Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.26 (GSK)
 6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Celecoxib is being evaluated as a chemopreventive agent. However, its mechanism of action is not clear because high doses were used for in vitro studies to obtain antitumor effects. We found that celecoxib inhibited the growth of premalignant and malignant human bronchial epithelial cells with IC(50) values between 8.9 and 32.7 micromol/L, irrespective of cyclooxygenase-2 (COX-2) expression. Normal human bronchial epithelial cells were less sensitive to celecoxib. Because these concentrations were higher than those attainable in vivo (<or=5.6 micromol/L), we surmised that combining celecoxib with the synthetic retinoid N-(4-hydroxyphenyl) retinamide (4HPR) might improve its efficacy. Treatment of premalignant lung cell lines with combinations of clinically relevant concentrations of celecoxib (<or=5 micromol/L) and 4HPR (<or=0.25 micromol/L) resulted in greater growth inhibition, apoptosis induction, and suppression of colony formation than did either agent alone. This combination also decreased the levels of Bcl-2, induced the release of mitochondrial cytochrome c, activated caspase-9 and caspase-3, and induced cleavage of poly(ADP-ribose)polymerase at concentrations at which each agent alone showed no or minimal effects. Furthermore, combinations of celecoxib and 4HPR suppressed the phosphorylation levels of serine/threonine kinase Akt and its substrate glycogen synthase kinase-3beta more effectively than the single agents did. Accordingly, overexpression of constitutively active Akt protected bronchial epithelial cells from undergoing apoptosis after incubation with both celecoxib and 4HPR. These findings indicate that activation of the mitochondrial apoptosis pathway and suppression of the Akt survival pathway mediate the augmented apoptosis and suggest that this combination may be useful for lung cancer chemoprevention.
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PMID:Involvement of mitochondrial and Akt signaling pathways in augmented apoptosis induced by a combination of low doses of celecoxib and N-(4-hydroxyphenyl) retinamide in premalignant human bronchial epithelial cells. 1701 36

Glycogen synthase kinase-3 is a serine/threonine kinase that has attracted significant drug discovery attention in recent years. To investigate the identification of new potential glycogen synthase kinase-3 inhibitors, a pharmacophore mapping study was carried out using a set of 21 structurally diverse glycogen synthase kinase-3 inhibitors. A hypothesis containing four features: two hydrophobic, one hydrogen bond donor and another hydrogen bond acceptor was found to be the best from the 10 common feature hypotheses produced by HipHop module of Catalyst. The best hypothesis has a high cost of 156.592 and higher best fit values were obtained for the 21 inhibitors using this best hypothesis than the other HipHop hypotheses. The best hypothesis was then used to screen electronically the NCI2000 database. The hits obtained were docked into glycogen synthase kinase-3beta active site. A total of five novel potential leads were proposed after: (i) visual examination of how well they dock into the glycogen synthase kinase-3beta-binding site, (ii) comparative analysis of their FlexX, G-Score, PMF-Score, ChemScore and D-Scores values, (iii) comparison of their best fit value with the known inhibitors and (iv) examination of the how the hits retain interactions with the important amino acid residues of glycogen synthase kinase-3beta-binding site.
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PMID:Investigation of potential glycogen synthase kinase 3 inhibitors using pharmacophore mapping and virtual screening. 1706 13

