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)

Activator concentration in the range 50 to 100 Ploug units urokinase is directly proportional to the reciprocal of the lysis time both in the presence and absence of the plasma or serum inhibitors. Inhibitory activity can be estimated, therefore, by the difference in lysis time between control clots containing a buffer or euglobulin component and plasma or serum containing clots both activated by a common concentration of urokinase selected from within the critical range. An experimental model for this purpose is described with an examination of the effects of each variable in this system and a reference curve in terms of a known inhibitor. In this study, it has been found that the effects of calcium are influenced by the plasminogen concentration and are biphasic in the presence of the serum inhibitors.
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PMID:Method of estimating the inhibitory effect of plasma or serum upon urokinase-activated fibrinolysis. 593 7

The effects of various concentrations of plasmin and activated protein C on the factor VIII procoagulant activity (VIII:C) and coagulant antigen (VIII:CAg) were studied in factor VIII concentrates and normal plasma. Small amounts (0.1 CTA U/ml) of plasmin rapidly destroyed VIII:C, and affected, but did not destroy VIII:CAg, in factor VIII concentrates. In normal plasma larger amounts of plasmin (1.8 CTA U/ml) was required to inactivate VIII:C in order to exceed the neutralizing capacity of alpha 2-antiplasmin. VIII:CAg was unchanged indicating a limited proteolysis. The difference between VIII:C and VIII:CAg was found also in urokinase-activated plasma. Activated protein C (5 micrograms/ml), in the presence of Ca2+ and phospholipids, inactivated VIII:C without affecting VIII:CAg in a high purity factor VIII concentrate. Higher concentrations of activated protein C (25 micrograms/ml) caused a slight decrease of VIII:CAg, even in the absence of Ca2+ and phospholipids, but did not change VIII:CAg in normal plasma or serum.
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PMID:The effects of plasmin and protein Ca on factor VIII:C and VIII:CAg. 622 18

Coagulum pyelolithotomy is a time-saving and tissue-conserving method which minimizes the danger of small crystallizations being left behind for new stone formation. A coagulum of excellent elasticity and tenacity can be obtained from the following mixture: first syringe, 20 ml thrombocyte-enriched plasma plus 5 ml human fibrinogen, and second syringe, 1 ml thrombin plus 4 ml calcium chloride. During the last 7 years this procedure has been employed in 120 selected patients; of these 84 involved multiple stones and 36 a single stone in a dilated intrarenal system. In only six cases were there residual caliceal fragments. The risk of hepatitis seems to be negligible since (1) only HBsAG-negative plasma and blood extracts are used, and (2) a comparison of two groups of 120 pyelolithotomies, with and without the coagulum, showed only two cases of hepatitis in each group while preoperative hepatitis occurred in five and seven cases, respectively. The enzymatic action or urokinase ensures that missing fibrin particles are dissolved before encrustation can occur. All free stones are caught and extracted with the coagulum. In 23% of cases additional fragments, not indicated by preoperative X-rays, were extracted as well.
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PMID:The value of coagulum pyelolithotomy. 722 99

A woman with mixed connective tissue disease (MCTD) developed pulmonary hypertension after delivery of a child, but had little evidence of parenchymal lung disease. This 29-year-old woman had been given a diagnosis of MCTD when she was 19 years old. She was admitted to our department two days after delivery of a child, because of dyspnea on exertion. Acute thromboembolism was suspected because of: (1) chest roentgenogram showing cardiomegaly and enlargement of the left main pulmonary artery, (2) a lung perfusion scan showing a segmental defect in the left S6 and S8 areas, (3) laboratory studies showing abnormally high WBC, LDH, FDP, and D-D dimer, and (4) arterial blood gas analyses showing mild hypoxemia and hypocapnia. Thrombolytic therapy with heparin and urokinase was begun, and was followed by a loop diurtic and anticoagulation with warfarin. One month after admission, cardiac enlargement and the A-aDO2 were found to have decreased. At that time, cardiac catheterization was done and revealed pulmonary hypertension (mean PA pressure: 45 mmHg) and low cardiac output with no detectable thrombosis in the left pulmonary artery. The patient was subsequently treated with a calcium antagonist and a prostacyclin derivative, and her condition was stable for 5 months. Then her exercise tolerance gradually decreased due to shortness of breath, and cardiomegaly gradually increased over the next 3 months. Eight months after delivery of the child, the patient died of right heart failure. In clinically stable patients with MCTD, delivery of a child may lead to pulmonary thromboembolism and pulmonary hypertension.
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PMID:[Puerperal secondary pulmonary hypertension in a patient with mixed connective tissue disease]. 747 71

