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:2.7.11.26 (GSK)
6,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Glycogen synthase kinase-3 (GSK-3) is a protein kinase highly abundant in brain and involved in signal transduction cascades, particularly neurodevelopment. Its activity and protein levels have been reported to be over 40% lower in postmortem frontal cortex of schizophrenic patients. GSK-3beta in occipital cortex of schizophrenic patients was not reduced, suggesting regional specificity. There was no reduction in GSK-3beta protein levels in fresh and immortalized lymphocytes and both GSK-3 activity and GSK-3beta mRNA levels in fresh lymphocytes from schizophrenic patients. In the schizophrenia-related neonatal ventral hippocampal lesion rat model, we measured GSK-3beta protein levels and GSK-3 activity in the frontal cortex. GSK-3beta protein levels in lesioned rats were significantly lower than in sham rats, favoring perinatal insult as a cause of low GSK-3beta in schizophrenia. Taken together, these studies suggest that low GSK-3 in postmortem brain of schizophrenic patients is a late consequence of perinatal neurodevelopmental insult in schizophrenia. In rats, acute or chronic cold restraint stress did not change GSK-3beta protein levels. Chronic treatment of rats with lithium, valproate, haloperidol or clozapine did not change rat cortical GSK-3beta protein levels ex vivo, supporting the concept that low GSK-3beta in schizophrenia is not secondary to stress or drug treatment. Our initial findings of low GSK-3beta protein levels in postmortem brain have been replicated by another group. Our own group has found additionally that GSK-3beta mRNA levels were 40% lower in postmortem dorsolateral prefrontal cortex (DLPFC) of schizophrenic patients, supporting our previous findings. Further studies will be aimed at determining whether nonspecific neonatal damage or only specific factors cause low GSK-3 as a late effect. We plan to study whether low GSK-3beta activity is associated with biochemical effects such as elevated beta-catenin levels.
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PMID:Low GSK-3beta in schizophrenia as a consequence of neurodevelopmental insult. 1557 68

Excessive apoptosis of trophoblast cells is thought to be a contributing factor in complications of pregnancy such as pre-eclampsia. Hepatocyte growth factor (HGF) inhibits apoptosis in trophoblasts and we have investigated the signalling pathways through which this anti-apoptotic effect is mediated. Treatment of cells with HGF led to rapid phosphorylation of Akt while an Akt inhibitor blocked the protective effect of HGF. Glycogen synthase kinase-3beta (GSK-3beta) was found to be one of the downstream targets of Akt. HGF treatment inactivated GSK-3beta which in turn led to the activation of the transcription factor beta-catenin. Pharmacological inhibition of GSK-3beta, independently of HGF treatment, strongly increased both beta-catenin activity and cell survival, suggesting that beta-catenin alone has a pronounced anti-apoptotic effect. We also found that both HGF treatment and pharmacological activation of beta-catenin leads to increased expression of inducible nitric oxide synthase (iNOS). We suggest that the Akt mediated activation of beta-catenin leads to inhibition of trophoblast apoptosis following increased expression of iNOS.
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PMID:Trophoblast apoptosis is inhibited by hepatocyte growth factor through the Akt and beta-catenin mediated up-regulation of inducible nitric oxide synthase. 1568 32

Glycogen synthase kinase 3 (GSK3) inhibits signaling pathways that are essential for bone development. To study the requirement for GSK activity during endochondral bone development, we inhibited GSK3 in cultured metatarsal bones with pharmacological antagonists. Interestingly, we find that inhibition of GSK3 strongly repressed chondrocyte and perichondrial osteoblast differentiation. Moreover, chondrocyte proliferation was inhibited, whereas perichondrial cell proliferation was stimulated. These results mirror the effects of fibroblast growth factor signaling (FGF), suggesting the FGF expression is induced. Indeed, we showed that (1) FGF18 expression is stimulated following inhibition of GSK3 and (2) GSK3 regulates FGF18 expression through the control of beta-catenin levels. Stimulation of cultured metatarsal with FGF18 had similar effects on the differentiation and proliferation of chondrocytes and perichondrial cells as GSK3 repression. This suggests that the regulation of FGF18 expression is a major function of GSK3 during endochondral bone development. Consistent with this, we showed that the effect of GSK3 inhibition on chondrocyte proliferation is repressed in tissues lacking a receptor for FGF18, FGF receptor 3.
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PMID:Glycogen synthase kinase 3 controls endochondral bone development: contribution of fibroblast growth factor 18. 1610 94