A reduced ability of insulin to activate glucose transport in skeletal muscle, termed insulin resistance, is a primary defect leading to the development of impaired glucose tolerance and type 2 diabetes. Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase with important roles in the regulation of glycogen synthesis, protein synthesis, gene transcription, and cell differentiation in various cell types. An emerging body of evidence has implicated GSK-3 in the multifactorial etiology of skeletal muscle insulin resistance in obese animal models and in obese human type 2 diabetic subjects. Overexpression and overactivity of GSK-3 in skeletal muscle of rodent models of obesity and obese type 2 diabetic humans are associated with an impaired ability of insulin to activate glucose disposal and glycogen synthase. New insights into the importance of GSK-3 as a regulator of insulin action on glucose transport activity in muscle have come from studies utilizing selective and sensitive inhibitors of GSK-3. These studies have demonstrated that selective inhibition of GSK-3 in insulin-resistant skeletal muscle causes improvements in insulin-stimulated glucose transport activity that are likely caused by enhanced post-insulin receptor insulin signaling and GLUT-4 glucose transporter translocation. An additional important action of these GSK-3 inhibitors in the context of obese-associated type 2 diabetes is a reduction of hepatic glucose production, likely via downregulation of genes associated with gluconeogensis. It is clear from these studies that selectively targeting GSK-3 in skeletal muscle may be an important new strategy for the treatment of obesity-associated insulin-resistant states characterized by GSK-3 overactivity in insulin-sensitive tissues.
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PMID:Role of glycogen synthase kinase-3 in insulin resistance and type 2 diabetes. 1710 May 83

G-protein coupled receptor kinases (GRKs) constitute a serine/threonine kinase family playing a major role in agonist-induced phosphorylation and desensitization of G-protein coupled receptors. Recently, GRK2 and GRK5 have been demonstrated to phosphorylate alpha-synuclein (Ser129) and other synuclein isoforms. We studied colocalization of GRK2, GRK5, alpha-synuclein, and tau in neurodegenerative disorders characterized by fibrillary tau inclusions and/or alpha-synuclein-enriched Lewy bodies. We found that Lewy bodies were negative for both GRK2 and GRK5 in Lewy body disease (LBD) and LBD mixed with Alzheimer disease (AD + LBD). Instead, GRK2 but not GRK5 colocalized with 40% to 50% of neurofibrillary tangles in AD + LBD and AD brains. In disorders with less prominent alpha-synucleinopathy, neuronal and glial fibrillary tau deposits known to contain distinct subsets of tau isoforms were also positive for GRK2. These deposits included tufted astrocytes and coiled bodies in progressive supranuclear palsy, astrocytic plaques in corticobasal degeneration, and Pick bodies in Pick disease. In addition, paired helical filaments isolated from AD and AD + LBD brains were found to immunogold-label for GRK2, suggesting that GRK2 could be a potential tau kinase associated with fibrillary tau. Our studies indicate that GRK2 is a novel component of neuronal and glial fibrillary tau deposits with no preference in tau isoform binding. GRK2 may play a role in hyperphosphorylation of tau in tauopathies.
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PMID:Identification of G-protein coupled receptor kinase 2 in paired helical filaments and neurofibrillary tangles. 1714 90

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase consisting of two isoforms, alpha and beta. The activities of GSK-3 are regulated negatively by serine phosphorylation but positively by tyrosine phosphorylation. GSK-3 inactivation has been proposed as a mechanism to promote neuronal survival. We used GSK-3 isoform-specific small interfering RNAs, dominant-negative mutants, or pharmacological inhibitors to search for functions of the two GSK-3 isoforms in regulating neuronal survival in cultured cortical neurons in response to glutamate insult or during neuronal maturation/aging. Surprisingly, RNA interference-induced depletion of either isoform was sufficient to block glutamate-induced excitotoxicity, and the resulting neuroprotection was associated with enhanced N-terminal serine phosphorylation in both GSK-3 isoforms. However, GSK-3beta depletion was more effective than GSK-3alpha depletion in suppressing spontaneous neuronal death in extended culture. This phenomenon is likely due to selective and robust inhibition of GSK-3beta activation resulting from GSK-3beta Ser9 dephosphorylation during the course of spontaneous neuronal death. GSK-3alpha silencing resulted in reduced tyrosine phosphorylation of GSK-3beta, suggesting that tyrosine phosphorylation is also a critical autoregulatory event. Interestingly, GSK-3 inhibitors caused a rapid and long-lasting increase in GSK-3alpha Ser21 phosphorylation levels, followed by a delayed increase in GSK-3beta Ser9 phosphorylation and a decrease in GSK-3alpha Tyr279 and GSK-3beta Tyr216 phosphorylation, thus implying additional levels of GSK-3 autoregulation. Taken together, our results underscore important similarities and dissimilarities of GSK-3alpha and GSK-3beta in the roles of cell survival as well as their distinct modes of regulation. The development of GSK-3 isoform-specific inhibitors seems to be warranted for treating GSK-3-mediated pathology.
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PMID:Regulation and function of glycogen synthase kinase-3 isoforms in neuronal survival. 1714 50

