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)

Since the beginning of the clinical use of low molecular weight (LMW) heparins their thrombolytic or profibrinolytic potency has been a matter of controversial discussions. Regarding this problem, the aim of our study was to test a LMW-heparin (Sandoparin) in an in vivo model comparing its lytic activity to unfractionated heparin and urokinase at different doses. For this purpose a newly developed short-term rabbit jugular vein clot lysis model was developed. Urokinase infused at doses of 3300, 6600 and 10,000 U/kg to control animals for one hour showed a clear dose-dependent clot lysis. Test animals were injected with a bolus of 0.5 mg/kg of LMW-heparin followed by a constant infusion of either 0.5, 1.0 or 2.0 mg/kg for one hour. A similar dose-dependent effect was observed for LMW-heparin as for urokinase. Unfractionated heparin did not exhibit a dose-dependent lytic activity in this model. No lysis was found in rabbits treated with saline. These findings suggest that the LMW-heparin tested exhibits a dose-dependent in vivo lytic activity which can be compared to clinically effective doses of urokinase, and that this activity is not present with unfractionated heparin.
 ...
PMID:The thrombolytic potency of LMW-heparin compared to urokinase in a rabbit jugular vein clot lysis model. 132 52

We have studied the expression of alpha-smooth muscle actin (alpha sm-1) by mesangial cells, and the expression of Thy-1 glycoprotein, antithrombin III (ATIII), and urokinase by tubular epithelial cells in normal kidneys and dysfunctional renal allografts. Kidney biopsies were studied immunocytochemically for changes in each of these markers and the findings were classified into two groups and compared with creatinine plasma levels at the time the biopsies were taken. In dysfunctional grafts, mesangial alpha sm-1 and tubular epithelial Thy-1 reactivities were greatly diminished, and urokinase and ATIII were missing from proximal renal tubular epithelial cells. Urokinase, which was absent from normal renal glomeruli, appeared in glomeruli of some dysfunctional allografts. The possible usefulness of these markers in patient evaluations was supported by our finding that the distribution of vinculin, fibronectin, myosin, actin B4, desmin, glomerular HLA-DR, and the tubular expression of CD15 remained unchanged. These data prompt us to suggest that the immunocytochemical localization and evaluation of alpha sm-1, Thy-1, ATIII, and urokinase in kidney allografts may be useful adjuncts in the assessment of function in renal allografts.
 ...
PMID:Novel immunohistochemical markers of human renal allograft dysfunction--antithrombin III, Thy-1, urokinase, and alpha-smooth muscle actin. 136 Dec 52

We have produced a line of transgenic mice carrying a hybrid bovine alpha S1 casein/human urokinase gene. Bovine alpha S1-casein gene regulatory sequences specifically direct expression of the human urokinase gene in lactating mammary tissue from these mice. Urokinase is a 54 kD protein with 9 disulfide bonds that is normally synthesized in the kidney; however, the casein/urokinase transgenic mice secrete active human urokinase into their milk at concentrations of 1-2 mg/ml. The mice show no other abnormalities. They give birth to, and nurse, normal sized healthy litters. Thus it is possible to produce high concentrations of a large, cysteine rich, non-milk protein in the milk of transgenic animals. This line of transgenic mice provides a model for the eventual production of transgenic farm animals producing high levels of recombinant proteins in their milk.
 ...
PMID:Bovine alpha S1-casein gene sequences direct high level expression of active human urokinase in mouse milk. 136 89

The effect of extracellular matrix composition on the location, amount, and activity of cell-associated urokinase-type plasminogen activator was tested using HT-1080 cells adherent to either fibronectin or vitronectin. Specific immunoprecipitation of newly synthesized urokinase indicated that cells adherent to fibronectin synthesized 2-3-fold more urokinase than cells adherent to vitronectin. Complexes of urokinase and plasminogen activator inhibitor type 1 (PAI-1) were detected in cell layers of vitronectin-adherent but not fibronectin-adherent cells. Inhibition of PAI-1 using a neutralizing monoclonal antibody resulted in a 3-fold increase in urokinase enzymatic activity on vitronectin adherent cells. Urokinase activity on fibronectin adherent cells was only slightly increased following PAI-1 neutralization. Examination of both HT-1080 and normal human fibroblast cells by immunofluorescent microscopy localized urokinase-type plasminogen activator to discrete, focal areas underneath cells adherent to vitronectin. Urokinase was not detectable by immunofluorescence on cells adherent to fibronectin. The addition of exogenous prourokinase to locate urokinase receptors on adherent HT-1080 cells indicated that the focal localization of cell-surface urokinase resulted from the clustering of urokinase receptors following adhesion to vitronectin but not fibronectin-coated substrates. These results suggest that vitronectin can contribute to the control of cell-surface plasmin activity by regulating the synthesis of urokinase and directing the localization of urokinase receptors.
 ...
PMID:Vitronectin regulates the synthesis and localization of urokinase-type plasminogen activator in HT-1080 cells. 137 87

