UMLS:C0001486 - FACTA Search

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Query: UMLS:C0001486 (Adenovirus)
3,125 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Studies of the regulation of androgen synthesis in steroidogenic cells have focused on both transcriptional and post-translational regulation of the proteins that catalyze these reactions: the P450c17 that catalyzes the production of DHEA or androstenedione in consecutive hydroxylase and lyase activities, and the 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) that catalyzes the conversion of androstenedione to testosterone. Our studies of the regulation of the CYP17 lyase activity at the molecular level have utilized species- and tissue-specific differences to identify target regulatory sequences. Adenovirus infection of rat CYP17 promoter/luciferase reporter gene constructs in primary cultures of rat adrenal and rat Leydig cells revealed a rat-specific domain between-1 and -108 bp that cause inhibition of both basal and cAMP-induced CYP17 transcription in the adrenal, but not the Leydig cell. In contrast, similar promoter constructs from other species exhibited substantial cAMP-induced transcriptional activity in the rat adrenal. Mutagenesis of the conserved region of the rat and human proteins reveals significant differences in the amino acid domains required for hydroxylase and lyase activities within and between the two species, consistent with their differential regulation of lyase activity. The 17 beta-hydroxysteroid dehydrogenase (17 beta-HSD) reaction requires a viable glucose transporter system for optimal activity, and a high-energy phosphate was discovered to be the requisite product of glucose metabolism in 17 beta-HSD activation. These studies have provided insight into potential mechanisms of control of androgen synthesis in the late steroidogenic pathway, at the transcriptional and post-translational levels.
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PMID:Regulation of androgen synthesis: the late steroidogenic pathway. 902 27

Adenovirus-mediated overexpression of the glucose phosphorylating enzyme glucokinase causes large changes in glycolytic flux and glucose storage in isolated rat hepatocytes, but not in pancreatic islets. We have used the well-differentiated insulinoma cell line INS-1 to investigate the basis for these apparent cell-type specific differences. We find that 2- or 5-[3H]glucose usage is increased at low (</=5 mM) but not high glucose concentrations in INS-1 cells treated with a recombinant adenovirus containing the glucokinase cDNA (AdCMV-GKI), while glucose usage is increased at both low and high glucose concentrations in similarly treated hepatocytes. Utilization of 2-[3H]glucose in INS-1 cells is suppressed in glucokinase overexpressing INS-1 cells in a rapid, glucose concentration-dependent, and reversible fashion, while such regulation is largely absent in hepatocytes. Levels of hexose phosphates (glucose-6-phosphate, fructose-6-phosphate, and fructose-1,6-bisphosphate) were profoundly and rapidly elevated following the switch to high glucose in either AdCMV-GKI-treated INS-1 cells or hepatocytes relative to controls. In contrast, triose phosphate levels (glyceraldehyde-3-phosphate + dihydroxyacetone phosphate) were much higher in AdCMV-GKI-treated INS-1 cells than in similarly treated hepatocytes, suggesting limited flux throught the glyceraldehyde-3-phosphate dehydrogenase (G3PDH) step in the former cells. Hepatocytes were found to contain approximately 62 times more lactate dehydrogenase (LDH) activity than INS-1 cells, and this was reflected in a 3-fold increase in lactate production in AdCMV-GKI-treated hepatocytes relative to similarly treated INS-1 cells. Since the amounts of G3PDH activity in INS-1 and hepatocyte extracts are similar, we suggest that flux through this step in INS-1 cells is limited by failure to regenerate NAD in the LDH reaction and that a fundamental difference between hepatocytes and islet beta-cells is the limited capacity of the latter to metabolize glycolytic intermediates beyond the G3PDH step.
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PMID:Fundamental metabolic differences between hepatocytes and islet beta-cells revealed by glucokinase overexpression. 952 75

