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: UNIPROT:P01275 (glucagon)
26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glucagon was found to increase the mRNA level of the uricase-encoding gene (UOX), but not that of genes encoding other peroxisomal enzymes, such as catalase, acyl-CoA oxidase and enoyl-CoA hydratase/3-hydroxyacyl-CoA dehydrogenase. The possible involvement of cAMP in the glucagon-induced transcription of rat UOX was studied by measuring the enhancer activity of the isolated 5'-untranslated region of the gene. An 84-bp sequence spanning positions -169 to -86 was found to be essential for cAMP-mediated expression of rat UOX, on deletional analysis of the upstream 1.4-kb portion by means of a transient transfection assay (CAT assay). The 30-mer oligodeoxyribonucleotide (positions from -169 to -140) was found to form a DNA-protein complex by an electrophoretic mobility shift assay. The core sequence for the DNA-protein complex formation, 5'-CAAAAATGTC-3', was found to be located in positions from -164 to -155. In addition, the binding assays suggested that the DNA-binding protein(s) was different from cAMP-response element binding protein (CREB). Thus, this report shows that a novel cis-acting element of rat UOX and the binding protein(s) possibly play an essential role in the glucagon-induced transcription via cAMP.
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PMID:Transcription of the rat liver uricase-encoding gene is regulated via a cis-acting element responsive to cAMP. 856 90

Phosphoenolpyruvate carboxykinase (PEPCK) catalyzes the rate-limiting step of gluconeogenesis. The activity of this enzyme is controlled by several hormones, including glucocorticoids, glucagon, retinoic acid, and insulin, that principally affect the rate of transcription of the PEPCK gene. Glucocorticoids induce PEPCK gene transcription through a complex glucocorticoid response unit that consists of, from 5' to 3', accessory factor elements AF1 and AF2; two noncanonical glucocorticoid receptor-binding sites, GR1 and GR2; a third accessory factor element, AF3; and a cAMP-response element, CRE. A complete glucocorticoid response is dependent on the presence of both GR-binding sites, all three accessory elements, and the CRE. In this study we assess the relative roles of GR1 and GR2 in the context of the glucocorticoid response unit and use a combination of binding and function assays to compare GR1 and GR2 to glucocorticoid response elements (GREs) that conform closely to the consensus sequence. The relative binding affinity of GR follows the order: consensus GRE >> GR1 > GR2. Mutations that disrupt the binding of GR to GR1 result in a major reduction of the glucocorticoid response, whereas similar mutations of GR2 have a much smaller effect. Unlike the simple consensus GRE, neither GR1 nor GR2 mediate a glucocorticoid response through a heterologous promoter. The accessory elements appear to have different functional roles. AF2 is still needed for a maximal glucocorticoid response when GR1 is converted to a high-affinity GR-binding element, but AF1 and AF3 are not required.
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PMID:Further characterization of the glucocorticoid response unit in the phosphoenolpyruvate carboxykinase gene. The role of the glucocorticoid receptor-binding sites. 954 84

The glucagon-stimulated transcription of the cytosolic phosphoenolpyruvate carboxykinase-1 (PCK1) gene is mediated by cAMP and positively modulated by oxygen in primary hepatocytes. Rat hepatocytes were transfected with constructs containing the first 2500, 493 or 281 bp of the PCK1 5'-flanking region in front of the chloramphenicol acetyltransferase (CAT) reporter gene. With all three constructs glucagon induced CAT activity with decreasing efficiency maximally under arterial pO2 and to about 65% under venous pO2. Rat hepatocytes were then transfected with constructs containing the first 493 bp of the PCK1 5'-flanking region in front of the luciferase (LUC) reporter gene, which were block-mutated at the CRE1 (cAMP-response element-1; -93/-86), putative CRE2 (-146/-139), promoter element (P) 1 (-118/-104), P2 (-193/-181) or P4 (-291/-273) sites. Glucagon induced LUC activity strongly when the P1 and P2 sites were mutated and weakly when the P4 site was mutated; induction of the P1, P2 and P4 mutants was positively modulated by the pO2. Glucagon also induced LUC activity strongly when the putative CRE2 site was altered; however, induction of the CRE2 mutant was not modulated by the pO2. Glucagon did not induce LUC activity when the CRE1 site was modified. These experiments suggested that the CRE1 but not the putative CRE2 was an essential site necessary for the cAMP-mediated PCK1 gene activation by glucagon and that the putative CRE2 site was involved in the oxygen-dependent modulation of PCK1 gene activation. To confirm these conclusions rat hepatocytes were transfected with simian virus 40 (SV40)-promoter-driven LUC-gene constructs containing three CRE1 sequences (-95/-84), three CRE2 sequences (-148/-137) or three CRE1 sequences plus two CRE2 sequences of the PCK1 gene in front of the SV40 promoter. Glucagon induced LUC activity markedly when the CRE1, but not when the CRE2, sites were in front of the SV40-LUC gene; however, induction of the (CRE1)3SV40-LUC constructs was not modulated by the pO2. Glucagon also induced LUC activity very strongly when the CRE1 and CRE2 sites were combined; induction of the (CRE1)3(CRE2)2SV40-LUC constructs was positively modulated by the pO2. These findings corroborated that sequences of the putative CRE2 site were responsible for the modulation by oxygen of the CRE1-dependent induction by glucagon of PCK1 gene transcription.
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PMID:Identification of an oxygen-responsive element in the 5'-flanking sequence of the rat cytosolic phosphoenolpyruvate carboxykinase-1 gene, modulating its glucagon-dependent activation. 1021 94

Glucagon-like peptide-2 (GLP-2) promotes the expansion of the intestinal epithelium through stimulation of the GLP-2 receptor, a recently identified member of the glucagon-secretin G protein-coupled receptor superfamily. Although activation of G protein-coupled receptors may lead to stimulation of cell growth, the mechanisms transducing the GLP-2 signal to mitogenic proliferation remain unknown. We now report studies of GLP-2R signaling in baby hamster kidney (BHK) cells expressing a transfected rat GLP-2 receptor (BHK-GLP-2R cells). GLP-2, but not glucagon or GLP-1, increased the levels of cAMP and activated both cAMP-response element- and AP-1-dependent transcriptional activity in a dose-dependent manner. The activation of AP-1-luciferase activity was protein kinase A (PKA) -dependent and markedly diminished in the presence of a dominant negative inhibitor of PKA. Although GLP-2 stimulated the expression of c-fos, c-jun, junB, and zif268, and transiently increased p70 S6 kinase in quiescent BHK-GLP-2R cells, GLP-2 also inhibited extracellular signal-regulated kinase 1/2 and reduced serum-stimulated Elk-1 activity. Furthermore, no rise in intracellular calcium was observed following GLP-2 exposure in BHK-GLP-2R cells. Although GLP-2 stimulated both cAMP accumulation and cell proliferation, 8-bromo-cyclic AMP alone did not promote cell proliferation. These findings suggest that the GLP-2R may be coupled to activation of mitogenic signaling in heterologous cell types independent of PKA via as yet unidentified downstream mediators of GLP-2 action in vivo.
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PMID:Identification of glucagon-like peptide-2 (GLP-2)-activated signaling pathways in baby hamster kidney fibroblasts expressing the rat GLP-2 receptor. 1052 25

The hormone glucagon is secreted by the alpha-cells of the endocrine pancreas (islets of Langerhans) during fasting and is essential for the maintenance of blood glucose levels by stimulation of hepatic glucose output. Excessive production and secretion of glucagon by the alpha-cells of the islets is a common accompaniment to diabetes. The resulting hyperglucagonemia stimulates hepatic glucose production, thereby contributing to hyperglycemia of diabetes. The reduced insulin secretion in diabetes and resultant failure to suppress glucagon secretion by intra-islet paracrine mechanisms is believed to cause the hypersecretion of glucagon. Here, we report the discovery of a new mechanism by which glucagon suppresses insulin secretion. We show that glucagon, but not glucagon-like peptide 1 (GLP-1), or pituitary adenylyl cyclase-activating peptide (PACAP) specifically induces the expression of the transcriptional repressor inducible cAMP early repressor (ICER) in pancreatic beta-cells, resulting in a repression of the transcriptional expression of the insulin gene. Remarkably, glucagon, GLP-1, and PACAP all stimulate the formation of cAMP to a comparable extent in rat pancreatic islets, but only glucagon activates the expression of ICER and represses insulin gene transcription in beta-cells. These findings lead us to propose that hyperglucagonemia may additionally aggravate the diabetic phenotype via a suppression of insulin gene expression mediated by the transcriptional repressor ICER.
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PMID:Glucagon stimulates expression of the inducible cAMP early repressor and suppresses insulin gene expression in pancreatic beta-cells. 1101 52

