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)

We analyzed the ability of cyclic AMP-response element binding proteins (CREBs) to interact with the CRE sequences derived from different genes and examined the role of sequences flanking the core CRE element in rendering cAMP-responsiveness to the enhancer. We were able to detect reproducibly, sing the Southwestern blotting technique, five major CREB factors of molecular weights 56, 47, 40, and 36-34 kDa which were present in various rat tissues and cultured cells. The 34-40 kDa proteins (CREB-327/341) were able to bind to the CRE of cAMP-inducible genes (somatostatin, c-fos, E2A), but not to genes whose expression is not controlled by cAMP (glucagon, parathyroid hormone). The novel 47 kDa CREB had a high specificity for the core octameric CRE sequence and it bound equally well to the consensus CRE of cAMP-inducible and noninducible genes. On the other hand, the 47 kDa CREB did not bind at all to the phorbol ester response element (TRE), whereas the 56 kDa protein, reminiscent of the CRE-BP1 protein, could bind to both elements. A computer aided sequence analysis of cAMP-inducible gene promoters revealed the presence of an additional conserved element starting 4-6 nucleotides 3' to the octomer with the consensus C/GAGA/C. We have shown this element to be essential for maximal cAMP-responsiveness of the enhancer in transient expression assays of CRE-CAT plasmid constructs indicating that the functional interaction of CREB proteins with the cAMP-inducible enhancer involves an additional 8-10 base pairs immediately downstream from the CRE core element.
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PMID:Evidence that an additional conserved element with the consensus C/GAGA/C is essential for maximal responsiveness of the cyclic AMP enhancer. 790 79

We have previously described the use of a chemically defined medium (CDM) supplemented with epidermal growth factor (EGF) and dimethylsulfoxide (DMSO) to maintain long-term cultures of rat hepatocytes in a highly differentiated state. In this study, conditions necessary to stimulate high levels of DNA synthesis in hepatocytes in long-term DMSO culture were defined. Hepatocytes were maintained in culture for 20 days in CDM containing DMSO and EGF, insulin, and glucagon. EGF, insulin, and glucagon were then removed for 7 days. Readdition of EGF, insulin, and glucagon at day 27 (shiftup) was accompanied by a three- to sixfold increase in labeling index. If DMSO or dexamethasone (dex) + DMSO were removed at time of shiftup, the labeling index increased by 18- to 54-fold. TGF beta inhibited DNA synthesis stimulated by EGF shiftup, TGF alpha shiftup, or EGF shiftup in combination with removal of dex + DMSO. Stimulation of DNA synthesis was accompanied by a specific, sequential induction of protooncogene mRNA levels; c-fos mRNA was induced 23-fold at 0.5 h after readdition of EGF; c-myc mRNA was induced three- to four-fold by 0.5 h; TGF alpha mRNA was induced sevenfold by 8 h; K-ras mRNA was induced fourfold by 26 h. Changes in protooncogene expression paralleled changes seen in regenerating liver. When DMSO was removed for greater than 48 h, the cells flattened and spread out, chords of cells were no longer well defined, albumin mRNA levels decreased, and fibronectin, beta 1 integrin, and TGF beta transcripts increased.
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PMID:Stimulation of DNA synthesis and protooncogene expression in primary rat hepatocytes in long-term DMSO culture. 843 3

The sequence of glucagon-like peptide-1 (7-36) amide (GLP-1) is completely conserved in all mammalian species studied, implying that it plays a critical physiological role. We have shown that GLP-1 and its specific receptors are present in the hypothalamus. No physiological role for central GLP-1 has been established. We report here that intracerebroventricular (ICV) GLP-1 powerfully inhibits feeding in fasted rats. ICV injection of the specific GLP-1-receptor antagonist, exendin (9-39), blocked the inhibitory effect of GLP-1 on food intake. Exendin (9-39) alone had no influence on fast-induced feeding but more than doubled food intake in satiated rats, and augmented the feeding response to the appetite stimulant, neuropeptide Y. Induction of c-fos is a marker of neuronal activation. Following ICV GLP-1 injection, c-fos appeared exclusively in the paraventricular nucleus of the hypothalamus and central nucleus of the amygdala, and this was inhibited by prior administration of exendin (9-39). Both of these regions of the brain are of primary importance in the regulation of feeding. These findings suggest that central GLP-1 is a new physiological mediator of satiety.
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PMID:A role for glucagon-like peptide-1 in the central regulation of feeding. 900 71

