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)

We hypothesize that in neurodegenerative disorders such as Alzheimer's disease and human immunodeficiency virus encephalitis the neuroprotective activity of fibroblast growth factor 1 (FGF1) against several neurotoxic agents might involve regulation of glycogen synthase kinase-3beta (GSK3beta), a pathway important in determining cell fate. In primary rat neuronal and HT22 cells, FGF1 promoted a time-dependent inactivation of GSK3beta by phosphorylation at serine 9. Blocking FGF1 receptors with heparinase reduced this effect. The effects of FGF1 on GSK3beta were dependent on phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) because inhibitors of this pathway or infection with dominant negative Akt adenovirus blocked inactivation. Furthermore, treatment of neuronal cells with FGF1 resulted in ERK-independent Akt phosphorylation and beta-catenin translocation into the nucleus. On the other hand, infection with wild-type GSK3beta recombinant adenovirus-associated virus increased activity of GSK3beta and cell death, both of which were reduced by FGF1 treatment. Moreover, FGF1 protection against glutamate toxicity was dependent on GSK3beta inactivation by the PI3K-Akt but was independent of ERK. Taken together these results suggest that neuroprotective effects of FGF1 might involve inactivation of GSK3beta by a pathway involving activation of the PI3K-Akt cascades.
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PMID:Fibroblast growth factor 1 regulates signaling via the glycogen synthase kinase-3beta pathway. Implications for neuroprotection. 1209 87

Despite our present knowledge of some of the cellular pathways that modulate central nervous system injury, complete therapeutic prevention or reversal of acute or chronic neuronal injury has not been achieved. The cellular mechanisms that precipitate these diseases are more involved than initially believed. As a result, identification of novel therapeutic targets for the treatment of cellular injury would be extremely beneficial to reduce or eliminate disability from nervous system disorders. Current studies have begun to focus on pathways of oxidative stress that involve a variety of cellular pathways. Here we discuss novel pathways that involve the generation of reactive oxygen species and oxidative stress, apoptotic injury that leads to nuclear degradation in both neuronal and vascular populations, and the early loss of cellular membrane asymmetry that mitigates inflammation and vascular occlusion. Current work has identified exciting pathways, such as the Wnt pathway and the serine-threonine kinase Akt, as central modulators that oversee cellular apoptosis and their downstream substrates that include Forkhead transcription factors, glycogen synthase kinase-3beta, mitochondrial dysfunction, Bad, and Bcl-x(L). Other closely integrated pathways control microglial activation, release of inflammatory cytokines, and caspase and calpain activation. New therapeutic avenues that are just open to exploration, such as with brain temperature regulation, nicotinamide adenine dinucleotide modulation, metabotropic glutamate system modulation, and erythropoietin targeted expression, may provide both attractive and viable alternatives to treat a variety of disorders that include stroke, Alzheimer's disease, and traumatic brain injury.
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PMID:Oxidative stress in the brain: novel cellular targets that govern survival during neurodegenerative disease. 1588 75

More than a century has elapsed since the description of Alois Alzheimer's patient Auguste D. Yet, the well-documented generation of beta-amyloid aggregates and neurofibrillary tangles that define Alzheimer's disease is believed to represent only a portion of the cellular processes that can determine the course of Alzheimer's disease. Understanding of the complex nature of this disorder has evolved with an increased appreciation for pathways that involve the generation of reactive oxygen species and oxidative stress, apoptotic injury that leads to nuclear degradation in both neuronal and vascular populations, and the early loss of cellular membrane asymmetry that mitigates inflammation and vascular occlusion. Recent work has identified novel pathways, such as the Wnt pathway and the serine-threonine kinase Akt, as central modulators that oversee cellular apoptosis and the formation of neurofibrillary tangles through their downstream substrates that include glycogen synthase kinase-3beta, Bad, and Bcl-xL. Other closely integrated pathways control microglial activation, release of inflammatory cytokines, and caspase and calpain activation for the processing of amyloid precursor protein, tau protein cleavage, and presenilin disposal. New therapeutic avenues that are just open to exploration, such as with nicotinamide adenine dinucleotide modulation, cell cycle modulation, metabotropic glutamate system modulation, and erythropoietin targeted expression, may provide both attractive and viable alternatives to treat Alzheimer's disease.
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PMID:Stress in the brain: novel cellular mechanisms of injury linked to Alzheimer's disease. 1596 Sep 84

