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Glycogen synthase kinase 3β inhibitors protect hippocampal neurons from radiation-induced apoptosis by regulating MDM2-p53 pathway.
Thotala DK, Hallahan DE, Yazlovitskaya EM
(2012) Cell Death Differ 19: 387-96
MeSH Terms: Animals, Apoptosis, Cell Line, Transformed, Enzyme Inhibitors, Gamma Rays, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Hippocampus, Mice, Neurons, Protein Transport, Proto-Oncogene Proteins c-mdm2, Radiation Tolerance, Tumor Suppressor Protein p53
Show Abstract · Added November 16, 2017
Exposure of the brain to ionizing radiation can cause neurocognitive deficiencies. The pathophysiology of these neurological changes is complex and includes radiation-induced apoptosis in the subgranular zone of the hippocampus. We have recently found that inhibition of glycogen synthase kinase 3β (GSK-3β) resulted in significant protection from radiation-induced apoptosis in hippocampal neurons. The molecular mechanisms of this cytoprotection include abrogation of radiation-induced accumulation of p53. Here we show that pretreatment of irradiated HT-22 hippocampal-derived neurons with small molecule inhibitors of GSK-3β SB216763 or SB415286, or with GSK-3β-specific shRNA resulted in accumulation of the p53-specific E3 ubiquitin ligase MDM2. Knockdown of MDM2 using specific shRNA or chemical inhibition of MDM2-p53 interaction prevented the protective changes triggered by GSK-3β inhibition in irradiated HT-22 neurons and restored radiation cytotoxicity. We found that this could be due to regulation of apoptosis by subcellular localization and interaction of GSK-3β, p53 and MDM2. These data suggest that the mechanisms of radioprotection by GSK-3β inhibitors in hippocampal neurons involve regulation of MDM2-dependent p53 accumulation and interactions between GSK-3β, MDM2 and p53.
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14 MeSH Terms
Binge cocaine administration in adolescent rats affects amygdalar gene expression patterns and alters anxiety-related behavior in adulthood.
Sillivan SE, Black YD, Naydenov AV, Vassoler FR, Hanlin RP, Konradi C
(2011) Biol Psychiatry 70: 583-92
MeSH Terms: Age Factors, Amygdala, Animals, Anxiety, Cocaine, Disease Models, Animal, Fear, Gene Expression, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Learning, Male, Rats, Rats, Sprague-Dawley, Wnt Signaling Pathway
Show Abstract · Added May 27, 2014
BACKGROUND - Administration of cocaine during adolescence alters neurotransmission and behavioral sensitization in adulthood, but the effect on the acquisition of fear memories and the development of emotion-based neuronal circuits is unknown.
METHODS - We examined fear learning and anxiety-related behaviors in adult male rats that were subjected to binge cocaine treatment during adolescence. We furthermore conducted gene expression analyses of the amygdala 22 hours after the last cocaine injection to identify molecular patterns that might lead to altered emotional processing.
RESULTS - Rats injected with cocaine during adolescence displayed less anxiety in adulthood than their vehicle-injected counterparts. In addition, cocaine-exposed animals were deficient in their ability to develop contextual fear responses. Cocaine administration caused transient gene expression changes in the Wnt signaling pathway, of axon guidance molecules, and of synaptic proteins, suggesting that cocaine perturbs dendritic structures and synapses in the amygdala. Phosphorylation of glycogen synthase kinase 3 beta, a kinase in the Wnt signaling pathway, was altered immediately following the binge cocaine paradigm and returned to normal levels 22 hours after the last cocaine injection.
CONCLUSIONS - Cocaine exposure during adolescence leads to molecular changes in the amygdala and decreases fear learning and anxiety in adulthood.
Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.
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15 MeSH Terms
Role of STRAP in regulating GSK3β function and Notch3 stabilization.
Kashikar ND, Zhang W, Massion PP, Gonzalez AL, Datta PK
(2011) Cell Cycle 10: 1639-54
MeSH Terms: Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Ankyrins, