Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:4.6.1.1 (adenylate cyclase)
19,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The continuous cell line, J774.2, exhibits many macrophage-like functions such as latex and Fc-mediated phagocytosis, antibody mediated phagocytosis, antibody mediated cytotoxicity, chemotaxis, and lysozyme secretion. Cyclic AMP stimulates Fc-mediated phagocytosis and inhibits the growth of J774.2. To further evaluate the relationship between cyclic AMP and the specialized functions exhibited by these cells. Variants deficient in phagocytosis, adenylate cyclase and cyclic AMP-dependent protein kinase were derived. We have now shown that J774.2 also secretes plasminogen activator and that this secretion is rapidly and specifically inhibited by 8-bromoadenosine 3':5'-cyclic monophosphoric acid (8 Br--cAMP) or cholera toxin under conditions where lysozyme secretion is unaltered. Utilizing protein kinase-deficient variants, the ability of cyclic AMP to inhibit plasminogen activator secretion was shown to be mediated by a cyclic AMP-dependent protein kinase. We conclude that cyclic AMP has diametrically opposing effects on two macrophage-like functions: Fc-mediated phagocytosis and plasminogen activator secretion.
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PMID:Inhibition of plasminogen activator secretion by cyclic AMP in a macrophage-like cell line. 21 71

Stable variants of the macrophage-like cell line J774.2, defective in adenylate cyclase and protein kinase activities, were selected by cloning cells resistant to the growth-inhibitory effect of cholera toxin and 8-bromo-adenosine 3':5' cyclic monophosphoric acid (8 Br-cAMP), respectively. These variants were analyzed for their ability to respond to cyclic AMP-mediated enhancement of phagocytosis and cyclic AMP-mediated inhibition of plasminogen activator secretion and growtn. The adenylate cyclase variants were unaffected by cholera toxin but were sensitive to 8 Br-cAMP-mediated inhibition of plasminogen activator secretion and growth. One of these variants exhibited a defect in phagocytosis that could be corrected by 8 Br-cAMP. The protein kinase variants exhibited normal basal phagocytosis that could not be stimulated by either 8 Br-cAMP or cholera toxin; they were also insensitive to cyclic AMP-mediated inhibition of plasminogen activator secretion and growth. The studies demonstrate that the three effects of cyclic AMP in J774.2--inhibition of growth and plasminogen activator secretion, and enhancement of basal Fc-mediated phagocytosis--are mediated by a cyclic AMP-dependent portein kinase. The results support the usefulness of variants in cyclic nucleotide metabolism in understanding the regulation of differentiated cell function by cyclic AMP.
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PMID:Properties of protein kinase and adenylate cyclase-deficient variants of a macrophage-like cell line. 21 4

To clarify a possible involvement of the vasoconstrictive peptide endothelin in the regulation of endothelial cell-mediated fibrinolytic system, confluent cultures of vascular endothelial cells from human umbilical vein were incubated in serum-free medium in the presence of endothelin-1 at 100 nM and below, and tissue plasminogen activator antigen (t-PA:Ag) in the medium was determined by enzyme immunoassay. Endothelin-1 at 1 nM and above significantly decreased the release of t-PA:Ag from the endothelial cells after a 24 h incubation. The t-PA:Ag release was also decreased by either endothelin-2 or endothelin-3 at 10 nM. The activity of lactate dehydrogenase in the medium was not changed by endothelin-1 at 100 nM and below, suggesting that the peptide did not cause nonspecific cell damage. The decrease in the t-PA:Ag release induced by endothelin-1 occurred in the presence or absence of 8-bromo cyclic AMP, which is an active congener of cyclic AMP; 3-isobutyl-1-methylxanthine, which is an inhibitor of phosphodiesterase; and forskolin, which is a stimulator of adenylate cyclase. These results strongly indicated that cyclic AMP which is known to down-regulate t-PA:Ag release was not involved in the endothelin-1 effect. However, endothelin-1 failed to decrease the t-PA:Ag release in the presence of either calcium ionophore A23187 or EGTA; the ionophore itself markedly decreased the release. The cytosolic calcium accumulation was significantly increased by endothelin-1. These results suggest that endothelin-1 decreases the release of t-PA:Ag from human endothelial cells through an excess accumulation of intracellular, especially cytosolic which would be mediated by an extracellular, calcium-dependent mechanism.
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PMID:Endothelin modulation of tissue plasminogen activator release from human vascular endothelial cells in culture. 137 54

