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)

Treatment of intact hepatocytes with glucagon, TH-glucagon [( 1-N-alpha-trinitrophenylhistidine, 12-homoarginine]glucagon), angiotensin or vasopressin led to a rapid time- and dose-dependent loss of the glucagon-stimulated response of the adenylate cyclase activity seen in membrane fractions isolated from these cells. Intracellular cyclic AMP concentrations were only elevated with glucagon. All ligands were capable of causing both desensitization/loss of glucagon-stimulated adenylate cyclase activity and stimulation of inositol phospholipid metabolism in the intact hepatocytes. Maximally effective doses of angiotensin precluded any further inhibition/desensitizing action when either glucagon or TH-glucagon was subsequently added to these intact cells, as has been shown previously for the phorbol ester TPA (12-O-tetradecanoylphorbol 13-acetate) [Heyworth, Wilson, Gawler & Houslay (1985) FEBS Lett. 187, 196-200]. Treatment of intact hepatocytes with these various ligands caused a selective loss of the glucagon-stimulated adenylate cyclase activity in a washed membrane fraction and did not alter the basal, GTP-, NaF- and forskolin-stimulated responses. Angiotensin failed to inhibit glucagon-stimulated adenylate cyclase activity when added directly to a washed membrane fraction from control cells. Glucagon GR2 receptor-stimulated adenylate cyclase is suggested to undergo desensitization/uncoupling through a cyclic AMP-independent process, which involves the stimulation of inositol phospholipid metabolism by glucagon acting through GR1 receptors. This action can be mimicked by other hormones which act on the liver to stimulate inositol phospholipid metabolism. As the phorbol ester TPA also mimics this process, it is proposed that protein kinase C activation plays a pivotal role in the molecular mechanism of desensitization of glucagon-stimulated adenylate cyclase. The site of the lesion in desensitization is shown to be at the level of coupling between the glucagon receptor and the stimulatory guanine nucleotide regulatory protein Gs, and it is suggested that one or both of these components may provide a target for phosphorylation by protein kinase C.
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PMID:The rapid desensitization of glucagon-stimulated adenylate cyclase is a cyclic AMP-independent process that can be mimicked by hormones which stimulate inositol phospholipid metabolism. 303 85

The mechanism of cAMP-inhibition by EGF was studied in isolated porcine thyroid follicles. EGF inhibited TSH-induced cAMP-formation maximally by 40%, this effect remained up to 1 h of pre-incubation. The calcium-ionophore A 23 187 also inhibited cAMP-formation, but its effect was relieved after 1 h. The phorbolester TPA had a biphasic influence on cAMP-formation, with a transient increase (5 min) before a sustained inhibition (60 min); the inhibitory effect was mimicked by the diacylglycerol 1-oleoyl-2-acetyl-glycerol. Exogenous arachidonic acid had only a small and transient inhibitory effect on cAMP-formation. We conclude, that EGF inhibits cAMP-formation by a raise of intracellular Ca++, as well as by the direct activation of proteinkinase C, indicating, that a phosphorylated product could be a mediator for the inhibition of adenylate cyclase.
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PMID:Inhibition of cAMP formation by EGF in thyroid follicles is mediated by intracellular Ca++. 303 76

We related the effects of c-myc expression on the ability of growth inhibitors to block the cells in the G0/G1 phase of the cell cycle. In two different B-cell lines, there was an association between the accumulation of cells in the middle to late G1 phase of the cell cycle and a rapid transient downregulation of c-myc mRNA levels. The phorbol ester TPA and the adenylate cyclase activator forskolin reduced the c-myc RNA, levels and after 3 days of treatment a proportion of the cells accumulated in G1. In contrast, neither interferon-gamma, tumor necrosis factor-alpha nor the monoclonal antibody 33-1 against DQ major histocompatibility antigens changed the cell-cycle distribution or regulated the c-myc RNA levels. Yet, all five growth inhibitors reduced the proliferation to approximately the same extent. The growth reduction was not accompanied by definite differentiation, as judged by the absence of the B-cell differentiation marker B1 (CD20).
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PMID:Downregulation of c-myc RNA is not a prerequisite for reduced cell proliferation, but is associated with G1 arrest in B-lymphoid cell lines. 311 97

