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)

Brain natriuretic peptide (BNP) produced by cardiac myocytes has antifibrotic and antigrowth properties and is a marker of cardiac hypertrophy. We previously showed that prostaglandin E2 (PGE2) is the main prostaglandin produced in myocytes treated with proinflammatory stimuli and stimulates protein synthesis by binding to its EP4 receptor. We hypothesized that PGE2, acting through EP4, also regulates BNP gene expression. We transfected neonatal ventricular myocytes with a plasmid encoding the human BNP (hBNP) promoter driving expression of a luciferase reporter gene. PGE2 increased hBNP promoter activity 3.5-fold. An EP4 antagonist reduced the stimulatory effect of PGE2 but not an EP1 antagonist. Because EP4 signaling can involve adenylate cyclase, cAMP, and protein kinase A (PKA), we tested the effect of H-89, a PKA inhibitor, on PGE2 stimulation of the hBNP promoter. H-89 at 5 muM decreased PGE2 stimulation of BNP promoter activity by 100%. Because p42/44 MAPK mediates the effect of PGE2 on protein synthesis, we also examined the role of MAPKs in the regulation of BNP promoter activity. PGE2 stimulation of the hBNP promoter was inhibited by a MEK1/2 inhibitor and a dominant-negative mutant of Raf, indicating that p42/44 MAPK was involved. In contrast, neither a p38 MAPK inhibitor nor a JNK inhibitor reduced the stimulatory effect of PGE2. Involvement of small GTPases was also studied. Dominant-negative Rap inhibited PGE2 stimulation of the hBNP promoter, but dominant-negative Ras did not. We concluded that PGE2 stimulates the BNP promoter mainly via EP4, PKA, Rap, and p42/44 MAPK.
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PMID:PGE2 stimulates human brain natriuretic peptide expression via EP4 and p42/44 MAPK. 1642 39

Gastroduodenal HCO3- secretion is a key process that aids in preventing acid-peptic injury. Endogenous prostaglandins (PGs) play a particularly important role in the local control of this secretion. The secretion of HCO3- in both the stomach and duodenum was increased in response to PGE2 as well as mucosal acidification, the latter occurring with concomitant enhancement of mucosal PG generation. These HCO3- responses in the duodenum were markedly reduced by prior administration of the EP4 antagonist in rats, and profoundly decreased in the animals lacking EP3 receptors but not EP1 receptors. In contrast, gastric HCO3- responses induced by PGE2 and mucosal acidification were prevented by the EP1 antagonist and disappeared in EP1, but not EP3-knockout mice. Consistent with these findings, duodenal HCO3- secretion was stimulated by both EP3 and EP4 agonists but not EP1 or EP2 agonists, while gastric HCO3- secretion was increased by the EP1 agonist but not EP2, EP3 or EP4 agonists. In addition, the HCO3- stimulatory action of sulprostone (EP1/EP3 agonist) in the stomach was inhibited by the Ca2+ antagonist verapamil but not affected by IBMX, the inhibitor of phosphodiesterase, while that in the duodenum was inhibited by verapamil and enhanced by IBMX. Forskolin, the stimulator of adenylate cyclase, increased HCO3- secretion in the duodenum but not the stomach. Thus, the HCO3- stimulatory action of PGE2 in the duodenum is mediated by both EP3 and EP4 receptors being coupled intracellularly with both Ca2+ and cAMP, while that in the stomach is mediated by EP1 receptors, coupled with Ca2+.
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PMID:Role of prostaglandin E receptor subtypes in gastroduodenal HCO3- secretion. 1678 96