Human mesangial cells in culture synthesize and secrete plasminogen activator inhibitor 1 (PAI-1) and tissue-type plasminogen activator (t-PA). Phorbol myristate acetate (PMA), a known activator of protein kinase C, induces a three to four-fold increase in t-PA and PAI-1 release over a period of 24 h, whereas cell-associated t-PA and PAI-1 levels remain relatively stable. A similar effect is obtained with oleylacetyl glycerol, a more physiologic protein kinase C activator. The effect of PMA is suppressed in the presence of H7, an inhibitor of cellular protein kinases, and by cycloheximide and actinomycin D, indicating a requirement for de novo protein and RNA synthesis, respectively. Northern blot analysis of PMA-treated cells reveals a rapid and transient increase in PAI-1 mRNA reaching a maximum after 4-8 h, whereas increase in t-PA mRNA levels requires 24 h. Activation of protein kinase A by addition of 8-bromocyclic AMP (8-bromo cAMP) has no significant effect on PAI-1 release but inhibits the PMA-mediated increases in PAI-1 antigen and mRNA. Addition of 8-bromo cAMP alone does not affect t-PA release. When added to PMA-stimulated cells, 8-bromo cAMP inhibits t-PA release in a dose-dependent manner, but causes a superinduction of t-PA mRNA. 8-bromo cAMP also induces a decrease in PMA-stimulated intracellular t-PA release. Similar inhibition is observed after stimulation of endogenous adenylate cyclase with prostaglandin E1 or isoproterenol. This indicates that protein kinase A activation may inhibit PMA-stimulated t-PA release via a post-transcriptional effect, e.g. inhibition of protein synthesis or activation of protein degradation. In conclusion, hormones or mediators which activate protein kinase C can stimulate t-PA and PAI-1 synthesis in human mesangial cells. Protein kinase A activation has no effect on the basal release of PAI-1 and t-PA by human mesangial cells, and, in contrast to endothelial cells, it inhibits both PMA-stimulated PAI-1 and t-PA releases. This cell-specific regulation of t-PA and PAI-1 seems to be mediated by differential transcriptional and post transcriptional mechanisms.
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PMID:Cell-specific regulation of plasminogen activator inhibitor 1 and tissue type plasminogen activator release by human kidney mesangial cells. 155 43

We have studied the effect of the adenylate cyclase-stimulating agent forskolin on expression of components of the plasminogen activation system in the human fibrosarcoma cell line HT-1080. By enzyme-linked immunosorbent assays, forskolin was found to cause a 2 to 4-fold decrease in intracellular and culture medium levels of type-1 inhibitor of plasminogen activators (PAI-1) and tissue-type plasminogen activator (t-PA). This was true for cells not treated with other agents and for cells, in which the PAI-1 and t-PA levels had been increased 5 to 10-fold by treatment with dexamethasone. This down-regulation could be traced back to corresponding decreases in the cellular levels of PAI-1 and t-PA mRNAs. Of the two PAI-1 mRNAs, the 2.4 kb species was 5-fold decreased by forskolin in cells treated with dexamethasone, while the 3.4 kb transcript was unaffected; in cells not treated with dexamethasone, forskolin affected the two PAI-1 transcripts in parallel. These studies show that in addition to the many inducers of PAI-1, PAI-1 gene expression is also subject to negative modulation by cyclic AMP. They also show that t-PA gene expression, in contrast to the induction by cyclic AMP observed in many other cell lines, may also be subject to negative regulation by cyclic AMP. Thus, hormonal agents acting with cyclic AMP as a second messenger may be involved in down-regulating PAI-1 and t-PA expression in vivo.
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PMID:Forskolin down-regulates type-1 plasminogen activator inhibitor and tissue-type plasminogen activator and their mRNAs in human fibrosarcoma cells. 170 20

