Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We isolated several senescence-associated genes (SAGs) from the petals of morning glory (Ipomoea nil) flowers, with the aim of furthering our understanding of programmed cell death. Samples were taken from the closed bud stage to advanced visible senescence. Actinomycin D, an inhibitor of transcription, if given prior to 4 h after opening, suppressed the onset of visible senescence, which occurred at about 9 h after flower opening. The isolated genes all showed upregulation. Two cell-wall related genes were upregulated early, one encoding an extensin and one a caffeoyl-CoA-3-O-methyltransferase, involved in lignin production. A pectinacetylesterase was upregulated after flower opening and might be involved in cell-wall degradation. Some identified genes showed high homology with published SAGs possibly involved in remobilisation processes: an alcohol dehydrogenase and three cysteine proteases. One transcript encoded a leucine-rich repeat receptor protein kinase, putatively involved in signal transduction. Another transcript encoded a 14-3-3 protein, also a protein kinase. Two genes have apparently not been associated previously with senescence: the first encoded a putative SEC14, which is required for Golgi vesicle transport, the second was a putative ataxin-2, which has been related to RNA metabolism. Induction of the latter has been shown to result in cell death in yeast, due to defects in actin filament formation. The possible roles of these genes in programmed cell death are discussed.
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PMID:Gene expression in opening and senescing petals of morning glory (Ipomoea nil) flowers. 1722 Dec 29

Nucleoside diphosphate kinase A (NDPK-A) regulates the alpha1 isoform of the AMP-activated protein kinase (AMPK alpha1) selectively, independent of [AMP] and surrounding [ATP], by a process termed substrate channelling. Here, we show, using a range of empirically validated biochemical techniques, that the muscle form (M-LDH or LDH-A) and the heart form (H-LDH or LDH-B) of lactate dehydrogenase are physically associated with the liver cytosolic substrate-channelling complex such that M-LDH associates with NDPK-A, AMPK alpha1 and casein kinase 2 (CK2), whereas H-LDH associates with local NDPK-B. We find that the species of LDH bound to the substrate-channelling complex regulates the in vivo enzymatic activities of both AMPK and CK2, and has a downstream effect on the phospho-status of acetyl CoA carboxylase, a key regulator of cellular fat metabolism known to be a part of the cytosolic substrate-channelling complex in vivo. We hypothesise that the regulatory presence of LDH in the complex couples the substrate-channelling mechanism to both the glycolytic and redox states of the cell, allowing for efficient sensing of cell metabolic status, interfacing with the substrate-channelling complex and regulating the enzymatic activities of AMPK and CK2, two critical protein kinases.
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PMID:M-LDH serves as a regulatory subunit of the cytosolic substrate-channelling complex in vivo. 1757 40

Mutation in PRKAG2 encoding the gamma2 subunit of the AMP activated protein kinase (AMPK) cause human cardiomyopathy characterized by hypertrophy, Wolff-Parkinson-White syndrome, conduction system disease and glycogen storage in the myocardium. AMPK is a master metabolic regulator activated by hormones and energy deficient states. A heterotrimer enzyme comprising the catalytic alpha- and regulatory beta-and gamma-subunits was preserved through evolution and is ubiquitously expressed among mammalian tissues. AMPK is activated by AMP and inhibited by ATP that competes for binding to the regulatory sites on the gamma-subunit. Upstream kinases which phosphorylate Thr172 on the catalytic subunit activate the enzyme during exercise, ischemia, in response to sympathetic stimulation and hormones such as leptin and adiponectin. AMPK operates by phosphorylating its target proteins such as Acetyl CoA Carboxylase. Its classic functions include decreased fat synthesis in liver and adipose tissues, increased fatty acid oxidation, stimulating muscle glucose uptake and glycolysis. Altogether, these activities serve to restore the cellular and whole body energy balance. Human mutations which disrupt the nucleotide-binding affinity of the gamma2 subunit lead to loss of inhibition by ATP and inappropriate activate AMPK under resting conditions. As a result, myocytes recruit energy metabolites in excess of demand, causing storage of glycogen. Will AMPK ever emerge as a therapeutic target? Bench experiments suggest its potential in treating diabetes, ischemia and cell cycle regulation but much work is needed until these developments reach the bedside.
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PMID:[AMP-activated protein kinase: how a mistake in energy gauge causes glycogen storage]. 1799 Mar 92

Acyl-CoA-binding protein (ACBP) acts as an acyl-CoA pool former, transporter, and regulator of gene transcription in vitro. We created a transgenic rat line overexpressing ACBP, as the physiological relevance of ACBP in lipid metabolism is unclear. Transgenic rats revealed increased levels of ACBP and significantly elevated acyl-CoA tissue levels while there was no effect on plasma triglyceride, cholesterol, or serum-free fatty acid levels. Metabolic regulators like peroxisome proliferator-activated receptors (PPARgamma, PPARdelta) and sterol regulatory element-binding protein-1 (SREBP-1) messenger RNA levels were significantly reduced (by 23-82%) in liver and adipose tissue of fed transgenic rats, whereas adenosine monophosphate-activated protein kinase (AMPK) protein levels were increased (by 60%). Fasting abolished PPAR downregulation in liver and caused an upregulation in adipose tissue. Administration of AMPK inhibitor reversed SREBP-1 but did not affect PPAR regulation. In conclusion, ACBP acts as an acyl-CoA pool former in transgenic rats and regulates lipid metabolism via SREBP-1 and PPAR regulation. Reduction of SREBP-1 is mediated via increased AMPK levels, whereas regulation of PPARs seems to be mediated by an AMPK-independent mechanism. ACBP itself is a target gene for both transcription factors demonstrating important feedback loops.
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PMID:Downregulation of PPARs and SREBP by acyl-CoA-binding protein overexpression in transgenic rats. 1815 44

AMP-activated protein kinase (AMPK) is activated in adipocytes during exercise and other states in which lipolysis is stimulated. However, the mechanism(s) responsible for this effect and its physiological relevance are unclear. To examine these questions, 3T3-L1 adipocytes were treated with cAMP-inducing agents (isoproterenol, forskolin, and isobutylmethylxanthine), which stimulate lipolysis and activate AMPK. When lipolysis was partially inhibited with the general lipase inhibitor orlistat, AMPK activation by these agents was also partially reduced, but the increases in cAMP levels and cAMP-dependent protein kinase (PKA) activity were unaffected. Likewise, small hairpin RNA-mediated silencing of adipose tissue triglyceride lipase inhibited both forskolin-stimulated lipolysis and AMPK activation but not that of PKA. Forskolin treatment increased the AMP:ATP ratio, and this too was reduced by orlistat. When acyl-CoA synthetase, which catalyzes the conversion of fatty acids to fatty acyl-CoA, was inhibited with triacsin C, the increases in both AMPK activity and AMP:ATP ratio were blunted. Isoproterenol-stimulated lipolysis was accompanied by an increase in oxidative stress, an effect that was quintupled in cells incubated with the AMPK inhibitor compound C. The isoproterenol-induced increase in the AMP:ATP ratio was also much greater in these cells. In conclusion, the results indicate that activation of AMPK in adipocytes by cAMP-inducing agents is a consequence of lipolysis and not of PKA activation. They suggest that AMPK activation in this setting is caused by an increase in the AMP:ATP ratio that appears to be due, at least in part, to the acylation of fatty acids. Finally, this AMPK activation appears to restrain the energy depletion and oxidative stress caused by lipolysis.
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PMID:AMP-activated protein kinase is activated as a consequence of lipolysis in the adipocyte: potential mechanism and physiological relevance. 1839 Sep 1

