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

The mechanism of the invasion and proliferation of endometrial cancer is closely related to interactions between the endometrial glands and stroma. In this study, we examined the biological role of sex steroids (estradiol; E2, progesterone; P) and growth factors (epidermal growth factor; EGF, transforming growth factor-beta; TGF-beta) on cell growth and laminin, collagen IV and tissue plasminogen activator (t-PA) production of normal endometrial cells and endometrial cancer cells in culture. Normal endometrial gland cells and stromal cells, and endometrial cancer cell lines (Ishikawa, OMC-2) were used. E2, P, EGF and TGF-beta were added to the culture in physiological concentrations. The growth of normal endometrial gland cells was promoted by E2 and EGF, whereas that of Ishikawa cells and OMC-2 cells was promoted by EGF. E2 enhanced the effects of EGF in normal endometrial gland cells. The growth of normal endometrial stromal cells was not affected by them. OMC-2 was inhibited by anti-EGF receptor antibody. On the other hand, the production of laminin and collagen IV of these cultured cells was inhibited by EGF and promoted by TGF-beta, whereas that of t-PA was promoted by EGF and inhibited by TGF-beta. These results suggest that the growth of normal endometrial gland cells with estrogen receptor (ER) is controlled by both E2 and EGF, whereas that of endometrial cancer cells is affected only by EGF, and those cells without ER depend particularly on the autocrine growth mechanism of EGF.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[In vitro study on the effect of sex steroid and growth factor on growth and laminin, collagen IV, and tissue plasminogen activator production of normal endometrial cells and endometrial cancer cells in culture]. 143 34

Fetal basal ganglia astrocytes and C6 glioma cells were plated on the surface of 1.5 cm thick hydrated collagen I wafers. Both cell types migrated through the entire thickness of the wafer within 1 day after plating. The collagen in the wafer was digested and the fine collagen I fibrils were clumped into large strands. By 2-3 days, the collagen strands were digested from the wafers and replaced by a mass of fetal astrocytes or C6 cells joined by their processes. The collagen I digestion and cell migration suggested protease production. In a second series of experiments, cultured C6 cells and E14 fetal astrocytes were immunohistochemically stained for the presence of plasminogen activators as an index of protease production. Both tissue (tPA) and urokinase (uPA) types were observed. Fetal astrocytes and C6 cells were also positive for guanidinobenzoatase, a serine protease associated with migrating cells. These data demonstrate that rapid migration of the cells on and through collagen I fibrils is concomitant with expression of plasminogen activators and proteases which can either activate or function as collagenases and release the cells from the substrate.
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PMID:Mechanisms of C6 glioma cell and fetal astrocyte migration into hydrated collagen I gels. 149 72

A mutant embryonal carcinoma cell line, NR1-6, was created through retroviral insertion. We have previously reported that due to a single insertional event the mutant cell line is altered in regard to both its morphology and its tumorigenic capacity. We now report that this same cell line is also aberrant in its differentiative potential following exposure to the morphogen retinoic acid (RA). Unlike the parental NR1-0 cells, the NR1-6 cells apparently do not respond to RA by elaborating primitive endodermal derivatives in monolayer culture but rather appear morphologically to differentiate into mesodermal cells. This hypothesis is substantiated by the observation that RA treatment induces the transcription of both Endo A and B mRNA in parental but not mutant cells. No differences have been observed in the transcription of other RA sensitive markers such as c-myc, tissue plasminogen activator, collagen type IV, and laminin. In addition, the mutant cells are quantitatively much more sensitive to RA induction than are the parental cells, achieving full differentiation within 72 h of treatment with 10(-10) M RA. The parental cells, in contrast, will only differentiate at concentrations of 10(-5) or 10(-6) M RA, following 5 to 7 days of treatment. A spontaneous revertant cell line, which was isolated from an NR1-6 population and lacks the retroviral insert, is identical to the parental population in all parameters. Therefore, these data indicate that, in this case at least, a single genetic locus is involved in regulating both the qualitative and quantitative response of EC cells to RA-induced differentiation, as well as their morphology and tumorigenic potential.
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PMID:Retinoic acid-induced differentiation of a nontumorigenic embryonal carcinoma cell mutant created through retroviral insertion. 154 72

