Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.4.21.68 (tissue plasminogen activator)
 11,311 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The total plasminogen activator (PA) activity and the activities of urokinase type (uPA) and tissue type (tPA) plasminogen activators were measured in 43 primary human breast cancer homogenates. The majority of the PA activity was found in the 100,000 X g crude membrane pellets (log mean of 490 milli-IU/mg of protein, +1169, -346), and little PA activity was present in the cytosolic supernatant (log mean of 19 milli-IU/mg of protein, +168, -17). The activities of total PA and of each type of PA were compared to the estrogen receptor (ER) and epidermal growth factor receptor (EGFR) status of the tumors and to their histological grade. Total PA activity and uPA activity were not significantly different in any group of tumors stratified according to receptor status or tumor grade. Tissue type PA levels, however, were significantly lower in ER-negative compared with ER-positive tumors and in EGFR-positive compared with EGFR-negative tumors (P less than 0.01 and less than 0.05, respectively). The tPA activity was also related to grade, decreasing with worsening differentiation (P = 0.04). The ER-negative tumors were further stratified into EGFR-positive and -negative subgroups. Only the ER-negative tumors possessing EGFR had significantly lower tPA levels than the ER-positive tumors (P less than 0.01). Low tPA levels in breast cancers were, therefore, associated with ER negativity combined with EGFR positivity and may be an indication of poorer differentiation and prognosis.
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PMID:Relationship of membrane-bound tissue type and urokinase type plasminogen activators in human breast cancers to estrogen and epidermal growth factor receptors. 314 Oct 47

In this study, we examined the effects of various plasminogen activators on arachidonic acid release and prostacyclin biosynthesis in cultured rat aortic smooth muscle cells and bovine pulmonary artery endothelial cells. Prostacyclin was the major product formed from arachidonic acid in aortic smooth muscle cells and endothelial cells. When intact cells were incubated with streptokinase, one of the plasminogen activators, a significant stimulatory effect on prostacyclin biosynthetic activity in cells was evident without any cellular damage at all concentrations used (1-5,000 units/ml). Streptokinase also caused a marked release of arachidonic acid. However, when it was incubated with cell-free homogenates and [3H]arachidonic acid, it did not show any effects on prostacyclin biosynthesis. The addition of urokinase and tissue-type plasminogen activator had no effect on prostacyclin biosynthesis. Urokinase stimulated the release of arachidonic acid from cells, but it did not show any effect on prostacyclin release at any concentration of urokinase (1-5,000 units/ml). The release of arachidonic acid and the increased prostacyclin synthesis were not observed when tissue-type plasminogen activator was added. These results indicate that, among various plasminogen activators investigated, only streptokinase causes the release of arachidonic acid and prostacyclin. This could be a beneficial effect in thrombolytic therapy.
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PMID:Effect of various plasminogen activators on prostacyclin synthesis in cultured vascular cells. 314 95

Three cases of multicentric reticulohistiocytosis showing typical clinical, histologic, and ultrastructural findings are reported. In one, gastric cancer occurred; in the other two cases, severe polyarthritis was the only detectable internal involvement. The serine proteinases, urokinase and tissue-type plasminogen activator, were evaluated both with the autohistographic technique and spectrophotometric assay in lesional skin and synovia. Urokinase levels appeared grossly increased in the lesional synovia and moderately increased in the lesional skin. We suggest that urokinase, presumably released by the activated proliferating histiocytes, may play a major role in the extracellular matrix degradation leading to erosion of cartilage and adjacent bone in multicentric reticulohistiocytosis.
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PMID:Multicentric reticulohistiocytosis. Report of three cases with the evaluation of tissue proteinase activity. 314 26

The effect of tissue plasminogen activator (TPA) or urokinase on the specific binding of human Glu-plasminogen to fibrin I formed in plasma by clotting with Reptilase was studied using 125I-plasminogen and 131I-fibrinogen. In the absence of TPA, small amounts of plasminogen were bound to fibrin I. TPA induced binding of plasminogen to plasma fibrin I that was dependent upon the concentrations of TPA and plasminogen as well as upon the time of incubation. Plasminogen binding occurred in association with fibrin clot lysis and the formation in the clot supernatant of alpha 2-plasmin inhibitor-plasmin complexes. Urokinase also induced binding of plasminogen to plasma fibrin I that was concentration- and time-dependent. The molecular form of plasminogen bound to the fibrin I plasma clot was identified as Glu-plasminogen by dodecyl sulfate-polyacrylamide gel electrophoresis and by fast performance liquid chromatography. Further studies demonstrated that fibrin I formed from fibrinogen that had been progressively degraded by plasmin-bound Glu-plasminogen. The mole ratio of plasminogen bound increased with the time of plasmin digestion. Glu-plasminogen did not bind to fibrin I formed from fibrinogen progressively digested by human leukocyte elastase, thereby demonstrating the specificity of plasmin. These studies demonstrate that plasminogen activators regulate the binding of Glu-plasminogen to fibrin I by catalyzing plasmin-mediated modifications in the fibrin substrate.
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PMID:Tissue plasminogen activator and urokinase mediate the binding of Glu-plasminogen to plasma fibrin I. Evidence for new binding sites in plasmin-degraded fibrin I. 315 57

