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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycogen, a branched polymer of glucose, is a storage molecule whose accumulation is under rigorous nutritional control in many cells. We report the identification of two Saccharomyces cerevisiae genes, GLG1 and GLG2, whose products are implicated in the biogenesis of glycogen. These genes encode self-glucosylating proteins that in vitro can act as primers for the elongation reaction catalyzed by glycogen synthase. Over a region of 258 residues, the Glg proteins have 55% sequence identify to each other and approximately 33% identity to glycogenin, a mammalian protein postulated to have a role in the initiation of glycogen biosynthesis. Yeast cells defective in either GLG1 or GLG2 are similar to the wild type in their ability to accumulate glycogen. Disruption of both genes results in the inability of the cells to synthesize glycogen despite normal levels of glycogen synthase. These results suggest that a self-glucosylating protein is required for glycogen biosynthesis in a eukaryotic cell. The activation state of glycogen synthase in glg1 glg2 cells is suppressed, suggesting that the Glg proteins may additionally influence the phosphorylation state of glycogen synthase.
Mol Cell Biol 1995 Dec
PMID:Requirement of the self-glucosylating initiator proteins Glg1p and Glg2p for glycogen accumulation in Saccharomyces cerevisiae. 852 28

Glycogen synthase, the regulatory enzyme of glycogen synthesis undergoes multisite phosphorylation leading to its inactivation. The kinases responsible for this covalent modification (ex. cAMP-dependent protein kinase, protein kinase C and glycogen synthase kinase-3) are controlled by the second messengers generated by different hormones. The isolated hepatocytes has been used as one of the experimental models for studying this complex regulatory process. Inactivation of glycogen synthase by glucagon and vasopressin has been shown to be accompanied with incorporation of phosphate into the enzyme protein. Insulin has been shown to activate glycogen synthase by inhibition of kinases and activation of synthase phosphatase. Glycogen synthase is activated by several gluconeogenic substrates, in addition to glucose. Studies in hepatocytes with activators and inhibitors of protein kinase C show that this enzyme negatively controls glycogen synthase. The differential effects of the phosphatase inhibitors, calyculin A and okadaic acid in liver cells provide supporting evidence that protein phosphatase type-1 plays a major role in the regulation of glycogen synthase. Hepatocytes isolated from diabetic rats of both types (insulin-dependent and non-insulin-dependent) mimic the defective glycogen synthase activation seen in vivo.
Mol Cell Biochem
PMID:Regulation of glycogen synthase activation in isolated hepatocytes. 856 54

In the yeast Saccharomyces cerevisiae, glycogen synthase is encoded by two genes: GSY1 and GSY2. The activity of the enzymes increases as cultures enter the stationary phase of growth. Using a GSY2::lacZ fusion gene, we have demonstrated that the increase in glycogen synthase activity resulted, at least in part, from an increase in the level of the protein rather than simply from a change in its phosphorylation state. Northern blot analysis showed a parallel increase in the level of the GSY2 mRNA, which is consistent with transcriptional activation of GSY2. Deletion analysis identified three regions upstream of GSY2 which are involved in GSY2 expression: regions A (-390 to -347 relative to the start of translation), B (-252 to -209) and C (-209 to -167). Region A or C independently activated expression of GSY2. In contrast, region B alone yielded only modest expression. Expression of GSY2 is induced by growth to stationary phase, heat shock or nitrogen starvation. Response to these stressors is mediated by elements within regions A and C. These elements appear to be related to the stress-response elements found in other stress-responsive genes.
Mol Microbiol 1995 Jun
PMID:Response of a yeast glycogen synthase gene to stress. 857 53

The role of phosphatidylinositol (PI) 3-kinase in specific aspects of insulin signaling was explored in 3T3-L1 adipocytes. Inhibition of PI 3-kinase activity by LY294002 or wortmannin significantly enhanced basal and insulin-stimulated GTPase-activating protein (GAP) activity in 3T3-L1 adipocytes. Furthermore, removal of the inhibitory influence of PI 3-kinase on GAP resulted in dose-dependent decreases in the ability of insulin to stimulate p21ras. This effect was specific to adipocytes, as inhibition of PI 3-kinase did not influence GAP in either 3T3-L1 fibroblasts, Rat-1 fibroblasts, or CHO cells. Immunodepletion of either of the two subunits of the PI 3-kinase (p85 or p110) yielded similar activation of GAP, suggesting that catalytic activity of p110 plays an important role in controlling GAP activity in 3T3-L1 adipocytes. Inhibition of PI 3-kinase activity in 3T3-L1 adipocytes resulted in abrogation of insulin-stimulated glucose uptake and thymidine incorporation. In contrast, effects of insulin on glycogen synthase and mitogen-activated protein kinase activity were inhibited only at higher concentrations of LY294002. It appears that in adipocytes, P1 3-kinase prevents activation of GAP. Inhibition of PI 3-kinase activity or immunodepletion of either one of its subunits results in activation of GAP and decreases in GTP loading of p21ras.
Mol Cell Biol 1996 Apr
PMID:Functional interactions of phosphatidylinositol 3-kinase with GTPase-activating protein in 3T3-L1 adipocytes. 865 18

