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 present study extends our investigations into the metastatic heterogeneity among four clonal cell lines (S2-007:H, S2-013:M1, S2-020:M2, and S2-028:L) from a human pancreatic cancer cell line (SUIT-2), and extends our discussion the positive correlation between metastatic potential and the type I collagenase activity of the cells, focusing on their interaction with extracellular matrix. Ability to attach to the reconstituted basement membrane (Matrigel) was higher for clone H than clone L during an observation period of 30-60 min, whereas clones M1 and M2 were found to be intermediate in ability. In densitometric and radioactive studies, clone L exhibited the lowest collagenolytic activity against mouse and human type IV collagen, while clone H exhibited the highest activity in the densitometric study and clone M1 was the highest in the radioactive study. The production of urinary-type plasminogen activator was highest in clone L and lowest in clone H. On the other hand, tissue-type plasminogen activator was highest in clone M2 and low in both clones H and L. Clone M2 exhibited the highest chemotactic activity toward diluted Matrigel, whereas clone L had the lowest activity. On the whole, these clones showed heterogenous interactions with an extracellular matrix. It is suggested that the attachment activity to basement membrane and the type IV collagenolytic activity of the cells may be positively correlated with their metastatic potential, whereas the production of urinary-type plasminogen activator was negatively correlated, but confirmation of these findings awaits further study.
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PMID:Heterogeneities of attachment, chemotaxis, and protease production among clones with different metastatic potentials from a human pancreatic cancer cell line. 819 99

Using immunohistochemistry and in situ hybridization, we have characterized the expression and localization of components of the plasminogen activator proteolytic cascade in an organotypic coculture system which consists of a "dermal" portion (human dermal fibroblasts throughout a collagen matrix) and a stratified, well-differentiated epidermal portion. Specifically, the following components were examined: the enzymes urokinase-type plasminogen activator and tissue-type plasminogen activator and their type 1 and type 2 inhibitors. Urokinase plasminogen activator mRNA and antigen were found predominantly in the least differentiated, basal keratinocytes; in some fields there was also faint deposition of antigen beneath the basal cells. The distribution of plasminogen activator inhibitor type 1 was similar to that of urokinase, except that inhibitor type 1 antigen deposition beneath the basal cells appeared more intense and uniform. In contrast to the results with urokinase plasminogen activator and inhibitor type 1, tissue plasminogen activator mRNA and antigen were localized focally in the suprabasal, i.e. more differentiated, keratinocytes. Plasminogen activator inhibitor type 2 mRNA and antigen were detected in most epidermal layers, but were more intense suprabasally and often spared the basal layer. These studies demonstrate that the same type of cell, i.e. the keratinocyte, can express different components of the plasminogen activator cascade depending on its state of differentiation. The change in expression of plasminogen activator cascade components with keratinocyte differentiation suggests distinct epidermal functions for these components, related to cell-matrix interaction and epidermal differentiation.
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PMID:Differential expression of plasminogen activators and their inhibitors in an organotypic skin coculture system. 827 Jun 42

In this paper, we investigated how epidermal growth factor (EGF) acts on growth and regulation of extracellular matrix components and their degenerative enzymes in uterine cervical adenocarcinoma cells in vitro. Effects of EGF on cell growth, DNA synthesis, and laminin, collagen IV, and tissue plasminogen activator (t-PA) production of human uterine cervical adenocarcinoma cell line OMC-4 were examined, together with the characteristics of its EGF receptors. Scatchard plot of EGF binding to OMC-4 indicated two classes of binding sites with a dissociation constant of 170 pM and 510 pM. The total binding sites were 1.6 x 10(5)sites/cell. The number of OMC-4 cells did not increase in the presence of EGF, whereas 3H-thymidine incorporation was inhibited by EGF at concentrations of 1 and 10 nM. The production of laminin and collagen IV by OMC-4 cells was inhibited by EGF, whereas that of t-PA was significantly promoted at the physiological concentration of 0.1 nM. These results suggest that EGF is closely associated with regulation of proliferation and extracellular matrix degradation of uterine cervical adenocarcinoma cells.
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PMID:Characterization of epidermal growth factor (EGF) receptor and biological effect of EGF on human uterine cervical adenocarcinoma cell line OMC-4. 829 19

To investigate the effects of the increased plasma lipid level on fibrinolysis, we measured the levels of fibrinolytic components in serially obtained plasma samples from healthy volunteers after the intake of different amounts of butter. Plasma triglyceride level increased significantly after butter intake compared to the control group. Eight hours after the intake of 100g of butter, plasminogen activator inhibitor 1 (PAI-1) level in plasma was significantly higher and euglobulin clot lysis time was significantly prolonged compared to those of the control group. There was no effect on plasma tissue plasminogen activator level. These results suggest that the temporary increase in plasma triglyceride level induced high PAI-1 level, resulting in impaired fibrinolytic activity. The effect of temporary hyperlipidemia on platelet function was also analyzed and revealed that the response of platelets to ADP and collagen was lower in the butter intake group compared to those of the control.
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PMID:Impaired fibrinolytic activity induced by ingestion of butter: effect of increased plasma lipids on the fibrinolytic activity. 832 87

The use of first generation plasminogen activators, urokinase, streptokinase and tissue plasminogen activator has revolutionized thrombolytic therapy for myocardial infarction and ischaemia, and potentially stroke. However, thrombolytic therapy employing these activators is limited by reocclusion of the very arteries being opened, which follows in a small but significant number of patients. The development of second generation plasminogen activators, e.g. staphylokinase and anisoylated plasminogen streptokinase activator complex, has not alleviated the problems encountered with classical plasminogen activators. It is now widely recognized that aberrant platelet aggregation induced primarily by thrombin, rather than plasmin, is one of the major causes of recurrent thrombosis following pharmacologic thrombolysis. Agents that (a) inhibit enzymatic and/or coagulant activity of thrombin, (b) block binding of thrombin to its receptor, and (c) interfere with the generation of thrombin by the prothrombinase complex may compromise haemostasis resulting in haemorrhage. We recently demonstrated that thrombin-induced platelet aggregation is accompanied by cleavage of aggregin, a putative ADP-receptor on the platelet surface, and that these events are indirectly mediated by intracellularly activated calpain expressed on the surface. In this review, we discuss the known mechanisms of thrombin-induced platelet aggregation and suggest relative advantages of potential pharmacological agents, being developed in our laboratory, over those that have been previously developed and tested. These inhibitors selectively prevent aggregation of platelets induced by thrombin by inhibiting calpain expressed on the surface. Moreover, one of these inhibitors which blocks thrombin-induced platelet aggregation does not interfere with other platelet responses mediated by thrombin or platelet aggregation induced by other agonists, such as, ADP, collagen, phorbol myristate acetate and thromboxane A2 mimetics. This selectivity could reduce the chances of perturbing the formation of a haemostatic plug.
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PMID:Reocclusion after thrombolytic therapy: strategies for inhibiting thrombin-induced platelet aggregation. 832 74

Fibronectin is a multidomain adhesive glycoprotein found in plasma, interstitial connective tissue, and basement membrane. Diverse biological activities have been associated with the fibronectin molecule including cell adhesion, cell migration, wound healing, hemostasis, and oncogenic transformation. Binding sites for heparin, fibrin, gelatin/collagen, and cells have been localized to various structural domains of the molecule. In addition, fibronectin also binds both plasminogen and tissue plasminogen activator (t-PA) via a 55-kDa amino-terminal fragment (Moser, T.L., Enghild, J.J., Pizzo, S.V., and Stack, M.S. (1993) J. Biol. Chem. 268, 18917-18923). Although intact fibronectin does not enhance the rate of t-PA-catalyzed plasminogen activation, a mixture of proteolytically degraded fibronectin fragments stimulates the activation reaction, resulting in an 11-fold increase in the kcat/Km. Based on these observations, we have synthesized a variety of peptides derived from the plasminogen/t-PA binding region of fibronectin and determined the effect of these peptides on the initial rate kinetics of plasminogen activation by t-PA as well as on plasmin and t-PA amidolytic activity. Here we report that a specific octapeptide, SRNRCNDQ-NH2, consisting of residues 196-203 of the fibronectin molecule is a potent stimulator of t-PA-catalyzed plasminogen activation, resulting in a 15-fold increase in the kcat/Km of the activation reaction.
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PMID:Modulation of tissue plasminogen activator-catalyzed plasminogen activation by synthetic peptides derived from the amino-terminal heparin binding domain of fibronectin. 836 Jan 82