A human epithelial cell line, WISH, and a mouse cell line, LB6-uPAR, transfected with the human urokinase receptor (uPAR), both expressed high affinity uPAR but undetectable levels of urokinase (uPA). In two independent assays, binding of exogenous pro-uPA produced an up to threefold enhancement of migration. The migration was time and concentration dependent and did not involve extracellular proteolysis. This biologic response suggested that uPAR can trigger an intracellular signal. Since this receptor is a glycosyl-phosphatidylinositol-linked protein, we postulated that it must do so by interacting with other proteins, among which, by analogy to other systems, would be a kinase. To test this hypothesis, we carried out a solid phase capture of uPAR from WISH cell lysates using either antibodies against uPAR or pro-uPA adsorbed to plastic wells, followed by in vitro phosphorylation of the immobilized proteins. SDS-PAGE and autoradiography revealed two phosphorylated protein bands of 47 and 55 kD. Both proteins were phosphorylated on serine residues. Partial sequence of the two proteins showed a 100% homology to cytokeratin 18 (CK18) and 8 (CK8), respectively. A similar pattern of phosphorylation was obtained with lysates from A459 cells, a lung carcinoma, but not HL60, LB6-uPAR or HEp3 cell lysates, suggesting that the identified multiprotein uPAR-complex may be specific for simple epithelia. Moreover, immunocapture with antibody to another glycosyl-phosphatidylinositol-linked protein, CD55, which is highly expressed in WISH cells, was ineffective. The kinase was tentatively identified as protein kinase C, because it was inhibited by an analogue of staurosporine more specific for PKC and not by a PKA or tyrosine kinase inhibitors. The kinase was tentatively identified as PKC epsilon because of its resistance to PMA down-modulation, independence of Ca2+ for activity, and reaction with a specific anti-PKC epsilon antibody in Western blots. Cell fractionation into cytosolic and particulate fractions revealed that all four proteins, the kinase, uPAR, CK18, and CK8, were present in the particulate fraction. In vivo, CK8, and to a lesser degree CK18, were found to be phosphorylated on serine residues. Occupation of uPAR elicited a time-dependent increase in the phosphorylation intensity of CK8, a cell shape change and a redistribution of the cytokeratin filaments. These results strongly suggest that uPAR serves not only as an anchor for uPA but participates in a signal transduction pathway resulting in a pronounced biological response.
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PMID:Induction of cell migration by pro-urokinase binding to its receptor: possible mechanism for signal transduction in human epithelial cells. 751 43

Primary or secondary hyperoxaluria is associated with calcium oxalate nephrolithiasis, interstitial fibrosis and progressive renal insufficiency. Monolayer cultures of nontransformed monkey kidney epithelial cells (BSC-1 line) and calcium oxalate monohydrate (COM) crystals were used as a model system to study cell responses to crystal interactions that might occur in the nephrons of patients during periods of hyperoxaluria. To determine if COM crystals signal a change in gene expression, Northern blots were prepared from total renal cellular RNA after the cells were exposed to crystals. The immediate early genes c-myc, EGR-1, and Nur-77 were induced at one hour. At two to six hours stimulated expression of the genes encoding plasminogen activator inhibitor (PAI-1) and platelet-derived growth factor (PDGF)-A chain was detected, but constitutive expression of urokinase-type plasminogen activator (u-PA) was not altered. Expression of connective tissue growth factor (CTGF) was induced at one hour and persisted up to 24 hours. The stimulation of gene expression by COM crystals was relatively crystal- and renal cell-type specific. Thus the interaction of kidney epithelial cells with COM crystals alters expression of genes that encode three classes of proteins: transcriptional activators, a regulator of extracellular matrix (ECM), and growth factors. Activation of PAI-1 gene expression without a change in u-PA favors accumulation of ECM proteins, as does increased expression of PDGF and CTGF which can also stimulate fibroblast proliferation in a paracrine manner. These results suggest that COM crystal-mediated stimulation of specific genes in renal tubular cells may contribute to the development of interstitial fibrosis in hyperoxaluric states.
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PMID:Calcium oxalate monohydrate crystals stimulate gene expression in renal epithelial cells. 756 19