In Saccharomyces cerevisiae, nutrient levels control multiple cellular processes. Cells lacking the SNF1 gene cannot express glucose-repressible genes and do not accumulate the storage polysaccharide glycogen. The impaired glycogen synthesis is due to maintenance of glycogen synthase in a hyperphosphorylated, inactive state. In a screen for second site suppressors of the glycogen storage defect of snf1 cells, we identified a mutant gene that restored glycogen accumulation and which was allelic with PHO85, which encodes a member of the cyclin-dependent kinase family. In cells with disrupted PHO85 genes, we observed hyperaccumulation of glycogen, activation of glycogen synthase, and impaired glycogen synthase kinase activity. In snf1 cells, glycogen synthase kinase activity was elevated. Partial purification of glycogen synthase kinase activity from yeast extracts resulted in the separation of two fractions by phenyl-Sepharose chromatography, both of which phosphorylated and inactivated glycogen synthase. The activity of one of these, GPK2, was inhibited by olomoucine, which potently inhibits cyclin-dependent protein kinases, and contained an approximately 36-kDa species that reacted with antibodies to Pho85p. Analysis of Ser-to-Ala mutations at the three potential Gsy2p phosphorylation sites in pho85 cells implicated Ser-654 and/or Thr-667 in PHO85 control of glycogen synthase. We propose that Pho85p is a physiological glycogen synthase kinase, possibly acting downstream of Snf1p.
Mol Cell Biol 1996 Aug
PMID:Pho85p, a cyclin-dependent protein kinase, and the Snf1p protein kinase act antagonistically to control glycogen accumulation in Saccharomyces cerevisiae. 875 36

The cDNA for mouse brain glycogen synthase has been isolated by screening a mouse cerebral cortical astrocyte lambda ZAP II cDNA library. The mouse brain glycogen synthase cDNA is 3.5 kilobases in length and encodes a protein of 737 amino acids. The coding sequence of mouse brain glycogen synthase cDNA shares approximately 87% nucleotide identity and approximately 96% amino acid identity with the muscle isozyme, while the degree of identity is lower with the liver isozyme. The regional distribution of glycogen synthase mRNA determined by in situ hybridization in the mouse brain reveals a wide distribution throughout the central nervous system with highest densities observed in the cerebellum, hippocampus and olfactory bulb. At the cellular level the expression of brain glycogen synthase mRNA is localized both in astrocytes and neurons with, however, the higher levels observed in astrocytes. Vasoactive intestinal peptide and noradrenaline, two neurotransmitters previously shown to induce a glycogen resynthesis in cultured astrocytes, upregulate the expression of glycogen synthase mRNA in this cell type but not in neurons.
Brain Res Mol Brain Res 1996 Jun
PMID:Cloning, localization and induction of mouse brain glycogen synthase. 879 7

It has been observed that in growth arrested vascular smooth muscle cells herbimycin A treatment completely inhibits the activation of mitogen activated protein kinase induced by phorbol 12-myristate 13-acetate (a phorbol ester). Since herbimycin A is a tyrosine kinase inhibitor, this finding raised the possibility of protein kinase C inhibition or down regulation by this compound. Herbimycin A significantly inhibited phorbol myristate acetate-mediated protein kinase C activation as measured by in situ glycogen synthase (GS) peptide and neurogranin peptide phosphorylation in vascular smooth muscle cells. Basal protein kinase activity, i.e. kinase activity without phorbol ester treatment to vascular smooth muscle cells, was also decreased by the treatment of herbimycin A. These findings suggest that herbimycin A also inhibits protein kinase C in vascular smooth muscle cells.
Biochem Mol Biol Int 1996 May
PMID:Herbimycin A inhibits protein kinase C in vascular smooth muscle cells. 879 53