Glycogen synthase kinase-3 (GSK-3) is critically involved in insulin signaling, and its selective inhibition may present a new therapy for treatment of insulin resistance and type 2 diabetes. The current studies were designed to examine the impact of long-term in vivo inhibition of GSK-3 and its effects in the specific tissues. ob/ob mice were treated daily with one dose (400 nmol, i.p.) of a selective GSK-3 peptide inhibitor, L803-mts, for 3 weeks. Treatment with L803-mts reduced blood glucose levels, improved glucose tolerance, and prevented elevation of hyperglycemia with age. However, L803-mts did not affect either body weight or food consumption and was not toxic, as judged by histopathology and blood chemistry analyses. Consistent with these results, L803-mts suppressed mRNA levels of hepatic phosphoenolpyruvate carboxykinase (PEPCK) (50%) and increased hepatic glycogen content by 50%. On the other hand, L803-mts did not affect glucose 6-phosphate (G-6-P) phosphatase (G-6-Pase) mRNA levels or its enzymatic activity in the liver. Investigation for possible mechanisms responsible for PEPCK suppression indicated that phosphorylation of cAMP-responsive element transcription factor (CREB) at Ser(133) was reduced remarkably by L803-mts, which was also associated with reduced phosphorylation at Ser(129) and no change in total CREB. This suggested that PEPCK was suppressed by GSK-3 inhibition-mediated inactivation of CREB. In skeletal muscle, treatment with L803-mts led both to up-regulation in GLUT4 expression and to a 20% increase in glycogen content. Our studies show that long-term treatment with GSK-3 inhibitor improves glucose homeostasis in ob/ob mice and demonstrates a novel role of GSK-3 in regulating hepatic CREB activity and expression of muscle GLUT4.
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PMID:Long-term treatment with novel glycogen synthase kinase-3 inhibitor improves glucose homeostasis in ob/ob mice: molecular characterization in liver and muscle. 1616 38

Glycogen synthase kinase-3beta (GSK-3beta) is a multifunctional enzyme involved in a variety of biological events including development, glucose metabolism and cell death. Its activity is inhibited by phosphorylation of the Ser9 residue and up-regulated by Tyr216 phosphorylation. Activated GSK-3beta increases phosphorylation of tau protein and induces cell death in a variety of cultured neurons, whereas phosphorylation of phosphatidylinositol-3 (PI-3) kinase-dependent protein kinase B (Akt), which inhibits GSK-3beta activity, is one of the best characterized cell survival signaling pathways. In the present study, the cholinergic immunotoxin 192 IgG-saporin was used to address the potential role of GSK-3beta in the degeneration of basal forebrain cholinergic neurons, which are preferentially vulnerable in Alzheimer's disease (AD) brain. GSK-3beta co-localized with a subset of forebrain cholinergic neurons and loss of these neurons was accompanied by a transient decrease in PI-3 kinase, phospho-Ser473Akt and phospho-Ser9GSK-3beta levels, as well as an increase in phospho-tau levels, in the basal forebrain and hippocampus. Total Akt, GSK-3beta, tau and phospho-Tyr216GSK-3beta levels were not significantly altered in these brain regions in animals treated with 192 IgG-saporin. Systemic administration of the GSK-3beta inhibitor LiCl did not significantly affect cholinergic marker or phospho-Ser9GSK-3beta levels in control rats but did preclude 192-IgG saporin-induced alterations in PI-3 kinase/phospho-Akt, phospho-Ser9GSK-3beta and phospho-tau levels, and also partly protected cholinergic neurons against the immunotoxin. These results provide the first evidence that increased GSK-3beta activity, via decreased Ser9 phosphorylation, can mediate, at least in part, 192-IgG saporin-induced in vivo degeneration of forebrain cholinergic neurons by enhancing tau phosphorylation. The partial protection of these neurons following inhibition of GSK-3beta kinase activity suggests a possible therapeutic role for GSK-3beta inhibitors in attenuating the loss of basal forebrain cholinergic neurons observed in AD.
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PMID:Selective loss of basal forebrain cholinergic neurons by 192 IgG-saporin is associated with decreased phosphorylation of Ser glycogen synthase kinase-3beta. 1618 30