The effect of sodium pentosan polysulphate (SPP) was investigated in calcium oxalate stone forming rats with respect to the urinary excretion of certain risk factors and enzymes. Calcium oxalate stones were induced by feeding 3% w/w sodium glycollate to the rats. Urinary calcium, oxalate, phosphorus and uric acid levels were increased in stone formers. In contrast magnesium excretion was low in this group. SPP treatment lowered oxalate and calcium levels in both controls and experimental animals. Magnesium levels were increased moderately. Increased excretion of urinary enzymes--LDH, alkaline phosphatase, gamma-GT and beta glucuronidase--in calculogenic rats indicates membranuria and damage to proximal tubules during stone formation. Decreased pyrophosphatase activity was observed in glycollate fed rats. SPP treatment decreased the excretion of the above enzymes in the treated groups. Stone formers exhibited decreased LAP and fibrinolytic (urokinase) activities. SPP being associated with fibrinolytic properties, increased the activities of the above two enzymes to that of control levels in calculogenic rats.
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PMID:Alterations in some risk factors and urinary enzymes in urolithiatic rats treated with sodium pentosan polysulphate. 768 93

Hepatocyte growth factor/scatter factor (HGF/SF) is a heparin-binding polypeptide which shares structural domains with enzymes of the blood clotting cascade. HGF/SF is secreted by cells of mesodermal origin and has powerful mitogenic, motogenic and morphogenic activity on epithelial and endothelial cells. HGF/SF is produced as a biologically inactive single-chain precursor (pro-HGF/SF) most of which is sequestered on the cell surface or bound to the extracellular matrix. Maturation into the active alpha beta heterodimer results from proteolytic cleavage by a urokinase-type protease, which acts as a pro-HGF/SF convertase. The primary determinant for receptor binding appears to be located within the alpha-chain. The interaction of the alpha-chain with the receptor is sufficient for the activation of the signal cascade involved in the motility response. However, the complete HGF/SF protein seems to be required to elicit a mitogenic response. HGF/SF binds with high affinity to a transmembrane receptor, p190MET, encoded by the MET proto-oncogene. p190MET is the prototype of a distinct subfamily of heterodimeric tyrosine kinases, including the putative receptors Ron and Sea. The mature form of p190MET is a heterodimer of two disulfide-linked subunits (alpha and beta). The alpha-subunit is extracellular and heavily glycosylated. The beta-subunit consists of an extracellular portion involved in ligand binding, a membrane spanning segment, and a cytoplasmic tyrosine kinase domain. Both subunits derive from glycosylation and proteolytic cleavage of a common precursor of 170 kDa. In polarized epithelial cells the HGF/SF receptor is selectively exposed in the basolateral plasmalemma, where it is associated with detergent-insoluble components. Two Met isoforms, carrying an intact ligand binding domain but lacking the kinase domain due to truncation of the beta-subunit, arise from alternative post-transcriptional processing of the mature form. One truncated form is soluble and released from the cells. HGF/SF binding triggers tyrosine autophosphorylation of the receptor beta-subunit. Autophosphorylation on the major phosphorylation site Y1235 upregulates the kinase activity of the receptor, increasing the Vmax of the phosphotransfer reaction. Negative regulation of the kinase activity occurs through phosphorylation of a unique serine residue (S985) located in the juxtamembrane domain of the receptor. This phosphorylation is triggered by two distinct pathways involving either protein kinase C activation or increase in intracellular Ca2+ concentration. Upon ligand binding, the HGF/SF receptor recruits and activates several cytoplasmic effectors, including phosphatidylinositol 3-kinase (PI 3-K), phospholipase C-gamma (PLC-gamma), pp60c-Src, a tyrosine phosphatase, and a Ras-guanine nucleotide exchanger.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Identification of functional domains in the hepatocyte growth factor and its receptor by molecular engineering. 776 52

