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

The effects of prostaglandins on the fibrinolytic activity of cultured human foreskin fibroblasts have been measured by a [125I]fibrin dish assay. Prostaglandin (PG) E1, added to fibroblasts in serum-containing medium, produced dose-dependent increases in the fibrinolytic activity of both cellular extracts and conditioned medium. PGE2 and PGI2, but not PGD2 or 6-keto-PGF1 alpha, also stimulated fibrinolytic activity. In each case, activity was due to the protease plasminogen activator because it was abolished by omitting plasminogen from the fibrinolytic assays. The effects of PGE1 were observed at 10 ng/ml and maximal stimulation occurred at 1 microgram/ml. Levels of both intra- and extracellular plasminogen activator increased, indicating that PGE1 stimulated the overall synthesis and release of the protease. The effects of PGE1 were slow in onset and persistent (greater than 48 hr) and were abolished by cycloheximide and actinomycin D. Cellular plasminogen activator was stimulated by 10 microM isoproterenol and 250 microM dibutyryl cyclic AMP; the effects of PGE1, isoproterenol and dibutyryl cyclic AMP were potentiated by the phosphodiesterase inhibitors 1-methyl-3-isobutylxanthine (100 microM) and dipyridamole (20 microM). The induction of plasminogen activator by PGE1 may therefore be initiated by stimulation of cellular adenylate cyclase. Increased fibrinolytic stimulation of cellular adenylate cyclase. Increased fibrinolytic activity could contribute to the prolonged beneficial effects which have been reported after the administration of PGE1 and PGI2 in the treatment of occlusive vascular disease.
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PMID:Stimulation of fibrinolytic activity in human skin fibroblasts by prostaglandins E1, E2 and I2. 705 Mar 42

Migration of astrocytes is thought to play a role in nerve regeneration and to be mediated, at least in part, by inflammation-associated cytokines. Plasminogen activators are secreted proteases that function in fibrinolysis and participate in cellular migration and invasion and, in some cases, are modulated by cytokines. Here, we show that two cytokines, tumor necrosis factor-alpha and interleukin-1 beta, can modulate plasminogen activation in astrocytes, each causing 90% reduction of total plasminogen activator activity. Direct and reverse zymography indicated that this reduction resulted from two simultaneous events, a pronounced decrease in tissue-type plasminogen activator activity and an induction of plasminogen activator inhibitor-1. Northern hybridization analysis indicated a 30-fold increase of the steady-state level of plasminogen activator inhibitor-1 mRNA following treatment with each of the two cytokines. Both of the cytokine-induced effects could be blocked by cycloheximide or actinomycin D. When signal transduction pathways were blocked, the results indicated the involvement of reduction in cyclic AMP levels, protein kinase activity, and arachidonic metabolites of the lipoxygenase pathway. The results thus show that the two cytokines reduce the ability of astrocytes to conduct fibrinolysis and extracellular proteolysis, and suggest that the effect of these cytokines on members of the plasminogen activation system is through a common signal transduction pathway.
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PMID:Components of the plasminogen activator system in astrocytes are modulated by tumor necrosis factor-alpha and interleukin-1 beta through similar signal transduction pathways. 756 46

We previously demonstrated that cultured human umbilical vein endothelial cells (HUVECs) overlaid with a fibrin clot induced a slight increase in tissue-type plasminogen activator (t-PA) secretion and marked reduction in plasminogen activator inhibitor-1 (PAI-1) secretion. In this study, the intracellular signal transduction after fibrin stimulation was further investigated by analyzing cyclic AMP (cAMP) and protein kinase C (PK-C). When HUVECs were stimulated by fibrin clots, t-PA mRNA increased to 130% but PAI-1 mRNA decreased to 42%. These changes concurred with the data on the protein levels of t-PA and PAI-1 as previously reported. The effect of fibrin on t-PA production in HUVECs was not significantly altered after the elevation of cAMP by either forskolin or dibutyryl cAMP. Furthermore, an effect of fibrin on t-PA production did not appear when the cells were treated by phorbol 12-myristate 13-acetate (PMA) or 1-(5-isoquinolinesulfonyl)-2-methylpiperazine (H-7). The suppressive effect of fibrin on PAI-1 secretion from HUVECs was not altered by elevation of cAMP. Regarding the activation of PK-C by PMA, PAI-1 secretion was enhanced, but was suppressed by fibrin stimulation. H-7 suppressed PAI-1 secretion and further stimulation by fibrin almost completely abolished PAI-1 secretion. These changes were well associated with mRNA levels of t-PA and PAI-1. These results suggested that fibrin on HUVECs preferably down-regulates PK-C resulting in a decrease of PAI-1 in both the protein and mRNA levels and that effect of fibrin on t-PA secretion is neither involved in PK-C nor cAMP pathway.
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PMID:Effects of fibrin on the secretion of plasminogen activator inhibitor-1 from endothelial cells and on protein kinase C. 767 18

