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Query: UNIPROT:P00750 (PLA)
 16,800 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transforming growth factor beta (TGF beta) treatment of rat osteoblast-rich calvarial cells or of the clonal osteogenic sarcoma cells, UMR 106-01, resulted in dose-dependent inhibition of plasminogen activator (PA) activity, and increased production of 3.2 kb mRNA and protein for PA inhibitor -1 (PAI-1). Although tissue-type PA (tPA) protein was not measured, TGF beta did not influence production of mRNA for tPA. Production of 2.3 kb mRNA for urokinase-type PA (uPA) was also increased by TGF beta in a dose-dependent manner. The effects of TGF beta on synthesis of mRNA for PAI-1 and uPA were maintained when protein synthesis was inhibited, and were abolished by inhibition of RNA synthesis. Although uPA had not been detected previously as a product of rat osteoblasts, treatment of lysates of osteoblast-like cells with plasmin yielded a band of PA activity on reverse fibrin autography, corresponding to a low Mr form of uPA. Untreated conditioned media from normal osteoblasts or UMR 106-01 cells contained no significant TGF beta activity, but activity could be detected in acidified medium. Treatment of conditioned media with plasmin resulted in activation of approximately 50% of the TGF beta detectable in acidified media. The results identify several effects of TGF beta on the PA-PA inhibitor system in osteoblasts. Net regulation of tPA activity through the stimulatory actions of several calciotropic hormones and the promotion of PAI-1 formation by TGF beta could determine the amount of osteoblast-derived TGF beta activated locally in bone. Stimulation of osteoblast production of mRNA for uPA could reflect effects on the synthesis of sc-uPA, a precursor for the active form of the enzyme.
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PMID:Transforming growth factor beta inhibits plasminogen activator (PA) activity and stimulates production of urokinase-type PA, PA inhibitor-1 mRNA, and protein in rat osteoblast-like cells. 183 80

The correlation between urokinase-type plasminogen activator (uPA) expression and tumor cell invasion and metastasis has been well documented. Urokinase converts the zymogen plasminogen to plasmin, a trypsin-like enzyme with broad substrate specificities. Net uPA activity is determined not only by the amount of the enzyme itself, but also by its state of activation and the amount of specific plasminogen activator inhibitors (PAIs) present. Both uPA and its substrate, plasminogen, can bind to cells via specific membrane-associated receptors. Expression of uPA, uPA receptor (uPAR), and PAIs is regulated by growth factors, oncogenes, and other effector molecules. In the present review we discuss the interactions of uPA with its receptor, inhibitors, and substrate and how these interactions influence malignant behavior. We also review recent reports in which investigators have used anti-catalytic antibodies and/or gene transfection to demonstrate that uPA is directly involved in tumor cell invasion and metastasis.
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PMID:The role of urokinase-type plasminogen activator in aggressive tumor cell behavior. 212 23

We have examined the effect of thrombin on the activity of plasminogen activator (PA) and plasminogen activator-inhibitor (PA-I) in medium conditioned by primary cultures of human umbilical vein endothelial cells. PA activity was measured by fibrinolytic and esterolytic assays, and total tissue-type PA (tPA) antigen by radioimmunoassay. Net PA-I activity was assayed by titration of human urokinase esterolytic activity. Incubation of confluent endothelial cell cultures with thrombin for 24 h caused a sixfold increase in PA-I activity. The effect of thrombin was half-maximal at approximately 0.4 U/ml (less than 4 nM), and required concomitant RNA and protein synthesis. The stimulation of PA-I activity required active alpha-thrombin and was not obtained with gamma-thrombin nor with thrombin catalytically inactivated with hirudin. Because of the excess of PA-I, PA activity was not measurable in either control or thrombin-treated cells. Thrombin did, however, increase medium concentration of tPA antigen by approximately fourfold. The thrombin-induced PA-I inhibited both tPA and urokinase, did not lose activity upon acidification, and was stable to sodium dodecyl sulfate and thiol reduction. We conclude that physiologic concentrations of thrombin increase both PA-I activity and tPA antigen in medium conditioned by human umbilical vein endothelial cells. Because there was always a several-fold increase in the net activity of free PA-I, these observations suggest that the net effect of thrombin is to decrease fibrinolytic activity in human endothelial cells. Thus, thrombin, in addition to its role in coagulation, may protect clots from premature lysis by increasing the amount of a specific fibrinolytic inhibitor.
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PMID:Thrombin induction of plasminogen activator-inhibitor in cultured human endothelial cells. 241 59

