UNIPROT:P01275 - FACTA Search

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)

Recently, it was shown that lipoprotein lipase (LPL) was produced in neonatal but not in adult rat liver. In an attempt to further define the mechanism involved in liver LPL expression, we identified a neonatal mouse hepatoma cell line, BWTG3, capable of producing LPL. The regulation of LPL expression by various extracellular stimuli was investigated in this cell line. Progesterone caused a rise in LPL production by BWTG3 cells. Other hormones tested, such as insulin, glucagon, adrenalin, testosterone, and thyroid hormone, had no effect on LPL production. The effects of progesterone on LPL production showed slow kinetics reaching a maximum 24 h after addition. Cotransfection of a progesterone receptor expression vector with a 5'-LPL-CAT reporter construct resulted in an induction of CAT activity, suggesting that the increase in LPL accumulation after progesterone was linked to transcriptional induction of the LPL gene. Stimuli causing an elevation of protein kinase A activity in the cells also increased LPL production. Three agents capable of elevating intracellular cAMP levels, i.e., forskolin, dBcAMP, and choleratoxin, caused an elevation of LPL production. The increase in LPL activity caused by forskolin and choleratoxin was paralleled by an elevation of LPL mRNA levels, while dBcAMP only induced a small elevation of LPL mRNA levels. The increase in LPL production was shown to be linked to the stimulation of the PKA signal transduction pathway and was apparently transmitted via the transcription factor CREB. No effect of the stimulation of protein kinase C or calcium/calmodulin-dependent kinase on LPL production was detected.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Lipoprotein lipase expression in undifferentiated hepatoma cells is regulated by progesterone and protein kinase A. 132 33

The expression of the genes encoding the hormones glucagon, insulin, somatostatin, and pancreatic polypeptide in the endocrine islets of the pancreas is regulated in a cell-specific manner, defining four distinct cellular phenotypes (A-, B-, D-, and F-cells, respectively). Binding of nuclear proteins to cognate DNA sequences within cis-acting regulatory elements mediates the transcriptional events that result in the cell-specific activation or repression of gene expression. In a parallel study, we describe the functional properties of the SMS-UE, a pancreatic islet D-cell specific enhancer element that regulates the expression of the somatostatin gene and contains two interdependent domains, A and B. In the studies described herein, we have characterized the nuclear proteins that recognize the SMS-UE. Domain A of the SMS-UE is a DNA enhancer sequence that is identical to that bound by the ubiquitously distributed CCAAT box-binding protein alpha-CBF, a transcription factor that regulates the expression of the human chorionic gonadotrophin alpha-subunit gene. The B-domain, on the other hand, binds an islet cell-specific protein with characteristics similar to those of Isl-1, a transcriptional activator protein that binds to the E2 enhancer of the rat insulin-1 gene. In addition, the SMS-UE binds transcription factor CREB but not CREM, the close homolog of CREB, on a site adjacent to, or overlapping, the 3' end of domain B. We show that the carboxyl-terminal bZIP domain of CREB binds to the cAMP response element of the somatostatin gene but is not sufficient for binding to the SMS-UE, and we present evidence suggesting that CREB.SMS-UE binding requires stabilization by a region of the protein located within the transactivation domain.
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PMID:Somatostatin gene upstream enhancer element activated by a protein complex consisting of CREB, Isl-1-like, and alpha-CBF-like transcription factors. 135 92