Expression of phosphoenolpyruvate carboxykinase (PEPCK), the rate-limiting step in hepatic gluconeogenesis, is primarily regulated at the level of gene transcription. Insulin and phorbol esters inhibit basal PEPCK transcription and antagonize the induction of PEPCK gene expression by glucocorticoids and glucagon (or its second messenger cAMP). Insulin activates a signaling cascade involving Ras --> Raf --> p42/p44 mitogen-activated protein (MAP) kinase kinase (MEK) --> p42/p44 MAP kinase (ERK 1 and 2). Recent reports suggest that activation of this Ras/MAP kinase pathway is critical for the effects of insulin on mitogenesis and c-fos transcription but is not required for insulin action on metabolic processes such as glycogen synthesis, lipogenesis, and Glut-4-mediated glucose transport. We have used three distinct approaches to examine the role of the Ras/MAP kinase pathway in the regulation of PEPCK transcription by insulin in H4IIE-derived liver cells: (i) chemical inhibition of Ras farnesylation, (ii) infection of cells with an adenovirus vector encoding a dominant-negative mutant of Ras, and (iii) use of a chemical inhibitor of MEK. Although each of these methods blocks insulin activation of MAP kinase, none alters insulin antagonism of cAMP- and glucocorticoid-stimulated PEPCK transcription. Although phorbol esters activate MAP kinase and mimic the effects of insulin on PEPCK gene transcription, inhibition of MEK has no effect on phorbol ester inhibition of PEPCK gene transcription. Using the structurally and mechanistically distinct phosphatidylinositol 3-kinase (PI 3-kinase) inhibitors, wortmannin and LY 294002, we provide further evidence supporting a role for PI 3-kinase activation in the regulation of PEPCK gene transcription by insulin. We conclude that neither insulin nor phorbol ester regulation of PEPCK gene transcription requires activation of the Ras/MAP kinase pathway and that insulin signaling to the PEPCK promoter is dependent on PI 3-kinase activation.
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PMID:Insulin regulation of phosphoenolpyruvate carboxykinase gene expression does not require activation of the Ras/mitogen-activated protein kinase signaling pathway. 856 35

Pituitary adenylate cyclase-activating polypeptide (PACAP), a neuropeptide belonging to the VIP/secretin/glucagon family, is present in the hypothalamus, anterior pituitary, and adrenal gland where it regulates hormone release, in the GI tract where it modulates motility, and in human tumoral cell lines where it shows a growth-promoting effect. It is now appreciated that alternative splicing of two exons of the rat PACAP-R gene generate four major rPACAP-R splice variants that are differentially expressed in tissues and variably coupled to intracellular second messengers. Because of the potential implications of these findings in human physiology, we cloned the hPACAP-R gene. Similar to the rat, two exons (SV-1 and SV-2) are alternatively spliced to account for four major hPACAP-R receptor splice variants. These splice variants (hPACAP-R-null, hPACAP-R-SV1, hPACAP-R-SV2, hPACAP-R-SV-3) were cloned from a human frontal cortex cDNA library, stably transfected in NIH/ 3T3 cells and each characterized for ligand affinity, stimulation of adenylate cyclase (AC) and phospholipase C (PLC), and ligand-induced expression of the proto-oncogenes, c-fos, and c-myc. Stably transfected NIH/3T3 cells expressing similar numbers of receptors of the four splice variants showed nearly identical responses for ligand affinity and potency for P-38- and P-27-stimulated increases in cAMP and total inositol phosphates. However, each receptor splice variant differed in their ligand-stimulated efficacy for total inositol phosphate stimulation. The hPACAP-R-SV2 showed the greatest efficacy for stimulating phospholipase C that was approximately seven-fold greater than the hPACAP-R-SV1, twofold greater than the hPACAP-R-Null, and 1.5-fold greater than the hPACAP-R-SV-3 splice variants. To determine whether the splice variants also differ in their ability to stimulate immediate early gene expression, c-fos and c-myc transcripts were assayed by Northern blot and quantified by densitometry. PACAP-38 increased c-fos and c-myc expression for all four of the receptor splice variants that paralleled the efficacy for PLC stimulation, with the the SV-2 splice variant showing the greatest stimulation. These results show that the hPACAP-R-SV2 exhibits enhanced efficacy for coupling to both PLC and activation of the protooncogenes, c-fos and c-myc suggesting a novel and potentially important mechanism for differentially activating signal transduction pathways that influence cellular growth and differentiation.
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PMID:Differential signaling and immediate-early gene activation by four splice variants of the human pituitary adenylate cyclase-activating polypeptide receptor (hPACAP-R). 899 93