The antiaggregatory and antithrombotic actions of MK-0852, a cyclic heptapeptide antagonist of the platelet GP IIb/IIIa, were evaluated in a variety of canine models. In vitro, MK-0852 inhibited the aggregation of canine platelet-rich plasma induced by 10 microM ADP in the presence of 1 microM epinephrine with an IC50 value of 0.10 microM. The i.v. infusion of 1.0 and 3.0 micrograms/kg/min MK-0852 to anesthetized dogs significantly inhibited ex vivo platelet aggregation responses to ADP and collagen, with the 3.0 micrograms/kg/min infusion completely inhibiting ex vivo aggregation responses to both agonists. The i.v. administrations of 100 and 300 micrograms/kg MK-0852 suppressed platelet-dependent cyclic flow reductions in stenosed canine left circumflex (LCX) coronary artery for periods of 24 +/- 3 and 64 +/- 4 min, respectively. In a canine model of copper coil-induced femoral arterial thrombosis, i.v. MK-0852 (100 micrograms/kg + 1 microgram/kg/min), initiated 15 min before coil placement, reduced the incidence of occlusive thrombosis during the 45-min post-coil time period of continued therapy (1/5 MK-0852 vs. 7/7 saline; P < .01). MK-0852 was administered as an adjunctive therapy with tPA to evaluate its effects on thrombolysis after copper coil-induced femoral arterial thrombus formation. MK-0852 (i.v.; 100 micrograms/kg + 1 microgram/kg/min), initiated 15 min before tPA, reduced the incidence of post-thrombolysis reocclusion. During the 60-min period of continued drug infusion after the termination of tPA, 0 of 5 animals receiving MK-0852 reoccluded vs. 7/8 saline (P < .01). In a canine model of electrically induced LCX coronary artery thrombosis, i.v. MK-0852 (100 micrograms/kg + 3 micrograms/kg/min), initiated 15 min before the initiation of electrical injury, prevented occlusive thrombosis in 4 of 6 preparations despite the continued electrical stimulation of the vessel for 180 min. Thrombotic occlusion was delayed in the remaining two preparations (99 and 100 min), compared with occlusion in 4 of 4 saline-treated preparations (69.3 +/- 6.3 min). When administered as an adjunct to thrombolytic agents for lysis of electrically induced LCX coronary artery thrombi, i.v. MK-0852 (300 micrograms/kg + 3 micrograms/kg/min), initiated 15 min before tPA or streptokinase, both increased the incidence of reperfusion (tPA: 8/8 MK-0852 vs. 3/8 saline; streptokinase: 5/8 MK-0852 vs. 2/8 saline) and accelerated reperfusion. The incidence of reocclusion during continued adjunctive therapy was reduced.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Antithrombotic effects of MK-0852, a platelet fibrinogen receptor antagonist, in canine models of thrombosis. 837 Nov 53