Plasminogen activator (PA) activity during epithelial wound healing in vitamin A-deficient rats was investigated to determine whether a relationship exists between corneal defect formation and PA activity. Uniform, central 3 mm diameter corneal epithelial wounds were made by scalpel debridement in vitamin A-deficient and in pair-fed control rats. Cryostat sections of such corneas, taken at various times post-scrape, were overlaid with fibrin films containing plasminogen to examine the distribution of PA activity; and antibodies to tissue plasminogen activator (tPA) or to urokinase-like activator (uPA) were incorporated into the films so that the immunochemical natures of detected PA activities could be determined. Corneas from pair-fed controls showed tPA-dependent lysis in association with the regenerating epithelium as well as in the defect region during epithelial wound healing. Corneas from vitamin A-deficient rats also demonstrated tPA activity in association with corneal epithelium post-scrape but showed no detectable tPA activity in the defect region. Histological examination of the vitamin A-deficient corneas demonstrated that a pseudomembrane composed of PMNs, cell debris, and fibrinous exudate had formed on the scrape-debrided stromal surface. The migrating edge of regenerating epithelium overlaid this membrane and was, therefore, not in contact with the stromal surface. The formation of the pseudomembrane, which delays reepithelialization, might have resulted from the absence of PA activity in the defect region. Both excessive and inadequate levels of PA activity may result in impaired epithelial wound healing.
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PMID:Plasminogen activator activity in vitamin A-deficient rat corneas. 319 70

The immunoperoxidase technique, using antibodies against human urinary urokinase (Mr 55,000), was used for the localization of this enzyme in histological preparations of human colon tumors and normal colon tissue. The localization of tissue (vascular) activator was also investigated using antibodies against enzyme purified from human malignant melanoma. Both the "indirect method" and the peroxidase-antiperoxidase technique were found to be useful. Urokinase-reactive material was found in all tissues examined (33 primary cancers, 11 metastases, and 8 adenomas). In the normal colon, urokinase was found only in some of the goblet cells of the mucosal epithelium. In colon cancer, diffuse specific staining was observed in the cytoplasm, but the most intense staining was localized at the edge of the cancer cells bordering the lumen of the glands. In some cases, intense supranuclear staining could be observed in a location corresponding to the Golgi apparatus. In a few instances, urokinase could be seen associated with fibroblasts near the advancing front of an invading tumor. Adenoma, a benign tumor but often a precursor of cancer, also showed the presence of urokinase. Most significant were the observations showing that, in regions of the mucosal glands where normal epithelial cells were abruptly replaced by cancer cells, the appearance of cytoplasmic urokinase showed strict and exclusive association with the malignant cells, and the same was the case in transitions from normal epithelium to adenoma. In contrast to urokinase, tissue plasminogen activator was not associated with cancer cells, but was consistently present in the stroma which separates the cancer glands and was localized in the endothelium of the blood vessels. This visual evidence was supported by results of extraction of plasminogen activators from tumors, and from the separated mucosal and submucosal layers of the normal colon of the same patients, which showed that urokinase is most abundant in the tumor tissue and least abundant in the submucosa, while tissue activator is most prevalent in the well-vascularized mucosa and submucosa and scarce in the usually poorly vascularized adenocarcinomas.
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PMID:Localization of plasminogen activators in human colon cancer by immunoperoxidase staining. 388 45

Considerable interest in plasminogen activators as human thrombolytic drugs has stimulated rapid biotechnologic progresses. These enzymes have been classified in two immunochemically distinct groups: "urokinase-like" activators or u-PA which do not interact with fibrin and "tissue activator-like" activators or t-PA which interact with fibrin. Plasminogen activators are widely distributed in normal and malignant tissues and they are implicated in various physiological and pathological processes. They maintain the functional integrity of the vascular system and their presence may be of importance in tissue remodeling and cell migration. Urokinase and streptokinase are used in human thrombolytic therapy. However, the properties displayed by t-PA suggest that this enzyme may be a superior fibrinolytic agent. The primary structures of urokinase and t-PA are known; both enzymes have been synthesized by DNA technology. In order to produce t-PA in large quantities by gene cloning, intensive studies are conducted by pharmaceutical industries. Clinical trials using t-PA for dissolving thrombi in coronary heart disease, strokes and pulmonary embolism are in progress. This review presents the molecular and structural properties of plasminogen activators, as well as related physiological, pathological and therapeutic aspects.
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PMID:[Plasminogen activators: general aspects and recent developments]. 391 65