The hemovascular abnormalities encountered in diabetes include platelet alterations, shifts in prostaglandin metabolism and disorders of fibrinolysis. Diabetes is thus associated with increased platelet adhesiveness, increased platelet aggregation with hypersensitivity to proaggregants, increased plasma levels of beta-thromboglobulin and platelet factor 4 as an expression of platelet hyperactivity, increased levels of thromboxane A2 (TXA2) and prostacyclin (PGI2), and reduced levels of tissue plasminogen activator (t-PA). It is not clear which, if any, of these abnormalities are generated by chronic hyperglycemia and can be corrected by adequate glycemic control. Studies with gliclazide have demonstrated that it exerts hemovascular effects which can be valuable to patients. Thus, treatment with gliclazide leads to a decrease in platelet adhesiveness and aggregability. This treatment also reduces thromboxane levels and increases TPA levels. The mechanisms of action of gliclazide are not fully known but it has been demonstrated that its antiplatelet action is independent of its hypoglycemic activity and is not accompanied by clinical abnormalities of blood clotting. The mechanism of direct action on platelet activity may be mediated by inhibition of activated glycogen synthetase, activation of adenylate cyclase, modulation of arachidonic acid release from platelet membranes, stimulation of PGI2 production, and inhibition of the proaggregant action of TXA2. Thus, gliclazide not only has a hypoglycemic action but also improves hemovascular parameters in type 2 diabetes when used at normal therapeutic doses.
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PMID:Hemobiological activity of gliclazide in diabetes mellitus. 179 71

Pro-opiomelanocortin-derived peptides, alpha-MSH and beta-endorphin, are synthesized and secreted by Leydig cells, and are believed to have paracrine effects on Sertoli cells in the testis. Peptides with MSH activity stimulate adenylate cyclase and cAMP accumulation in Sertoli cell-enriched cultures. The purpose of the present study was to determine whether such peptides would affect Sertoli cell parameters, such as aromatase and plasminogen activator activities, that are known to be regulated by cAMP. alpha-MSH stimulated aromatase activity in Sertoli cell-enriched cultures prepared from 10-day-old rats and this effect was potentiated by methyl isobutylxanthine (MIX). The combination of alpha-MSH plus MIX was not as potent as FSH. alpha-MSH, des-acetyl-alpha-MSH, beta-MSH, ACTH(1-13), and ACTH(1-24) stimulated aromatase activity to a similar extent, suggesting that Sertoli cells do not distinguish between the activities of these peptides. alpha-MSH potentiated the action of dbcAMP and forskolin on Sertoli cell aromatase, but unexpectedly had no effect on the action of either half-maximal or maximal doses of FSH. The regulation of plasminogen activator was examined next; urokinase was markedly suppressed by FSH in 10-day-old Sertoli cells. Although neither alpha-MSH nor MIX alone had an effect on urokinase secretion, in combination they were as effective as FSH. In 10-day-old Sertoli cells each of these peptides had little or no effect on tissue plasminogen activator.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Estradiol and plasminogen activator secretion by cultured rat Sertoli cells in response to melanocyte-stimulating hormones. 247 57

The protein kinase C inhibitor H7 (10(-5) mol/l) is able to inhibit the thrombin-induced t-PA release in the isolated perfused pig ear. The thrombin-induced t-PA release can be blocked by increasing the intracellular c-AMP via either the activation of adenylate cyclase by means of forskolin, or the inhibition of the phosphodiesterase by means of motapizone or milrinone. Protein kinase C is assumed to be involved in the process of thrombin-induced t-PA release.
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PMID:[Mechanisms of thrombin-induced plasminogen activator release]. 248 8

