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 participation of second messenger pathways in 1,25(OH)2D3-induced stimulation of protein synthesis in chick embryo myoblasts undergoing proliferation was studied. Double-labelling experiments with 14C- and 3H-leucine showed the induction by the hormone of proteins with apparent molecular masses (treatment interval) of 60 kDa (1 to 2 h). 70 kDa (2 to 4 h), 80 kDa (4 h) and a 19 kDa protein (6 to 12 h) previously identified as calmodulin. The PKC activator TPA and the Ca2+ ionophore X-537 A did not mimic the effects of the sterol on protein synthesis whereas similar double-labelling patterns were obtained with forskolin, an adenylate cyclase activator. Dot-blot and Northern hybridization analysis revealed increased calmodulin mRNA levels in response to both the hormone and forskolin. These results involve the cAMP messenger system in 1,25(OH)2D3 stimulation of calmodulin synthesis and may be relevant to understand hormone regulation of muscle cell proliferation.
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PMID:Involvement of the 3',5'-cyclic AMP pathway in the induction of calmodulin synthesis in myoblasts by 1,25(OH)2-vitamin D3. 838 93

We show that the cyclin D1 gene is regulated by a variety of growth factors in human diploid fibroblasts (WI-38). Expression of cyclin D1 mRNA is low in quiescent WI-38 cells and reaches a maximum around 10 hours after serum stimulation, i.e. approximately 8 hours prior to the onset of DNA synthesis. A cyclin D1-specific antiserum raised against a bacterially expressed fusion protein detected a 39 kDa polypeptide in WI-38 cells. In agreement with the RNA expression data, cyclin D1 protein synthesis is also serum-inducible, reaching a maximum around 9 hours post-stimulation. The results obtained by pulse-chase experiments, cell fractionation and immunostaining techniques strongly suggest that cyclin D1 is a labile protein (t1/2 approximately 38 min), which is located in the nucleus. Cyclin D1 is directly induced by growth factors, i.e. in the presence of cycloheximide, and its expression does not significantly fluctuate during the cell cycle in synchronized cells. Cyclin D1 therefore fundamentally differs from "classical" cyclins, such as the mitotic cyclin B, whose expression is clearly cell cycle-dependent. Cyclin D1 may rather establish a direct link between growth control mechanisms and the cell cycle. Interestingly, cyclin D1 expression is stimulated by the protein kinase C activator TPA, but suppressed by dibutyryl-cAMP and the adenylate cyclase inducer forskolin, pointing to multiple regulatory pathways controlling cyclin D1 expression.
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PMID:Human cyclin D1 encodes a labile nuclear protein whose synthesis is directly induced by growth factors and suppressed by cyclic AMP. 838 78

Prostaglandin (PG) has been reported to be one of the important protective factors in the gastric mucosa. However the mechanism of the regulation of endogenous PG production has not been well studied. We investigated the possible roles of Ca2+, cAMP, and protein kinase C (PKC) in the regulation of PGE2 release from cultured rabbit gastric mucosal cells. PGE2 was measured by radioimmunoassay. A23187 (Ca2+ ionophore) at 2 x 10(-6) M significantly increased PGE2 release. Deprivation of Ca2+ from the medium blocked the A23187-induced increase of PGE2. TMB-8 (a putative inhibitor of Ca2+ release from intracellular stores) did not have any significant effects on the increase of PGE2-induced by A23187. Thus, A23187 increased PGE2 through the influx of extracellular Ca2+. W7 or compound 48/80 (calmodulin inhibitors) did not alter the response of PGE2 caused by A23187. Exogenous administration of cAMP, forskolin (an activator of adenylate cyclase), or 2-chloroadenosine (a possible activator of adenylate cyclase through adenosine A2 receptor) had neither significant effects on PGE2 release nor an effect on A23187-induced increase of PGE2 release. 12-O-tetradecanoylphorbol 13-acetate (TPA, an activator of PKC) significantly stimulated PGE2 release in a dose-dependent fashion, whereas another phorbol ester with no biological activity did not. A23187 at 0.8 x 10(-6) M, but not cAMP, potentiated the TPA-induced increase of PGE2. Mepacrine (a phospholipase A2 inhibitor) reduced the A23187- and TPA-induced increase of PGE2. These results suggest that Ca2+ and protein kinase C may play important roles in the regulation of PGE2 release by cultured rabbit gastric cells.
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PMID:Roles of Ca2+ and protein kinase C in regulation of prostaglandin E2 release by cultured rabbit gastric epithelial cells. 839 56