We studied the interaction of two thrombolytic agents, recombinant-tissue plasminogen activator (r-TPA) and low molecular weight urokinase (UK), with platelet aggregation in the absence or presence of unfractionated heparin (UH). With platelet rich plasma (PRP), a dose dependent inhibition was seen for both r-TPA and UK. However, this effect was more evident in the presence of r-TPA. UH did not modify this effect. However, it enhanced platelet aggregation induced by ADP and decreased the aggregation induced by collagen (COL) as already shown by us. With washed platelets, only r-TPA decreased platelet aggregation in a dose dependent manner in the presence of COL and only at the highest dose (100 micrograms) in the presence of TH. The presence of ten units of plasminogen (PLG) together with 10 micrograms of r-TPA or 1250 units of UK totally inhibited TH-induced platelet aggregation. UH reversed this effect. In contrast, when COL was the aggregating agent, the inhibition of platelet aggregation in presence of PLG, seems to be further increased by UH. Since UH is an adjunct of thrombolytic therapy to prevent rethrombosis, this double edged sword could partially explain the lack of therapeutic effect in some patients.
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PMID:Effect of recombinant-tissue plasminogen activator, low molecular weight urokinase and unfractionated heparin on platelet aggregation. 840 76

In contrast to the central nervous system (CNS), the peripheral nervous system (PNS) displays an important regenerative ability which is dependent, at least in part, on Schwann cell properties. The mechanisms which stimulate Schwann cells to adapt their behavior after a lesion to generate adequate conditions for PNS regeneration remain unknown. In this work, we report that adult rat dorsal root ganglion (DRG) neurons are able, after a lesion performed in vivo or when they are dissociated and cultured in vitro, to synthesize transforming growth factor beta (TGF beta), a pleiotropic growth factor implicated in wound healing processes and in carcinogenesis. This TGF beta is tentatively identified as the beta-1 isoform. Adult rat DRG neurons release a biologically active form of TGF beta which is able to elicit multiple Schwann cell responses including a stimulation to proliferate. Moreover, purified TGF beta-1 produces a Schwann cell morphology alteration and decreases the secretion of tissue-type plasminogen activator (tPA) and enhances the secretion of plasminogen activator inhibitor (PAI) by Schwann cells. This generates conditions which are thought to favor a successful neuritic regrowth. Furthermore, purified TGF beta-1 stimulates type IV collagen mRNA expression in Schwann cells. This subtype of collagen is associated with the process of myelinization. Finally, TGF beta-1 decreases nerve growth factor (NGF) mRNA expression by Schwann cells, an effect which could participate in the maintenance of a distoproximal NGF gradient during nerve regeneration. We propose that neuronal TGF beta plays an essential role as a neuronoglial signal that modulates the response of Schwann cells to injury and participates in the successful regeneration processes observed in the PNS.
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PMID:Transforming growth factor beta as a neuronoglial signal during peripheral nervous system response to injury. 842 35

Constitutive overexpression of both urokinase and matrix metalloproteinase (MMP) activity is frequently observed in individual malignant tumors. In this study we describe the combined contribution of these distinct enzyme systems to the invasive phenotype of a highly metastatic human melanoma cell line (M24met). M24met cells were found to secrete a spectrum of MMPs, including interstitial collagenase, type IV collagenases (M(r) 92,000 and 72,000 progelatinases), and stromelysin. Urokinase, but not tissue-type plasminogen activator, was detected in M24met-conditioned media and on cell surfaces. The contribution of these enzymes to extracellular matrix dissolution was determined by exploiting specific inhibitors, namely tissue inhibitor of the metalloproteinases-2 and plasminogen activator inhibitor-2. Due to the coexpression of urokinase and MMP-dependent activity, M24met cells were observed to degrade multiple components of the extracellular matrix and to significantly degrade both interstitial and basement membrane matrices. Urokinase-dependent removal of matrix glycoprotein was observed to precede MMP-dependent collagenolysis as a prerequisite rate-limiting step. We present evidence which suggests that this temporal relationship is imposed by the structural architecture of the matrix such that matrix glycoprotein serves to protect associated collagen from MMP-dependent degradation. In addition to mediating significant collagenolysis, MMP activity was further implicated in the dissolution of matrix tropoelastin. Urokinase/plasmin activity was not found to be required for MMP-zymogen activation.
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PMID:Melanoma-mediated dissolution of extracellular matrix: contribution of urokinase-dependent and metalloproteinase-dependent proteolytic pathways. 842 5


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