Plasminogen, the zymogen form of the serine proteinase plasmin, has been implicated in numerous physiological and pathological processes involving extracellular-matrix remodelling. We have previously demonstrated that the activation of plasminogen catalysed by tissue plasminogen activator is dramatically stimulated in the presence of basement-membrane-specific type IV collagen [Stack, Gonzalez-Gronow & Pizzo (1990) Biochemistry 29, 4966-4970]. The present paper describes the binding of plasminogen to type IV collagen. Plasminogen binds to both the alpha 1(IV) and alpha 2(IV) chains of basement-membrane collagen, with binding to the alpha 2(IV) chain preferentially inhibited by 6-aminohexanoic acid. This binding is specific and saturable, with Kd,app. values of 11.5 and 12.7 nM for collagen and gelatin respectively. Although collagen also binds to immobilized plasminogen, this interaction is unaffected by 6-aminohexanoic acid. Limited elastase proteolysis of plasminogen generated distinct collagen-binding fragments, which were identified as the kringle 1-3 and kringle 4 domains. No binding of collagen to mini-plasminogen was observed. These studies demonstrate a specific interaction between plasminogen and type IV collagen and provide further evidence for regulation of plasminogen activation by protein components of the extracellular matrix.
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PMID:Binding of human plasminogen to basement-membrane (type IV) collagen. 159 90

TFC-612 inhibited thrombus formation on wire coils inserted into the lumen of the inferior vena cava of rats after 5 oral doses of 1.0 and 3.2 mg/kg and subcutaneous doses of 1.0 and 3.2 micrograms/rat/hr. This compound showed slight inhibition of platelet aggregation induced by collagen at 1.0 and 3.2 mg/kg (po) and significant inhibition at 10 mg/kg. TFC-612 had no effect on the plasma coagulation system at 3.2 mg/kg. Conversely, oral doses of 0.32-3.2 mg/kg dose- dependently enhanced fibrinolytic activity as measured by euglobulin clot lysis time and lysis area on fibrin plates by euglobulin fraction. TFC-612 did not enhance fibrinolytic activity in vitro. These results suggest that the enhancement of fibrinolytic activity by TFC-612, which may be due to an increase in tissue plasminogen activator release or reduction of plasminogen activator inhibitors release, contributes to its inhibition of thrombus formation.
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PMID:TFC-612, a prostaglandin E1 derivative, enhances fibrinolytic activity in rats. 160 43

The aim of this study is to evaluate the relationship between tissue plasminogen activator (tPA)/PA inhibitor (PAI) complex and PAI, and platelet in the circulating blood. tPA/PAI complex and active PAI (act PAI; Teijin Co., Japan), and PAI antigen (PAI ant; Biopool AB, Sweden) were assayed by enzyme immunoassay (EIA). The mean concentrations (ng/10(9) platelets) in supernatant from lysate of platelet rich plasma (PRP) and washed platelets were 27.1 +/- 9.2, 1.5 +/- 1.2 in tPA/PAI complex, 188.7 +/- 46.1, 83.3 +/- 7.5 in act PAI and 236.2 +/- 41.6, 191.9 +/- 45.1 in PAI ant, respectively. PRP was mixed with ADP (10(-5), 10(-4), 10(-3) M), for 3 min and the supernatant after centrifugation then was provided for assay of PAI and tPA/PAI complex. Concentrations of act PAI, PAI ant and tPA/PAI complex dose-dependently increased with ADP. Almost the same results were obtained, when collagen and other agents were used instead of ADP. This study revealed that platelets contained quantities PAI (as free PAI) and released PAI during aggregation, and that a part of the PAI immediately formed a complex with tPA. Those findings suggested that platelets may play an important role on the formation of thrombus, in the way of anti-fibrinolysis, in addition to novel platelet functions, such as aggregation.
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PMID:[Study on fibrinolysis and platelet function]. 161 83

