Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
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We isolated a cDNA, B12, that was down-regulated by thyroid hormone (TH) in the goat cerebellum, using a polymerase chain reaction (PCR)-based subtractive hybridization and differential screening procedure. Northern blot analysis of RNA from cerebellum of T4-treated and untreated hypothyroid goats confirmed that clone B12 was TH-regulated with an average reduction in expression of 21% after 4 days of T4 supplementation. Other tissues from a T4-treated and an untreated hypothyroid goat also revealed down-regulation of B12, with the highest reduction in expression found in the thyroid gland (38%). Steady-state levels of the approximately 1.8 kb B12 mRNA were higher in brain than in peripheral tissues. In situ hybridization showed that B12 mRNA in the brain is mainly present in various layers of the cerebellum and the cerebral cortex, the hippocampus, and the olfactory tubercle and is predominantly expressed in neurons. Sequence analysis of the caprine B12 cDNA clone, and the murine homologue, revealed 61% similarity to SNF4/CAT3, a regulator involved in the transcriptional control of glucose-repressible genes in yeast, and 99% identity to a rat 5'-AMP-activated protein kinase subunit, which is involved in the regulation of fatty acid, glycogen and isoprenoid metabolism. In view of these homologies, B12 might encode a regulator involved in distinct metabolic pathways and therefore, TH might also affect gene expression indirectly by down-regulation of regulators like B12.
Brain Res Mol Brain Res 1996 Sep 01
PMID:Caprine homologue of rodent 5'-AMP-activated protein kinase subunit and yeast SNF4/CAT3 is down-regulated by thyroid hormone. 887 8

During ischemia and reperfusion, increased palmitate oxidation is associated with diminished function of the myocardium. Palmitate, but not oleate, has been implicated in the induction of apoptosis in isolated neonatal rat ventricular myocytes. We report that extended incubation (20 h) of cultured neonatal rat cardiomyocytes, in the presence of palmitate, causes a decrease in the ability of these cells to oxidize fatty acids, an increase in cellular malonyl-CoA and a decrease in the activity of 5' AMP-activated protein kinase (AMPK) compared to myocytes incubated in the presence of oleate. While palmitate decreases the oxidative metabolism of fatty acids, it increases the formation of intracellular triglyceride and ceramide. Increased ceramide formation is associated with an increase in apoptosis in many cell systems and we also observe an increase in caspase-3 like activity and DNA-laddering in these cells. At the onset of cardiac failure, a switch in myocardial substrate utilization from fatty acids to glucose occurs. Our data suggest that decreased palmitate oxidation in cardiac myocytes in culture may signal the initiation of programmed cell death and ceramide elevation previously documented in ischemic, reperfused hearts.
J Mol Cell Cardiol 2000 Mar
PMID:Palmitate-mediated alterations in the fatty acid metabolism of rat neonatal cardiac myocytes. 1073 49

In the liver, glucose induces the expression of a number of genes involved in glucose and lipid metabolism, e.g., those encoding L-type pyruvate kinase and fatty acid synthase. Recent evidence has indicated a role for the AMP-activated protein kinase (AMPK) in the inhibition of glucose-activated gene expression in hepatocytes. It remains unclear, however, whether AMPK is involved in the glucose induction of these genes. In order to study further the role of AMPK in regulating gene expression, we have generated two mutant forms of AMPK. One of these (alpha1(312)) acts as a constitutively active kinase, while the other (alpha1DN) acts as a dominant negative inhibitor of endogenous AMPK. We have used adenovirus-mediated gene transfer to express these mutants in primary rat hepatocytes in culture in order to determine their effect on AMPK activity and the transcription of glucose-activated genes. Expression of alpha1(312) increased AMPK activity in hepatocytes and blocked completely the induction of a number of glucose-activated genes in response to 25 mM glucose. This effect is similar to that observed following activation of AMPK by 5-amino-imidazolecarboxamide riboside. Expression of alpha1DN markedly inhibited both basal and stimulated activity of endogenous AMPK but had no effect on the transcription of glucose-activated genes. Our results suggest that AMPK is involved in the inhibition of glucose-activated gene expression but not in the induction pathway. This study demonstrates that the two mutants we have described will provide valuable tools for studying the wider physiological role of AMPK.
Mol Cell Biol 2000 Sep
PMID:Characterization of the role of AMP-activated protein kinase in the regulation of glucose-activated gene expression using constitutively active and dominant negative forms of the kinase. 1095 68