Exposure of bovine aortic or capillary endothelial cells to basic FGF (bFGF) for 1 h resulted in an approximately sixfold increase in plasminogen activator (PA) activity by 18 h that returned nearly to basal levels by 36 h. We hypothesized that the decrease in PA activity following bFGF stimulation was mediated by transforming growth factor beta (TGF-beta) formed from its inactive precursor. Conditioned medium collected from endothelial cells 36 h after a 1-h exposure to bFGF, but not control medium, inhibited basal levels of PA activity when transferred to confluent monolayers of bovine aortic endothelial cells. Antibody to TGF-beta neutralized the inhibitory activity of this conditioned medium, indicating that the medium contained active TGF-beta. Northern blot analysis and quantitation of acid activatable latent TGF-beta in conditioned medium demonstrated that bFGF exposure did not increase the amount of transcription or secretion of latent TGF-beta by the endothelial cells. Both aprotinin, an inhibitor of plasmin, and anti-urokinase type PA IgG blocked the generation of active TGF-beta in cultures exposed to bFGF. These results demonstrated that plasmin generated by uPA activity is required for the activation of latent TGF-beta in endothelial cell cultures treated with bFGF. Activation of TGF-beta by endothelial cells exposed to bFGF appears to limit both the degree and duration of PA stimulation. Thus, in bFGF-stimulated endothelial cell cultures, PA levels are controlled by a negative feedback loop: PA, whose expression is stimulated by bFGF, contributes to the formation of TGF-beta, which in turn opposes the effects of bFGF by limiting PA synthesis and activity. These studies suggest a role for TGF-beta in reversing the invasive stage of angiogenesis and contributing to the formation of quiescent capillaries.
 ...
PMID:Basic fibroblast growth factor-induced activation of latent transforming growth factor beta in endothelial cells: regulation of plasminogen activator activity. 138 1

The cellular receptor for urokinase-type plasminogen activator (uPAR) is a glycolipid-anchored three-domain membrane protein playing a central role in pericellular plasminogen activation. We have found that urokinase (uPA) can cleave its receptor between domains 1 and 2 generating a cell-associated uPAR variant without ligand-binding properties. In extracts of U937 cells there are two uPAR variants which after complete deglycosylation have apparent molecular masses of 35,000 and 27,000. Analysis with monoclonal antibodies showed that these variants represented the intact uPAR and a two-domain form, uPAR(2+3), lacking ligand-binding domain 1. Trypsin treatment showed that both variants are present on the outside of the cells. Addition to the culture medium of an anticatalytic monoclonal antibody to uPA inhibited the formation of the uPAR(2+3), indicating that uPA is involved in its generation. Purified uPAR can be cleaved directly by uPA as well as by plasmin. The uPA-catalyzed cleavage does not require binding of the protease to the receptor through its epidermal growth factor-like receptor-binding domain, since low molecular weight uPA that lacks this domain also cleaves uPAR. This unusual reaction in which a specific binding protein is proteolytically inactivated by its own ligand may represent a regulatory step in the plasminogen activation cascade.
 ...
PMID:Urokinase plasminogen activator cleaves its cell surface receptor releasing the ligand-binding domain. 138 66