To identify agents and mechanisms responsible for the thickened basement membranes characteristic of diabetic angiopathy we examined the effects of high glucose (30 mM) on the expression of genes related to extracellular matrix composition and turnover and investigated whether the changes induced by high glucose were mimicked and sustained by activation of protein kinase C or A. In human umbilical vein endothelial cells high glucose increased fibronectin, collagen IV, tissue plasminogen activator (tPA), and plasminogen activator-inhibitor 1 (PAI-1) mRNA levels 2-fold but did not affect type IV and interstitial collagenase expression. Acute treatment with phorbol esters resulted in increased collagen IV, tPA, PAI-1, and interstitial collagenase mRNAs; the type IV collagenase mRNA levels were instead suppressed to 50% of control. Upon longer exposure to phorbol esters (48 h) suppression of fibronectin and PAI-1 mRNAs also occurred. Intracellular elevation of cAMP led to over-expression of fibronectin and type IV collagenase and potentiated the effects of phorbol esters on collagen IV, tPA, and interstitial collagenase expression. The mRNA changes induced by high glucose occurred in the absence of protein kinase C activation or cAMP elevation. These studies indicate that events other than activation of protein kinase C or A bridge high ambient glucose to changes in endothelial cell gene expression that may contribute to diabetic angiopathy.
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PMID:Expression of genes related to the extracellular matrix in human endothelial cells. Differential modulation by elevated glucose concentrations, phorbol esters, and cAMP. 171 80

Both augmentation of thrombin activity and activation of platelets have been reported to accompany administration of plasminogen activators in vivo. To determine whether the platelet activation is a consequence or a cause of the procoagulant effects, we assessed the effects of t-PA on spontaneous activation and aggregation of platelets and on clotting in recalcified human whole blood. Spontaneous activation of platelets occurred in the stirred samples 8.9 +/- 2 minutes (n = 5) after recalcification. Aggregation and clotting followed immediately afterward. Activation, aggregation and clotting were accelerated in a dose-dependent manner by 3 minutes of preincubation with t-PA (2-30 micrograms/ml) before recalcification. The procoagulant effect of t-PA (5 micrograms/ml) was abolished by concomitant incubation with hirudin (0.5 nM) or aprotinin (200 KIU/ml) consistent with the hypothesis of plasmin-mediated evolution of thrombin being responsible for the procoagulant effect. However, platelets could be activated independently by other agonists (collagen, 3 micrograms/ml; and ADP, 25 microM) in the presence of hirudin. Despite the procoagulant effect of t-PA, aggregation to collagen (2-5 micrograms/ml) and PAF (0.9 microM) was diminished in samples incubated with t-PA for 30 minutes (37 degrees C). Fibrinogen degradation products elaborated during this interval (25.6 micrograms/ml; n = 3) were responsible for this anti-aggregatory effect. The results indicate that platelet activation in recalcified whole blood depends on procoagulant effects of t-PA.
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PMID:The dependence of activation of platelets by a plasminogen activator on the evolution of thrombin activity. 172 1

Venous thromboembolism is complex with a multifactorial etiology. The Virchow triad (changes in blood flow, changes in vessel wall, and changes in the properties of blood) gives the main factors involved in venous thromboembolism. Venous stasis during immobilization in general anesthesia, stroke with hemiparesis, and heart failure plays a central role. The thromboembolic process can be initiated by a disturbance in the normal "hemostatic balance," with an increased thrombogenic potential, due to release of thromboplastin and collagen exposure during vessel wall injury by stasis and hypoxia, decreased fibrinolysis during surgery, malignancy, among others. Many substances modify these processes, including heparan sulfate, AT III, protein C, t-PA inhibitor, and alpha 2-antiplasmin.
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PMID:Pathophysiology of venous thromboembolism. 175 82

The influence of molsidomine on endogenous fibrinolytic activity was studied in a double-blind, randomized, placebo-controlled trial involving 12 male healthy volunteers. When measured 3 h after oral intake of molsidomine (16 mg, slow-release formulation) the activity of tissue plasminogen activator (t-PA) in plasma was significantly increased from 1.1 +/- 0.1 to 1.6 +/- 0.1 IU/ml. In contrast, the activity of plasminogen activator inhibitor (PAI-I) decreased from 17 +/- 2 to 12 +/- 1 AU/ml. The ratio of t-PA/PAI-I (x 100), calculated as index for the endogenous fibrinolytic activity increased significantly from 8.1 +/- 1.1 to 14.5 +/- 1.6. The ratio was unaltered after intake of placebo. Additionally, collagen-induced platelet aggregation was significantly inhibited following intake of molsidomine. The results demonstrate a significant increase in endogenous fibrinolytic activity after oral intake of molsidomine. These effects may be of therapeutic value in patients with coronary heart disease and unstable angina.
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PMID:[Effect of molsidomine on fibrinolytic activity: a double-blind, randomized study]. 177 35


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