Multiple neuroactive substances are secreted by neurons and/or glial cells and modulate the sensitivity to cell death. In the developing retina, it has been shown that increased intracellular levels of cAMP protect cells from degeneration. We tested the hypothesis that the neuroactive peptide pituitary adenylyl cyclase-activating polypeptide (PACAP) has neuroprotective effects upon the developing rat retina. PACAP38 prevented anisomycin-induced cell death in the neuroblastic layer (NBL) of retinal explants, and complete inhibition of induced cell death was obtained with 1 nm. A similar protective effect was observed with PACAP27 and with the specific PAC1 receptor agonist maxadilan but not with glucagon. Photoreceptor cell death induced by thapsigargin was also prevented by PACAP38. The neuroprotective effect of PACAP38 upon the NBL could be reverted by the competitive PACAP receptor antagonist PACAP6-38 and by the specific PAC1 receptor antagonist Maxd.4. Molecular and immunohistochemical analysis demonstrated PAC1 receptors, and treatment with PACAP38 induced phospho-cAMP-response element-binding protein immunoreactivity in the anisomycin-sensitive undifferentiated postmitotic cells within the NBL. PACAP38 produced an increase in cAMP but not inositol triphosphate, and treatment with the cAMP-dependent protein kinase inhibitor R(p)-cAMPS blocked the protective effect of PACAP38. The results indicate that activation of PAC1 receptors by PACAP38 modulates cell death in the developing retina through the intracellular cAMP/cAMP-dependent protein kinase pathway.
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PMID:Pituitary adenylyl cyclase-activating polypeptide prevents induced cell death in retinal tissue through activation of cyclic AMP-dependent protein kinase. 1184 14

Liver carnitine palmitoyltransferase I catalyzes the transfer of long-chain fatty acids into mitochondria. L-CPT I is considered the rate-controlling enzyme in fatty acid oxidation. Expression of the L-CPT I gene is induced by starvation in response to glucagon secretion from the pancreas, an effect mediated by cAMP. Here, the molecular mechanisms underlying the induction of L-CPT I gene expression by cAMP were characterized. We demonstrate that the cAMP response unit of the L-CPT I gene is composed of a cAMP-response element motif and a DR1 sequence located 3 kb upstream of the transcription start site. Our data strongly suggest that the coactivator PGC-1 is involved in the regulation of this gene expression by cAMP in combination with HNF4 alpha and cAMP-response element-binding protein (CREB). Indeed, (i) cotransfection of CREB or HNF4 alpha dominant negative mutants completely abolishes the effect of cAMP on the L-CPT I promoter, and (ii) the cAMP-responsive unit binds HNF4 alpha and CREB through the DR1 and the cAMP-response element sequences, respectively. Moreover, cotransfection of PGC-1 strongly activates the L-CPT I promoter through HNF4 alpha bound at the DR1 element. Finally, we show that the transcriptional induction of the PGC-1 gene by glucagon through cAMP in hepatocytes precedes that of L-CPT-1. In addition to the key role that PGC-1 plays in glucose homeostasis, it may also be critical for lipid homeostasis. Taken together these observations suggest that PGC-1 acts to coordinate the process of metabolic adaptation in the liver.
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PMID:The coactivator PGC-1 is involved in the regulation of the liver carnitine palmitoyltransferase I gene expression by cAMP in combination with HNF4 alpha and cAMP-response element-binding protein (CREB). 1210 81

