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)

Current research in the area of breast malignancies is focusing on identification of pathogenetic risk factors, chemoprevention, screening policies, local treatment modalities that minimize disfigurement, and improved adjuvant therapeutic and palliative systemic therapies. Although epidemiologic studies have produced contradictory results, oral contraceptive use before age 25 years and before 1st full-term pregnancy appears to increase the breast cancer risk. In need of thorough study is the safest form of estrogen replacement therapy in postmenopause. Screening programs aimed at early detection have been shown to reduce breast cancer mortality by 30% in women 50-69 years of age, but no preventive strategies have been identified for younger and older women. A trend toward breast-conserving primary therapy represents a major shift in this area. As long as the tumor is less than 4 cm in diameter and the resection margins are free of tumor, lumpectomy produces disease-free survival rates comparable to those obtained through total mastectomy. In node-positive patients, hormonal adjuvant systemic therapy is effective in postmenopausal women while chemotherapy is effective in premenopausal women. The data are insufficient to allow recommendations regarding adjuvant treatment of node-negative patients, whose overall survival rate is about 70%. In metastatic breast cancer, tamoxifen is the drug of choice for palliation. Prognostic factors currently under study include oncogene amplification, urokinase plasminogen activator level, expression of growth factors and growth factor receptors, proliferation parameters, mutations, and cathepsin D levels.
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PMID:Breast malignancy. 187 98

Immunoblotting analysis of purified human urokinase plasminogen activator (u-PA), gives a positive signal when reacted with anti-phosphotyrosine monoclonal antibodies (MoAb anti-P-Tyr); competition with o-phospho-DL-tyrosine (P-Tyr) but not o-phospho-DL-threonine or serine (P-Treo, P-Ser) completely suppresses this signal. Either the 55 kDa u-PA form and the lower Mw form (33 kDa) derived from the 55 kDa u-PA are Tyr-phosphorylated also the u-PA secreted in the culture media of human fibrosarcoma cells (HT-1080) is phosphorylated in tyrosine as well as u-PA present in tissue extracts of tumors induced in nude mice by HT-1080 cells. These data show that urine purified human u-PA and u-PA produced by human fibrosarcoma cells, in vitro and in vivo, are phosphorylated in tyrosine; furthermore our data show that u-PA is the major Tyr-phosphorylated protein present in these human tumor cells.
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PMID:Tyrosine phosphorylation of human urokinase-type plasminogen activator. 190

A colloidal gold-urokinase plasminogen activator complex (u-PAGC) was prepared and characterized. It was used as an ultrastructural marker to study binding sites for urokinase in human and dermal fibroblasts and bovine adrenal endothelial cells in culture. Both the preparation conditions for 15 nm in diameter gold particles and their labeling with urokinase molecules are reported. The complex was stable for at least 4 weeks and had efficient binding and biological activity. Colloidal gold conjugate was observed as single particles or small clusters scattered on the plasma membrane of the cells at 0 degree C and within vesicles in the cytoplasm after a few minutes at 37 degrees C. These data suggest that urokinase-gold complex is a useful marker for the specific labeling of urokinase binding sites.
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PMID:Gold labeling of urokinase plasminogen activator. Characterization and specific binding in cultured mammalian cells. 190 72

The localization of tissue plasminogen activator (t-PA) on microthrombi in various organs of disseminated intravascular coagulation rats (DIC rats) was investigated by using microautoradiographic technique. After the injection of [125I]fibrinogen, experimental DIC rats induced by the infusion of thrombin for 1 h were submitted to microautoradiograms (MARGMs) of some major organs. The radioactivity of [125I]fibrin thrombi, which were observed as silver grains, was localized in the glomeruli and parts of small vessels in the kidney. In the liver, microthrombi were seen in sinusoid vessels and on Kupffer cells. In addition, many microthrombi were noted in small vessels in the lung and marginal zones in the spleen. Two min after the intravenous administration of [125I]t-PA to DIC rats, many silver grains were observed on each MARGM of the kidney, lung, liver and spleen showing the formation of microthrombi. From the identical results with the observations of MARGMs after the injection of [125I]fibrinogen, we confirmed that t-PA was highly accumulated to microthrombi formed in small vessels of the organs. The scattered silver grains were widely observed on the hepatocytes. This result suggested that t-PA bound to the parenchymal cell surface might be transported into the hepatocytes by receptor-mediated endocytosis. On the other hand, when [125I]urokinase plasminogen activator [( 125I]u-PA) was administered intravenously to DIC rats, many silver grains were observed on MARGM of the proximal tubules in the kidney but not seen on MARGMs of the glomeruli in the kidney, nor in the lung, liver, and spleen. This observation suggested that u-PA might not have a characteristic to accumulate to thrombi.
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PMID:Localization of tissue plasminogen activator on experimental microthrombi in rats. Microautoradiographic observations. 190 22