It has been suggested that insulin secretion from pancreatic islets may be mediated in part by activation of phospholipases C (PLCs) and phosphoinositide hydrolysis. The purpose of this study was to determine whether the relatively modest fuel-stimulated insulin secretion responses of rodent beta-cell lines might be explained by inadequate expression or activation of PLC isoforms. We have found that two insulinoma cell lines, INS-1 and betaG 40/110, completely lack PLC-delta1 expression but have levels of expression of PLC-beta1, -beta2, -beta3, -delta2, and -gamma1 that are similar to or slightly reduced from those found in fresh rat islets. Adenovirus-mediated overexpression of PLC-delta1, -beta1, or -beta3 in INS-1 or betaG 40/110 cells results in little or no enhancement in inositol phosphate (IP) accumulation and no improvement in insulin secretion when the cells are stimulated with glucose or carbachol, despite the fact that the overexpressed proteins are fully active in cell extracts. Overexpression of PLC-beta1 or -beta3 in normal rat islets elicits a larger increase in IP accumulation but, again, has no effect on insulin secretion. Because the effect of carbachol on insulin secretion is thought to be mediated through muscarinic receptors that link to the Gq/11 class of heterotrimeric G proteins, we also overexpressed G11alpha in INS-1 cells, either alone or in concert with overexpression of PLC-beta1 or -beta3. Overexpression of G11alpha enhances IP accumulation, an effect slightly potentiated by co-overexpression of PLC-beta1 or -beta3, but these maneuvers do not affect glucose or carbachol-stimulated insulin secretion. In sum, our studies show a lack of correlation between IP accumulation and insulin secretion in INS-1 cells, betaG 40/110 cells, or cultured rat islets. We conclude that overexpression of PLC isoforms and/or G11alpha is not an effective means of enhancing fuel responsiveness in the insulinoma cell lines studied.
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PMID:Overexpression of G11alpha and isoforms of phospholipase C in islet beta-cells reveals a lack of correlation between inositol phosphate accumulation and insulin secretion. 1033 8

Previous investigations revealed low activities of lactate dehydrogenase (LDH) and plasma membrane monocarboxylate transporters (MCT) in the pancreatic beta cell. In this study the significance of these characteristics was explored by overexpressing type A LDH (LDH-A) and/or type 1 MCT (MCT-1) in the clonal INS-1 beta cells and isolated rat islets. Inducible overexpression of LDH-A resulted in an 87-fold increase in LDH activity in INS-1 cells. Adenovirus-mediated overexpression of MCT-1 increased lactate transport activity 3.7-fold in INS-1 cells. Although overexpression of LDH-A, and/or MCT-1 did not affect glucose-stimulated insulin secretion, LDH-A overexpression resulted in stimulation of insulin secretion even at a low lactate concentration with a concomitant increase in its oxidation in INS-1 cells regardless of MCT-1 co-overexpression. Adenovirus-mediated overexpression of MCT-1 caused an increase in pyruvate oxidation and conferred pyruvate-stimulated insulin release to isolated rat islets. Although lactate did not stimulate insulin secretion from control or MCT-1-overexpressing islets, co-overexpression of LDH-A and MCT-1 evoked lactate-stimulated insulin secretion with a concomitant increase in lactate oxidation in rat islets. These results suggest that low expression of MCT and LDH is requisite to the specificity of glucose in insulin secretion, protecting the organism from undesired hypoglycemic actions of pyruvate and lactate during exercise and other catabolic states.
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PMID:Overexpression of monocarboxylate transporter and lactate dehydrogenase alters insulin secretory responses to pyruvate and lactate in beta cells. 1058 26

The operation of glucose 6-phosphatase (EC 3.1.3.9) (Glc6Pase) stems from the interaction of at least two highly hydrophobic proteins embedded in the ER membrane, a heavily glycosylated catalytic subunit of m 36 kDa (P36) and a 46-kDa putative glucose 6-phosphate (Glc6P) translocase (P46). Topology studies of P36 and P46 predict, respectively, nine and ten transmembrane domains with the N-terminal end of P36 oriented towards the lumen of the ER and both termini of P46 oriented towards the cytoplasm. P36 gene expression is increased by glucose, fructose 2,6-bisphosphate (Fru-2,6-P2) and free fatty acids, as well as by glucocorticoids and cyclic AMP; the latter are counteracted by insulin. P46 gene expression is affected by glucose, insulin and cyclic AMP in a manner similar to P36. Accordingly, several response elements for glucocorticoids, cyclic AMP and insulin regulated by hepatocyte nuclear factors were found in the Glc6Pase promoter. Mutations in P36 and P46 lead to glycogen storage disease (GSD) type-1a and type-1 non a (formerly 1b and 1c), respectively. Adenovirus-mediated overexpression of P36 in hepatocytes and in vivo impairs glycogen metabolism and glycolysis and increases glucose production; P36 overexpression in INS-1 cells results in decreased glycolysis and glucose-induced insulin secretion. The nature of the interaction between P36 and P46 in controling Glc6Pase activity remains to be defined. The latter might also have functions other than Glc6P transport that are related to Glc6P metabolism.
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PMID:New lessons in the regulation of glucose metabolism taught by the glucose 6-phosphatase system. 1071 83