Glucagon-like peptide 1 (GLP-1) is an incretin hormone that is secreted from the enteroendocrine L-cells of the gut in response to nutrient ingestion. GLP-1 enhances both insulin secretion and insulin gene expression in a glucose-dependent manner via activation of its putative G-protein-coupled receptor on pancreatic beta-cells. In the presence of DMSO (0.5-2.5%), these functional responses were enhanced significantly (2- to 2.5-fold) in a concentration-dependent manner in the beta-cell line INS-1, although basal levels were not affected. Rat insulin 1 (rINS1) promoter activity appeared to be augmented in a cAMP-response element (CRE)-dependent manner as the effect of DMSO was abolished following a mutation in the CRE of the rINS1 promoter. Also, expression of a generic cAMP-driven reporter gene was enhanced by 1.5% DMSO in response to GLP-1 (3.5-fold), forskolin (2-fold), and 3-isobutyl-1-methylxanthine (2-fold). Analysis of intracellular signaling components revealed that DMSO did not elevate cAMP levels, protein kinase A activity, or phosphorylated levels of CRE-binding protein (CREB), CRE-modulator (CREM), and activating transcription factor-1 (ATF-1). These data suggest that GLP-1 induces insulin gene transcription in a CREB, CREM, and ATF-1-independent manner in beta-cells. The mechanism by which DMSO imparts this amplifying action is unclear but may involve redistribution of intracellular compartments or a direct molecular interaction with a downstream target of the GLP-1 receptor signaling pathway in the beta-cell. These effects of DMSO on incretin action may provide novel applications with respect to further characterizing GLP-1 receptor signaling, identifying incretin-like compounds in screening assays, and as a therapeutic treatment in type 2 diabetes.
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PMID:Synergistic effect of dimethyl sulfoxide on glucagon-like peptide 1 (GLP-1)-stimulated insulin secretion and gene transcription in INS-1 cells: characterization and implications. 1216 88

Glucagon-like peptide-1 [GLP-1; formerly GLP-1(7-36)amide] and somatostatin (SS) are two postprandially or paracrine released peptide hormones that regulate insulin secretion from pancreatic islets. Using the rat insulinoma cell line RINm5F as a model, we investigated the effects of both peptides alone and in combination on insulin release, proliferation, and intracellular signal transduction. In addition, we determined the SS receptor subtypes expressed and involved by reverse transcription-polymerase chain reaction and use of selective SS agonists. GLP-1 stimulated insulin release, cell proliferation, intracellular cAMP accumulation and activation of the transcription factor cAMP-response element binding protein (CREB) which all could be reduced to basal values by co-incubation with SS. Incubation with SS alone did not affect basal levels. RINm5F cells express the somatostatin receptor (sst) subtypes sst1 and sst2 as well as traces of sst3. In accordance, the sst1- or sst2-selective non-peptide agonists L-797591 or L-054522 and peptide agonist octreotide (SMS 201995; sst2, sst3, and sst5 selective) potently inhibited GLP-1-induced insulin secretion whereas the sst3-selective agonist L-796778 showed little effect. Moreover, the sst1- and sst2-selective agonists slightly reduced also basal insulin release. The experiments show that GLP-1 and SS are perfect opponents for regulating pancreatic beta-cell insulin secretion.
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PMID:Somatostatin inhibits glucagon-like peptide-1-induced insulin secretion and proliferation of RINm5F insulinoma cells. 1222 Jul 32

The proglucagon gene encodes several peptide hormones that regulate blood glucose homeostasis, growth of the small intestine, and satiety. Among them, glucagon-like peptide 1 (GLP-1) lowers blood glucose levels in patients with diabetes and inhibits eating and drinking in fasted rats. Although proglucagon transcription and GLP-1 synthesis were shown to be activated by forskolin and other protein kinase A (PKA) activators, deleting or mutating the cAMP-response element (CRE) only moderately attenuates the proglucagon gene promoter in response to PKA activation. Therefore, PKA may activate proglucagon transcription via a mechanism independent of the CRE motif. Recently, PKA was shown to phosphorylate and inactivate GSK-3beta, a key mediator in the Wnt signaling pathway. We show here that lithium, an inhibitor of GSK-3beta, activates proglucagon gene transcription and stimulates GLP-1 synthesis in an intestinal endocrine L cell line, GLUTag. The activation was also observed in primary fetal rat intestinal cell (FRIC) cultures, but not in a pancreatic A cell line. Co-transfection of beta-catenin, a downstream effector of GSK-3beta activities, activated the proglucagon gene promoter without a CRE. Furthermore, forskolin and 8-Br-cAMP phosphorylated GSK-3beta at serine 9 in intestinal proglucagon-producing cells, and both lithium and forskolin induced the accumulation of free beta-catenin in these cell lines. These observations indicate that the proglucagon gene is among the targets of the Wnt signaling pathway.
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PMID:Transcriptional activation of the proglucagon gene by lithium and beta-catenin in intestinal endocrine L cells. 1242 27


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