The detailed properties of the enzyme from Pseudomonas aeruginosa, which catalyzes the N-acyl linkage between myristic acid and the N-terminal glycine residue of the octapeptide GNAAAARR-NH(2) (PKA) in aqueous solution without ATP and CoA, were studied. The substrate specificity for the acyl peptide in the synthetic reaction was examined, and it was found that at least eight amino acid residues are required for the reaction and that the N-terminal glycine residue is not absolutely essential for the reaction because the activity was detected using the octapeptide that has an N-terminal alanine. The activity was also strongly affected by the amino acid sequence because the activity was very weak in the reaction using GARASVLS-NH(2) (HIV-1p17(gag)). The substrate specificity for fatty acids was also examined. In the reactions using lauric acid and decanoic acid, only slight activities were detected; however, those activities were very small compared with the activity in the reaction using myristic acid. In addition, the degradation of myristoyl PKA by the enzyme was detected, although there are only a few reports on demyristoylation. The optimum pH and temperature of the degradation reaction were consistent with those of the synthetic reaction. The degradation reaction was inhibited by divalent cations.
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PMID:Synthesis and degradation of acyl peptide using enzyme from Pseudomonas aeruginosa. 1839 80

After birth dramatic decreases in cardiac malonyl CoA levels result in the rapid maturation of fatty acid oxidation. We have previously demonstrated that the decrease in malonyl CoA is due to increased activity of malonyl CoA decarboxylase (MCD), and decreased activity of acetyl CoA carboxylase (ACC), enzymes which degrade and synthesize malonyl CoA, respectively. Decreased ACC activity corresponds to an increase in the activity of 5'-AMP activated protein kinase (AMPK), which phosphorylates and inhibits ACC. These alterations are delayed by myocardial hypertrophy. As rates of fatty acid oxidation can influence the ability of the heart to withstand an ischemic insult, we examined the expression of MCD, ACC, and AMPK in the newborn human heart. Ventricular biopsies were obtained from infants undergoing cardiac surgery. Immunoblot analysis showed a positive correlation between MCD expression and age. In contrast, a negative correlation in both ACC and AMPK expression and age was observed. All ventricular samples displayed some degree of hypertrophy, however, no differences in enzyme expression were found between moderate and severe hypertrophy. This indicates that increased expression of MCD, and the decreased expression of ACC and AMPK are important regulators of the maturation of fatty acid oxidation in the newborn human heart.
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PMID:Myocardial hypertrophy and the maturation of fatty acid oxidation in the newborn human heart. 1861 68

Kainic acid (KA)-induced seizure induces the hippocampal cell death. There are reports that AMP-activated protein kinase (AMPK), which is an important regulator of energy homeostasis of cells, has been proposed as apoptotic molecule. In this study, we investigated the altered expression of AMPK cascade in the hippocampus of mice during KA-induced hippocampal cell death. Mice were killed at 2, 6, 24 or 48 h after KA (30 mg/kg) injection. Histological evaluation of KA-treated hippocampus revealed hippocampal cell death first at 6 h and appearing prominently by 48 h after KA injection. Immunoreactivity of Ca(2+)/calmodulin-dependent protein kinase kinasebeta (CaMKKbeta) was increased after KA treatment. In Western blot analysis, AMPK activation was increased 2 h after KA treatment. The proteins of downstream AMPK, including those of glucose transporter1 (GLUT1) and phosphorylation of Acetyl CoA Carboxylase (ACC) were increased in the hippocampus after KA treatment. These results indicate that sustained AMPK activation might be a mechanism by which KA-induced seizure causes hippocampal cell death of mice.
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PMID:Temporal expression of AMP-activated protein kinase activation during the kainic acid-induced hippocampal cell death. 1903 Jul 75