In the present study, we have examined the influence of transforming growth factor-alpha (TGF alpha) and FSH in vitro on the granulosa cell plasminogen activator (PA) system accompanying cell proliferation and differentiation during follicular development. Undifferentiated and differentiated rat granulosa cells from diethylstilbestrol (DES)- and eCG-treated immature rats, respectively, were cultured in medium containing FSH (400 ng/ml), TGF alpha (0.5-50 ng/ml), and/or transforming growth factor-beta (TGF beta; 25-100 ng/ml). Net secreted PA (PAs) and cell-associated PA (PAc) activities were higher in differentiated cells and were stimulated by TGF alpha (but not by TGF beta) in a concentration-dependent manner. Basal and FSH-stimulated PAs was higher than PAc and accounted for 70-80% of the total PA activity in both cell preparations. FSH-stimulated PA activities increased in undifferentiated granulosa cells but decreased in differentiated cells with increased duration of culture. A biphasic effect (stimulatory in the first 24 h and inhibitory thereafter) of TGF alpha on FSH-induced PA activities was observed in the cultures of undifferentiated granulosa cells. Whereas both urokinase (uPA) and tissue (tPA) PA appeared to be present in cultures of granulosa cells from DES-treated rats, only tPA could be detected in those from eCG-treated animals. TGF alpha increased basal tPA activity at both stages of follicular development but inhibited activities of uPA in undifferentiated granulosa cells, irrespective of the presence of FSH. This growth factor stimulated basal progesterone (P) and 20 alpha-dihydroprogesterone (20 alpha-OH-P) secretion (an index of granulosa cell differentiation), the effect being more pronounced at the late stage of follicular development.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Follicular stage-dependent regulation of rat granulosa cell plasminogen activator system by transforming growth factor-alpha in vitro. 771 Dec 10

Growth hormone-releasing factor (GRF) and vasoactive intestinal peptide (VIP) are two structurally homologous peptides sharing common target cell receptor and known to enhance FSH-induced steroidogenesis of undifferentiated granulosa cell in vitro. Although VIP, has been reported to stimulate plasminogen activator (PA) activity in rat granulosa cells, our knowledge on the actions and interactions of these two peptides with FSH in the regulation of rat granulosa cell PA system during follicular development remains incomplete. Undifferentiated and differentiated rat granulosa cells from pre-antral (DES-treated rats) and antral (eCG-treated rats) follicles, respectively, were cultured in a chemically defined medium in the absence and presence of FSH (400 ng/ml), GRF (10(-8)-10(-5) M) and/or VIP (10(-9)-10(-5) M). Net secreted (PAs) and cell-associated (PAc) PA activities was measured by the fibrinolysis assay and characterized by the fibrin overlay method. Granulosa cell differentiative (progestin secretion) and proliferative (DNA synthesis) responses were analyzed by radioimmunoassay and [3H]thymidine incorporation, respectively. Both GRF and VIP stimulated PAs and PAc activities in a concentration-dependent manner in 24-h cultures of granulosa cells from the two stages of follicular development. They (10(-5) M) enhanced FSH-stimulated PAs activity in granulosa cell cultures of pre-antral follicles, with GRF being more effective than VIP. On the contrary, only GRF (10 microM) potentiated FSH-induced PAs and PAc activities in cultures of granulosa cell from antral follicles. The stimulation of PA activity by these agonists decreased with the duration of culture irrespective of the stage of follicular development.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Growth hormone releasing factor and vasoactive intestinal peptide stimulate rat granulosa cell plasminogen activator activity in vitro during follicular development. 779 29