Effects of phorbol myristate acetate (PMA), dibutyryl cyclic AMP (dbcAMP), 6-dimethylaminopurine (6-DMAP), and okadaic acid (OA) on plasminogen activator (PA) activity in porcine oocyte-cumulus cell complexes (POCC) in vitro were determined. Cumulus cell-enclosed oocytes were collected from 1-4 mm antral follicles and cultured in TCM-199 with 0.3% polyvinylpyrrolidone for 48 hr. PA activities in POCC were quantified using SDS-PAGE, casein-agar zymography, and densitometry. Two plasminogen-dependent lytic zones (93-96 kD and 71-79 kD) were observed in POCC. Addition of amiloride to the zymography, a competitive inhibitor of urokinase-type PA, failed to reduce activities in either zone, suggesting that the 71-79 kD band is a tissue-type PA (tPA) and the 93-96 kD band is possibly a tPA-inhibitor complex. Changes in PA activity due to the various treatments were expressed relative to the PA activity in 40 POCC. Increasing dbcAMP increased PA (P < 0.05) activity in dose-dependent fashion, whereas 6-DMAP and 10 and 100 ng/ml PMA inhibited (P < 0.05) PA activity. PA activity increased (P < 0.05) in POCC treated with up to 25 nM OA; however, activity decreased (P < 0.05) at concentrations > 75 nM. Treatment with 25 nM OA also induced the expression of an amiloride-sensitive PA (49-52 kD). Germinal vesicle breakdown and progression to metaphase II were inhibited (P < 0.05) by 2.5 mM dbcAMP and 2 mM 6-DMAP, whereas 100 ng/ml PMA and 25 nM OA inhibited (P < 0.05) only progression to metaphase II.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Effects of stimulators of protein kinases A and C and modulators of phosphorylation on plasminogen activator activity in porcine oocyte-cumulus cell complexes during in vitro maturation. 777 47

The production of proteolytic enzymes by osteoblasts is considered important for initiating osteoclastic bone resorption. Using the established cell line NY as an example of osteoblast-like cells, the effect of intracellular cyclic AMP (cAMP) and protein kinase C (PKC) on plasminogen activator secretion and its specific binding to the cells were investigated. HT-1080 cells were used as the control. NY cells predominantly secrete single-chain urokinase-type plasminogen activator (scu-PA) and some two-chain u-PA. Both scu-PA and u-PA were present in the cell surface and cell lysate of NY cells, and their distribution in HT-1080 cells was quite similar to that of NY cells. Exposing cells to phorbol myristate acetate (PMA) or dibutyryl cyclic AMP (db cAMP) enhanced the secretion of scu-PA and two-chain u-PA, whereas 1-(5-isoquinolinylsulfonyl)-2-methylpiperazine (H7) decreased scu-PA secretion, indicating that it is enhanced by protein kinase C (PKC) as well as by cAMP in NY cells. On the other hand, in HT-1080 cells, PMA decreased the level of two-chain u-PA secretion into the conditioned medium. The binding assay of 125I-DFP-u-PA to NY cells revealed the presence of a single class of binding sites with a Kd of 2.23 nM and Bmax of 0.82 x 10(6) binding sites/cell. PMA however, altered neither the Kd nor the Bmax. Dibutyryl cAMP increased the Bmax 1.9 fold. Thus, NY cells secrete u-PA and express specific binding sites on the cell surface, which are modulated by cAMP and PKC.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of scu-PA secretion and u-PA receptor expression in osteoblast-like cells. 816 59

