Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.11 (AMPK)
 12,425 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To create precise neural circuits in the nervous system, neuritogenesis and synaptogenesis are the critical cellular processes during neuronal differentiation. We examined the cyclic AMP (cAMP)-responsible signaling pathways for regulating neuritogenesis and synaptogenesis in NG108-15 cells. A rise in intracellular cAMP concentration by a membrane-permeable cAMP analog, dibutyryl cAMP (DBcAMP), led to an increase in the number of neurites and varicosities. Inhibition of cAMP-dependent protein kinase (PKA) activity by a PKA inhibitor (H89) accelerated this neuritogenesis and neurite outgrowth rate. Treatment with H89, however, decreased the number of varicosities and the frequency of postsynaptic miniature current recorded in the cultured cells, resulting in suppression of synaptogenesis. Immunoblot analyses revealed that PKA activity mediates phosphorylation of a gene transcription factor, cAMP-response element binding protein (CREB). On the other hand, inhibition of a mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway by a MAPK/ERK kinase (MEK) inhibitor (PD98059) suppressed both neuritogenesis and neurite outgrowth without CREB phosphorylation. These results suggest strongly that PKA simultaneously plays two different roles in neuronal differentiation: inhibition of neuritogenesis and stimulation of synaptogenesis, via CREB-mediated gene expression.
 ...
PMID:Dual role of cyclic AMP-dependent protein kinase in neuritogenesis and synaptogenesis during neuronal differentiation. 1464 87

By using the MIN6 cell line and pancreatic islets, we show that in the presence of a low glucose concentration, corresponding to physiological glucagon release from alpha cells, glucagon treatment of the beta cell caused a rapid, time-dependent phosphorylation and activation of p44/p42 mitogen-activated protein kinase (ERK1/2) independently from extracellular calcium influx. Inhibition of either cAMP-dependent protein kinase (PKA) or MEK completely blocked ERK1/2 activation by glucagon. However, no significant activation of several upstream activators of MEK, including Shc-p21(Ras) and phosphatidylinositol 3-kinase, was observed in response to glucagon treatment. Chelation of intracellular calcium (intracellular [Ca(2+)]) reduced glucagon-mediated ERK1/2 activation. In addition, internalization of glucagon receptors through clathrin-coated pits formation is required for ERK1/2 activation. Remarkably, glucagon promotes the nuclear translocation of ERK1/2 and induces the phosphorylation of cAMP-response element-binding protein (CREB). Miniglucagon, produced from glucagon and released together with the mother hormone from the alpha cells in low glucose situations, blocks the insulinotropic effect of glucagon, whereas it does not inhibit the glucagon-induced PKA/ERK1/2/CREB pathway. We conclude that glucagon-induced ERK1/2 activation is mediated by PKA and that an increase in [Ca(2+)](i) is required for maximal ERK activation. Our results uncover a novel mechanism by which the PKA/ERK1/2 signaling network engaged by glucagon, in situation of low glucose concentration, regulates phosphorylation of CREB, a transcription factor crucial for normal beta cell function and survival.
 ...
PMID:Glucagon promotes cAMP-response element-binding protein phosphorylation via activation of ERK1/2 in MIN6 cell line and isolated islets of Langerhans. 1498 13

Phosphodiesterase (PDE) 7B, a cAMP-specific PDE which is dominantly expressed in striatum, is expected to be involved in dopaminergic signaling in striatal neurons. Here we show, for the first time, the involvement of the dopaminergic signaling pathway in transcriptional activation of rat PDE7B in primary striatal culture. RT-PCR analysis revealed that dopamine, D1 agonist, forskolin and 8-Br-cAMP stimulation potentiated PDE7B transcription in striatal neurons, while D2 agonist failed to activate the PDE7B transcription. Pre-treatment with D1 antagonist abolished the dopamine- or D1 agonist-induced transcriptional activation of PDE7B. The activation of PDE7B transcription by these stimulators was completely ablated by pre-treatment of the cells with a cAMP-dependent protein kinase inhibitor, H-89. RT-PCR using splice variant-specific primers revealed that transcription of PDE7B1, but not of other splice variants, was activated by D1 agonist. We determined the putative transcription start site of PDE7B1, a brain-specific splice variant of PDE7B, by 5'-RACE and identified a promoter region of PDE7B1. Sequence analysis of the PDE7B1 promoter revealed the presence of a canonical cAMP-response element at 166 bp upstream of the putative transcription start site. The cAMP-responsiveness of the PDE7B1 promoter was demonstrated by functional promoter analysis using the luciferase reporter system. Deletion and mutation of the cAMP-response element site in the PDE7B1 promoter abolished the forskolin-induced activation of the PDE7B1 promoter activity. Electrophoretic mobility shift assay showed the binding of cAMP-response element binding protein to the PDE7B1 promoter. These data demonstrate the dopamine D1 receptor-mediated transcriptional activation of PDE7B through the cAMP/cAMP-dependent protein kinase/cAMP-response element binding protein pathway in striatal neurons.
 ...
PMID:Transcriptional activation of phosphodiesterase 7B1 by dopamine D1 receptor stimulation through the cyclic AMP/cyclic AMP-dependent protein kinase/cyclic AMP-response element binding protein pathway in primary striatal neurons. 1505 90

The expression of carbamoylphosphate synthetase-I (CPS), the first and rate-determining enzyme of the urea cycle, is regulated at the transcriptional level by glucocorticoids and glucagon, the latter acting via cyclic AMP (cAMP). The hormonal response is mediated by a distal enhancer located 6.3 kb upstream of the transcription-start site. Within this enhancer, a cAMP-response unit (CRU) is responsible for mediating cAMP-dependent transcriptional activity. The CPS CRU contains binding sites for cAMP-response element (CRE)-binding protein (CRE-BP), forkhead box A (FoxA), CCAAT/enhancer-binding protein (C/EBP), and an unidentified protein P1. To gain insight in the protein-DNA interactions that activate the CPS CRU in living cells, we have employed in vivo footprinting assays. Comparison of the fibroblast cell line Rat-1 and the hepatoma cell lines FTO-2B and WT-8 showed that FoxA binds the CPS CRU constitutively in CPS-expressing cells only. Comparison of FTO-2B and WT-8 hepatoma cells, which only differ in cAMP responsiveness, demonstrated that the binding of the other transcription factors is dependent on cAMP-dependent protein kinase (PKA) activity. Finally, we observed a footprint between the CRE and the P1-binding site in the in vivo footprint assay that was not detectable by in vitro footprint assays, implying a major change in CRU-associated chromatin conformation upon CRU activation. These findings indicate that activation of the CRU is initiated in a tissue-specific manner by the binding of FoxA. When cellular cAMP and glucocorticoid levels increase, CRE-BP becomes activated, allowing the binding of the remaining transcription factors and the transactivation of the CPS promoter.
 ...
PMID:In vivo footprinting of the carbamoylphosphate synthetase I cAMP-response unit indicates important roles for FoxA and PKA in formation of the enhanceosome. 1682 61

The nuclear PXR (pregnane X receptor) was originally characterized as a key transcription factor that activated hepatic genes encoding drug-metabolizing enzymes. We have now demonstrated that PXR also represses glucagon-activated transcription of the G6Pase (glucose-6-phosphatase) gene by directly binding to CREB [CRE (cAMP-response element)-binding protein]. Adenoviral-mediated expression of human PXR (hPXR) and its activation by rifampicin strongly repressed cAMP-dependent induction of the endogenous G6Pase gene in Huh7 cells. Using the -259 bp G6Pase promoter construct in cell-based transcription assays, repression by hPXR of PKA (cAMP-dependent protein kinase)-mediated promoter activation was delineated to CRE sites. GST (glutathione transferase) pull-down and immunoprecipitation assays were employed to show that PXR binds directly to CREB, while gel-shift assays were used to demonstrate that this binding prevents CREB interaction with the CRE. These results are consistent with the hypothesis that PXR represses the transcription of the G6Pase gene by inhibiting the DNA-binding ability of CREB. In support of this hypothesis, treatment with the mouse PXR activator PCN (pregnenolone 16alpha-carbonitrile) repressed cAMP-dependent induction of the G6Pase gene in primary hepatocytes prepared from wild-type, but not from PXR-knockout, mice, and also in the liver of fasting wild-type, but not PXR-knockout, mice. Moreover, ChIP (chromatin immunoprecipitation) assays were performed to show a decreased CREB binding to the G6Pase promoter in fasting wild-type mice after PCN treatment. Thus drug activation of PXR can repress the transcriptional activity of CREB, down-regulating gluconeogenesis.
 ...
PMID:Human nuclear pregnane X receptor cross-talk with CREB to repress cAMP activation of the glucose-6-phosphatase gene. 1763 6

Addition of an inhaled long-acting beta(2)-adrenoceptor agonist (LABA) to an inhaled corticosteroid (ICS) is more effective at improving asthma control and reducing exacerbations than increasing the dose of ICS. Given that LABA monotherapy is not anti-inflammatory, pathways may exist by which LABAs enhance ICS actions. In the current study, the glucocorticoid dexamethasone had no effect on beta(2)-adrenoceptor agonist-induced cAMP-response element-dependent transcription in the human bronchial epithelial cell line BEAS-2B. In contrast, simple glucocorticoid response element (GRE)-dependent transcription induced by dexamethasone, budesonide, and fluticasone was synergistically enhanced by beta(2)-adrenoceptor agonists, including salmeterol and formoterol, to a level that could not be achieved by glucocorticoid alone. This enhancement was mimicked by other cAMP-elevating agents, and a cAMP mimetic, and was blocked by an inhibitor of cAMP-dependent protein kinase (PKA). Thus, beta(2)-adrenoceptor agonists synergistically enhance simple GRE-dependent transcription via the classical cAMP-PKA pathway. Consistent with the clinical situation, the addition of a beta(2)-adrenoceptor agonist to a glucocorticoid is steroid-sparing in that maximal GRE-dependent responses, evoked by glucocorticoid, are achieved at approximately 10-fold lower concentrations in the presence of beta(2)-adrenoceptor agonist. Finally, analysis of dexamethasone-inducible genes, including glucocorticoid-inducible leucine zipper (GILZ), aminopeptidase N, FKBP51, PAI-1, tristetraprolin, DNB5, p57KIP2, metallothionein 1X, and MKP-1, revealed enhanced inducibility of some genes by glucocorticoid/beta(2)-adrenoceptor agonist combinations in a manner that was consistent with the GRE-reporter. Because such effects also occur in primary human airway smooth muscle cells, we propose that enhancement of glucocorticoid-inducible gene expression may contribute to the superior efficacy of LABA/ICS combination therapies, over ICS alone, in asthma treatment.
 ...
PMID:Long-acting beta2-adrenoceptor agonists synergistically enhance glucocorticoid-dependent transcription in human airway epithelial and smooth muscle cells. 1790 Nov 97

Impaired cognition and memory may be associated with down-regulation of cAMP-response element-binding protein (CREB) in the brain in patients with Alzheimer disease, but the molecular mechanism leading to the down-regulation is not understood. In this study, we found a selective reduction in the levels of the regulatory subunits (RIIalpha and RIIbeta) and the catalytic subunit (Cbeta) as well as the enzymatic activity of cAMP-dependent protein kinase (PKA), which is the major positive regulator of CREB. We also observed that PKA subunits were proteolyzed by calpain and the levels of PKA subunits correlated negatively with calpain activation in the human brain. These findings led us to propose that in the brain in patients with Alzheimer disease, over-activation of calpain because of calcium dysregulation causes increased degradation and thus decreased activity of PKA, which, in turn, contributes to down-regulation of CREB and impaired cognition and memory.
 ...
PMID:Down-regulation of cAMP-dependent protein kinase by over-activated calpain in Alzheimer disease brain. 1790 36

