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 endothelial cells (ECs) are antithrombotic in the physiological states and maintains the integrity of blood circulation. However, ECs turn to be thrombotic upon being stimulated by various physiological mediators. These functions are mainly achieved by changing specific protein synthesis in ECs. Type 1 plasminogen activator inhibitor (PAI-1) is a serine protease inhibitor synthesized by ECs and thought to play a crucial role in the regulation of fibrinolysis. Basic research as well as clinical studies support this hypothesis. PAI-1 is a physiological inhibitor of both tissue-type plasminogen activator and urokinase-type plasminogen activator, key enzymes in the initiation of fibrinolysis. Thus PAI-1 regulates not only blood clot lysis but also a wide variety of biological reactions occurring in extracellular matrices such as tumor metastasis, neovascularization, inflammation, and cell migration. PAI-1 is a glycoprotein, of which molecular weight is approximately 50,000. Molecular biological analyses indicate that PAI-1 is synthesized as a single polypeptide composed of 402 amino acids containing a signal peptide. After post-translational modification, PAI-1 is secreted from ECs as a polypeptide composed of 379 amino acids and three N-linked carbohydrates. PAI-1 lacks Cys residues, indicating that PAI-1 may not be rigid and thus thermolabile. In fact, PAI-1 is unstable even at 37 degrees C decaying into an inactive form with a biological half life of 2-3 hours. PAI-1 binds to a cell adhesion molecule, vitronectin. The association of PAI-1 with vitronectin appears to stabilize PAI-1. PAI-1 in complex with vitronectin is still accessible to plasminogen activators.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Type 1 plasminogen activator inhibitor: its role in biological reactions]. 187 Feb 65

Decreased expression of the cell-cell adhesion molecule, E-cadherin, promotes dedifferentiation and invasiveness of human carcinoma cells, whereas this process can be reversed by reexpression of E-cadherin (U. H. Frixen et al., J. Cell Biol., 113: 173-185, 1991; J. H. Schipper et al., Cancer Res., 51: 6328-6337, 1991). In this work we studied the involvement of extracellular matrix-degrading proteases in E-cadherin-dependent tumor cell invasion. When T47D and MCF-7 human differentiated breast carcinoma cells were treated with the E-cadherin antibody DECMA (decompacting monoclonal antibody) the cells dissociated from each other and lost their epithelioid morphology, paralleled with a rise in the secretion of urokinase-type plasminogen activator (uPA) into the extracellular milieu as determined by zymography. The stimulation of uPA required protein and RNA synthesis. Furthermore, when DECMA-treated T47D cells were cultured on artificial collagen matrices the induced invasiveness correlated with accumulation of uPA in the culture medium, and uPA antibodies inhibited this invasion process. Actin filaments which are thought to be associated with the cytoplasmic part of E-cadherin were disrupted after treatment of T47D cells with DECMA. These results suggest a link between cell-cell adhesion, the integrity of actin filaments, and the regulation of uPA biosynthesis.
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PMID:Stimulation of urokinase-type plasminogen activator expression by blockage of E-cadherin-dependent cell-cell adhesion. 833 68