A cosmid (cos pUK0322) harboring the complete human urokinase-type plasminogen activator (u-PA) gene and Geneticin resistance as a selectable marker was isolated from a human genomic library and characterized. After transfection of cos pUK0322 into mouse L cells and selection, several plasminogen activator (PA)-expressing clones were obtained and one (LuPA) was chosen for additional study. The PA expressed was identical to human pro-u-PA in enzymatic, electrophoretic, and antigenic properties. The expression of PA was stable over 50 population doublings. The regulation of the transfected gene was studied by treatment of the cells with various hormones and other effectors. Expression of PA activity was inhibited fivefold by dexamethasone and stimulated two- to threefold by agonists of the adenylate cyclase dependent pathway of signal transduction, such as dibutyryl cyclic AMP and cholera and pertussis toxins. The modulation of PA activity was associated with corresponding changes in mRNA steady-state levels. The phenotypic changes associated with pro-u-PA expression were analyzed in vitro by degradation of 3H-labeled extracellular matrix (ECM), invasion of a matrigel basement membrane analogue, and by light and electron microscopy. LuPA cells and reference HT-1080 fibrosarcoma cells, in contrast to control Lneo cells transfected with the neomycin resistance gene, degraded the ECM and invaded the matrigel basement membrane. Matrix degradation correlated with the modulation of pro-u-PA gene expression as it was inhibited by dexamethasone and promoted by dibutyryl cyclic AMP. Inhibition of PA or plasmin using anti-u-PA IgG or aprotinin prevented ECM degradation and invasion. These results demonstrate that u-PA expression alone is sufficient to confer to a cell an experimental invasive phenotype.
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PMID:Mouse L cells expressing human prourokinase-type plasminogen activator: effects on extracellular matrix degradation and invasion. 250 27

We investigated the effect of agents which raise intracellular levels of cyclic AMP (cAMP) on the secretion of tissue-type plasminogen activator (t-PA) and type 1 plasminogen activator inhibitor (PAI-1) by cultured human umbilical-vein endothelial cells. Significant inhibition of baseline (unstimulated) t-PA and PAI-1 secretion was observed in response to several agents which, when added exogenously, cause increased intracellular cAMP: cholera toxin, 1-methyl-3-isobutylxanthine (MIX), dibutyryl-cAMP, and prostaglandin E1. These agents also significantly reduced or abolished the previously reported stimulatory effects of thrombin and histamine on t-PA secretion, and, with the exception of MIX, significantly reduced the previously reported stimulatory effect of thrombin on PAI-1 secretion. MIX at a concentration (10 microM) below that required to inhibit t-PA and PAI-1 secretion when tested alone, significantly increased the inhibitory effects of cholera toxin, dibutyryl-cAMP, and prostaglandin E1 on both t-PA and PAI-1 secretion. The data suggest that elevated intracellular levels of cAMP inhibit both spontaneous endothelial secretion of t-PA and PAI-1, and secretion induced by agents (thrombin and histamine) which stimulate endothelial phosphoinositide metabolism, consistent with bidirectional regulation of endothelial fibrinolytic protein secretion by the adenylate cyclase and phosphoinositide signal transduction pathways. The inhibitory effects of cAMP do not appear to be specific for t-PA and PAI-1, since cholera toxin and MIX also inhibited endothelial secretion of the adhesive protein, fibronectin. Significant inhibition of baseline endothelial t-PA and PAI-1 secretion was also caused by the stable prostacyclin analogue iloprost (ZK 36 374) and by arachidonic acid, which is converted by endothelial cells to prostacyclin, suggesting that prostacyclin produced endogenously by endothelial cells may inhibit secretion of fibrinolytic proteins by increasing intracellular cAMP.
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PMID:Inhibition of endothelial secretion of tissue-type plasminogen activator and its rapid inhibitor by agents which increase intracellular cyclic AMP. 254 66


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