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase regulating diverse cellular functions including metabolism, transcription and cell survival. Numerous intracellular signalling pathways converge on GSK-3 and regulate its activity via inhibitory serine-phosphorylation. Recently, GSK-3 has been involved in learning and memory and in neurodegeneration. Here, we present evidence that implicates GSK-3 in synaptic plasticity. We show that phosphorylation at the inhibitory Ser9 site on GSK-3beta is increased upon induction of long-term potentiation (LTP) in both hippocampal subregions CA1 and the dentate gyrus (DG) in vivo. The increase in inhibitory GSK-3beta phosphorylation is robust and persists for at least one hour postinduction. Furthermore, we find that LTP is impaired in transgenic mice conditionally overexpressing GSK-3beta. The LTP deficits can be attenuated/rescued by chronic treatment with lithium, a GSK-3 inhibitor. These results suggest that the inhibition of GSK-3 facilitates the induction of LTP and this might explain some of the negative effects of GSK-3 on learning and memory. It follows that this role of GSK-3beta in LTP might underlie some of the cognitive dysfunction in diseases where GSK-3 dysfunction has been implicated, including Alzheimer's and other dementias.
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PMID:Glycogen synthase kinase-3 inhibition is integral to long-term potentiation. 1724 Dec 69

Beta-adrenergic receptor (beta-AR) stimulation induces apoptosis in adult rat ventricular myocytes (ARVM). beta1 integrin signaling plays a protective role in beta-AR-stimulated apoptosis. Glycogen synthase kinase-3beta (GSK-3beta), a multifunctional serine/threonine kinase, negatively regulates cardiac hypertrophy. Here we show that beta-AR stimulation (isoproterenol; 15 min) increases tyr(216) phosphorylation and GSK-3beta activity. Inclusion of LiCl, inhibitor of GSK-3beta, in the reaction mix or expression of catalytically inactive GSK-3beta (KM-GSK) inhibited beta-AR-stimulated GSK-3beta activity. Inhibition of tyrosine kinase using genistein or chelation of intracellular Ca(2+) using BAPTA-AM inhibited beta-AR-stimulated increases in tyr(216) phosphorylation and GSK-3beta activity. Inhibition of GSK-3beta using pharmacological inhibitors or infection with KM-GSK decreased beta-AR-stimulated cytosolic cytochrome C release and apoptosis. Expression of beta1 integrins increased ser(9) phosphorylation and inhibited beta-AR-stimulated increase in GSK-3beta activity. Wortmannin, inhibitor of PI3-kinase, reversed the effects of beta1 integrins on GSK-3beta activity and apoptosis. Purified active matrix metalloproteinase-2 (MMP-2), shown to interfere with beta1 integrin signaling, increased GSK-3beta activity, while inhibition of MMP-2 inhibited beta-AR-stimulated increases in GSK-3beta activity. beta-AR stimulation induced nuclear accumulation of GSK-3beta. beta-AR stimulation (3 h) increased the expression of transcription factor Gadd153 (growth arrest- and DNA damage-inducible gene 153). These data suggest that beta-AR stimulation increases GSK-3beta activity. Activation of GSK-3beta plays a pro-apoptotic role in beta-AR-stimulated apoptosis via the involvement of mitochondrial death pathway. beta1 integrins inactivate GSK-3beta and play an anti-apoptotic role via the involvement of PI3-kinase pathway. The apoptotic effects of GSK-3beta may be mediated, at least in part, via its nuclear localization and induction of pro-apoptotic genes, such as Gadd153.
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PMID:Glycogen synthase kinase-3beta plays a pro-apoptotic role in beta-adrenergic receptor-stimulated apoptosis in adult rat ventricular myocytes: Role of beta1 integrins. 1729 11