We carried out an immunohistochemical study of tissue-type plasminogen activator (PA) and urokinase-type PA, and their inhibitors, PA inhibitor-1 and PA inhibitor-2, using renal biopsy specimens obtained from 86 patients with various forms of glomerulonephritis. The controls were four normal renal tissue specimens. On immunofluorescent observation, granular staining for tissue-type PA was found to be distributed along the glomerular capillary walls. The fluorescence was weak in the normal renal tissue and occasionally intense in the tissues of patients with IgA nephritis, minimal change nephrotic syndrome, and lupus nephritis. PA inhibitor-1 was abundant in the glomerular epithelial cells and scarce in the mesangial area and glomerular capillary lumens of the normal renal tissues. This was confirmed by immunoelectron microscopy using gold staining. The fluorescence of PA inhibitor-1 was weaker in some specimens of nephritic tissues than in the normal renal tissues. Urokinase-type PA and PA inhibitor-2 were negative within the glomeruli in all the specimens. In the glomerulonephritic tissues which were fibrin deposition-positive, tissue-type PA expression in the glomeruli tended to be strong. An association between fibrin deposition and PA inhibitor-1 staining was not clear. These data suggest that expression of tissue-type PA in the glomeruli increases in association with fibrin deposition.
 ...
PMID:Tissue-type plasminogen activator and its inhibitor in human glomerulonephritis. 138 27

Urokinase-type (uPA) and tissue-type (tPA) plasminogen activators were identified by fibrinolytic autography in the sulcus epithelium of human gingival mucosa but not in the orthokeratinized gingival epithelium. Fibrinolytic activity was present only over blood vessels in frozen sections of oral squamous cell carcinomas, the malignant epithelial cells showing no plasminogen activator activity. Plasminogen activators could not be demonstrated in either the sulcus or gingival epithelium by immunofluorescence, but both uPA and tPA were found in occasional squamous carcinoma cells. Fibrinolytic activity of culture fluids from epithelial explants grown in vitro from human gingival mucosa showed marked variation, but activity was much higher in the culture supernatants than in the cell lysates. Fibrinolytic activity of culture fluids from epithelial explants of squamous cell carcinomas was low both in supernatants and lysates. Zymogram overlays of sodium dodecyl sulphate-polyacrylamide electrophoretic gels from culture supernatants showed that the low fibrinolytic activity of culture supernatants of oral squamous cell carcinomas was due to the associated presence of plasminogen activator inhibitors. The fibrinolytic activity in the zymogram was due predominantly to uPA but some lysis was due also to tPA.
 ...
PMID:Plasminogen activators in normal and malignant oral epithelium in vivo and in vitro. 141 24

The study of the plasminogen-plasmin system has, in the past, contributed much to the understanding of fibrinolysis and thrombolysis. Attention is now focused on the role of the components of this system in many biologic functions. Findings of uPA, its receptor and its inhibitor in many tumor tissues and tumor cell lines, strongly implicate their involvement in tumor invasion, tumor cell proliferation and metastasis. The characteristics of the plasminogen activators, the uPA receptor and the plasminogen activator inhibitors as well as their expression and regulation in tumors and tumor cell lines are reviewed.
 ...
PMID:The plasminogen-plasmin system in malignancy. 142 20

Invasion and metastasis of malignant cells require the disruption of the extracellular matrix, degradation of basement membranes, and intrusion into connective tissue and vascular and lymphatic spaces. Several studies have indicated a role for urokinase (u-PA) in proteolysis of the extracellular matrix and hence in stromal invasion and metastasis. Many malignant cells are known to secrete u-PA. Plasminogen activator inhibitor-type 2 (PAI-2) is an inhibitor of u-PA and is present in several neoplastic cell lines and malignant ascites. We measured u-PA and PAI-2 antigen in tissue homogenates of normal and malignant endometrium from 21 postmenopausal patients. Enzyme-linked immunoassays which measure the bound and unbound, single-and two-chain form of the activator and bound and unbound form of the inhibitor were used. Urokinase was present in four of seven normal (range, 0.15-0.5; median, 0.15 ng/mg protein) and in significantly higher concentrations in all malignant endometrial homogenates (range, 0.41-9.2; median, 3.4 ng/mg protein), P < 0.001. PAI-2 was detectable in four of seven normal endometrial homogenates at low concentrations (range, 1.1-3.1; median, 1.1 ng/mg protein) and in all malignant tissue homogenates at significantly higher levels (range, 1.6-27.3; median, 4.9 ng/mg protein), P < 0.01. Levels of endometrial PAI-2 were higher in stages IC or greater compared to those in stages IA and 1B cancers (P < 0.05). PAI-2 may be useful as a prognostic marker in endometrial cancer.
 ...
PMID:The plasminogen activator urokinase and its inhibitor PAI-2 in endometrial cancer. 142 3


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>