A method for the simultaneous preparation of highly enriched human placental trophoblast populations (villous and extravillous) from first-trimester placental villi (5 to 12 weeks) by using sequential trypsinization, percoll gradient centrifugation, and negative selection with anti-CD9 immunomagnetic separation is described. The purification method resulted in the isolation of four distinct trophoblast populations identified on the basis of morphology and phenotyping: (i) mononuclear villous cytotrophoblast cells which, through differentiation, become committed to syncytium formation; (ii) an extravillous trophoblast population which appeared as a "crazy pavement" and, with subsequent subculturing, differentiated morphologically to mononuclear cells; (iii) an extravillous trophoblast fraction which fused to form multinucleated trophoblast giant cells; and (iv) floating intermediate extravillous trophoblast cells which fused together to form cell clumps and which further differentiated to a mononuclear anchoring intermediate extravillous trophoblast. Short-term cultures of the freshly isolated cell fractions consisted of heterogeneous trophoblasts at different differentiation stages as determined by their varied biochemical and morphological properties. All the isolated trophoblast populations expressed the cytokeratin intermediate filament and the epithelium-specific cell-cell adhesion molecule E-cadherin. The isolated villous trophoblasts in culture expressed integrins alpha 6 and beta 4 and reduced levels of beta 1 subunits, whereas the proliferating extravillous trophoblast cultures expressed alpha 1, alpha 3, and alpha 5 and high levels of beta 1 integrin subunits, vitronectin receptor (alpha V beta 3/beta 5), and major histocompatibility complex class 1 molecules. Furthermore, the isolated trophoblast populations secreted metalloproteases (such as type IV collagenases [mainly 72- and 92-kDa enzymes, i.e., gelatinases A and B]) and urokinase plasminogen activator, as evaluated by substrate gel zymography. This method of isolation should facilitate in vitro studies of trophoblast proliferation, differentiation, invasion, virus interactions, cytokenesis, and immunology.
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PMID:Isolation and characterization of human placental trophoblast subpopulations from first-trimester chorionic villi. 877 Apr 98

Neoplastic transformation in the normal human brain occurs as a result of the accumulation of a series of genetic alterations. These genetic alterations include the loss, gain or amplification of different chromosomes which lead to altered expression of proteins that play important roles in the regulation of cell proliferation. Several common genetic alterations at the chromosomal level (loss of 17p, 13q, 9p, 19, 10, 22q, 18q and amplification of 7 and 12q) have been observed. These alterations lead to changes in the expression of several genes; protein 53 (p53), retinoblastoma (RB), interferon (INF) alpha/beta, cyclic AMP dependent kinase number 2 (CDKN2), mutated in multiple advanced cancers 1 (MMAC1), deleted-in-colon carcinoma (DCC), epidermal growth factor receptor (EGFR), platelet derived growth factor (PDGF), platelet derived growth factor receptor (PDGFR), MDM2, GL1, CDK4 and SAS during the genesis and progression of human gliomas. Recent studies suggest that altered expression of several other genes [MET; MYC; transforming growth factor beta (TGF beta); CD44; vascular endothelial growth factor (VEGF); human neurological-related cell adhesion molecule (hNr-CAM); neuroglial cell adhesion molecule (NCAM L1); p21waf1/Cip1; TRKA; mismatch repair genes (MMR); C4-2; D2-2] and proteins [e.g., cathepsins, tenascin, matrix metalloproteases, tissue inhibitors of metalloproteases, nitric oxide synthase, integrins, interleukin-13 receptor (IL-13R), Connexin43, urokinase-type plasminogen activator receptors (uPARs), extracellular matrix proteins and heat shock proteins] are associated with the genesis of human gliomas. Taken together, these findings point to the accumulation of multiple genetic mutations coupled with extensive changes in gene expression in the etiology of human gliomas.
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PMID:Molecular changes during the genesis of human gliomas. 940 26

Two types of gastric adenocarcinoma can be distinguished histopathologically: the diffuse and the intestinal type. Molecular pathology supports this theory by showing differences in the genetic pathways of both tumor types. In addition to known pathomorphological factors of prognosis, e.g., depth of tumor infiltration, number of lymph node metastases and resection margins, a few genes have been suggested to have prognostic impact in gastric carcinoma. Clinically relevant molecules whose expression or structure is altered include the plasminogen activator (uPA) and its inhibitor PAI-1 (plasminogen activator inhibitor type 1), the cell cycle regulator cyclin E, epidermal growth factor (EGF), the apoptosis inhibitor bcl-2, the cell adhesion molecule E-cadherin, and the multifunctional protein beta-catenin. Gene amplification and protein overexpression of the growth factor receptors c-erbB-2 and K-sam may be prognostic factors for intestinal-type and diffuse-type gastric cancer, respectively. In addition, genetic instability is commonly seen. There has long been evidence for a genetic predisposition to gastric cancer by epidemiological studies and case reports. Very recently, germ line mutations of E-cadherin have been identified that are responsible for a dominantly inherited form of diffuse-type gastric cancer and could be used to identify individuals that are at high risk.
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PMID:Gastric adenocarcinoma: pathomorphology and molecular pathology. 1131 54