Low passage cultures of normal human keratinocytes produce several components of the plasminogen activator/plasmin proteolytic cascade, including urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), and two specific inhibitors. Studies here presented demonstrate that these cells also contain a high-affinity (Kd = 3 x 10(-10) M) plasma membrane-binding site for uPA. High molecular weight uPA, either as the single-chain precursor or two-chain activated form, bound to the receptor; however, low molecular weight (33 kD) uPA, tPA, or epidermal growth factor did not compete for binding, demonstrating specificity. Acid treatment, which removed endogenous uPA from the receptor, was required to detect maximal binding (45,000 sites per cell). To investigate the possibility that the uPA receptor on keratinocytes may be involved in epithelial migration during wound repair, cultures were wounded and allowed to migrate into the wounded site. Binding sites for uPA were localized by autoradiographic analysis of 125I-uPA binding as well as by immunocytochemical studies using anti-uPA IgG. With both techniques uPA binding sites were detected selectively on the plasma membrane of cells at the leading edge of the migrating epithelial sheet. This localization pattern suggests that uPA receptor expression on keratinocytes may be coupled to cell migration during cutaneous wounding.
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PMID:A high-affinity receptor for urokinase plasminogen activator on human keratinocytes: characterization and potential modulation during migration. 196 51

Currently there are five thrombolytic substances undergoing evaluation: streptokinase, tissue plasminogen activator, acylated plasminogen streptokinase activator complex, urokinase and single chain urokinase plasminogen activator. Equal results for mortality reduction (25 per cent) and reocclusion (6-24 per cent) has been reported in the literature for the five substances. Reocclusion can be divided into an early (greater than 24 hours) and a late phase. The early phase is most likely due to an imbalance between thrombolysis and the formation of a thrombus. During late reocclusion there is formation of a thrombus on the underlying coronary plaque or residual thrombotic mass, following thrombolytic therapy. The residual stenosis following thrombolysis seems to be the most important prognostic factor for reocclusion. A residual stenosis of over 75 per cent is unfavourable. Early reocclusion is prevented through simultaneous antithrombotic and thrombolytic therapy. Patients with a residual stenosis of over 75 per cent should be considered for some sort of active intervention to prevent late reocclusion.
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PMID:[Reocclusion following thrombolytic treatment in acute myocardial infarct]. 199 31

Malignant tumors are generally characterized by extensive local tissue invasion and destruction of ECM which may be due to increased constitutive expression and activity of secreted proteases. Moreover, a large number of diverse protease activities may be constitutively over-expressed in a simultaneous or co-ordinated fashion, thereby significantly increasing cellular invasive potential of the cells. To explore this relationship, we have measured steady-state levels of mRNA coding for urokinase plasminogen activator (uPA), tissue plasminogen activator (tPA), transin and tissue-specific inhibitor of metalloproteinases (TIMP); as well as gelatinolytic, caseinolytic and plasminogen activator activities secreted by SPI, a non-metastatic mouse mammary carcinoma cell line and 4 metastatic sublines derived from it. mRNA encoding metalloproteinase transin was increased 15- to 20-fold, while TIMP transcripts were decreased 3-fold in the metastatic sublines compared to parental SPI tumor cells. Metastatic sublines secreted higher levels of gelatinase (i.e., 92 kDa and 64 kDa) as well as proteases with caseinolytic activity (i.e., 115 kDa and 57 kDa) when compared with SPI cells. Moreover, these enzymes were identified as neutral metalloproteinases. Although the amount of uPA mRNA appeared to be the same in SPI and the metastatic sublines, the latter secreted 1.5-3 times more uPA activity into the culture supernatants. Metastatic competence in the SPI tumor model is therefore associated with increased secretion of several metalloproteinase activities and uPA, as well as decreased TIMP expression, consistent with a more invasive phenotype.
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PMID:Constitutive expression and secretion of proteases in non-metastatic SP1 mammary carcinoma cells and its metastatic sublines. 204