The HGT-1 gastric cancer cell line was used to determine the actions of protein kinase C on the stimulation of adenylate cyclase by the human histamine H2 receptor, and the receptors for gastric inhibitory polypeptide and truncated glucagon like peptide 1 (TGLP-1). Suspensions of HGT-1 cells were preincubated with the activator of protein kinase C, 12-O-tetradecanoylphorbol 13-acetate (TPA, 100 nmol/l), for 10 minutes. The subsequent cyclic adenosine monophosphate (AMP) response to 0.5 mmol/l histamine or 100 nmol/l TGLP-1 was reduced by comparison with control cells preincubated in the absence of TPA. The cyclic AMP response to 100 nmol/l gastric inhibitory polypeptide was enhanced by preincubation with TPA, while the responses to cholera toxin and forskolin were unaffected. Preincubation with pertussis toxin prevented the enhancement of the gastric inhibitory polypeptide response by TPA, suggesting an involvement of an inhibitory guanine nucleotide regulatory subunit of the Gi class, but did not change the inhibition of histamine stimulation. In conclusion, activation of protein kinase C produces a specific inhibition of the effects of histamine and TGLP-1 on adenylate cyclase activity in a human gastric cancer cell line by acting at a site close to their receptors.
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PMID:Protein kinase C inhibits cyclic adenosine monophosphate generation by histamine and truncated glucagon like peptide 1 in the human gastric cancer cell line HGT-1. 839 30

ATP stimulates phosphatidylcholine secretion in type II cells, an effect that is mediated by both adenosine A2 receptors coupled to adenylate cyclase and P2 receptors coupled to phosphoinositide-specific phospholipase C. Activation of these effector enzymes leads to formation of cAMP, diacylglycerols and inositol trisphosphate (IP3). cAMP in turn activates cAMP-dependent protein kinase, diacylglycerols activate protein kinase C and IP3 promotes Ca2+ mobilization. To further investigate the signal-transduction mechanisms mediating the ATP effect, we examined its action in combination with that of other surfactant secretagogues: 5'(N-ethylcarboxyamido)adenosine (NECA), a A2 agonist that activates adenylate cyclase; TPA (12-O-tetradecanoylphorbol-13-acetate), a direct activator of protein kinase C; and ionomycin, an ionophore that increases intracellular Ca2+. The effects of NECA, TPA and ionomycin were additive and thus consistent with independent signaling mechanisms. However, the effects of all combinations of three or four secretagogues that contained ATP were 10-20% less than additive. This suggested that ATP and other secretagogues act via common mechanisms. Calmodulin antagonists decreased the effects of ionomycin and ATP by approx. 60% and 30%, respectively, but did not decrease the effects of NECA, terbutaline or TPA. Complete inhibition of the effect of ATP was achieved with a combination of a calmodulin antagonist, an A2 antagonist and a protein kinase C inhibitor. These and previous data suggest that the stimulatory effect of ATP on phosphatidylcholine secretion in type II cells is mediated by three signal-transduction mechanisms: activation of cAMP-dependent protein kinase; activation of protein kinase C; and a calmodulin-dependent mechanism.
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PMID:Signal-transduction mechanisms of ATP-stimulated phosphatidylcholine secretion in rat type II pneumocytes: interactions between ATP and other surfactant secretagogues. 846 37

The expression of vascular endothelial growth factor (VEGF) in cultured bovine granulosa cells has been studied. As shown by northern blot analysis, granulosa cells express the VEGF gene. Analysis of the VEGF transcripts by the polymerase chain reaction technique shows that granulosa cells express predominantly the smallest VEGF coding forms (VEGF121 and VEGF164). Since in the promoter region of the VEGF gene there are four potential AP-1 sites and two potential AP-2 sites we have studied if TPA and forskolin could regulate VEGF gene expression. TPA induces VEGF transcription in a time- and dose-dependent fashion. Maximal VEGF mRNA levels are detected 6 h after TPA treatment. Induction apparently requires de novo protein synthesis since it does not occur when translation is inhibited by cycloheximide. Forskolin, a naturally occurring diterpene that activates adenylylcyclase, also increases VEGF mRNA content in a time-dependent manner. Induction does not require de novo protein synthesis and, in contrast to TPA, induction is strongly potentiated by cycloheximide. Luteotrophic hormone, a known activator of adenylylcyclase, also induces VEGF transcription. These results imply that granulosa cells may be a source of VEGF which could play a role in the angiogenic process associated with ovulation and corpus luteum formation.
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PMID:Transcriptional regulation of vascular endothelial growth factor gene expression in ovarian bovine granulosa cells. 846 53