Increases in glucose concentration control the transcription of the preproinsulin (PPI) gene and several other genes in the pancreatic islet beta-cell. Although recent data have demonstrated that secreted insulin may regulate the PPI gene (Leibiger, I. B., Leibiger, B., Moede, T., and Berggren, P. O. (1998) Mol. Cell 1, 933-938), the role of insulin in the control of other beta-cell genes is unexplored. To study the importance of insulin secretion in the regulation of the PPI and liver-type pyruvate kinase (L-PK) genes by glucose, we have used intranuclear microinjection of promoter-luciferase constructs into MIN6 beta-cells and photon-counting imaging. The activity of each promoter was increased either by 30 (versus 3) mm glucose or by 1-20 nm insulin. These effects of insulin were not due to enhanced glucose metabolism since culture with the hormone had no impact on the stimulation of increases in intracellular ATP concentration caused by 30 mm glucose. Furthermore, the islet-specific glucokinase promoter and cellular glucokinase immunoreactivity were unaffected by 30 mm glucose or 20 nm insulin. Inhibition of insulin secretion with the Ca(2+) channel blocker verapamil, the ATP-sensitive K(+) channel opener diazoxide, or the alpha(2)-adrenergic agonist clonidine blocked the effects of glucose on L-PK gene transcription. Similarly, 30 mm glucose failed to induce the promoter after inhibition of phosphatidylinositol 3'-kinase activity with LY294002 and the expression of dominant negative-acting phosphatidylinositol 3'-kinase (Deltap85) or the phosphoinositide 3'-phosphatase PTEN (phosphatase and tensin homologue). LY294002 also diminished the activation of the L-PK gene caused by inhibition of 5'-AMP-activated protein kinase with anti-5'-AMP-activated protein kinase alpha2 antibodies. Conversely, stimulation of insulin secretion with 13 mm KCl or 10 microm tolbutamide strongly activated the PPI and L-PK promoters. These data indicate that, in MIN6 beta-cells, stimulation of insulin secretion is important for the activation by glucose of L-PK as well as the PPI promoter, but does not cause increases in glucokinase gene expression or glucose metabolism.
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PMID:Regulation of gene expression by glucose in pancreatic beta -cells (MIN6) via insulin secretion and activation of phosphatidylinositol 3'-kinase. 1096 19

Familial hypertrophic cardiomyopathy (HCM) has been widely studied as a genetic model of cardiac hypertrophy and sudden cardiac death. HCM has been defined as a disease of the cardiac sarcomere, but mutations in the known contractile protein disease genes are not found in up to one-third of cases. Further, no consistent changes in contractile properties are shared by these mutant proteins, implying that an abnormality of force generation may not be the underlying mechanism of disease. Instead, all of the sarcomeric mutations appear to result in inefficient use of ATP, suggesting that an inability to maintain normal ATP levels may be the central abnormality. To test this hypothesis we have examined candidate genes involved in energy homeostasis in the heart. We now describe mutations in PRKAG2, encoding the gamma(2) subunit of AMP-activated protein kinase (AMPK), in two families with severe HCM and aberrant conduction from atria to ventricles in some affected individuals (pre-excitation or Wolff-Parkinson-White syndrome). The mutations, one missense and one in-frame single codon insertion, occur in highly conserved regions. Because AMPK provides a central sensing mechanism that protects cells from exhaustion of ATP supplies, we propose that these data substantiate energy compromise as a unifying pathogenic mechanism in all forms of HCM. This conclusion should radically redirect thinking about this disorder and also, by establishing energy depletion as a cause of myocardial dysfunction, should be relevant to the acquired forms of heart muscle disease that HCM models.
Hum Mol Genet 2001 May 15
PMID:Mutations in the gamma(2) subunit of AMP-activated protein kinase cause familial hypertrophic cardiomyopathy: evidence for the central role of energy compromise in disease pathogenesis. 1137 14

Eukaryotic cells possess systems for sensing nutritional stress and inducing compensatory mechanisms that minimize the consumption of ATP while utilizing alternative energy sources. Such stress can also be imposed by increased energy needs, such as in skeletal muscle of exercising animals. In these studies, we consider the role of the metabolic sensor, AMP-activated protein kinase (AMPK), in the regulation of glucose transport in skeletal muscle. Expression in mouse muscle of a dominant inhibitory mutant of AMPK completely blocked the ability of hypoxia or AICAR to activate hexose uptake, while only partially reducing contraction-stimulated hexose uptake. These data indicate that AMPK transmits a portion of the signal by which muscle contraction increases glucose uptake, but other AMPK-independent pathways also contribute to the response.
Mol Cell 2001 May
PMID:A role for AMP-activated protein kinase in contraction- and hypoxia-regulated glucose transport in skeletal muscle. 1138 54

The rate of glucose transport into cells is of fundamental importance in whole body homeostasis and adaptation to metabolic stresses, and this review examines the signalling mechanisms controlling this process. The events that mediate the action of insulin on glucose transport, which is by far the best characterized paradigm for glucose transport regulation, are discussed. There are several excellent reviews on various aspects of this subject, which are referred to while highlighting very recent developments in the field, including the recently described CAP pathway, and emerging mechanisms for feedback regulation of insulin signalling. The manner in which hormonal signalling is modulated by stimuli such as oxidative and osmotic stress is then discussed. The second major physiological event where glucose transport regulation is critical is the contraction of skeletal muscle, due to the large metabolic demands of this activity. The mechanism of this regulation is distinct from that initiated by insulin, and recent developments will be examined that have begun to clarify how contraction stimulates glucose transport in skeletal muscle, including the roles performed by AMP-activated protein kinase and nitric oxide synthase.
Mol Membr Biol
PMID:Intracellular signalling mechanisms regulating glucose transport in insulin-sensitive tissues (review). 1168 86