The recent findings demonstrating that insulin and leptin are expressed in and secreted by human ejaculated spermatozoa raise the controversial issue related to mRNA function in male gamete. Capacitated sperm display an increased metabolism and overall energy expenditure presumably to affect the changes in sperm signaling and function during capacitation. However the relationship between the signaling events associated with capacitation and the change in sperm metabolism energy is poorly understood. It emerges from the findings here reported that both leptin and insulin may be crucial in ejaculated spermatozoa to manage their energy status. Immunoistochemical analysis revealed that in uncapacitated sperm insulin was located at the subacrosomial level, in the midpiece and through the tail while leptin was immunodetected at the equatorial segment and at the midpiece. Capacitated sperm display an overall decrease and a more uniform distribution in the signal for both hormones and this is in agreement with their enhanced release in the medium. Both hormones in ejaculated sperm somehow recapitulate the cross-talk between their signalling transductional pathways in somatic cells, resulting in the increase of phosphoinositide 3-kinase (PI3K) activity, AKT S473 and Glycogen synthase kinase 3 (GSK-3)-S9 phosphorylations. During capacitation GSK-3 phosphorylation was abolished suggesting how in capacitating sperm there is a block in glycogen synthesis. This reasonably indicates how during capacitation glycogen reserve is mobilized and this makes the glucose as energy substrate available. For instance insulin dismissed by ejaculated spermatozoa up-regulates Glucose 6-Phosphate Dehydrogenase (G6PDH), the rate-limiting enzyme in the pentose phosphate pathway (PPP), which has be shown to be crucial in the acquisition of fertilizing capability as well as to mediate gamete fusion. Insulin immunoneutralization or blockage of its release, dramatically down regulated G6PDH. Interestingly, in the presence of a disruptor of insulin signaling wortmannin, an inhibitor of PI3K, the intrinsic activity of G6PDH drops. Leptin appears to play similar action to that of insulin on G6PDH in sperm (data in progress). The enhanced activity of this enzyme induced by both hormones produces an increase of NADPH that is essential for fatty acid synthesis from acetyl CoA. These fatty acids have two possible fates: beta-oxidation to produce ATP or reesterification back into triacylglycerol. Inter-relationships of the classes of substrates of free fatty acids (FFA) and glucose utilized for energy, has been long established [Randle, P.J., 1964. The interrelationships of hormones, fatty acid and glucose in the provision of energy. Postgrad. Med. J. 40, 457-463]. The authors observed in ejaculated spermatozoa what it occurs in somatic cells: FFA beta-oxidation tested utilizing the octanoil-CoA as substrate, appears to be stimulated by leptin and down-regulated by the contemporaneous presence of insulin in uncapacitated sperms. FFA beta-oxidation activity dramatically increases when capacitation starts, so it may be assumed the possibility that leptin may work to stimulate such enzymatic activity providing additional metabolic fuel to triggering capacitation process. The autonomous capability of sperm to release insulin and leptin suggests that they through an autocrine short loop may provide the recruitment of energy substrate according to sperm metabolic needs. This occurs independently by the systemic regulation and may represent a protective mechanism which preserves sperm fertilizing capability by any detrimental effects produced by long calorie restriction or by alterations occurring in the energy homeostasis at systemic level.
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PMID:Arguments raised by the recent discovery that insulin and leptin are expressed in and secreted by human ejaculated spermatozoa. 1627 24

Glycogen synthase kinase-3beta (GSK-3beta) is a serine/threonine kinase that has recently emerged as a key target for neurodegenerative diseases and diabetes. As an initial step of our lead discovery program, we developed a virtual screen to discriminate known GSK-3beta inhibitors and inactive compounds using FlexX, FlexX-Pharm, and FlexE. The maximal enrichment factor (EF = 28) suggests that our protocol identifies potential GSK-3beta inhibitors effectively from large compound collections. The effectiveness of our screening protocol was further investigated by comparative experimental and virtual high-throughput screens (HTSs) performed for the same subset of our corporate library. Enrichment factors, the significantly higher hit rate of virtual screening (12.9%) than that of the HTS (0.55%), and also the comparison of active clusters suggest that our virtual screening protocol is an effective tool in GSK-3beta-based library focusing. Head-to-head comparison of true/false positives and negatives revealed the two approaches to be complementary rather than competitive.
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PMID:Comparative virtual and experimental high-throughput screening for glycogen synthase kinase-3beta inhibitors. 1633 19