We have characterized tissue type plasminogen activator (tPA) promoter elements and nuclear factors required for follicle-stimulating hormone (FSH)-induced transcription of the rat tPA gene in granulosa cells and constitutive expression of the gene in the rat neuroblastoma cell line B103. Run-on transcription analysis of isolated nuclei revealed that B103 cells transcribe the tPA gene at a high and constitutive level, while FSH was found to induce tPA gene transcription in a rapid and transient manner in granulosa cells. The maximal FSH-induced transcription rate was obtained after 20 min and was similar in the absence or presence of the protein synthesis inhibitor cycloheximide. However, in the presence of cycloheximide, tPA transcription was not turned off but continued at a high rate for several hours. This phenomenon may at least partly explain the earlier finding that tPA mRNA is superinduced by FSH in the presence of cycloheximide. DNase I footprinting analysis of the first 621 bp of the tPA promoter revealed a total of six regions that interact with nuclear factors from B103 and granulosa cells. Deletion of the promoter region from positions -269 to -621, a region that includes the two most-upstream footprints, had no effect on constitutive or FSH-induced transcription in transient expression experiments. Nuclear extracts from both granulosa cells and B103 cells showed strong binding to a consensus cyclic AMP-responsive element (CRE) at positions -178 to -185 and a neighboring binding site for nuclear factor 1 (NF1) at positions -145 to -158. The factors binding to these two regions were identified as members of the CRE-binding protein and NF1 families of transcription factors, respectively. Footprints were also obtained over two GC boxes at positions -64 to -71 and -41 to -49. These footprints were more pronounced with nuclear extracts from B103 cells than with extracts from untreated or FSH-treated granulosa cells, but gel shift assays indicate that similar amounts of two distinct factors bind to the two GC boxes in both cell types. Transfection experiments using promoter constructs with inactivated promoter elements indicate that both the CRE and NF1 sites contribute to the FSH responsiveness of the rat tPA gene in granulosa cells, while only the NF1 site is important for constitutive expression in B103 cells. The two GC boxes were found to be necessary both for constitutive expression in B103 cells and for FSH-induced expression in granulosa cells, and inactivation of both GC boxes essentially eliminated the tPA promoter activity in both cell types.
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PMID:Transcriptional regulation of the rat tissue type plasminogen activator gene: localization of DNA elements and nuclear factors mediating constitutive and cyclic AMP-induced expression. 838 Feb 22

In vitro prostacyclin (PGI2) and nitric oxide (NO) synergise in their anti-aggregatory actions on blood platelets. Presently, we have studied an interaction of molsidomine (ML--pro-drug for the NO-donor SIN-1) and PGI2 in 20 patients with peripheral arterial disease (PAD) on the plasma fibrinolytic system and platelet aggregability. A synergism of these drugs in their fibrinolytic action as measured by shortening of euglobulin clot lysis time (ECLT) and in their anti-platelet action as measured by an increase in the ratio of free platelets to platelet aggregates was observed. It seems that PGI2 and ML activated the fibrinolytic system by two independent mechanisms i.e. by a PGI2-induced direct release of pro-fibrinolytic t-PA from endothelial cells and by a ML-induced suppression of the release of anti-fibrinolytic PAI-1 from platelets. This may constitute a basis for the synergism. A synergism between PGI2 and ML in their anti-platelet action seems to be rooted in the potentiation by cyclic-GMP on the anti-aggregatory action of cyclic-AMP in platelets. On the other hand, no synergism between PGI2 and ML was observed in their hypotensive effects as measured by systolic and diastolic arterial blood pressure. It may well be that the synergism in fibrinolytic and anti-platelet actions between stimulators of adenylate and guanylate cyclases accompanied by a lack of synergism in their hypotensive actions may allow reduction of the therapeutic doses of either stimulator, thus avoiding hazards of their hypotensive side effects.
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PMID:Prostacyclin and molsidomine synergise in their fibrinolytic and anti-platelet actions in patients with peripheral arterial disease. 843 99