We have expressed a truncated form of the alpha1 kinase domain of AMP-activated protein kinase (AMPK) in Escherichia coli as a glutathione-S-transferase fusion (GST-KD). A T172D mutant version did not require prior phosphorylation and was utilized for most subsequent studies. We have also created a recombinant substrate (GST-ACC) by expressing 34 residues around the major phosphorylation site (Ser79) on rat acetyl-CoA carboxylase-1/alpha (ACC1) as a GST fusion. This was an excellent substrate that was phosphorylated with similar kinetic parameters to ACC1 by both native AMPK and the bacterially expressed kinase domain. We also constructed a structural model for the binding of the ACC1 sequence to the kinase domain, based on crystal structures for related protein kinases. The model was tested by making a total of 25 mutants of GST-ACC and seven mutants of GST-KD, and measuring kinetic parameters with different combinations. The results reveal that AMPK and ACC1 interact over a much wider region than previously realized (>20 residues). The features of the interaction can be summarised as follows: (i) an amphipathic helix from P-16 to P-5 on the substrate binds in a hydrophobic groove on the large lobe of the kinase; (ii) basic residues at P-6 and P-4 bind to two acidic patches (D215/D216/D217 and E103/D100/E143, respectively), on the large lobe; (iii) a histidine at P+3 interacts with D56 on the small lobe; (iv) the side-chain of P+4 leucine could not be precisely positioned, but a new finding was that asparagine or glutamine could replace a hydrophobic residue at this position. These interactions position the serine residue to be phosphorylated in close proximity to the gamma-phosphate group of ATP. Although based on modelling rather than a determined structure, this represents one of the most detailed studies of the interaction between a kinase and its substrate achieved to date.
J Mol Biol 2002 Mar 22
PMID:Protein kinase substrate recognition studied using the recombinant catalytic domain of AMP-activated protein kinase and a model substrate. 1190 45

At the onset of nutrient limitation, the yeast Saccharomyces cerevisiae synthesizes glycogen to serve as a carbon and energy reserve. We undertook a systematic survey for the genes that affect glycogen accumulation by taking advantage of the strain deletion set generated by the Saccharomyces Genome Deletion Project. The strain collection analyzed contained some 4600 diploid homozygous null deletants, representing approximately 88% of all viable haploid disruptants. We identified 324 strains with low and 242 with elevated glycogen stores, accounting for 12.4% of the genes analyzed. The screen was validated by the identification of many of the genes known already to influence glycogen accumulation. Many of the mutants could be placed into coherent families. For example, 195 or 60% of the hypoaccumulators carry mutations linked to respiratory function, a class of mutants well known to be defective in glycogen storage. The second largest group consists of approximately 60 genes involved in vesicular trafficking and vacuolar function, including genes encoding 13 of 17 proteins involved in the structure or assembly of the vacuolar ATPase. These data are consistent with our recent findings that the process of autophagy has a significant impact on glycogen storage (Wang, Z., Wilson, W. A., Fujino, M. A., and Roach, P. J. (2001) Antagonistic controls of autophagy and glycogen accumulation by Snf1p, the yeast homolog of AMP-activated protein kinase, and the cyclin-dependent kinase Pho85p. Mol. Cell. Biol. 21, 5742-5752). Autophagy delivers glycogen to the vacuole, and we propose that the impaired vacuolar function associated with ATPase mutants (vma10 or vma22) results in reduced degradation and subsequent hyperaccumulation of glycogen.
Mol Cell Proteomics 2002 Mar
PMID:Systematic identification of the genes affecting glycogen storage in the yeast Saccharomyces cerevisiae: implication of the vacuole as a determinant of glycogen level. 1209 23

This article will discuss the role of two classes of serine/threonine protein kinases in the regulation of gene transcription in mammals. The first is AMP-activated protein kinase (AMPK), which is responsive to changes in the intracellular energy status. The second is the 'stress-activated" family of protein kinases, members of the mitogen-activated protein (MAP) kinase superfamily, whose regulation by a number of extracellular agents (including osmotic stresses, cytokines, and heat) is less well understood. Interest in these enzymes has grown in the past few years due to mounting evidence (both pharmacological and genetic) which has implicated them in the regulation of a number genes important in mammalian metabolism.
Prog Nucleic Acid Res Mol Biol 2002
PMID:AMP- and stress-activated protein kinases: key regulators of glucose-dependent gene transcription in mammalian cells? 1210 61


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