Glycogen synthase kinase 3 (GSK-3) inhibition is an important research topic because of its wide range of associated health implications. The interaction mode of a series of N-phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amine compounds with human GSK-3 has been studied using molecular docking and 3D-QSAR approaches. In the 3D-QSAR studies, the molecular alignment and conformation determination are so important that they affect the success of a model. Flexible docking (AutoDock3.0.5) was used for the determination of 'active' conformation and molecular alignment. Comparative molecular field analysis (CoMFA) and comparative molecular similarity indices analysis (CoMSIA) were used to develop 3D-QSAR models of 80 N-phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amine compounds. The r(2) values were 0.870 and 0.861 for CoMFA and CoMSIA models, respectively. The predictive ability of these models was validated by 10 compounds of the test set. Mapping these models back to the topology of the active site of GSK-3 led to a better understanding of the vital N-phenyl-4-pyrazolo[1,5-b]pyridazin-3-ylpyrimidin-2-amines-GSK-3 interactions. The results demonstrate that combination of ligand-based and receptor-based modeling is a powerful approach to build 3D-QSAR models. The interaction mode from this study may be helpful for the design of a novel inhibitor and guide the selection of candidate sites for further experimental studies on site-directed mutagenesis.
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PMID:Inhibitory mode of N-phenyl-4-pyrazolo[1,5-b] pyridazin-3-ylpyrimidin-2-amine series derivatives against GSK-3: molecular docking and 3D-QSAR analyses. 1633 68

Glycogen synthase kinase-3beta (GSK-3beta) has been implicated in the pathogenesis of major psychoses. In this paper, the T-50C polymorphism of the GSK-3beta gene has been studied in patients with schizophrenia (n=432), patients with bipolar disorder (n=416) and in a healthy control group (n=408). Consensus diagnosis by at least two psychiatrists was made for each patient, according to DSM-IV and ICD-10 criteria, using the Structured Clinical Interview for DSM-IV Axis I Disorders. Genotypes were established by the polymerase chain reaction-restriction fragment length polymorphism method. We have found a trend towards an association for the C allele in the whole group of schizophrenic patients (p=0.088) and for the heterozygous T/C genotype of bipolar patients (0.095). Significant differences of genotype distribution and allele frequencies of the T-50C polymorphism were found in the female group of bipolar II patients (p=0.015 for genotypes and p=0.009 for alleles). In conclusion, this polymorphism may be associated with female gender in bipolar II disorder.
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PMID:Association analysis of the GSK-3beta T-50C gene polymorphism with schizophrenia and bipolar disorder. 1639 5

Aberrant phosphorylated tau is the major component of the neurofibrillary tangles in Alzheimer's disease (AD) brains. Glycogen synthase kinase-3beta (GSK-3beta) phosphorylates tau protein, and increased GSK-3beta expression has been associated with neurofibrillary tangles. Saitohin (STH) is a recently identified protein that shares tissue expression pattern with tau, and previous evidence in the Spanish population indicated that a polymorphism at codon 7 (Q7R) of the STH gene was associated with late-onset AD. Since both GSK-3beta and STH are related to tau, we examined the association between a polymorphism in the promoter region (-50) of the GSK-3beta gene and AD, either through an independent effect or through interaction with the STH (Q7R) polymorphism, in a well-defined group of 333 sporadic AD patients and 307 control subjects from Spain. The current study reveals that GSK-3beta (-50) TT genotype is associated with an increased risk (OR 1.99, p = 0.003) for late-onset (after the age of 72 years) AD. Our results indicate that both the GSK-3beta (-50) and STH (Q7R) polymorphisms increase the risk of late-onset (subjects >72 years) AD, although they appear to be independent and thus not to interact synergistically.
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PMID:Association between glycogen synthase kinase-3beta genetic polymorphism and late-onset Alzheimer's disease. 1642 84


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