Cyclosporin A and the macrolide tacrolimus (FK506) are powerful immunosuppressive drugs that in T cells inhibit the calcium/calmodulin-dependent phosphatase calcineurin thereby preventing the activation of T-cell-specific transcription factors, such as NF-AT, involved in lymphokine gene expression. While this may explain, at least in part, the mechanism of cyclosporin A/FK506 immunosuppression, additional mechanisms have to be invoked in order to explain the pharmacological properties and toxic effects of these drugs, such as nephrotoxicity and neurotoxicity. We have studied the effects of cyclosporin A and FK506 on calcineurin phosphatase activity and gene transcription mediated by the cAMP-responsive element (CRE), a binding site of the ubiquitous transcription factor CREB. A reporter gene was placed under the transcriptional control of the CRE of the rat glucagon gene and transiently transfected into the glucagon-expressing cell line alpha TC2. Cyclosporin A and FK506 inhibited depolarization-induced gene transcription in a concentration-dependent manner (IC50 of about 1 nM and 30 nM for FK506 and cyclosporin A, respectively). Both cyclosporin A and FK506 inhibited calcineurin phosphatase activity at drug concentrations that inhibited gene transcription. The FK506 analogue rapamycin had no effect on calcineurin activity and gene transcription, but excess concentrations of rapamycin prevented the effects of FK506 on both calcineurin activity and gene transcription. These results support the notion that the interaction of drug-immunophilin complexes with calcineurin may be the molecular basis of cyclosporin A/FK506-induced inhibition of CREB/CRE-mediated gene transcription. The ability to interfere with CREB/CRE-mediated gene transcription represents a novel mechanism of cyclosporin A/FK506 action which may underlie pharmacological effects and toxic manifestations of these potent immunuosuppressive drugs.
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PMID:The immunosuppressive drugs cyclosporin A and FK506 inhibit calcineurin phosphatase activity and gene transcription mediated through the cAMP-responsive element in a nonimmune cell line. 750 60

cAMP has neutrotrophic effects in the nervous system. We have investigated whether there is a correlation between cAMP-induced neurite outgrowth and induction of chromogranin B and synapsin I gene expression. These genes encode marker proteins of distinct populations of vesicles in neurons, neuroendocrine and endocrine cells, and in addition, they contain a cAMP response element (CRE) in their upstream regions, making it likely that cAMP-induced neuronal differentiation might be accompanied by increased transcription of these genes. We increased intracellular cAMP levels in neuronal and neuroendocrine cells and analyzed the levels of chromogranin B and synapsin I mRNA. Our data revealed that, while chromogranin B mRNA was in fact induced following cAMP stimulation, synapsin I mRNA was not affected. To analyze the cis-acting sequences, we constructed hybrid genes containing the upstream region of the mouse chromogranin B gene fused to a reporter gene. Similar plasmids containing the synapsin I or the glucagon promoter were constructed. Transfections of neuronal and endocrine cells, together with deletion mutagenesis, revealed that the CRE of the chromogranin B gene mediated the effect of cAMP upon transcription. This effect was mimicked by overexpression of the catalytic subunit of the cAMP-dependent protein kinase. In addition, overexpression of the negative-acting CRE-binding protein CREB-2 revealed that the chromogranin B CRE functions as a bifunctional genetic regulatory element in that it mediates basal as well as cAMP-stimulated transcription. Synapsin I gene expression, however, was not induced by either elevated intracellular cAMP concentration or by overexpression of protein kinase A, although a similar pattern of proteins, including CREB, bound to the synapsin I and chromogranin B CRE in vitro. Thus while the CRE element in the chromogranin B gene promoter is responsive to cAMP, the same element, when present in the synapsin I promoter, does not confer cAMP inducibility.
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PMID:Differential regulation of chromogranin B and synapsin I gene promoter activity by cAMP and cAMP-dependent protein kinase. 752 78

The cAMP-responsive element (CRE)-binding transcription factor CREB confers basal as well as cAMP- and calcium-induced transcription. Activation of CREB occurs by phosphorylation on serine-119 stimulating its transactivating potency. However, the regulation of CREB-DNA binding by posttranslational modification is not established. In this study, using binding and functional assays, the interaction of CREB with pancreatic islet cell-specific enhancer elements of the rat somatostatin (SMS-UE), glucagon (Glu-G3) and insulin I genes (Ins-E1) was investigated, which share a functional regulatory sequence, PISCES, with islet-specific activity. CREB bound to the SMS-UE. Bacterially expressed recombinant CREB bound equally well to the SMS-UE and to the somatostatin CRE. However, cellular CRE-binding proteins with CREB-like immunoreactivity recognized the SMS-UE markedly less well than the somatostatin CRE suggesting the existence of a posttranslational modification of CREB that alters its binding specificity.
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PMID:Interaction of the transcription factor CREB with pancreatic islet cell-specific enhancer elements. 761 87