The regulation of insulin secretion from RINm5F cells exposed to high voltage discharge has been investigated. Electron microscopy revealed that the overall structure of the cells was preserved after permeabilization. In this preparation insulin release was stimulated by Ca2+ (EC50 = 2.4 microM). The stable GTP analogue GTP gamma S enhanced secretion both at intermediate (nano- to micromolar) and vanishingly low (less than 10 pM) Ca2+ concentrations. At optimal Ca2+ (10 microM) the effect of GTP gamma S was greatly reduced. We investigated whether the secretory response to GTP analogues was mediated by any of three enzyme systems regulated by GTP-binding proteins, i.e. generation of cyclic AMP by adenylate cyclase, of diacylglycerol by phospholipase C and of arachidonic acid by phospholipase A2. The involvement of these messenger systems could be excluded as (i) cyclic AMP only had minor, Ca2+ dependent effects, (ii) phospholipase C was not activated in the absence of Ca2+ and insulin secretion due to the phorbol ester TPA displayed a different Ca2+ dependency, (iii) arachidonic acid did not elicit Ca2+ independent insulin secretion. These results, taken together with the finding that insulin secretion due to Ca2+ or TPA is attenuated by the inhibitory guanine nucleotide GDP beta S, suggest the existence of a regulatory site in exocytosis which is sensitive to guanine nucleotides.
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PMID:Regulation of exocytosis in electrically permeabilized insulin-secreting cells. Evidence for Ca2+ dependent and independent secretion. 331 34

The rat thyroid cell line (FRTL5) is dependent on thyrotropic hormone (TSH) for its growth. c-fos and c-myc oncogenes expression was measured in these cells after addition of their specific growth factor TSH and after treatment with either forskolin, an activator of adenylate cyclase or with a tumor promoter, TPA. Transient expression of oncogenes coding for nuclear products and a slight increase in ras-h oncogene expression were observed in normal rat thyroid cells after all treatments. In contrast, in v-ras-transformed rat thyroid cells, which express very high levels of p21, treatment with either TSH, forskolin or TPA does not induce c-fos gene expression, while c-myc expression was constitutive. Normal unstimulated cells show no c-myc expression.
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PMID:Forskolin and a tumor promoter are able to induce c-fos and c-myc expression in normal, but not in a v-ras-transformed rat thyroid cell line. 332 19

The effects of 12-O-tetradecanoylphorbol-13-acetate (TPA, an activator of C-kinase), the cation ionophore A23187, forskolin (an activator of adenylate cyclase) and thyrotropin-releasing hormone (TRH) on prolactin release from anterior pituitary cells in primary culture were investigated and compared to the effects of these same agents on prolactin release from GH4C1 cells. In both GH4C1 cells and primary pituitary cultures, 100 nM TRH increased prolactin release 3- to 5-fold within 4 min after the stimulation started. This peak response was followed by a fall to a sustained increased rate of release approximately 1.5-fold above the basal rate. The decline after the early peak was slower in primary cultures than in GH4C1 cells. Addition of 20 microM A23187 to primary cultures caused a rapid 2- to 4-fold increase in release that fell to basal values within 12 min after the stimulation started. In GH4C1 cells, A23187 caused a rise in prolactin release of less than 2-fold that was sustained longer than the rise seen in primary cultures. Perifusion of either type of cells with 50 nM TPA caused a rapid 2- to 2.5-fold increase in release that also was sustained for 30 min or more in both types of cells. Perifusion with combined TPA and A23187 caused a 3- to 5-fold increase in rate of release from each cell type that declined rapidly to a 2-fold sustained release in primary cultures, and that declined more slowly in GH4C1 cells. Forskolin, 1 microM, had only a small effect by itself, but potentiated the effect of TPA or combined TPA and A23187 in both types of cells.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Comparison of patterns of prolactin release in GH4C1 cells and primary pituitary cultures. 393 15

Topical application of prostaglandin E1 or E2 onto the mouse skin results in a 2- to 3-fold increase of the cyclic AMP level in epidermis within 5 min. (15S)-15-methyl-PGE1 is more active in this respect, whereas PGD2 and PGF2 alpha are ineffective. The level of cyclic GMP is not altered by E- or F-prostaglandins. A single PGE2 application desensitizes the cyclic AMP response of mouse epidermis to further treatments in a dose dependent and agonist-specific manner. Delayed and longlasting refractoriness of PGE2-induced cyclic AMP accumulation is also caused by hyperplasiogenic skin irritants such as the phorbol ester tumor promoter TPA or the nonpromoting agents RPA and A23187. The non-irritant skin mitogen 4-O-methyl-TPA does not evoke desensitization. TPA-induced PGE2 refractoriness cannot be prevented by inhibitors of protein synthesis, anti-inflammatory steroids, indomethacin or phentolamine. The development of tachyphylaxis does not seem to be related to endogenous formation of PGE or cyclic AMP. A 2-fold increase of epidermal cyclic AMP observed within 1-2 h of TPA application can be inhibited by indomethacin treatment and correlates with delayed accumulation of PGE2 in TPA-treated epidermis, whilst immediate PGE accumulation (5-10 min after TPA application) which has been shown to be critical for development of TPA-induced epidermal hyperplasia is not accompanied by any change of the intraepidermal cyclic AMP level. It is concluded that mouse epidermis contains two types of PGE-regulated effector systems, one of which is coupled to adenylate cyclase, one of which is not. Only the latter system is involved in the induction of hyperplasia. At least as far as the mitogenic effect is concerned, cyclic AMP does not seem to be involved in TPA action.
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PMID:Prostaglandins, cyclic nucleotides and the effect of phorbol ester tumor promoters on mouse skin in vivo. 631 56