The mechanism of cholera toxin (CT)-stimulated arachidonate metabolism was evaluated. CT caused rapid in vitro synthesis of prostaglandin E2 (PGE2) in murine smooth muscle-like cells (BC3H1), reaching maximal levels within 3 to 4 min. In comparison, cyclic AMP (cAMP) levels were unchanged, and addition of dibutyryl cAMP did not affect PGE2 synthesis. CT-induced PGE2 synthesis was prevented by actinomycin D or cycloheximide, indicating a need for de novo protein synthesis. Northern blot analysis of total RNA from BC3H1 cells revealed that exposure to CT resulted in an increase in abundance of mRNA encoding phospholipase A2 (PLA2)-activating protein (PLAP). PLAP is a regulatory protein that increases the enzymatic activity of cellular PLA(2), which in turn causes increased hydrolysis of arachidonate from membrane phospholipids. Furthermore, CT evoked the accumulation of PLAP mRNA in J774 (murine monocyte/macrophage) and Caco-2 (human intestinal epithelial) cells in vitro, but the responses were more delayed than that of BC3H1 cells. A protein band of approximately 35 kDa, which corresponded to the size of PLAP, was observed in sodium dodecyl sulfate extracts of Caco-2 cells by Western blot (immunoblot) analysis using affinity-purified antibodies to PLAP synthetic peptides. Synthesis of PLAP protein was increased after 2 h of exposure to CT. Exposure of mouse intestinal loops to either CT or live Salmonella typhimurium for 3 h increased mucosal PLAP mRNA levels. The role of PLAP in CT-induced PGE2 synthesis provides an attractive explanation for the reported suppression of CT-induced intestinal secretion by inhibitors of protein synthesis.
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PMID:Cholera toxin induces synthesis of phospholipase A2-activating protein. 867 18

To elucidate the possible role of plasminogen activator (PA) in spermatogenesis and spermiation in mammals, we studied the hormonal regulation of PA secretion in cultured rat and mouse seminiferous tubules during defined stages of spermatogenesis. Results indicated that: (1) under basal conditions, segments of rat seminiferous tubules released primarily urokinase-type PA (uPA) at all stages of the cycle. The highest level of PA secretion occurred at stages VIIab, VIIcd and VIII. FSH, 8-bromo cyclic AMP and forskolin (FK) stimulated PA secretion, predominantly tissue-type PA (tPA). (2) In contrast, mouse seminiferous tubules secreted only tPA under basal conditions. In the presence of 50 microM MIX, seminiferous tubules at stages VII and VIII secreted higher levels of both types of PA than at the other stages. Both tPA and uPA secretion was enhanced by addition of FSH and FK to the organ culture media. (3) Segments of both rat and mouse seminiferous tubules at stages IX-XII in which the sperm residual bodies are absorbed into the Sertoli cells were also very sensitive to the addition of FSH to the organ culture. These results suggest that tPA in rat and mouse testes may play an essential role in the process of spermatogenesis and spermiation as well as in sperm residual body absorption.
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PMID:Hormonal regulation of plasminogen activator in rat and mouse seminiferous epithelium. 872 Jun 90

Retinoic acid (RA) induced differentiation of F9 embryonal carcinoma cells is accompanied by changes in cellular responsiveness to extracellular signals. These changes include an increase in the AP1 transcription factor that is associated with the expression of differentiation markers (e.g., cytokeratin 18 and plasminogen activator). Since AP1 activity is a target for protein kinase C (PKC)-regulated changes in gene expression, we have examined the effects of RA on the expression and function of the PKC isozymes. F9 stem cells express PKC beta, delta, epsilon, and zeta. RA-induced differentiation to primitive endoderm led to a transition from PKC beta to PKC alpha expression. Additional treatment with dibutyryl cyclic AMP (dbcAMP), required for terminal differentiation into parietal endoderm, further increased PKC alpha expression and total PKC activity. RA and dbcAMP had negligible effects on the expression of PKC delta, epsilon, and zeta. The PKC beta to PKC alpha transition was specific for parietal endoderm; aggregation of RA-treated F9 cells induced visceral endoderm differentiation with elevated expression of PKC beta. The PKC activation with phorbol esters induced the expression of c-fos, c-jun, and junB proto-oncogenes in F9 stem cells. In the presence of either RA or RA and dbcAMP, phorbol ester treatment enhanced the expression of type IV collagen, a parietal endoderm marker. It also increased the expression of c-jun gene but not c-fos. The specific involvement of PKC beta in c-fos induction and PKC alpha in type IV collagen induction was confirmed in each PKC isozyme-transfected F9 cells. Together, our data demonstrate that the RA-induced (and dbcAMP-induced) changes in conventional PKC expression alters gene expression during parietal endoderm formation.
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PMID:Retinoic acid-induced transition from protein kinase C beta to protein kinase C alpha in differentiated F9 cells: correlation with altered regulation of proto-oncogene expression by phorbol esters. 873 69


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