The cAMP-responsive element (CRE) and its cognate transcription factor CREB can mediate induction of gene transcription in response to membrane depolarization and calcium influx. In this study, the effect of cyclosporin A (CsA) and FK506 on depolarization-induced glucagon gene transcription was investigated in a pancreatic islet cell line by transfection of reporter fusion genes. CsA and FK506 inhibited depolarization-induced glucagon gene transcription, FK506 being more potent than CsA. CsA/FK506 responsiveness was mediated by the glucagon CRE and also by well characterized CREs of the choriogonadotropin and somatostatin genes. Rapamycin antagonized the inhibitory effect of FK506 but not CsA, suggesting that FK506 and CsA may act through complex formation with distinct intracellular immunophilins. Overexpression of calcineurin, which is known to be inhibited by drug-immunophilin complexes, rendered pancreatic islet cells more resistant to the inhibitory effects of CsA and FK506. These results demonstrate an inhibition by CsA and FK506 of CRE-mediated, calcium-induced transcription and suggest that membrane depolarization relies on calcineurin phosphatase activity for activation of CREB/CRE-mediated gene transcription. The interference with CRE-mediated gene transcription represents a novel mechanism of CsA/FK506 action, which may underlie pharmacological effects and toxic manifestations of these potent immunosuppressive drugs.
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PMID:Inhibition of cAMP-responsive element-mediated gene transcription by cyclosporin A and FK506 after membrane depolarization. 769 84

Carnitine-deficient jvs mice expressed reduced levels of a group of genes which are preferentially expressed in the liver, including urea cycle enzyme genes (Biochim. Biophys. Acta 1138, 167-171, 1992). The expression of alpha-fetoprotein and aldolase A was elevated, indicating that the liver of jvs mice is undifferentiated or dedifferentiated (FEBS Lett. 311, 63-66, 1992). Studies of the hormone signal transduction pathway showed that serum cortisol and plasma glucagon levels of jvs mice were 2 and 3 times higher, respectively, than those of normal mice, and that the hormone binding activity of glucocorticoid receptor (GR) in the cytosol of jvs liver was 50% of normal mice, which reflected the amount of receptor protein in the cytosol. On the other hand, GR protein accumulated in the nuclear fraction in jvs mice. Exogenously administrated dexamethasone induced carbamoyl phosphate synthetase (CPS) and tyrosine aminotransferase (TAT) mRNAs in jvs mice, indicating that CPS and TAT genes in jvs mice are responsive to induction by glucocorticoid and cAMP. Analysis of transacting factors by gel retardation assay revealed that HNF-1, COUP-TF and SP-1 were detected at almost the same level in the hepatic nuclear fraction of jvs mice as in normal littermates, and C/EBP and CREB were a little higher in jvs mice, suggesting that these factors are probably not targets of jvs mutation causing abnormal gene expression in the liver. On the other hand, AP-1 binding activity was much higher in jvs mice from an early age, preceding the abnormal expression of urea cycle enzyme, and carnitine administration normalized AP-1 binding activity. We suggest that elevated AP-1 binding induced by carnitine deficiency is closely connected with the abnormal gene expression in the liver.
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PMID:Abnormal gene expression and regulation in the liver of jvs mice with systemic carnitine deficiency. 791 32