Glucokinase has a very high flux control coefficient (greater than unity) on glycogen synthesis from glucose in hepatocytes (Agius et al., J. Biol. Chem. 271, 30479-30486, 1996). Hepatic glucokinase is inhibited by a 68-kDa glucokinase regulatory protein (GKRP) that is expressed in molar excess. To establish the relative control exerted by glucokinase and GKRP, we applied metabolic control analysis to determine the flux control coefficient of GKRP on glucose metabolism in hepatocytes. Adenovirus-mediated overexpression of GKRP (by up to 2-fold above endogenous levels) increased glucokinase binding and inhibited glucose phosphorylation, glycolysis, and glycogen synthesis over a wide range of concentrations of glucose and sorbitol. It decreased the affinity of glucokinase translocation for glucose and increased the control coefficient of glucokinase on glycogen synthesis. GKRP had a negative control coefficient of glycogen synthesis that is slightly greater than unity (-1.2) and a control coefficient on glycolysis of -0.5. The control coefficient of GKRP on glycogen synthesis decreased with increasing glucokinase overexpression (4-fold) at elevated glucose concentration (35 mM), which favors dissociation of glucokinase from GKRP, but not at 7.5 mM glucose. Under the latter conditions, glucokinase and GKRP have large and inverse control coefficients on glycogen synthesis, suggesting that a large component of the positive control coefficient of glucokinase is counterbalanced by the negative coefficient of GKRP. It is concluded that glucokinase and GKRP exert reciprocal control; therefore, mutations in GKRP affecting the expression or function of the protein may impact the phenotype even in the heterozygote state, similar to glucokinase mutations in maturity onset diabetes of the young type 2. Our results show that the mechanism comprising glucokinase and GKRP confers a markedly extended responsiveness and sensitivity to changes in glucose concentration on the hepatocyte.
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PMID:The role of the regulatory protein of glucokinase in the glucose sensory mechanism of the hepatocyte. 1074 55

Glycogen-targeting subunits of protein phosphatase-1 facilitate interaction of the phosphatase with enzymes of glycogen metabolism. We have shown that overexpression of one member of the family, protein targeting to glycogen (PTG), causes large increases in glycogen storage in isolated hepatocytes or intact rat liver. In the current study, we have compared the metabolic and regulatory properties of PTG (expressed in many tissues), with two other members of the gene family, G(L) (expressed primarily in liver) and G(M)/R(Gl) (expressed primarily in striated muscle). Adenovirus-mediated expression of these proteins in hepatocytes led to the following key observations. 1) G(L) has the highest glycogenic potency among the three forms studied. 2) Glycogen synthase activity ratio is much higher in G(L)-overexpressing cells than in PTG or G(M)/R(Gl)-overexpressing cells. Thus, at moderate levels of G(L) overexpression, glycogen synthase activity is increased by insulin treatment, but at higher levels of G(L) expression, insulin is no longer required to achieve maximal synthase activity. In contrast, cells with high levels of PTG overexpression retain dose-dependent regulation of glycogen synthesis and glycogen synthase enzyme activity by insulin. 3) G(L)- and G(M)/R(Gl)-overexpressing cells exhibit a strong glycogenolytic response to forskolin, whereas PTG-overexpressing cells are less responsive. This difference may be explained in part by a lesser forskolin-induced increase in glycogen phosphorylase activity in PTG-overexpressing cells. Based on these results, we suggest that expression of either G(L) or G(M)/R(Gl) in liver of diabetic animals may represent a strategy for lowering of blood glucose levels in diabetes.
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PMID:Distinctive regulatory and metabolic properties of glycogen-targeting subunits of protein phosphatase-1 (PTG, GL, GM/RGl) expressed in hepatocytes. 1086 64

