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)

Plasminogen activator inhibitor-1 (PAI-1) inhibits the tissue plasminogen activator (tPA) and urokinase activation of plasminogen to plasmin, a protease of trypsin-like specificity which is involved in a number of processes, including fibrinolysis, matrix degradation and angiogenesis. Both phorbol esters and cAMP elevating compounds have been shown to modulate PAI-1 and tPA expression in endothelial cell culture. HBGF-1 (previously designated endothelial cell growth factor) stimulates endothelial cell growth in vitro and is angiogenic in vivo. We have reported that removal of HBGF-1 from human umbilical vein endothelial cell (HUVEC) media results in an approximately 5-fold increase in PAI-1 mRNA levels and in PAI-1 protein secreted into the media by 20 h. Here we report the effects of HBGF-1 on the phorbol ester and cAMP modulation of HUVEC PAI-1 expression. The phorbol ester PMA induced an approximate 5-fold increase in PAI-1 mRNA levels at 4 h, which returned to base line by 20 h, with or without HBGF-1 present in the media. This increase in PAI-1 mRNA levels was mediated by an increase in PAI-1 gene transcription and was abated in the presence of cycloheximide. Treatment of cells with the adenylate cyclase activator forskolin or the phosphodiesterase inhibitor HL 725, in the presence of HBGF-1 or immediately after its withdrawal, decreased PAI-1 mRNA levels and protein secreted into the conditioned media by 20 h. However, forskolin or HL 725 addition had little or no effect on PAI-1 mRNA when added 20 h after HBGF-1 withdrawal. Both the PMA and HBGF-1 modulation of PAI-1 were abolished by treatment with the protein kinase inhibitor H-7. Treatment of HUVEC with HBGF-1 had no acute effect on intracellular inositol phosphate hydrolysis or cAMP levels. Further studies on intracellular pathways involved in HBGF-1 modulation of PAI-1 will enhance our understanding of the role these factors play in cellular proliferation and angiogenesis.
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PMID:Heparin-binding growth factor-1 modulation of plasminogen activator inhibitor-1 expression. Interaction with cAMP and protein kinase C-mediated pathways. 170 36

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

Picotamide is the most interesting compound of 4-OH isophthalic acid. It is effective in vitro and in vivo. Picotamide induces inhibition of platelet aggregation: it is a thromboxane synthetase inhibitor and a thromboxane receptor antagonist. Picotamide causes cyclic endoperoxide accumulation and diverts their metabolism toward PgI2 synthesis in endothelial cells. PGI2 stimulates the adenylate cyclase with cAMP synthesis which makes platelets less sensitive to aggregatory stimulation. Picotamide induces enhancement of fibrinolytic activity, with significant reduction in the level of circulating plasminogen but in the same time it does not affect antithrombin III and FDP levels. In the present study picotamide or placebo were administered in a double blind trial at 600 mg daily for six months to 51 patients effected by diabetic macro and/or microangiopathy. The patients were 38 men and 13 women, the age was between 20 and 80 years (mean age 62.34). Twenty-seven patients were affected by type I diabetes and 24 by type II diabetes. Twenty-three of these patients presented macro-angiopathic lesions, 9 only microangiopathic lesions and 13 both. Twenty-five patients received picotamide and the other 25 an identical placebo for six months. One patient manifested myocardial infarction during the wash-out period and failed to enter the study. The following determinations were carried out: at T0 clinical examination, Doppler ultrasonography, Winsor Index, laboratory parameters; after 90 days (T90) clinical examination and Winsor Index and after 180 days (T180) were repeated photoplethysmography and clinical parameters too. Patients were not only evaluated for the vascular disease of lower extremities, but also for the other complications of diabetes, as retinopathy, nephropathy, cardiac and cerebrovascular disease.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Picotamide: prevention and therapy of diabetic vasculopathies. A double-blind clinical study]. 214 11