Within the central nervous system, glucagon-like peptide-1-(7-36) amide (GLP-1) acts as a transmitter, inhibiting feeding and drinking behavior. Hypothalamic neuroendocrine neurons are centrally involved in the regulatory mechanisms controlling these behaviors, and high densities of GLP-1 binding sites are present in the rat hypothalamus. In the present study we have, over a period of 4 h, followed the effect of centrally injected GLP-1 on plasma levels of the neurohypophysial hormones vasopressin and oxytocin. Plasma levels of corticosterone and glucose were also followed across time after central administration of GLP-1. In conscious, freely moving, and unstressed rats, central injection of GLP-1 significantly elevated plasma levels of vasopressin 15 and 30 min after administration (basal, 0.8 +/- 0.2 pg/ml; 15 min, 7.5 +/- 2.0 pg/ml; 30 min, 5.6 +/- 1.1 pg/ml; mean +/- SEM) and elevated corticosterone 15 min after administration (52 +/- 13 vs. 447 +/- 108 ng/ml, basal vs. 15 min; mean +/- SEM). In contrast, plasma oxytocin levels were unaffected by intracerebroventricular (icv) injections of GLP-1 over a period of 4 h after the injection. The animals given a central injection of GLP-1 developed transient hypoglycemia 20 min after the injection, which was fully restored to normal levels at 30 min. Furthermore, we used c-fos immunocytochemistry as an index of stimulated neuronal activity. The distribution and quantity of GLP-1-induced c-fos immunoreactivity were evaluated in a number of hypothalamic neuroendocrine areas, including the magnocellular neurons of the paraventricular (PVN) and supraoptic (SON) nuclei and the parvicellular neurons of the medial parvicellular subregion of the PVN. The number of c-fos-expressing nuclei in those areas was assessed 30, 60, and 90 min after icv administration of GLP-1. Intracerebroventricular injection of GLP-1 induced c-fos expression in the medial parvicellular subregion of the PVN as well as in magnocellular neurons of the PVN and SON. A slight induction of c-fos expression was seen in the arcuate nucleus and the nucleus of the solitary tract, including the area postrema. In contrast, the subfornical organ, which is a rostrally situated circumventricular organ, was free of c-fos-positive cells after central administration of GLP-1. When the GLP-1 antagonist exendin-(9-39) was given before the GLP-1, c-fos expression in these neuroendocrine areas was almost completely abolished, suggesting that the effect of GLP-1 on c-fos expression is mediated via specific receptors. A dual labeling immunocytochemical technique was used to identify the phenotypes of some of the neurons containing c-fos-immunoreactive nuclei. Approximately 80% of the CRH-positive neurons in the hypophysiotropic medial parvicellular part of the PVN coexpressed c-fos 90 min after icv GLP-1 administration. In contrast, very few (approximately 10%) of the vasopressinergic magnocellular neurons of the PVN/SON contained c-fos-positive nuclei, whereas approximately 38% of the magnocellular oxytocinergic neurons expressed c-fos-positive nuclei in response to GLP-1 administration. This study demonstrates that central administration of the anorectic neuropeptide GLP-1 activates the central CRH-containing neurons of the hypothalamo-pituitary-adrenocortical axis as well as oxytocinergic neurons of the hypothalamo-neurohypophysial tract. Therefore, we conclude that GLP-1 activates the hypothalamo-pituitary-adrenocortical axis primarily through stimulation of CRH neurons, and this activation may also be responsible for the inhibition of feeding behavior.
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PMID:Central administration of glucagon-like peptide-1 activates hypothalamic neuroendocrine neurons in the rat. 932 62