Prostaglandin E2 (PGE2) is a lipid mediator that displays important immunomodulatory properties, such as polarization of cytokine production by T cells. Recent investigations have revealed that the effect of PGE2 on cytokine production is greatly influenced by external stimuli; however, it is unclear whether PGE2 plays a significant role in major histocompatibility complex-mediated antigen-specific T-cell responses via binding to one of four subtypes of E prostanoid (EP) receptor alone or in combination. In the present study, we sought to determine the effect of PGE2 on antigen-specific CD4+ T-cell responses in humans, especially in terms of receptor specificity. We used purified protein derivative (PPD) and Cry j 1 as T helper type 1 (Th1) and Th2-inducing antigens, respectively. We generated several different Cry j 1- and PPD-specific T-cell lines (TCLs). PGE2 significantly and dose-dependently inhibited the proliferation and subsequent production of interleukin-4 by Cry j 1-specific TCLs and of interferon-gamma by PPD-specific TCLs upon antigen stimulation. Administration of EP2 receptor agonist and EP4 receptor agonist suppressed these responses in an adenylate cyclase-dependent manner, while EP1 and EP3 receptor agonists did not. Messenger RNA for EP2, EP3 and EP4, but not EP1, receptors were detected in Cry j 1- and PPD-specific TCLs, and no differences in EP receptor expression were observed between them. Furthermore, PGE2 and EP2 receptor agonist significantly inhibited interleukin-5 and interferon-gamma production by peripheral blood mononuclear cells in response to Cry j 1 and PPD stimulation, respectively. These results suggest that PGE2 suppresses both Th1- and Th2-polarized antigen-specific human T-cell responses via a cAMP-dependent EP2/EP4-mediated pathway.
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PMID:E prostanoid 2 (EP2)/EP4-mediated suppression of antigen-specific human T-cell responses by prostaglandin E2. 1682 95

Dysregulation of enzymes involved in prostaglandin biosynthesis plays a critical role in influencing the biological behavior and clinical outcome of several tumors. In human gliomas, overexpression of cyclooxygenase-2 has been linked to increased aggressiveness and poor prognosis. In contrast, the role of prostaglandin E synthase in influencing the biological behavior of human gliomas has not been established. We report that constitutive expression of the microsomal prostaglandin E synthase-1 (mPGES-1) is associated with increased prostaglandin E(2) (PGE(2)) production and stimulation of growth in the human astroglioma cell line U87-MG compared with human primary astrocytes. Consistently, pharmacologic and genetic inhibition of mPGES-1 activity and expression blocked the release of PGE(2) from U87-MG cells and decreased their proliferation. Conversely, exogenous PGE(2) partially overcame the antiproliferative effects of mPGES-1 inhibition and stimulated U87-MG cell proliferation in the absence of mPGES-1 inhibitors. The EP2/EP4 subtype PGE(2) receptors, which are linked to stimulation of adenylate cyclase, were expressed in U87-MG cells to a greater extent than in human astrocytes. PGE(2) increased cyclic AMP levels and stimulated protein kinase A (PKA) activity in U87-MG cells. Treatment with a selective type II PKA inhibitor decreased PGE(2)-induced U87-MG cell proliferation, whereas a selective type I PKA inhibitor had no effect. Taken together, these results are consistent with the hypothesis that mPGES-1 plays a critical role in promoting astroglioma cell growth via PGE(2)-dependent activation of type II PKA.
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PMID:Microsomal prostaglandin E synthase-1 regulates human glioma cell growth via prostaglandin E(2)-dependent activation of type II protein kinase A. 1689 68

Prostaglandin E2 (PGE2) has been shown to induce expression of vascular endothelial growth factor (VEGF) and other signaling molecules in several cancers. PGE2 elicits its functions though four G-protein coupled membrane receptors (EP1-4). In this study, we investigated the role of EP receptors in PGE2-induced molecular events in prostate cancer cells. qRT-PCR analysis revealed that PC-3 cells express a substantially higher level of EP2 and moderately higher EP4 than DU145 and LNCaP cells. LNCaP cells had virtually no detectable EP2 mRNA. EP1 and EP3 mRNAs were not detected in these cells. Treatment of prostate cancer cells with PGE2 (1 nM-10 microM) increased both VEGF secretion and cyclic adenosine monophosphate (cAMP) production. Levels of induction in PC-3 cells were greater than in DU145 and LNCaP cells. The selective EP2 agonist CAY10399 also significantly increased VEGF secretion and cAMP production in PC-3 cells, but not in DU145 and LNCaP cells. Moreover, PGE2 and CAY10399 increased mitogen activated protein kinase/extracellular signal regulated kinase (MAPK/Erk) and Akt phosphorylation in PC-3 and DU145 cells, but not in LNCaP cells. However, neither the MAPK/Erk inhibitor U0126 nor the PI3K/Akt inhibitor LY294002 abolished PGE2-induced VEGF secretion in PC-3 cells. We further demonstrated that the adenylate cyclase activator forskolin and the cAMP anologue 8-bromo-cAMP mimicked the effects of PGE2 on VEGF secretion in PC-3 cells. Meanwhile, the adenylate cyclase inhibitor 2'5'-dideoxyadenosine, at concentrations that inhibited PGE2-induced cAMP, significantly blocked PGE2-induced VEGF secretion in PC-3 cells. We conclude that PGE2-induced VEGF secretion in prostate cancer cells is mediated through EP2-, and possibly EP4-, dependent cAMP signaling pathways.
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PMID:Prostaglandin E2 induces vascular endothelial growth factor secretion in prostate cancer cells through EP2 receptor-mediated cAMP pathway. 1742 62