In pancreatic beta-cells, voltage-dependent K(+) (Kv) channels are potential mediators of repolarization, closure of Ca(2+) channels, and limitation of insulin secretion. The specific Kv channels expressed in beta-cells and their contribution to the delayed rectifier current and regulation of insulin secretion in these cells are unclear. High-level protein expression and mRNA transcripts for Kv1.4, 1.6, and 2.1 were detected in rat islets and insulinoma cells. Inhibition of these channels with tetraethylammonium decreased I(DR) by approximately 85% and enhanced glucose-stimulated insulin secretion by 2- to 4-fold. Adenovirus-mediated expression of a C-terminal truncated Kv2.1 subunit, specifically eliminating Kv2 family currents, reduced delayed rectifier currents in these cells by 60-70% and enhanced glucose-stimulated insulin secretion from rat islets by 60%. Expression of a C-terminal truncated Kv1.4 subunit, abolishing Kv1 channel family currents, reduced delayed rectifier currents by approximately 25% and enhanced glucose-stimulated insulin secretion from rat islets by 40%. This study establishes that Kv2 and 1 channel homologs mediate the majority of repolarizing delayed rectifier current in rat beta-cells and that antagonism of Kv2.1 may prove to be a novel glucose-dependent therapeutic treatment for type 2 diabetes.
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PMID:Members of the Kv1 and Kv2 voltage-dependent K(+) channel families regulate insulin secretion. 1146 64

Insulin biosynthesis and secretion are critical for pancreatic beta-cell function, but both are impaired under diabetic conditions. We have found that hyperglycemia induces the expression of the basic helix-loop-helix transcription factor c-Myc in islets in several different diabetic models. To examine the possible implication of c-Myc in beta-cell dysfunction, c-Myc was overexpressed in isolated rat islets using adenovirus. Adenovirus-mediated c-Myc overexpression suppressed both insulin gene transcription and glucose-stimulated insulin secretion. Insulin protein content, determined by immunostaining, was markedly decreased in c-Myc-overexpressing cells. In gel-shift assays c-Myc bound to the E-box in the insulin gene promoter region. Furthermore, in betaTC1, MIN6, and HIT-T15 cells and primary rat islets, wild type insulin gene promoter activity was dramatically decreased by c-Myc overexpression, whereas the activity of an E-box mutated insulin promoter was not affected. In HeLa and HepG2 cells c-Myc exerted a suppressive effect on the insulin promoter activity only in the presence of NeuroD/BETA2 but not PDX-1. Both c-Myc and NeuroD can bind the E-box element in the insulin promoter, but unlike NeuroD, the c-Myc transactivation domain lacked the ability to activate insulin gene expression. Additionally p300, a co-activator of NeuroD, did not function as a co-activator of c-Myc. In conclusion, increased expression of c-Myc in beta-cells suppresses the insulin gene transcription by inhibiting NeuroD-mediated transcriptional activation. This mechanism may explain some of the beta-cell dysfunction found in diabetes.
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PMID:Induction of c-Myc expression suppresses insulin gene transcription by inhibiting NeuroD/BETA2-mediated transcriptional activation. 1179 23

Using adenovirus-mediated gene transfer into FTO-2B cells, a rat hepatoma cell line, we have overexpressed hexokinase I (HK I), glucokinase (GK), liver glycogen synthase (LGS), muscle glycogen synthase (MGS), and combinations of each of the two glucose-phosphorylating enzymes with each one of the GS isoforms. FTO-2B cells do not synthesize glycogen even when incubated with high doses of glucose. Adenovirus-induced overexpression of HK I and/or LGS, two enzymes endogenously expressed by these cells, did not produce a significant increase in the levels of active GS and the total glycogen content. In contrast, GK overexpression led to the glucose-dependent activation of endogenous or overexpressed LGS and to the accumulation of glycogen. Similarly overexpressed MGS was efficiently activated by the glucose-6-phosphate (Glc-6-P) produced by either endogenous or overexpressed HK I and by overexpressed GK. These results indicate the existence of at least two pools of Glc-6-P in the cell, one of them is accessible to both isoforms of GS and is replenished by the action of GK, whereas LGS is excluded from the cellular compartment where the Glc-6-P produced by HK I is directed. These findings are interpreted in terms of the metabolic role that the two pairs of enzymes, HK I-MGS in the muscle and GK-LGS in the hepatocyte, perform in their respective tissues.
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PMID:Liver glycogen synthase but not the muscle isoform differentiates between glucose 6-phosphate produced by glucokinase or hexokinase. 1217 43

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