The ability of glucagon (10 nM) to increase hepatocyte intracellular cyclic AMP concentrations was reduced markedly by the tumour-promoting phorbol ester TPA (12-O-tetradecanoyl phorbol-13-acetate). The half-maximal inhibitory effect occurred at 0.14 ng/ml TPA. This action occurred in the presence of the cyclic AMP phosphodiesterase inhibitor isobutylmethylxanthine (1 mM) indicating that TPA inhibited glucagon-stimulated adenylate cyclase activity. TPA did not affect either the binding of glucagon to its receptor or ATP concentrations within the cell. TPA did inhibit the increase in intracellular cyclic AMP initiated by the action of cholera toxin (1 microgram/ml) under conditions where phosphodiesterase activity was blocked. TPA did not inhibit glucagon-stimulated adenylate cyclase activity in a broken plasma membrane preparation unless Ca2+, phosphatidylserine and ATP were also present. It is suggested that TPA exerts its inhibitory effect on adenylate cyclase through the action of protein kinase C. This action is presumed to be exerted at the point of regulation of adenylate cyclase by guanine nucleotides.
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PMID:The phorbol ester, TPA inhibits glucagon-stimulated adenylate cyclase activity. 632 75

Myosin light chain phosphorylation may not regulate the sustained phase of vascular smooth muscle contraction. Another, unidentified, calcium-dependent pathway may be involved in this process. TPA, an activator of C-kinase, at concentrations of 10 to 333 nM induces a calcium-dependent contraction of vascular smooth muscle which develops slowly but progressively to reach values of 50-300 mm Hg. Arteries exposed to the ionophore A23187, in a calcium-free medium, display a uniform series of contractile responses when exposed to 1.5 mM Ca2+ for 2 min once every 10 min. Exposure to 100 nM TPA as well as ionophore leads to a progressive enhancement of these calcium-induced, contractile responses. Arteries stimulated by brief (10 sec), repetitive (every 3 min) electrical pulses, respond with a series of comparable phase 1 responses. Prior exposure of vessels to 10 nM TPA, causes a progressive increase in the magnitude of these responses to repetitive electrical stimulation. Addition of 25 microM forskolin, an activator of adenylate cyclase, to TPA-treated, partially-contracted muscle leads to the immediate inhibition of the TPA-induced contraction. These data suggest that the activation of C-kinase plays a significant role in regulating vascular smooth muscle contraction.
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PMID:TPA-induced contraction of isolated rabbit vascular smooth muscle. 643 75

Phorbol 12-myristate 13-acetate (TPA) augmented the effects of forskolin, and inhibited the effects of isoproterenol on cAMP accumulation in mouse parotid acini. Treatment of intact cells with the phosphodiesterase inhibitor, 3-isobutyl-1-methylxanthine (MIX), blocked TPA inhibition of isoproterenol but not forskolin-stimulated cAMP accumulation. TPA also caused the translocation of protein kinase C (PKC) from cytosol to membrane. Pre-treatment of parotid acini with TPA for 30 min enhanced the forskolin and isoproterenol-stimulated adenylate cyclase activity in isolated parotid membranes. Addition of purified PKC (pPKC) to parotid membranes mimicked the effects of TPA in increasing cAMP synthesis; the effects were blocked in the absence of calcium and phospholipid, and in the presence of the synthetic peptide (PKC 19-36). Purified PKC also mimicked the effects of TPA in augmenting forskolin and isoproterenol-stimulated adenylate cyclase activities in the cell-free system. Data suggest that the differential regulation of forskolin and isoproterenol-stimulated cAMP accumulation by TPA results from modification of enzymes that synthesize and degrade cAMP.
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PMID:Phorbol ester has different effects on forskolin and beta-adrenergic-stimulated cAMP accumulation in mouse parotid acini. 750 31


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