Treatment with 100 microM adenosine triphosphate (ATP) for 120 min augmented migration of cultured rat microglia by about 4-fold. This augmentation was effectively reduced by 0.1-10 microM prostaglandin E(2) (PGE(2)). PGE(2)-mediated reduction was reversed by the EP2 antagonist AH6809 at 10 microM. The EP2 agonist butaprost also reduced ATP-induced migration at 10 microM, whereas the EP1 agonist 17-phenyl trinor PGE(2), the EP3 agonist sulprostone, and the EP4 agonist PGE(1) alcohol all had no effect at 10 microM. In addition, ATP-induced migration was reduced by the adenylate cyclase activator forskolin at 100 microM, whereas the adenylate cyclase inhibitor SQ22536 reversed the effect of PGE(2) on ATP-induced migration at 100 microM. Over the same experimental duration, PGE(2), butaprost, and forskolin had little effect on cell viability. These findings indicate that ATP-induced microglial migration is reduced by PGE(2) through EP2 and adenylate cyclase.
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PMID:Prostaglandin E2 reduces extracellular ATP-induced migration in cultured rat microglia. 1856 97

We investigated possible involvement of prostaglandin (PG) E2 in regulation of AMP-activated protein kinase (AMPK). When osteoblastic MG63 cells were cultured in serum-deprived media, Thr-172 phosphorylation of AMPK alpha-subunit was markedly increased. Treatment of the cells with PGE2 significantly reduced the phosphorylation. Ser-79 phosphorylation of acetyl-CoA carboxylase, a direct target for AMPK, was also reduced by PGE2. On the other hand, PGE2 reciprocally increased Ser-485 phosphorylation of the alpha-subunit that could be associated with inhibition of AMPK activity. These effects of PGE2 were mimicked by PGE2 receptor EP2 and EP4 agonists and forskolin, but not by EP1 and EP3 agonists, and the effects were suppressed by an adenylate cyclase inhibitor SQ22536 and a protein kinase A inhibitor H89. Additionally, the PGE2 effects were duplicated in primary calvarial osteoblasts. Together, the present study demonstrates that PGE2 negatively regulates AMPK activity via activation of protein kinase A signaling pathway.
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PMID:Prostaglandin E2 negatively regulates AMP-activated protein kinase via protein kinase A signaling pathway. 1883 41

Of the four prostaglandin (PG) E receptor subtypes (EP1-EP4), EP2 and EP4 have been proposed to mediate the anabolic action of PGE(2) on bone formation but comparative evaluation studies of EPs on bone formation do not necessarily share a common mechanism, implying that their additional features including downstream MAPK pathways may be beneficial to resolve this issue. We systematically assessed the roles of EPs in the rat calvaria (RC) cell culture model by using four selective EP agonists (EPAs). Consistent with relative expression levels of the respective receptors, multiple phenotypic traits of bone formation in vitro, including proliferation of nodule-associated cells, osteoblast marker expression and mineralized nodule formation were upregulated not only by PGE(2) but equally by EP2A and EP4A, but not by EP1A and EP3A. EP2A and EP4A were effective when cells were treated chronically or pulse-treated during nascent nodule formation. EP2A and EP4A equally stimulated the endogenous PGE(2) production, while EP2A caused a greater increase in cAMP production and c-Fos gene expression compared to EP4A. EP2A and EP4A activated predominantly p38 MAPK and ERK respectively, while c-Jun N-terminal kinase (JNK) was equally activated by both agonists. SB203580 (p38 MAPK inhibitor) blocked the PGE(2) effect on mineralized nodule formation, while U0126 (ERK inhibitor) and dicumarol (JNK inhibitor) were less effective. PGE(2)-dependent phosphorylation of the MAPKs was affected not only by protein kinase (PK)A and PKC inhibitors but also by adenylate cyclase and PKC activators. Co-treatment of RC cells with EP2A or EP4A and bone morphogenetic protein (BMP)2, whose effects on bone nodule formation is known to be, in part, mediated through the PKA and p38 MAPK pathways, resulted in an additive effect on mineralized nodule formation. Further, PGE(2), EP2A and EP4A did not increase BMP2/4 mRNA levels in RC cells, and EP2-induced phosphorylation of p38 MAPK was not eliminated by Noggin. These results suggest that, in the RC cell model, the anabolic actions of PGE(2) on mineralized nodule formation are mediated at least in part by activation of the EP2 and EP4 receptor subtype-specific MAPK pathways, independently of BMP signaling, in cells associated with nascent bone nodules.
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PMID:EP2 and EP4 receptors differentially mediate MAPK pathways underlying anabolic actions of prostaglandin E2 on bone formation in rat calvaria cell cultures. 1923 24