Simvastatin inhibits 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which catalyses conversion of HMG-CoA to mevalonate, a rate-limiting step in cholesterol synthesis. We demonstrated that simvastatin at 1 microM markedly inhibited adipocyte differentiation measured by Oil Red O staining in preadipocyte cells (3T3-L1), while expression of leptin, a marker of adipocyte differentiation, was suppressed by 1 muM simvastatin for up to 12 days of culture. Next, to elucidate mechanisms underlying the reduction of leptin expression induced by simvastatin, differentiated 3T3-L1 adipocytes were treated with various inhibitors with mevalonate or its metabolite in the presence or absence of simvastatin. Simvastatin time- and dose-dependently suppressed leptin mRNA expression. Heterogeneous nuclear RNA related to leptin mRNA was inhibited by 10 muM simvastatin, while stability of the mRNA was not changed by treatment with simvastatin in transcription-arrested 3T3-L1 cells. Simvastatin inhibition of leptin gene transcription was not abrogated by pre-treatment with cycloheximide, an inhibitor of protein synthesis. Addition of mevalonate or geranylgeranyl pyrophosphate (GGPP), a mevalonate metabolite, abolished simvastatin-induced inhibition of leptin expression in 3T3-L1 cells. Suppression of expression was observed upon addition of GGTI-298, a geranylgeranyl transferase I inhibitor, but not FTI-277, a farnesyl transferase inhibitor. Expression was suppressed by treatment with hydroxyfasudil, a protein prenylation inhibitor. Treatment with phosphatidylinositol 3-kinase (PI3K) inhibitors, LY294002 and wortmannin, reduced leptin expression in 3T3-L1 cells. Simvastatin dose-dependently increased intra-cellular cyclic AMP (cAMP) concentrations in 3T3-L1 cells, with maximal stimulation obtained at 10 muM. Addition of GGPP abolished simvastatin-induced stimulation of cAMP accumulation and protein kinase A (PKA) activity. H89, an inhibitor of PKA, completely abolished simvastatin-induced suppression of leptin expression. These results suggested that simvastatin reduced geranylgeranylprotein prenylation followed by deactivation of PI3K, leading to cAMP accumulation and subsequent activation of PKA in differentiated 3T3-L1 adipocytes. Finally, PKA inhibited leptin gene transcription without new protein synthesis.
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PMID:Simvastatin suppresses leptin expression in 3T3-L1 adipocytes via activation of the cyclic AMP-PKA pathway induced by inhibition of protein prenylation. 1925 25

In the ovary, the matrix metalloproteinases (MMPs) and the tissue inhibitors of metalloproteinase (TIMPs) have been postulated to regulate extracellular matrix remodeling associated with ovulation. In the present study, we investigated the regulatory mechanisms controlling expression of Timp1 and Timp3 mRNA in periovulatory granulosa cells. Granulosa cells were isolated from immature pregnant mare serum gonadotropin-primed (10 IU) rat ovaries and treated with human chorionic gonadotropin (hCG; 1 IU/ml). At 4 h after hCG treatment, Timp1 expression was highest and then decreased gradually over the remaining 24 h of culture. In contrast, hCG induced a biphasic increase of Timp3 expression at 2 and 16 h. The hCG stimulated expression of Timp1 and Timp3 mRNA was blocked by inhibitors of the protein kinase A (H89), protein kinase C (GF109203), and MAPK (SB2035850) pathways. To further explore Timp1 and Timp3 regulation, cells were cultured with the progesterone receptor antagonist RU486, which blocked the hCG induction of Timp3 expression, whereas the epidermal growth factor receptor tyrosine kinase inhibitor AG1478 blocked the hCG stimulation of both Timp1 and Timp3 expression. The prostaglandin-endoperoxide synthase 2 inhibitor NS-398 had no effect. The potential function of TIMP3 was investigated with Timp3-specific small interfering RNA treatment. Timp3 small interfering RNA resulted in a 20% decrease in hCG-induced progesterone levels and microarray analysis revealed an increase in cytochrome P450 Cyp 17, ubiquitin conjugating enzyme E2T, and heat shock protein 70. IGF binding protein 5, stearyl-CoA desaturase, and annexin A1 were decreased. The differential regulation between Timp1 and Timp3 may correlate with their unique roles in the processes of ovulation and luteinization. For TIMP3, this may include regulating fatty acid synthesis, steroidogenesis, and protein turnover.
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PMID:Regulation and function of tissue inhibitor of metalloproteinase (TIMP) 1 and TIMP3 in periovulatory rat granulosa cells. 1938 37


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