Metabotropic glutamate receptors are expressed throughout the nervous system, but their function as well as their ability to promote neuronal survival rests heavily upon the intracellular mechanisms governed by this family of G-proteins. In this regard, we examined one of the primary pathways that can oversee cell survival, namely protein kinase B (Akt1), and its functional integration with some of its substrates that may work in concert with group I metabotropic glutamate receptor (mGluRI) activation to protect primary hippocampal neurons during oxidative stress. We demonstrate that neuroprotection against free radical injury through mGluRI activation with DHPG requires the activation of Akt1, since loss of Akt1 activity assessed through its GSK-3alpha/beta substrate by pharmacological blockade of the phosphatidylinositide-3-kinase pathway or the gene silencing of Akt1 expression prevents neuronal protection during mGluRI activation. Closely coupled to the robust neuroprotection by mGluRI activation are the inhibitory phosphorylation and prevention of caspase 3 cleavage of the Forkhead transcription factor FOXO3a, the down-regulation of Bim expression, and the protection of beta-catenin by Akt1 against phosphorylation and degradation to promote its translocation from the cytoplasm to the nucleus and allow it to assist with a "pro-survival" cellular program. Further insight into the cellular mechanisms that determine neuronal protection by the metabotropic glutamate system will foster the successful therapeutic development of mGluRs for neurodegenerative disorders.
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PMID:Group I metabotropic receptor neuroprotection requires Akt and its substrates that govern FOXO3a, Bim, and beta-catenin during oxidative stress. 1671 94

During cerebral ischemia, part of the damage associated with the hyperactivation of glutamate receptors results from the hyperphosphorylation of the microtubule-associated protein Tau. Previous studies have shown that estradiol treatment reduces neural damage after cerebral ischemia. Here, we show that transient occlusion of the middle cerebral artery results in the hyperphosphorylation of Tau and in a significant increase in the association of Tau with glycogen synthase kinase-3beta and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid type glutamate receptor subunits 2/3 in the hippocampus. Estradiol treatment decreased hippocampal injury, inhibited glycogen synthase kinase-3beta and decreased the hyperphosphorylation of Tau and the interaction of Tau with glycogen synthase kinase-3beta and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor. These findings suggest that ischemia produces a strong association between Tau and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor, and estradiol can exert at least part of its neuroprotective activity through inhibition of glycogen synthase kinase-3beta.
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PMID:Estrogen dissociates Tau and alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor subunit in postischemic hippocampus. 1695 81

We have shown that endogenous activation of type 5 metabotropic glutamate (mGlu5) receptors supports the maintenance of a pluripotent, undifferentiated state in D3 mouse embryonic stem cells cultured in the presence of leukaemia inhibitory factor (LIF). Here, we examined the interaction between LIF and mGlu5 receptors using as a read-out the immediate early gene, c-Myc. The selective mGlu5 receptor antagonist, 2-methyl-6-(phenylenthynyl)pyridine (MPEP; 1 mum), reduced the increase in c-Myc protein levels induced by LIF by enhancing c-Myc ubiquitination. A reduction in c-Myc levels was also observed following small interfering RNA-mediated mGlu5 receptor gene silencing. MPEP reduced glycogen synthase kinase-3beta phosphorylation on Ser9, but increased phosphorylation of the phosphatidylinositol-3-kinase (PI-3-K) substrate, AKT. In our hands, activated PI-3-K reduced the stability of c-Myc, because (i) the PI-3-K inhibitor, LY294002, prevented the reduction in c-Myc levels induced by MPEP; and (ii) over-expression of AKT promoted c-Myc ubiquitination. All effects of MPEP were mimicked by protein kinase C (PKC) inhibitors and reversed by the PKC activator, tetradecanoylphorbol-13-acetate. We conclude that endogenous activation of mGlu5 receptors sustains the increase in c-Myc induced by LIF in embryonic stem cells by inhibiting both glycogen synthase kinase-3beta and PI-3-K, both effects resulting from the activation of PKC.
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PMID:Endogenously activated mGlu5 metabotropic glutamate receptors sustain the increase in c-Myc expression induced by leukaemia inhibitory factor in cultured mouse embryonic stem cells. 1698 52