Adhesion and proteolysis are basic reactions of tumor growth and metastasis. During these complex processes malignant cells change their adhesion behaviour and proteolytic capacity. Therefore, an extensive characterization of tumor cells is necessary if results of functional assays e.g., tests for tumor cell invasion are to be correlated with the presence of tumor antigens. This paper describes the detection of CD44 variant sequences, urokinase-type plasminogen activator (uPA) and uPA-receptor (uPAR) by immunoluminescence and activity measurements. For these investigations the melanoma cell line IGR 1 was used. The expression of CD44 (v5), uPA and uPAR on the cell surface was shown by indirect labelling with monoclonal antibodies (mAb). The marker enzyme horseradish peroxidase (HRP) of the secondary Ab was used to release luminescence and fluorescence with suitable substrates. The enhanced luminescent assay was superior to fluorescence analysis. uPA-activity in intact cells was examined with the substrates plasminogen, Z-Gly-Gly-Arg-AMC and Z-Lys-SBzl including selective inhibitors. The immunoluminescent assay can be alternatively used with well-tried immunofluorescent methods e.g. flow cytometry, for the detection of cellular cancer markers (1).
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PMID:Co-localization of CD44 and urokinase-type plasminogen activator on the surface of human melanoma cells. 1132 65

The catalog of gene alterations in human cancer grows rapidly. Gastric cancer is no exception and displays gene changes in multiple oncogenes, suppressor genes, and DNA repair genes. Clinically relevant molecules whose expression or structure is altered include the plasminogen activator (uPA) and its inhibitor PAI-1 (plasminogen activator inhibitor type 1), the cell-cycle regulator cyclin E, epidermal growth factor (EGF), the apoptosis inhibitor bcl-2, the cell adhesion molecule E-cadherin, and the multifunctional protein beta-catenin. In addition, genetic instability is commonly seen. Gene amplification and protein overexpression of the growth factor receptors c-erbB2 and K-sam may be prognostic factors for intestinal-type and diffuse-type gastric cancer, respectively. The clinical implications of some of the recent findings for diagnosis and therapy are discussed.
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PMID:Molecular mechanisms of carcinogenesis in gastric cancer. 1279 Mar 21

The migration of endothelial cells in response to various stimulating factors plays an essential role in angiogenesis. The p38 MAPK pathway has been implicated to play an important role in endothelial cell migration because inhibiting p38 MAPK activity down-regulates vascular endothelial growth factor (VEGF)-stimulated migration. Currently, the signaling components in the p38 MAPK activation pathway and especially the mechanisms responsible for p38 MAPK-regulated endothelial cell migration are not well understood. In the present study, we found that p38 MAPK activity is required for endothelial cell migration stimulated by both VEGF and nongrowth factor stimulants, sphingosine 1-phosphate and soluble vascular cell adhesion molecule. By using dominant negative forms of signaling components in the p38 MAPK pathway, we identified that a regulatory pathway consisting of MKK3-p38alpha/gamma-MAPK-activated protein kinase 2 participated in VEGF-stimulated migration. In further studies, we showed that a minimum of a 10-h treatment with SB203580 (specific p38 MAPK inhibitor) was needed to block VEGF-stimulated migration, suggesting an indirect role of p38 MAPK in this cellular event. Most interestingly, the occurrence of SB203580-induced migratory inhibition coincided with a reduction of urokinase plasminogen activator (uPA) expression. Furthermore, agents disrupting uPA and uPA receptor interaction abrogated VEGF-stimulated cell migration. These results suggest a possible association between cell migration and uPA expression. Indeed, VEGF-stimulated migration was not compromised by SB203580 in endothelial cells expressing the uPA transgene; however, VEGF-stimulated migration was inhibited by agents disrupting uPA-uPA receptor interaction. These results thus suggest that the p38 MAPK pathway participates in endothelial cell migration by regulating uPA expression.
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PMID:p38 Mitogen-activated protein kinase regulation of endothelial cell migration depends on urokinase plasminogen activator expression. 1537 54