The self-glucosylating proteins, Glg1p and Glg2p, are required for glycogen synthesis in Saccharomyces cerevisiae (Cheng, C., Mu., J., Farkas, I., Huang, D., Goebl M. G., and Roach, P. J. (1995) Mol. Cell. Biol. 15, 6632-6640). Glg2p was shown to be associated with carbohydrate in vivo and was released from the high molecular weight glycogen fraction by treatment with alpha-amylase. In addition, some Glg2p exists as a protein of Mr approximately 43,000, whose proportion is increased in cells lacking glycogen synthase. Unlike the mammalian counterpart, glycogenin, the yeast Glg proteins appear to require multiple Tyr residues for functionality. In Glg2p, mutation of both Tyr230 and Tyr232 is necessary to suppress self-glucosylation of purified protein in vitro. The mutant protein is still capable of transferring glucose to an exogeneous acceptor, n-dodecyl beta-D-maltoside. A small COOH-terminal region, conserved between Glg1p and Glg2p, is also important for function; mutation of Tyr367 or truncation at residue 362 impairs the ability of primed Glg2p to be elongated by glycogen synthase. Complete suppression of glycogen accumulation in vivo requires mutation of all three Tyr residues. In Glg1p, two Tyr residues are implicated, Tyr232 and Tyr600, mutation of both being required to eliminate glycogen accumulation in vivo.
 ...
PMID:Initiation of glycogen synthesis in yeast. Requirement of multiple tyrosine residues for function of the self-glucosylating Glg proteins in vivo. 890 Jan 26

The insulin-mimetic action of vanadate is well established but the exact mechanism by which it exerts this effect is still not clearly understood. The role of insulin in the regulation of hepatic glycogen metabolizing and lipogenic enzymes is well known. In our study, we have, therefore, examined the effects of vanadate on these hepatic enzymes using four different models of diabetic and insulin-resistant animals. Vanadate normalized the blood glucose levels in all animal models. In streptozotocin-induced diabetic rats, the amount of liver glycogen and the activities of the active-form of glycogen synthase, both active and inactive-forms of phosphorylase, and lipogenic enzymes like glucose 6-phosphate dehydrogenase and malic enzyme were decreased and vanadate treatment normalized all of these to near normal levels. The other three animal models (db/db mouse, sucrose-fed rats and fa/fa obese Zucker rats) were characterized by hyperinsulinemia, hypertriglyceridemia, increases in activities of lipogenic enzymes, and marginal changes in glycogen metabolizing enzymes. Vanadate treatment brought all of these values towards normal levels. It should be noted that vanadate shows differential effects in the modulation of lipogenic enzymes activities in type I and type II diabetic animals. It increases the activities of lipogenic enzymes in streptozotocin-induced diabetic animals and prevents the evaluation of activities of these enzymes in hyperinsulinemic animals. The insulin-stimulated phosphorylation of insulin receptor beta subunit and its tyrosine kinase activity was increased in streptozotocin-induced diabetic rats after treatment with vanadate. Our results support the view that insulin receptor is one of the sites involved in the insulin-mimetic actions of vanadate.
Mol Cell Biochem
PMID:In vivo effects of vanadate on hepatic glycogen metabolizing and lipogenic enzymes in insulin-dependent and insulin-resistant diabetic animals. 892 52

Phosphatidylinositol 3-kinase (PI3K) activation is necessary for many insulin-induced metabolic and mitogenic responses. However, it is unclear whether PI3K activation is sufficient for any of these effects. To address this question we increased PI3K activity in differentiated 3T3-L1 adipocytes by adenovirus-mediated expression of both the inter-SH2 region of the regulatory p85 subunit of PI3K (iSH2) and the catalytic p110 alpha subunit (p110). Coexpression resulted in PI3K activity that exceeded insulin-stimulated activity by two- to fivefold in cytosol, total membranes, and the low density microsome (LDM) fraction, the site of greatest insulin stimulation. While insulin increased glucose transport 15-fold, coexpression of iSH2-p110 increased transport (5.2-) +/- 0.7-fold with a parallel increase in GLUT4 translocation to the plasma membrane. Constitutive activation of PI3K had no effect on maximally insulin-stimulated glucose transport. Neither basal nor insulin-stimulated activity of glycogen synthase or mitogen-activated protein kinase was altered by iSH2-p110 coexpression. DNA synthesis was increased twofold by insulin in control 3T3-L1 adipocytes transduced with beta-galactosidase-encoding recombinant adenovirus, while iSH2-p110 coexpression increased DNA synthesis fivefold. These data indicate that (i) increased PI3K activity is sufficient to activate some but not all metabolic responses to insulin, (ii) activation of PI3K to levels exceeding the effect of insulin in adipocyte LDM results in only a partial stimulation of glucose transport, and (iii) increased PI3K activity in the absence of growth factor or oncoprotein stimulation is a potent stimulus of DNA synthesis.
Mol Cell Biol 1997 Jan
PMID:Differential effects of constitutively active phosphatidylinositol 3-kinase on glucose transport, glycogen synthase activity, and DNA synthesis in 3T3-L1 adipocytes. 897 99


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