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

Phytoestrogens prevent neuronal damage, however, mechanism of their neuroprotective action has not been fully elucidated. This study aimed to evaluate the effects of genistein on glutamate-induced apoptosis in mouse primary neuronal cell cultures. Glutamate (1 mM) enhanced caspase-3 activity and lactate dehydrogenase (LDH) release in the hippocampal, neocortical and cerebellar neurons in time-dependent manner, and these data were confirmed at the cellular level with Hoechst 33342 and calcein AM staining. Genistein (10-10,000 nM) significantly inhibited glutamate-induced apoptosis, and the effect of this isoflavone was most prominent in the hippocampal cells. Next, we studied an involvement of estrogen and aryl hydrocarbon receptors in anti-apoptotic effects of genistein. A high-affinity estrogen receptor antagonist, ICI 182, 780 (1 microM), reversed, whereas less specific antagonist/partial agonist, tamoxifen (1 microM), either intensified or partially inhibited genistein effects. Aryl hydrocarbon receptor antagonist, alpha-naphthoflavone (1 microM), exhibited a biphasic action: it enhanced genistein action toward a short-term exposure (3 h) to glutamate, but antagonized genistein action toward prolonged exposure (24 h) to that insult. SB 216763 (1 microM), which preferentially inhibits glycogen synthase kinase-3beta (GSK-3beta), potentiated genistein effects. These data point to strong effects of genistein at low micromolar concentrations in various brain tissues against glutamate-evoked apoptosis. Moreover, this study provided evidence for involvement of aryl hydrocarbon receptor and estrogen receptor/GSK-3beta intracellular signaling pathway in anti-apoptotic action of genistein.
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PMID:Genistein inhibits glutamate-induced apoptotic processes in primary neuronal cell cultures: an involvement of aryl hydrocarbon receptor and estrogen receptor/glycogen synthase kinase-3beta intracellular signaling pathway. 1726 53

Recent evidence supports a role of the Wnt pathway in neurodegenerative disorders such as Alzheimer's disease (AD). A relationship between amyloid-beta-peptide (Abeta)-induced neurotoxicity and a decrease in the cytoplasmatic levels of beta-catenin has been proposed. Also, the inhibition of glycogen synthase kinase (GSK-3beta), a central modulator of the pathway, protects rat hippocampal neurons from Abeta-induced damage. Interestingly, during the progression of AD, it has been described that active GSK-3beta is found in neuronal cell bodies and neurites, co-localizing with pre-neurofibrillary tangles observed in disease brains. Since Abeta oligomers are associated with the post-synaptic region and we have found that the non-canonical Wnt signaling modulates PSD-95 and glutamate receptors, we propose that the synaptic target for Abeta oligomers in AD is the postsynaptic region and at the molecular level is the non-canonical Wnt signaling pathway. Altogether, our evidence suggests that a sustained loss of Wnt signaling function may be involved in the Abeta-dependent neurodegeneration observed in AD brains and that the activation of this signaling pathway could be of therapeutic interest in AD.
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PMID:Synaptotoxicity in Alzheimer's disease: the Wnt signaling pathway as a molecular target. 1750 71

Although GSK-3 activity can be regulated by phosphorylation and through interaction with GSK-3-binding proteins, here we describe N-terminal proteolysis as a novel way to regulate GSK-3. When brain extracts were exposed to calcium, GSK-3 was truncated, generating two fragments of approximately 40 and 30 kDa, a proteolytic process that was inhibited by specific calpain inhibitors. Interestingly, instead of inhibiting this enzyme, GSK-3 truncation augmented its kinase activity. When we digested recombinant GSK-3 alpha and GSK-3beta protein with calpain, each isoform was cleaved differently, yet the truncated GSK-3 isoforms were still active kinases. We also found that lithium, a GSK-3 inhibitor, inhibits full-length and cleaved GSK-3 isoforms with the same IC(50) value. Calpain removed the N-terminal ends of His-tagged GSK-3 isoenzymes, and exposing cultured cortical neurons with ionomycin, glutamate, or N-methyl-d-aspartate led to the truncation of GSK-3. This truncation was blocked by the calpain inhibitor calpeptin, at the same concentration at which it inhibits calpain-mediated cleavage of NMDAR-2B and of p35 (the regulatory subunit of CDK5). Together, our data demonstrate that calpain activation produces a truncation of GSK-3 that removes an N-terminal inhibitory domain. Furthermore, we show that GSK-3 alpha and GSK-3beta isoenzymes have a different susceptibility to this cleavage, suggesting a means to specifically regulate these isoenzymes. These data provide the first direct evidence that calpain promotes GSK-3 truncation in a way that has implications in signal transduction, and probably in pathological disorders such as Alzheimer disease.
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PMID:N-terminal cleavage of GSK-3 by calpain: a new form of GSK-3 regulation. 1756 62


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