We have previously reported that 1) inhibition of cyclooxygenase-2 and PGE(2) production reduces hypertrophy after myocardial infarction in mice and 2) PGE(2) acting through its EP4 receptor causes hypertrophy of neonatal ventricular myocytes (NVMs) via ERK1/2. It is known that EP4 couples to adenylate cyclase, cAMP, and PKA. The present study was designed to determine interactions between the cAMP-PKA pathway and ERK1/2 and to further characterize events downstream of ERK1/2. We hypothesized that PKA and the small GTPase Rap are upstream of ERK1/2 and that 90-kDa ribosomal S6 kinase (p90RSK) is activated downstream. Treatment of NVMs with PGE(2) activated Rap, and this activation was inhibited in part by an EP4 antagonist and PKA inhibition. Transfection of a dominant negative mutant of Rap reduced PGE(2) activation of ERK1/2. PGE(2) activation of p90RSK was also dependent on EP4, PKA, and Rap. We also tested the involvement of Rap, ERK1/2, and p90RSK in PGE(2) regulation of gene expression. PGE(2) stimulation of brain natriuretic peptide promoter activity was blocked by either ERK1/2 inhibition or a dominant negative mutation of p90RSK. PGE(2) stimulation of c-Fos was dependent on EP4, PKA, ERK1/2, and p90RSK, whereas only the latter two kinases were involved in PGE(2) regulation of early growth response-1. Finally, we tested the involvement of EP4-dependent signaling in the NVM growth response and found that the overexpression of EP4 increased NVM cell size. We conclude that EP4-dependent signaling in NVMs in part involves PKA, Rap, ERK1/2, and p90RSK and results in the increased expression of brain natriuretic peptide and c-Fos.
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PMID:PKA, Rap1, ERK1/2, and p90RSK mediate PGE2 and EP4 signaling in neonatal ventricular myocytes. 1988 Jun 70

Posttransplant diabetes mellitus is a frequent complication among transplant recipients. Ligation of advanced glycation end products (AGEs) with their receptor on monocytes/macrophages plays a role in diabetes complications. The enhancement of adhesion molecule expression on monocytes/macrophages activates T cells, reducing allograft survival. In previous work, we found that toxic AGEs, AGE-2 and AGE-3, induced the expression of intracellular adhesion molecule-1, B7.1, B7.2, and CD40 on monocytes, production of interferon-gamma and tumor necrosis factor alpha, and lymphocyte proliferation during human mixed lymphocyte reaction. AGE-induced up-regulation of adhesion molecule expression was involved in cytokine production and lymphocyte proliferation. Prostaglandin E2 (PGE2) concentration-dependently inhibited the actions of AGE-2 and AGE-3. The effects of PGE2 were mimicked by an EP2 receptor agonist, ONO-AE1-259-01 (11,15-O-dimethyl PGE2), and an EP4 receptor agonist, ONO-AE1-329 [16-(3-methoxymethyl)phenyl-omega-tetranor-3,7dithia PGE1]. An EP2 receptor antagonist, AH6809 (6-isopropoxy-9-oxaxanthene-2-carboxylic acid), and an EP4 receptor antagonist, AH23848 [(4Z)-7-[(rel-1S,2S,5R)-5-((1,1'-biphenyl-4-yl)methoxy)-2-(4-morpholinyl)-3-oxocyclopentyl]-4-heptenoic acid], inhibited the actions of PGE2. The stimulation of EP2 and EP4 receptors is reported to increase cAMP levels. The effects of PGE2 were reversed by protein kinase A (PKA) inhibitors and mimicked by dibutyryl cAMP and an adenylate cyclase activator, forskolin. These results as a whole indicate that PGE2 inhibited the actions of AGE-2 and AGE-3 via EP2/EP4 receptors and the cAMP/PKA pathway.
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PMID:Prostaglandin E2 inhibits advanced glycation end product-induced adhesion molecule expression on monocytes, cytokine production, and lymphocyte proliferation during human mixed lymphocyte reaction. 2055 73


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