Eosinophils migrate from the vascular circulation to the inflamed airways during asthma exacerbations. While the mechanism(s) of this process is not known, the expression of urokinase-type plasminogen activator receptor (uPAR) has been found to modulate neutrophil adhesion and migration to inflammatory sites. We hypothesized that increased expression of uPAR and its ligand, uPA, enhance eosinophil adhesion in patients with asthma. Patients with allergic asthma underwent segmental bronchoprovocation with allergen; 48 h later, peripheral blood and airway (from bronchoalveolar lavage fluid) eosinophils were isolated. uPA and uPAR protein expression were measured by flow cytometry and Western blot; mRNA was quantified by real-time PCR. Eosinophil adhesion to intercellular adhesion molecule (ICAM)-1 and vascular cell adhesion molecule (VCAM)-1 was assessed by eosinophil peroxidase activity. Airway eosinophils expressed significantly more uPA and uPAR protein and uPAR mRNA than peripheral blood eosinophils. Removal of cell-bound uPA and/or addition of exogenous uPA had no effect on blood eosinophil adhesion to ICAM-1 or VCAM-1. In contrast, exogenous uPA stimulated ICAM and VCAM adhesion of airway eosinophils. N-formyl-methionyl-leucyl-phenylalanine-activated airway eosinophil adherence to VCAM-1 and ICAM-1 (VCAM-1, 52.8 +/- 4.7%; ICAM-1, 49.2 +/- 5.3%) was increased over blood eosinophil adhesion (VCAM-1, 38.4 +/- 3.6%; ICAM-1, 27.7 +/- 4.9%; P < 0.05). Removal of cell-bound uPA from airway eosinophils decreased adhesion to blood cell levels; reintroduction of exogenous uPA completely restored adhesion levels. These data suggest that constitutive uPA primes, and exogenous uPA can activate, airway eosinophil adhesion following segmental allergen challenge and that increased uPA expression may be a mechanism of increased eosinophil infiltration and function in asthma.
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PMID:Urokinase-type plasminogen activator modulates airway eosinophil adhesion in asthma. 1672 4

Isoliquiritigenin (ISL, 4,2',4'-trihydroxychalcone), which is found in licorice, shallot and bean sprouts, is a potent antioxidant with anti-inflammatory and anti-carcinogenic effects. The purpose of this study was to investigate the effects of ISL treatment on the migration, invasion and adhesion characteristics of DU145 human prostate cancer cells. DU145 cells were cultured in the presence of 0-20 micromol/L ISL with or without 10 microg/L epidermal growth factor (EGF). ISL inhibited basal and EGF-induced cell migration, invasion and adhesion dose dependently. ISL decreased EGF-induced secretion of urokinase-type plasminogen activator (uPA), matrix metalloproteinase (MMP)-9, tissue inhibitor of metalloproteinase-1 (TIMP-1), and vascular endothelial growth factor (VEGF), but increased TIMP-2 secretion in a concentration-dependent manner. In addition, ISL decreased the protein levels of integrin-alpha2, intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM), and mRNA levels of uPA, MMP-9, VEGF, ICAM and integrin-alpha2. Furthermore, basal and EGF-induced activator protein (AP)-1 binding activity and phosphorylation of Jun N-terminal kinase (JNK), c-Jun and Akt were decreased after ISL treatment. However, phosphorylation of extracellular signal-regulated kinase (ERK)1/2 and p38 mitogen-activated protein kinase was not altered. The JNK inhibitor SP600125 inhibited basal and EGF-induced secretion of uPA, VEGF, MMP-9 and TIMP-1, as well as AP-1 DNA binding activity and cell migration. These results provide evidence for the role of ISL as a potent antimetastatic agent, which can markedly inhibit the metastatic and invasive capacity of prostate cancer cells. The inhibition of JNK/AP-1 signaling may be one of the mechanisms by which ISL inhibits cancer cell invasion and migration.
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PMID:Isoliquiritigenin inhibits migration and invasion of prostate cancer cells: possible mediation by decreased JNK/AP-1 signaling. 1882 45


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