We have previously shown that plasma levels of endothelium-derived tissue-type plasminogen activator (t-PA) increase during mental stress. The aim of the study was to investigate in vivo release in an intact human muscle vascular bed. Eleven healthy young males (22-36 yrs) were studied at rest and during 10 min of mental stress (forced arithmetic). Net release or uptake were assessed by arterio-venous (AV) concentration gradients across the forearm of t-PA antigen and t-PA activity, and plasminogen activator inhibitor antigen type 1 (PAI-1). Forearm blood flow was measured by venous occlusion plethysmography. At rest, there was a positive AV-difference of t-PA activity across the forearm indicating a net release of t-PA activity of approximately 3.7 fmol x min-1 x 100 ml-1 (Wilcoxon's signed rank test vs 0, p = 0.01). However, t-PA antigen showed a variable release pattern. On the average, there was a net release of 0.17 ng x min-1 x 100 ml-1 after 60 min of rest (Wilcoxon vs 0, p = 0.07). PAI-1 antigen showed net release at rest. In response to stress, forearm blood flow increased from 1.9 to 2.9 ml x min-1 x 100 ml-1 (ANOVA, p = 0.007), and net release of t-PA activity increased to 9.8 fmol x min-1 x 100 ml-1 (ANOVA, p = 0.01 compared with rest). Arterial and venous plasma t-PA levels also increased significantly during stress (ANOVA, p < 0.01). t-PA antigen showed a similar but less pronounced release pattern during stress.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vivo release of tissue-type plasminogen activator across the human forearm during mental stress. 783 66

We have recently shown that mental stress increases local net release of tissue-type plasminogen activator (t-PA) across the forearm vascular bed. However, the mechanisms responsible for the t-PA release in man during stress are undefined. To study the effects of endothelial cell receptor stimulation and fluid shear stress we used the perfused forearm model to characterize the in vivo tissue plasminogen activator (t-PA) response in man to methacholine (Mch) and sodium nitroprusside (SNP), at doses calculated to cause similar degrees of vasodilation. The study was performed in 7 healthy young men (age 22-24 yrs) without hypertension, diabetes mellitus, or hypercholesterolemia. Each subject received double-blind step-wise i. a. infusions of Mch (0.1-0.8-4.0 micrograms/min) and SNP (0.5-2.5-10 micrograms/min) in randomized order. Each dose step was infused for 5 min. Forearm blood flow was assessed by plethysmography. Net release/uptake was expressed as the product of arterio-venous concentration gradient and forearm plasma flow. At pre-infusion baseline, there was a significant net release of t-PA antigen of approximately 0.9 ng x min-1 x 100 ml-1 and t-PA activity of 3.5 fmol x min-1 x 100 ml-1 across the forearm. I.a. infusion of Mch and SNP increased forearm blood flow from 1.9 to 14.9 and from 1.8 to 12.1 ml x min-1 x 100 ml-1, respectively (Mch vs SBP N.S.).(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Release of tissue-type plasminogen activator in response to muscarinic receptor stimulation in human forearm. 787 38