Studies on humoral hypercalcemia of malignancy have shown that tumors produce a protein that acts through the parathyroid hormone (PTH) receptor but is immunologically distinct from PTH. We have recently purified and cloned a parathyroid hormone-related protein (PTHrP) from a human lung cancer cell line. Full length cDNA clones were isolated and found to encode a prepropeptide of 36 amino acids and a mature protein of 141 amino acids. Eight of the first 13 amino terminal residues are identical with human PTH, although antisera directed at the amino terminus of PTHrP do not recognize PTH. A 34-amino acid synthetic peptide, PTHrP(1-34), was several times more potent than bovine or human PTH(1-34) in bioassays promoting the formation of cAMP and plasminogen activity in osteogenic sarcoma cells and activation of adenylate cyclase in chick kidney membranes. PTHrP(1-34) was also more potent than PTH(1-34) in stimulating cAMP and phosphate excretion and reducing calcium excretion in the isolated perfused rat kidney. PTHrP has been consistently demonstrated by immunohistochemistry in squamous cell carcinomas and in keratinocytes present in normal skin, but not in normal or hyperplastic parathyroid tissues or other tumors. PTHrP-like activity has been extracted from ovine placenta and fetal parathyroid tissue, suggesting that PTHrP may play a role in fetal calcium homeostasis.
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PMID:Humoral hypercalcemia of malignancy. 233 5

The sequence of events within the ovary during the process of ovulation discussed in this review is schematically represented in Fig. 1. It is obvious that LH, perhaps with some contribution from FSH, is the normal physiological trigger for the ovulatory sequence of events, and it appears from the available information that the effects of LH are mainly mediated via adenylate cyclase and increased cAMP levels. The cAMP in turn, via cAMP-dependent protein kinase, influences at least three distinct steps in the ovulatory process which seem to be of crucial importance, namely 1) the stimulation of steroidogenesis; 2) the stimulation of cyclooxygenase/lipooxygenase leading to increased prostaglandin/leukotriene synthesis; and 3) the stimulation of plasminogen activator which catalyzes the conversion of plasminogen to plasmin. A fourth crucial step in the ovulatory mechanism is the LH-induced increase in latent collagenase, but it remains to be determined if this step is mediated via cAMP. Concomitant with the increase in latent collagenase, there also appears to be an LH-dependent increase in collagenase inhibitors. The latent collagenase is then activated, and it appears that leukotrienes and prostaglandins, as well as plasmin, may be involved in this process. The active collagenase causes a digestion of the collagen in the follicle wall, and plasmin, as well as possibly other proteolytic enzymes such as proteoglycanases, may cause a further dissociation of the follicular wall. These processes of digestion of collagen and dissociation of the collagen fibers result in an opening in the follicular wall with the formation of the stigma and rupture. While the weakening of the follicular wall takes place throughout the entire wall, rupture remains for the most part a localized process at the apex of the follicle. This localization of the rupture may be explained on the basis of mechanical factors operating when the follicle wall thins and weakens. While it is clear that prostaglandins and leukotrienes can influence smooth muscle by causing contractions and that these compounds can cause vascular changes such as increased permeability, vasodilation, and vasoconstriction, it is not clear what the exact role of these latter processes are in ovulation. It appears that progesterone and not estrogen play an important role in the mechanism of LH-induced follicular rupture, but the locus of action of progesterone and its mechanism of action remains to be determined.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanism of mammalian ovulation. 255 97

The sequence of ovarian events during the process of ovulation discussed in this review is schematically represented in Figure 1. It is obvious that LH, perhaps with some contribution from FSH, is the normal physiological trigger for the ovulatory sequence of events and it appears from the available information that LH's effects are mainly mediated via adenylate cyclase and increased cAMP. The cAMP in turn, via cAMP-dependent protein kinase, influences at least three distinct steps in the ovulatory process which seem to be of crucial importance, namely 1) the stimulation of steroidogenesis; 2) the stimulation of cyclooxygenase/lipooxygenase leading to increased prostaglandin/leukotriene synthesis; and 3) the stimulation of plasminogen activator which catalyzes the conversion of plasminogen to plasmin. A fourth crucial step in the ovulatory mechanism is the LH-induced increase in latent collagenase, but it remains to be determined if this step is mediated via cAMP. Concomitant with the increase in latent collagenase, there also appears to be an LH-dependent increase in collagenase inhibitors. The latent collagenase is then activated and it appears that leukotrienes and prostaglandins as well as plasmin may be involved in this process. The active collagenase causes a digestion of the collagen in the follicle wall. Plasmin as well as possibly other proteolytic enzymes such as proteoglycanases (Too et al., 1984) may cause a further dissociation of the follicular wall. These processes of digestion of collagen and dissociation of the collagen fibers result in an opening in the follicular wall with the formation of the stigma and rupture. While the weakening of the follicular wall takes place throughout the entire wall, rupture remains for the most part a localized process at the apex of the follicle. This localization of the rupture may be explained on the basis of mechanical factors operating when the follicle wall thins and weakens (Rodbard, 1984). While it is clear that prostaglandins and leukotrienes can influence smooth muscle by causing contractions and that these compounds can cause vascular changes such as increased permeability, vasodilatation and vasoconstriction, it is not clear what the exact role of these latter processes are in ovulation. It appears that progesterone and not estrogen play an important role in the mechanism of LH induced follicular rupture, but the locus of action of progesterone and its mechanism of action remains to be determined.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Mechanism of mammalian ovulation. 265 83