Glycogen synthase kinase 3 (GSK-3) is a serine/threonine kinase that has captured great attention in drug discovery projects. Structure based design has been successfully carried out to find a novel class of GSK-3 inhibitors using the Ludi de novo ligand design program. A total of 15 potential leads are suggested from the study. The structures have been validated through detailed analysis of the Ludi score values and by molecular docking experiment using FlexX. The hits have been further verified through: (1) visual examination of how well the hits dock into the GSK-3beta binding site; (2) comparative analysis of their FlexX, G_Score, PMF_Score, ChemScore, and D_scores values; (3) a comparative investigation of the docking scores of the hits with those of the reported inhibitors after calibration of the docking procedure with 17 previously reported inhibitors; (4) determination of the binding mode of the hits and comparison with that of the so far known inhibitors. Hits retaining interactions with the common amino acids of GSK-3beta binding site were taken to represent potential leads. Structurally the hits designed are mainly flat nitrogen heterocycles. These hits are expected to be important additions to the search of GSK-3 inhibitors and may provide invaluable insights to further understand the structural basis of catalysis and inhibition of this kinase.
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PMID:Structure based de novo design of novel glycogen synthase kinase 3 inhibitors. 1739 89

Glycogen synthase kinase-3 (GSK3) is a serine/threonine kinase that has attracted much drug discovery attention in recent years. Structural crystallography of the kinase has produced several high resolution inhibitor-GSK3 complexes and this is offering valuable information about the important pharmacophoric features present in the inhibitor, the protein target and the bioactive conformation. The availability of several GSK3-inhibitor co-crystals was successfully exploited to derive a pharmacophore query which retains the all important inhibitor-GSK3 interaction chemistry. A hypothesis containing three features: two hydrogen bond donors and one hydrogen acceptor was found to explain much of the inhibitor-GSK3 interaction. Subsequently, the query has been submitted to three databases for electronic screening. The hits obtained were docked into glycogen synthase kinase-3beta active site. A total of 21 novel potential leads were proposed after thorough examination by a combination of methods: (i) visual examination of how well they dock into the glycogen synthase kinase-3beta binding site, (ii) detailed analysis of their FlexX, G_Score, PMF_Score, ChemScore and D_Score values, (iii) comparative investigation of the docking scores of the hits with that of the thus far reported inhibitors (iv) determination of the binding mode and examination of how the hits retain interactions with the important amino acid residues of the kinase binding site. The hydrophobic heterocycles identified in this investigation are expected to be important additions to the armamentarium of GSK3 hyperactivity antagonism. Further more, the present work may further our current knowledge of the molecular basis of activation, inhibition and regulation of this pharmaceutically important kinase.
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PMID:Identification of potential glycogen kinase-3 inhibitors by structure based virtual screening. 1748 49

The serine/threonine kinase glycogen synthase kinase-3 (GSK-3) was initially identified as a key regulator of insulin-dependent glycogen synthesis. GSK-3 was subsequently shown to function in a wide range of cellular processes including differentiation, growth, motility and apoptosis. Aberrant regulation of GSK-3 has been implicated in a range of human pathologies including Alzheimer's disease, non-insulin-dependent diabetes mellitus (NIDDM) and cancer. As a consequence, the regulation of GSK-3 and the therapeutic potential of GSK-3 inhibitors have become key areas of investigation. This review will focus on the mechanisms of GSK-3 regulation, with emphasis on modulation by upstream signals, control of substrate specificity and GSK-3 localisation. The details of these mechanisms will be discussed in the context of specific signalling pathways.
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PMID:Glycogen synthase kinase 3: a key regulator of cellular fate. 1753 Apr 63


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