Hepatocyte growth factor/scatter factor (HGF/SF) and keratinocyte growth factor (KGF, also designated FGF-7) are paracrine growth factors secreted by mesenchymal cells and active on a variety of epithelial cell types. In this study, the biologic responses of keratinocytes to these paracrine growth factors were compared. Stimulation of mitogenesis, migration, plasminogen activator (PA) activity, and fibronectin production were examined using human foreskin keratinocytes cultured in serum-free MCDB 153 medium. Although the two factors stimulated a similar level of proliferation when cells were maintained for 5 d in 1.8 mM Ca++, the peak effect of KGF, observed at 10 ng/ml, was approximately threefold higher than that of HGF/SF when cells were in medium containing 0.15 mM Ca++. Both agents promoted the migration of cells in low-calcium medium (0.08 mM Ca++). However, the magnitude of the response was approximately twofold greater for HGF/SF at 10 ng/ml than KGF at the same concentration. None of the matrix proteins such as type I collagen, type IV collagen, laminin, or fibronectin either stimulated or suppressed HGF/SF- or KGF-stimulated keratinocyte migration. Both factors stimulated PA activity of the cell extracts, especially urokinase-type, with similar potencies. Promoted PA activity was maximal with the addition of 10 ng/ml of either factor. Neither factor increased the production of fibronectin under conditions in which transforming growth factor-beta 1 was active. These results indicate that HGF/SF and KGF, both recognized as paracrine growth factors, elicit distinctive patterns of response by keratinocytes, implying that they have different roles in epidermal physiology.
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PMID:Comparative study of hepatocyte growth factor/scatter factor and keratinocyte growth factor effects on human keratinocytes. 776 66

Urokinase-type plasminogen activator (uPA), which binds to cells via a specific receptor (uPAR), participates in pericellular proteolysis during leukocyte migration. Previous studies have indicated that uPAR is physically associated with CR3 (CD11b/CD18). To test the functional interactions of CR3 and uPAR, we have examined the ability of uPA to elicit changes in cytosolic calcium levels of normal neutrophils, neutrophils from a leukocyte adhesion deficiency (LAD) patient, and 3T3 transfectants expressing CR3, uPAR, or both. We found that calcium levels of neutrophils increased from 106 +/- 6 nM in untreated cells to 199 +/- 25 nM in the presence of uPA. In contrast, no significant change in calcium was observed when neutrophils from an leukocyte adhesion deficiency patient were examined. The uPA-dependent calcium rise was inhibited by mAb directed against either CR3 or uPAR and required intact uPA. To substantiate further these findings, we prepared transfectants expressing genes encoding uPAR, CR3, and both receptors; only cells expressing both receptors experienced a rise in intracellular calcium. Although uPA's calcium signal is insufficient to trigger superoxide production, FMLP dose-dependent superoxide production was greatly enhanced by incubating neutrophils with intact, but not fragmented, uPA. Flow cytometry experiments utilizing an FMLP analogue exclude the possibilities that urokinase binds to the FMLP receptor or up-regulates its expression. We suggest that calcium is a second messenger of uPA, that this message is mediated in a CR3-dependent fashion, and that this signal primes neutrophils for superoxide production.
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PMID:Human urokinase-type plasminogen activator primes neutrophils for superoxide anion release. Possible roles of complement receptor type 3 and calcium. 783 67


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