The fibrinolytic and thrombolytic properties of a tissue plasminogen activator (tPA) purified from the conditioned medium of an established guinea pig keratocyte (GPK) cell line were investigated in in vitro systems and compared with urokinase. Using the fibrin clot lysis assay, GPK activator appears to be similar to human melanoma tPA and not to human urokinase. GPK activator also caused negligible fibrinogen breakdown, when incubated with human plasma at 37 degrees C over 23 hr. Urokinase on the other hand caused significant fibrinogenolysis, under similar conditions. Comparison of the lysis of plasma clots by GPK activator and human urokinase have shown that GPK activator was a much more effective fibrinolytic agent than urokinase, especially at lower concentrations (less than 50 IU/ml). Studies on the thrombolytic effect of GPK activator on the lysis of aged and cross-linked whole human blood clots and plasma clots hanging in artificially circulating human plasma suggest that GPK activator can lyse both these types of clots equally well. The lysis is dose dependent, attaining complete lysis within 3-6 hr with the concentration of GPK activator in the range of 1-5 micrograms/ml plasma. It is concluded that GPK activator has a higher fibrinolytic and thrombolytic activity and lower fibrinogenolytic activity than urokinase.
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PMID:In vitro studies on the fibrinolytic, thrombolytic and fibrinogenolytic properties of a tissue plasminogen activator from guinea pig keratocytes. 404 Jun 59

The effect of testosterone propionate (TP) or estradiol-17 beta (E2) on the activities of thymidine kinase (TK) and tissue plasminogen activator (Act) in the prostates of 22 day old immature SD rats was studied. The Tailor and fibrin plate methods were applied to measure the activities of TK and Act respectively. Act activity was expressed in terms of the Urokinase International Unit. After a single TP injection im, TK activity began to increase at 24 h and peaked at 48 h followed by a rapid decrease. The maximum activity, 40.0 +/- 11.5 pmol/mg protein/15 min, was 50 times higher at 48 h and peaked at 96 h, with a subsequent decline to the control value within 14 days. The maximum Act activity, 5.1 +/- 0.4 U/prostate, was 1.6 times the control value. The activities of both TK and Act altered depending on TP doses, 1 mg/100 g BW of TP brought about their maximum activities at 48 h and 96 h respectively. Three TK isozymes were obtained from the prostates by DEAE-cellulose column chromatography. Fraction A, which was eluted in O M NaCl, differed from other isozymes in that its activity was only slightly suppressed by dCTP and was elevated most conspicuously after TP injection. Elevated activities of both TK and Act after TP injection were completely inhibited by Puromycin or Actinomycin D. The results of the present experiment demonstrated that TK and Act were synthesized in the prostate cells after TP injection and were androgen dependent. E2 did not inhibit the elevation of TK and Act activities by TP injection. In the present study estrogen showed a synergetic effect with androgen on these two activities, especially TK, in the rat prostate.
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PMID:[The effects of androgen and estrogen on thymidine kinase and tissue plasminogen activator in the prostate of immature rats (author's transl)]. 646 66

Human tissue-type plasminogen activator (t-PA), obtained by expression in mammalian cells of recombinant DNA coding for the entire sequence of t-PA (rt-PA), was compared with natural activator from melanoma cell culture (mt-PA). In an in vitro system, composed of [125I]fibrinogen-labeled plasma clot suspended in circulating human plasma, rt-PA and mt-PA caused a very similar dose-related degree of fibrinolysis without causing extensive fibrinolytic activation and fibrinogen breakdown in the surrounding plasma. Urokinase only induced fibrinolysis at a 5- to 10-fold higher concentration and in association with extensive fibrinogenolysis. Intravenous injection of mixtures of labeled (0.4 microCi/kg) and unlabeled (2000 I.U./kg) mt-PA or rt-PA resulted in a rapid but similar disappearance of activity from plasma (T1/2 of 3 min) and specific accumulation of tracer in the liver. In rabbits with experimental jugular vein thrombosis, rt-PA and mt-PA caused a very similar dose-dependent thrombolysis without causing substantial systemic activation of the fibrinolytic system and fibrinogenolysis. Urokinase induced significant thrombolysis only at a 10-fold higher dose and this was associated with systemic fibrinolytic activation. Infusion of 96,000 I.U./kg (approximately equal to 1 mg/kg) of mt-PA or rt-PA over 4 hr induced approximately 70% lysis, whereas a 10-fold higher dose of urokinase yielded 35 to 40% lysis. Two subfractions of rt-PA differing in the extent of glycosylation had very similar thrombolytic properties. It is concluded that the potentially more readily available rt-PA could constitute a specific, fibrin-selective thrombolytic agent.
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PMID:Biological properties of human tissue-type plasminogen activator obtained by expression of recombinant DNA in mammalian cells. 654 93


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