Fibrin is an important mediator of injury in severe proliferative forms of glomerulonephritis (GN). Normal glomeruli express fibrinolytic activity, which may protect against the injurious effects of fibrin deposition. Changes in glomerular fibrinolytic activity (GFA) may play an important role in modulating fibrin accumulation in GN. To study the changes in GFA associated with fibrin deposition in GN, autologous phase anti-glomerular basement antibody initiated GN (anti-GBM GN) was studied in rabbits. Net GFA was significantly reduced in association with glomerular fibrin deposition (1.3 +/- 0.8 ng fibrin lysed/10(3) glomeruli/2 hr, normal 57.1 +/- 25.4 ng fibrin lysed/10(3) glomeruli/2 hr, P < 0.02). Reduced GFA in fibrin associated GN was associated with decreased expression of tissue type plasminogen activator (tPA) and increased expression of plasminogen activator inhibitor type-1 (PAI-1) and glomerular macrophage infiltration. In a fibrin independent model of anti-GBM induced GN (heterologous phase), with equivalent injury (proteinuria), net GFA was increased (174 +/- 64 ng fibrin lysed/10(3) glomeruli/2 hr). This was associated with increased tPA and uPA, and decreased PAI-1 in the absence of significant macrophage infiltration. These studies demonstrate that fibrin deposition in GN is associated with a net reduction of GFA, attributable to reduced expression of plasminogen activators and augmentation of PAI-1. Reduction of GFA may potentiate glomerular fibrin deposition and consequent glomerular injury. The association between glomerular macrophage influx and reduction in GFA suggests that this change may be directed by macrophages.
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PMID:Glomerular fibrinolytic activity in anti-GBM glomerulonephritis in rabbits. 823 Oct 28

Tumor cell adherence (TCA) to sites of surgical injury is a requisite step in implantation-mediated tumor recurrence. This study examined the relationship between tumor-associated plasminogen activator (PA) and the ability of tumor cells to remain adherent to surgical injury sites. High (1E8) and low (3A9) PA producing clones from the murine transitional carcinoma cell line 4909 were selected using an in vitro 125I fibrinolysis assay. Net cellular PA activity of each clone was determined from cell lysates using a chromogenic substrate assay. In vitro TCA and fibrin substrate lysis as a function of time were simultaneously measured using a tetrazolium dye assay in combination with an 125I fibrinolysis assay. In vivo TCA to in situ cautery-injured rat bladders was measured 30 minutes (n = 12 animals/cell line) and 24 hours (n = 18 animals/cell line) following tumor exposure with a radiolabeled TCA assay. In vitro and in vivo competitive binding assays evaluated the relative adherence of mixtures of the 1E8 and 3A9 clones. Cellular PA activity was 0.022, 0.014 and 0.007 units per mg. protein for the 1E8, 4909 and 3A9 cell lines. In vitro TCA to fibrin in the presence of plasminogen was significantly different for each cell line and demonstrated an inverse relationship with both plasminogen-dependent fibrin lysis and cellular PA activity (p < 0.0001). The in vivo assay showed that the percentage of 1E8 cells remaining adherent 24 hours after tumor exposure was significantly less than that of the 3A9 cells (p = 0.01). Both in vitro and in vivo competitive binding assays demonstrated preferential adherence of the 3A9 cell line. Cellular PA production appears to be a tumor-intrinsic variable that modulates TCA to surgical injury sites.
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PMID:Plasminogen activators: regulators of tumor cell adherence to sites of lower urinary tract surgical trauma. 834 79

Based on previous cross-sectional findings, we hypothesized that weight loss could improve several hemostatic factors associated with cardiovascular disease. In a randomized controlled trial, moderately overweight men and women were assigned to one of four weight loss treatment groups or to a control group. Measurements of plasminogen activator inhibitor-1 (PAI-1) antigen, tissue-type plasminogen activator (t-PA) antigen, D-dimer antigen, factor VII activity, fibrinogen, and protein C antigens were made at baseline and after 6 months in 90 men and 88 women. Net treatment weight loss was 9.4 kg in men and 7.4 kg in women. There was no net change (p > 0.05) in D-dimer, fibrinogen, or protein C with weight loss. Significant (p < 0.05) decreases were observed in the combined treatment groups compared with the control group for mean PAI-1 (31% decline), t-PA antigen (24% decline), and factor VII (11% decline). Decreases in these hemostatic variables were correlated with the amount of weight lost and the degree that plasma triglycerides declined; these correlations were stronger in men than women. These findings suggest that weight loss can improve abnormalities in hemostatic factors associated with obesity.
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PMID:Impact of weight loss on plasminogen activator inhibitor (PAI-1), factor VII, and other hemostatic factors in moderately overweight adults. 842 53


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