The extent to which the prostacyclin (IP) receptor regulates the release of two proinflammatory chemokines from human airway epithelial cells was investigated using the novel and competitive IP-receptor antagonist 4,5-dihydro-1H-imidazol-2-yl)-[4-(4-isopropoxy-benzyl)-phenyl]-amine (RO1138452). In BEAS-2B human airway epithelial cells, taprostene, a selective IP-receptor agonist, suppressed interferon-gamma-induced CXCL9 and CXCL10 release in a concentration-dependent manner. These effects were mimicked by 8-bromo-cAMP, and they were abolished in cells infected with an adenovirus vector encoding a highly selective inhibitor of cAMP-dependent protein kinase (PKA). RO1138452 blocked the inhibitory effect of taprostene on chemokine output in a manner inconsistent with surmountable competitive antagonism. Comparable results were obtained using primary cultures of human airway epithelial cells. The basis of the antagonism imposed by RO1138452 was studied further using BEAS-2B cells stably transfected with a cAMP-response element (CRE) luciferase reporter. On this output, RO1138452 also behaved insurmountably. Mechanistically, this could not be attributed to covalent receptor inactivation, allosterism, or a state of hemiequilibrium. Other studies established that the degree by which RO1138452 antagonized taprostene-induced CRE-dependent transcription was not reversed over a 20-h "washout" period. This pharmacological profile is consistent with the behavior of a pseudo-irreversible antagonist where dissociation from its cognate receptor is so slow that re-equilibration is not achieved at the time the response is measured. Collectively, these data provide compelling evidence that human airway epithelial cells express inhibitory IP-receptors linked to the activation of PKA. Moreover, contrary to existing literature, RO1138452 behaved pseudoirreversibly, emphasizing the need, in drug discovery, to screen potential new medicines in the target tissue(s) of interest.
 ...
PMID:4,5-Dihydro-1H-imidazol-2-yl)-[4-(4-isopropoxy-benzyl)-phenyl]-amine (RO1138452) is a selective, pseudo-irreversible orthosteric antagonist at the prostacyclin (IP)-receptor expressed by human airway epithelial cells: IP-receptor-mediated inhibition of CXCL9 and CXCL10 release. 1796 17

Many of the effects of prototypical second messenger cyclic adenosine 3',5'-monophosphate (cAMP) on complex processes such as the regulation of fuel metabolism, spermatogenesis and steroidogenesis are mediated via changes in target gene transcription. A large body of research has defined members of the cAMP-response element binding (CREB) protein family as the principal mediators of positive changes in gene expression in response to cAMP following phosphorylation by cAMP-dependent protein kinase (PKA). However, persistent observations of cAMP-mediated induction of specific genes occurring via PKA-independent mechanisms have challenged the generality of the PKA-CREB pathway. In this review, we will discuss in detail both PKA-dependent and -independent mechanisms that have been proposed to explain how cAMP influences the activation status of multiple transcription factors, and how these influence critical biological processes whose defective regulation may lead to disease.
 ...
PMID:Regulating gene transcription in response to cyclic AMP elevation. 1799 58

AMP-activated protein kinase (AMPK) has been identified as a regulator of gene transcription, increasing mitochondrial proteins of oxidative metabolism as well as hexokinase expression in skeletal muscle. In mice, muscle-specific knockout of LKB1, a component of the upstream kinase of AMPK, prevents contraction- and 5-aminoimidazole-4-carboxamide-1-beta-D-ribofuranoside (AICAR)-induced activation of AMPK in skeletal muscle, and the increase in hexokinase II protein that is normally observed with chronic AICAR activation of AMPK. Since previous reports show a cAMP response element in the promoter region of the hexokinase II gene, we hypothesized that the cAMP-response element (CRE) binding protein (CREB) family of transcription factors could be targets of AMPK. Using radioisotopic kinase assays, we found that recombinant and rat liver and muscle AMPK phosphorylated CREB1 at the same site as cAMP-dependent protein kinase (PKA). AMPK was also found to phosphorylate activating transcription factor 1 (ATF1), CRE modulator (CREM), and CREB-like 2 (CREBL2), but not ATF2. Treatment of HEK-293 cells stably transfected with a CREB-driven luciferase reporter with AICAR increased luciferase activity approximately threefold over a 24-h time course. This increase was blocked with compound C, an AMPK inhibitor. In addition, AICAR-induced activation of AMPK in incubated rat epitrochlearis muscles resulted in an increase in both phospho-acetyl-CoA carboxylase and phospho-CREB. We conclude that CREB and related proteins are direct downstream targets for AMPK and are therefore likely involved in mediating some effects of AMPK on expression of genes having a CRE in their promoters.
 ...
PMID:AMP-activated protein kinase phosphorylates transcription factors of the CREB family. 1806 5


<< Previous 1 2 3 4 5 Next >>