HBGF-1 modulation of PAI-1 were abolished by treatment with the protein kinase inhibitor H-7. Treatment of HUVEC with HBGF-1 had no acute effect on intracellular inositol phosphate hydrolysis or cAMP levels. Further studies on intracellular pathways involved in HBGF-1 modulation of PAI-1 will enhance our understanding of the role these factors play in cellular proliferation and angiogenesis.
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PMID:Heparin-binding growth factor-1 modulation of plasminogen activator inhibitor-1 expression. Interaction with cAMP and protein kinase C-mediated pathways. 170 36

To explore mechanisms of coagulation activation in adenocarcinoma of the prostate, the occurrence and distribution of components of coagulation and fibrinolysis pathways in situ were studied by means of immunohistochemical techniques applied to frozen sections of fresh malignant and benign hyperplastic prostatic tissue obtained at transurethral resection. Fibrinogen was distributed throughout the perivascular and tumor connective tissue in both malignant and benign disease but was not present in adjacent areas of normal prostate. Antibodies specific for fibrin and D-dimer crosslink sites stained vascular endothelium focally in both malignant and benign tissues. Both neoplastic cells and benign hyperplastic glandular epithelial cells stained weakly and in a patchy distribution for tissue factor and focally for low-molecular-weight urokinase-type plasminogen activator. Focal staining of vascular endothelium was also observed for tissue plasminogen activator and plasmin-antiplasmin complex neoantigen. By contrast, no tissue staining was observed for factor VII, factor X, factor XIII "a" subunit, high-molecular-weight urokinase-type plasminogen activator, plasminogen activator inhibitors 1 to 3, protein C, and protein S. Thus, the similarity in findings between benign hyperplastic and neoplastic prostate tissue, the lack of either an intact tumor cell-associated coagulation pathway or fibrin formation, and the presence of fibrin on vascular endothelium are consistent with the concept that coagulation activation in prostatic cancer may not be due to a direct effect of the tumor cells on the clotting mechanism. Rather, such activation may be induced by a soluble tumor product that activates procoagulant activity on certain host (for example, vascular endothelial) cells. These findings, together with the lack of effect of warfarin anticoagulation on the clinical course of patients with prostatic cancer, contrast with findings in certain other tumor types and suggest that coagulation activation may not contribute to progression of adenocarcinoma of the prostate.
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PMID:Fibrin formation on vessel walls in hyperplastic and malignant prostate tissue. 170 19

Three murine monoclonal antibodies (designated alpha Pg-28, alpha Pg-96, and alpha Pg-247) against human plasminogen were prepared. All three antibodies bound plasminogen and the elastase-digestion product of plasminogen consisting of residues Val442-Asn790 (miniplasminogen). The epitopes recognized by each antibody were distinct. Antibodies alpha Pg-96 and alpha Pg-247 blocked tissue plasminogen activator-dependent lysis in a fibrin plate assay while antibody alpha Pg-28 had no effect. Antibody alpha Pg-96 blocked urokinase- and tissue plasminogen activator-catalyzed, and streptokinase-mediated, plasminogen activation. Antibodies alpha Pg-28 and alpha Pg-247 partially inhibited tissue plasminogen activator-catalyzed plasminogen activation. Antibodies alpha Pg-28 and alpha Pg-247 also inhibited streptokinase-mediated plasminogen activation, but not urokinase-catalyzed activation. Antibody alpha Pg-247 inhibited plasmin catalysis of substrate S-2251 by decreasing the VMAX and increasing the KM of plasmin for the synthetic substrate S-2251 four-fold. The other antibodies had no significant effect on plasmin activity. This differential inhibition of plasminogen activation suggests that activation by urokinase, tissue plasminogen activator, and streptokinase possibly involve distinct regions of miniplasminogen structure.
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PMID:Inhibition of plasminogen activation by monoclonal antibodies to the kringle 5-B chain segment of human plasminogen. 172 59

The human U373 glioblastoma/astrocytoma cell line was found to constitutively produce and secrete a plasminogen activator and a plasminogen activator inhibitor. The plasminogen activator was identified as urokinase based on apparent molecular weight, immunoblotting with anti-urokinase antibodies, and Northern blotting with a human urokinase cDNA probe. The inhibitor secreted by U373 cells was found to be related to the PAI-1 molecule based on reactivity with anti-human PAI-1 antibodies, apparent molecular weight, and Northern blot analysis with a human PAI-1 cDNA probe. The expression of both urokinase and the PAI-1-like molecule by U373 cells could be modulated by phorbol myristate acetate or by inflammatory mediators such as interferon-gamma and interleukin-1. In the case of interleukin-1, the alpha form exhibited no detectable effect while the beta form not only elevated inhibitor levels, it also appeared to induce the production of tissue plasminogen activator. Thus, in these cells interleukin-1 beta induces alterations in PA and PAI expression and interleukin-1 alpha does not, even though the two forms are reported to utilize the same cellular receptor.
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PMID:Modulation of plasminogen activator and plasminogen activator inhibitor expression in the human U373 glioblastoma/astrocytoma cell line by inflammatory mediators. 172 61


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