As major signal transduction cascades, the protein kinase-A and -C (PKA and PKC) pathways have been implicated in the regulation of GnRH synthesis and secretion in the hypothalamus. We have investigated the roles of these pathways in the regulation of GnRH transcription, mRNA levels, propeptide processing, and secretion in GT1-7 cells, a mouse hypothalamic GnRH neuronal cell line. Forskolin, which activates adenylate cyclase to raise cAMP levels, had no effect on GnRH mRNA levels at 10 microM, but induced c-fos mRNA at 30 min. An activator of PKC, 12-O-tetradecanoylphorbol-13-acetate (TPA; 100 nM), also induced c-fos at 30 min, but produced a progressive decline in GnRH mRNA, resulting in a 70% decrease by 16 h. Coadministration of 10 nM TPA and 20 microM of a PKC inhibitor, NPC 15437 [2,6-diamino-N-([1-(1-oxotridecyl)2-piperidinyl]methyl)hexanami de], prevented c-fos induction, but did not antagonize GnRH repression. Instead, the inhibitor itself reduced GnRH mRNA levels by 56% at 16 h (with no effect on c-fos mRNA). Thus, since extended exposure to TPA can down-regulate PKC, suppression of GnRH mRNA by TPA may be due to decreased PKC activity, indicating a role for PKC in the maintenance of the GnRH gene expression (a role that is unlikely to involve c-fos). In transient transfections, the transcriptional activity from 3 kilobases of GnRH 5'-flanking sequence was repressed 2-fold by either 100 nM TPA or 20 microM NPC 15437 at 24 h, demonstrating that suppression of GnRH mRNA is at least, in part, at the level of transcription. In contrast, both TPA (100 nM) and forskolin (10 microM) stimulated secretion. Enhancement of GnRH secretion by TPA was robust and rapid (2.5 min), while the response to forskolin was relatively delayed (2 h). Over a 24-h period, unstimulated cells released primarily unprocessed prohormone, whereas forskolin and TPA stimulated the secretion of processed products. These data indicate that PKC and PKA may influence propeptide processing and/or the route of GnRH secretion. These data demonstrate that the PKA and PKC pathways regulate GnRH at the multiple levels of transcription, pro-GnRH processing, and GnRH secretion.
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PMID:Regulation of gonadotropin-releasing hormone by protein kinase-A and -C in immortalized hypothalamic neurons. 850 41

The effect of pituitary adenylate cyclase-activating polypeptide1-38 (PACAP1-38) on the synthesis of dopamine in cultured bovine adrenal chromaffin cells was examined. PACAP1-38 stimulated [14C]dopamine synthesis from [14C]tyrosine, in a concentration-dependent manner, causing maximal stimulation at 10(-7)M. This stimulatory action of PACAP1-38 was not significantly inhibited by staurosporine (an inhibitor of protein kinase C) or in the cells in which protein kinase C was down-regulated by prolonged exposure to TPA (an activator of protein kinase C), whereas it was partially attenuated in Ca(2+)-free medium. PACAP1-38 increased the formation of [3H] inositol phosphates, [Ca2+]i, 45Ca2+ uptake and cAMP level. The peptide also stimulated the phosphorylation of tyrosine hydroxylase, the enzyme catalyzing the rate-limiting step in dopamine synthesis. Dopamine synthesis and tyrosine hydroxylase phosphorylation stimulated by the maximal effective concentration of dibutyryl cAMP or high K+, which activates Ca2+ uptake, were further enhanced by PACAP1-38. These results indicated that PACAP1-38 may stimulate the activities of cAMP- and calcium-dependent protein kinases in cultured bovine adrenal chromaffin cells, resulting in increase in the synthesis of dopamine probably by stimulation of phosphorylation of tyrosine hydroxylase.
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PMID:Pituitary adenylate cyclase-activating polypeptide stimulates the synthesis of dopamine in cultured bovine adrenal chromaffin cells. 852 52