Studies of humoral hypercalcemia of malignancy (HHM) have provided evidence that tumors produce a protein that acts through the parathyroid (PTH) receptor but is immunologically distinct from PTH. We have recently purified and cloned a parathyroid hormone-related protein (PTHrP) implicated in HHM from a human lung cancer cell line (BEN). Full-length cDNA clones have been isolated and found to encode a prepropeptide of 36 amino acids and a mature protein of 141 amino acids. Eight of the first 13 amino-terminal residues are identical with human PTH, although antisera directed to the amino-terminus of PTHrP do not recognize PTH. The striking homology with PTH about the amino-terminal region is not maintained in the remainder of the molecule. PTHrP therefore represents a previously unrecognized hormone. A 34-amino acid synthetic peptide, PTHrP(1-34) was 2-4 times more potent than bovine or human PTH(1-34) in bioassays promoting the formation of cAMP and plasminogen activity in osteogenic sarcoma cells and activation of adenylate cyclase in chick kidney membranes. Like PTH, PTHrP peptides of less than 30 residues from the amino-terminus showed substantially reduced activity. PTHrP(1-34) was also more potent than hPTH(1-34) in stimulating cAMP and phosphate excretion and reducing calcium excretion in the isolated perfused rat kidney. Immunohistochemical localization of PTHrP was consistently demonstrated in squamous cell carcinomas. In normal tissues PTHrP has been immunohistochemically localized in keratinocytes and PTHrP-like activity has been extracted from ovine placenta and fetal ovine parathyroids.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Humoral hypercalcemia of malignancy. 269 18

Plasminogen activators are highly selective proteases that activate the proenzyme plasminogen to the general protease, plasmin. We studied a porcine kidney cell line, originally isolated as a high producer of plasminogen activator, in which activities of cellular adenylate cyclase and cAMP-dependent protein kinase are increased in response to calcitonin. We found that salmon calcitonin, in the concentration range 0.03-300 nM, increased plasminogen activator production up to approximately 1,000-fold and concurrently inhibited cell multiplication; both of these effects were reversible. Human calcitonin was approximately 0.01 times as potent as salmon calcitonin, corresponding to potency differences observed in other biological systems. Plasminogen activator production was also stimulated by other agents that raise cellular cAMP levels such as cholera toxin, phosphodiesterase inhibitors, and vasopressin, but not to the same extent as by calcitonins. The rapidity and sensitivity of the plasminogen activator determination and other cellular responses may make it possible in the future to use this cell stain in a convenient bioassay for calcitonins and their analogues.
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PMID:Calcitonin stimulates plasminogen activator in porcine renal tubular cells: LLC-PK1. 627 91

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

Hypoxia induces angiogenesis in ischemized tissues by means of pro-angiogenic factor expression. The key role in the growth processes and blood vessel functioning belongs to the matrix metalloproteinases, plasminogen, and its activator systems. Effect of hypoxia on expression of the urokinase activating agent plasminogen and its receptor in endothelium was studied in human umbilical vein endothelial cell model. Incubation of the endothelial cells under the conditions of hypoxia proved to reduce both urokinase formation in these cells and its secreting into the culture medium. The hypoxia-induced reduction of urokinase contents was accompanied by enhancement of expression of the urokinase receptor. The hypoxia also entailed reduction of the adenylate cyclase activity and cAMP contents in the endothelial cells. The data obtained suggest that reduction of the adenylate cyclase activity and cAMP contents under the conditions of hypoxia provide basis for suppression of the urokinase expression by the endothelial cells and, consequently, inhibition of blood vessel formation in the ischemized tissue.
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PMID:[The effect of hypoxia on the urokinase and adenylate cyclase systems in the culture of endothelial cells of the human umbilical vein]. 1611 48


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