Single-chain urokinase plasminogen activator (scu-PA) that had been modified with N-succinimidyl-3-(2-pyridyldithio)propionate was covalently linked by disulfide bonds to the Fab' of a monoclonal antibody specific for the beta-chain of fibrin (antibody 59D8). scu-PA-59D8 Fab' conjugate was separated from free scu-PA and two-chain urokinase coupled to 59D8 Fab' by two-step affinity chromatography. First, the reaction mixture was chromatographed on a column containing Sepharose linked to the peptide that had been used as immunogen for antibody 59D8; scu-PA-59D8 Fab' conjugate and unconjugated 59D8 Fab' were retained but not unconjugated scu-PA. Then, the eluate from the peptide-Sepharose column was chromatographed on a column containing Sepharose linked to benzamidine, which acts as a ligand for two-chain urokinase. The molecular weight of the scu-PA-59D8 Fab' conjugate was approximately 100 kDa when electrophoresed on a nonreducing sodium dodecylsulfate-polyacrylamide gel. Enzymatic assay after purification revealed that more than 97% of the scu-PA present in the conjugate retained the single-chain form. The Fab' portion of the conjugate functioned in a manner indistinguishable from that of native antibody 59D8. In an in vitro assay for lysis of fibrin monomer, the fibrinolytic potency of scu-PA-59D8 Fab' was 33-fold more than that of tissue plasminogen activator (p less than 0.001), 230-fold more than that of unconjugated scu-PA (p less than 0.0001), and 420-fold more than that of urokinase (p less than 0.0001).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Conjugation to antifibrin Fab' enhances fibrinolytic potency of single-chain urokinase plasminogen activator. 211 44

Phosphorylation is a potent mechanism regulating the activity of many intracellular enzymes. We have discovered that the product of the human urokinase plasminogen activator gene, pro-uPA, is phosphorylated in serine in at least two human cell lines. Phosphorylation occurs within the cell during biosynthesis, and phosphorylated intracellular pro-uPA is secreted into the medium. Of the secreted pro-uPA molecules, 20-50% are phosphorylated in serine, thus representing a meaningful fraction of the total biosynthetic pro-uPA. Although the sites of phosphorylation have not yet been determined, at least two such sites must exist; in fact plasmin cleavage of phosphorylated single chain pro-uPA yields a two chain uPA in which both chains are phosphorylated. A specific function for pro-uPA phosphorylation has not yet been identified; however, it is tempting to speculate that, as in many other cases, phosphorylation may affect the activity of the enzyme, its response to inhibitors or the conversion of pro-uPA zymogen to active two-chain uPA. This would represent an additional way of regulating extracellular proteolysis, an important pathway involved in both intra- and extravascular phenomena like fibrinolysis, cell migration and invasiveness.
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PMID:Serine phosphorylation of biosynthetic pro-urokinase from human tumor cells. 211 15

Isotopically labeled [( 3H]serine, [3H]proline, and [35S]sulfate) subendothelial cell basement membranes were used to determine the role of urokinase plasminogen activator (uPA) and its specific inhibitor plasminogen activator inhibitor 2 (PAI-2) in colon cancer cell extracellular matrix degradation. Recombinant PAI-2 irreversibly inhibited low and high molecular weight purified human uPA in addition to both colon cancer cell-associated and secreted uPA, particularly if pro-uPA had been preactivated. Two selected lines (COLO394 and LIM1215) preferentially degraded differently labeled matrices in a time- and plasminogen-dependent manner. This process was inhibitable by PAI-2 in the medium at levels which suggested that some degree of "shielding" of cell surface uPA from inhibitor occurred. The ability of PAI-2 to regulate the invasive phenotype of cells which express cell surface or receptor-bound uPA is discussed.
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PMID:Inhibition of cancer cell urokinase plasminogen activator by its specific inhibitor PAI-2 and subsequent effects on extracellular matrix degradation. 211 45


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