I.c.v. administration of glucagon-like peptide-1 (7-36) amide (GLP-1) dose dependently suppresses food intake in rats, and induces activation of c-fos within rat paraventricular hypothalamus (PVN). The present study sought to determine whether GLP-1 (7-36) amide may act within the PVN by examining the effects of intra-PVN administration of GLP-1 (7-36) amide on food intake in rats. Adult male rats (n = 11) were prepared with indwelling guide cannulae aimed at the PVN. Rats were allowed access to a palatable liquid diet (Ensure) and water during a daily 60-min test period with intakes measured every 15 min. Intra-PVN administration of GLP-1 (7-36) amide (10, 50, 100 and 200 ng) did not alter latency to feed, but did suppress liquid diet intake over a 1-h testing period, as a function of dose. These results suggest that GLP-1 (7-36) amide may act, in part, to suppress feeding through interactions with cells within the PVN.
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PMID:Decreased intake of a liquid diet in nonfood-deprived rats following intra-PVN injections of GLP-1 (7-36) amide. 932 57

Luminal and systemic short chain fatty acids (SCFA) stimulate mucosal proliferation but the mechanism(s) is unclear. This study examined acute effects of systemic SCFAs on gastrointestinal structure and function and signals potentially mediating SCFA-induced mucosal proliferation. Male Sprague-Dawley rats (246+/-2 g) received nutrients as either standard total parenteral nutrition (TPN) or an isoenergetic, isonitrogenous formulation containing SCFAs (TPN + SCFA). Animals were randomized to one of five treatments: standard TPN for 72 hr, TPN + SCFA for 72 hr, or standard TPN followed by TPN + SCFA for the final 6, 12, and 24 hr. SCFAs reduced (P < 0.003) ileal protein within 6 hr. Jejunal GLUT2 expression was increased (P=0.0001) in all SCFA groups and ileal GLUT2 protein in the 6-, 12-, and 24-hr SCFA groups (P < 0.05). SCFAs increased (P < 0.003) ileal proglucagon abundance following 6, 12, and 24 hr, and plasma GLP-2 concentration following 12 hr (P < 0.03). Jejunal c-myc expression was increased (P < 0.001) following 6, 12, and 24 hr of SCFAs. SCFAs increased ileal c-myc, c-jun, and c-fos expression following 24 hr (P < 0.02), 12 hr (P < 0.05) and 6, 12, and 24 hr (P=0.0001), respectively. In conclusion, systemic SCFAs increase plasma GLP-2 and ileal proglucagon mRNA, GLUT2 expression and protein, and c-myc, c-jun, and c-fos expression.
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PMID:Systemic short-chain fatty acids rapidly alter gastrointestinal structure, function, and expression of early response genes. 969 Mar 91

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

Glucose controls long-term processes in the pancreatic beta-cell such as metabolic enzymes gene expression, cell growth, and apoptosis. Such control is likely mediated via the expression of immediate-early response genes since several of these genes including c-fos are strongly induced by glucose in the beta-cell line INS-1, provided costimulation with cAMP-raising glucoincretin hormones. This study addresses the mechanism of c-fos gene activation by glucose. Glucose in the presence of chlorophenylthio-cAMP generated a low threefold induction of the c-fos/basic luciferase reporter gene, which includes only the c-fos promoter. In contrast, the c-fos/intron construct containing the first intron in addition to promoter elements showed a pronounced 16-fold induction, comparable to the increased c-fos mRNA accumulation. Similar observations were made with glucose in combination with the glucoincretins glucagon-like peptide 1, glucose-dependent insulinotropic polypeptide, and pituitary adenylyl cyclase-activating peptide 38. Deletion of a 119 bp region in intron 1 that includes a transcriptional arrest site did not affect the inductive process. In contrast, a 534 bp deletion comprising a major part of the intron reduced the induction by 75%. At the promoter level, mutating the cAMP response element reduced by more than 60% the transcriptional activation whereas mutating the serum response element had no effect. Inhibitors of protein kinase A and Ca(2+)/calmodulin-dependent protein kinases each reduced by 50% the reporter gene activation and together fully prevented the glucose-glucoincretin effect. In conclusion, the strong induction of c-fos by glucose and glucoincretins results from Ca(2+) and cAMP signaling pathways addressing both the CRE in the promoter and essential response element(s) in the first intron that are unrelated to the transcription arrest site.
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PMID:Essentiality of intron control in the induction of c-fos by glucose and glucoincretin peptides in INS-1 beta-cells. 1062 87


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