In order to determine whether tachykinins alter the function of chief cells and to characterize the receptors mediating the effect, we investigated the abilities of various substance P (SP)-related peptides to inhibit the binding of 125I-Bolton-Hunter labeled substance P (125I-BH-SP) and their abilities to alter cell function in dispersed chief cells from guinea pig stomach. Binding of 125I-BH-SP was saturable, reversible, time- and temperature-dependent and was inhibited by several SP-related peptides with relative potencies of SP = physalaemin (IC50:0.19 nM) > SP methyl ester (SP-ME) (IC50:3.3 nM) > eledoisin (IC50:6.1 nM) > neurokinin A (NKA) (IC50: 65 nM) > neurokinin B (NKB) (IC50:80 nM). Analyses of these binding data demonstrated that chief cells possess a high and low affinity class of binding sites. Neither 125I-NKA nor [phenylalanyl-3,4,5-3H]senktide demonstrated saturable binding to chief cells. Acid stripping experiments demonstrated rapid ligand internalization with 55% of the bound radioligand internalized by 10 min. Phospholipase C activating agents (carbachol, CCK-8), adenylate cyclase activating agents (secretin, VIP), TPA and the calcium ionophore, A23187, all inhibited the binding of 125I-BH-SP and it was due to inhibition of ligand internalization with no change in surface bound parameters. SP (0.1 microM) stimulated pepsinogen secretion but was 4-times less efficacious than CCK-8 (10 nM) or carbachol (1 mM). 10 nM SP stimulated a rapid increase in cytoplasmic free calcium concentration ([Ca2+]i) followed by a sustained elevation lasting 2 min. Single cell spectroscopy demonstrated SP (10 pM to 1 microM) did not cause calcium oscillations. The NK1 receptor antagonist, CP96,345 specifically inhibited the SP-stimulated changes in [Ca2+]i and pepsinogen secretion. The relative potencies of SP-related peptides to stimulate pepsinogen secretion and [Ca2+]i demonstrated a close agreement with their abilities to inhibit the binding of 125I-BH-SP, and comparison of the dose-response curves suggests occupation of the low affinity sites mediate changes in biologic activity. In conclusion, the present study demonstrates that chief cells possess a NK1 subtype of tachykinin receptor, occupation of the low affinity sites of this receptor cause calcium mobilization and pepsinogen secretion, and that binding to this receptor is regulated by agents that activate phospholipase C, adenylate cyclase, protein kinase C and calcium mobilization.
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PMID:Gastric chief cells possess NK1 receptors which mediate pepsinogen secretion and are regulated by agents that increase cAMP and phospholipase C. 867 32

Prolonged stimulation of gonadotropin receptors in granulosa cells leads to desensitization of the cellular response to gonadotropic hormones which is evident by decrease in cAMP formation. In order to explore the mechanism of desensitization and to examine whether protein phosphorylation may play a role in this phenomenon, we have studied the effect of various stimulators and inhibitors of protein phosphorylation on FSH-induced cAMP formation in the FSH-responsive cell line, GFSHR-17, recently established in our laboratory. Both ovine and human FSH activated the hormone sensitive adenylate cyclase in a dose-dependent manner with an ED50 of 0.5 nM. This stimulation was followed by a sharp decrease in cAMP formation after 30 min incubation of the cell with the hormone. When cells were preincubated for 60 min with staurosporine, cAMP accumulation during 20 min of FSH stimulation was elevated about 500%, compared to cells stimulated by FSH alone. Staurosporine alone showed a negligible effect on cAMP accumulation in these cells. In cells stimulated with forskolin, a non-specific activator of adenylate cyclase, or with cholera toxin (CT), an inhibitor of GTPase activity associated with Gs of adenylate cyclase, preincubation with staurosporine increased cAMP formation in these cells by only 50-70 or 80-120%, respectively. Preincubation of cells with the protein kinase C (PKC) inhibitors chelerythrine and GF109203X increased FSH-stimulated accumulation of cAMP by 50 and 30%, respectively. These drugs exhibit a similar effect on forskolin-stimulated cells. Preincubation of cells for 60 min with a PKC stimulator, TPA, suppressed FSH-mediated cAMP response in these cells by 40%. Tyrosine kinase inhibitors such as AG18, AG33 and genistein exhibit a modest inhibitory effect of up to 20% on FSH-stimulated cAMP accumulation. All the above results were obtained both in the presence and absence of IBMX, a potent inhibitor of the cellular phosphodiesterases. Upon prolonged incubation with FSH (3 h) cells pretreated with staurosporine exhibited a much slower rate of decline in intracellular cAMP levels. Moreover, in desensitized cells, following 1 or 2 h of continuous stimulation with FSH, staurosporine could markedly enhance cAMP formation in the presence of FSH. Our data suggest that staurosporine-sensitive phosphorylation of serine or threonine in the FSH receptor-cyclase system may be responsible for desensitization of the FSH coupled activation of cAMP formation, while reactivation of the system can be achieved by protein dephosphorylation at these specific sites. Because specific inhibition of PKC could not mimic the staurosporine effect on FSH-stimulated cAMP formation, nor could activation of kinase C antagonize it, it is suggested that a specific staurosporine-sensitive receptor kinase may be responsible for modulation of the coupling between the gonadotropin receptor and the adenylate cyclase system.
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PMID:Activation of FSH-responsive adenylate cyclase by staurosporine: role for protein phosphorylation in gonadotropin receptor desensitization. 882 63


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