The cAMP response element (CRE)-binding transcription factor CREB can mediate induction of gene transcription in response to calcium as well as to cAMP. Since the rat insulin I gene 5'-flanking region contains a CRE with an octamer-like motif (TGACGTCC), CREB binding and cAMP/calcium responsiveness of the insulin CRE were investigated. In an electrophoretic mobility shift assay and in Southwestern blot experiments, bacterially expressed recombinant CREB bound to the insulin CRE as it did to the rat glucagon and rat somatostatin gene CREs. However, in nuclear extracts of the pancreatic islet cell line HIT, protein complexes binding to the insulin CRE did not contain proteins with CREB-like immunoreactivity, although these bound to the glucagon and somatostatin CREs. When reporter fusion genes were transfected into HIT cells, the isolated insulin CRE increased basal activity and mediated transcriptional activation by cAMP. However, cAMP stimulation of transcription through the insulin CRE was weak when compared with the response through the glucagon and somatostatin CREs. Furthermore, the insulin CRE did not confer responsiveness to membrane depolarization and calcium influx, in contrast to the glucagon and somatostatin CREs. These results demonstrate that the functional properties of the rat insulin I gene CRE are different from those of the rat glucagon and somatostatin CREs which may be explained by a distinct pattern of nuclear protein binding and suggest the existence of post-translational mechanisms that decrease the binding of cellular CREB to the insulin CRE.
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PMID:Distinct properties of the cAMP-responsive element of the rat insulin I gene. 792 45

Glucagon-producing pancreatic islet cells generate calcium-dependent action potentials. By the control of calcium influx through voltage-gated calcium channels, calcium is a tightly regulated second messenger in these cells. It is unknown whether calcium is a signal for glucagon gene transcription. Therefore, rat glucagon reporter fusion genes were transiently transfected into pancreatic islet cell lines. High potassium-induced membrane depolarization activated glucagon gene transcription. The effects of a calcium chelator, calcium channel blockers, calmodulin antagonists, and an inhibitor of calcium/calmodulin-dependent protein kinase II (CaM kinase II) indicate that depolarization-induced glucagon gene transcription depends on calcium influx and CaM kinase II. The depolarization-responsive element was mapped to the glucagon cAMP-responsive element (CRE). The CRE-binding protein CREB was shown, by using GAL4-CREB fusion proteins, to function as a depolarization-regulated transcription factor in pancreatic islet cells. Membrane depolarization and cAMP had synergistic effects on glucagon gene transcription. These results suggest that rat glucagon gene transcription is regulated by membrane electrical activity and calcium influx in pancreatic islet cells. This signal may be transmitted via CaM kinase II and CREB to the glucagon CRE.
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PMID:Membrane depolarization and calcium influx induce glucagon gene transcription in pancreatic islet cells through the cyclic AMP-responsive element. 838 30

The cyclic AMP (cAMP) response element (CRE) of the rat glucagon gene (Glu-CRE, 5'-TGACGTCA-3') mediates transcriptional responses to 8-bromo-cAMP and protein kinase A (PKA) in a glucagon-producing hamster islet cell line (InR1G9). By several different DNA-protein binding assays, we show that the transcription factor CREB binds to the CRE octamer and that additional nuclear proteins bind to sequences adjacent to the CRE. Mutation of the Glu-CRE octamer attenuates both the binding of CREB and cAMP-dependent PKA-stimulated transcriptional activity in transient transfection experiments but does not affect the binding of adjacent CREB-associated proteins. Progressive deletions and clustered point mutations of the sequences flanking the Glu-CRE identify sequences (5'-TCATT-3') located both 5' and 3' to the core CRE octamer that bind several proteins. Two proteins with molecular masses of 80 and 100 kDa bind to each of the 5' and 3' TCATT sites. Formation of additional protein-DNA complexes containing 45- and 20-kDa proteins depends upon the integrity of both TCATT sequences. Deletion or point mutation of the TCATT motif located on the 3' side of the CRE octamer results in enhanced transcriptional responses to PKA, suggesting that the CREB-associated proteins decrease the ability of CREB to mediate PKA-stimulated transcription. Results from these studies demonstrate that nucleotides flanking the core CRE octamer can influence the activity of the CRE by serving as binding sites for proteins that modulate the function of CREB and suggest a mechanism to explain why some consensus palindromic CREs are less responsive to cAMP stimulation than others.
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PMID:Transcription of the rat glucagon gene by the cyclic AMP response element-binding protein CREB is modulated by adjacent CREB-associated proteins. 841 97

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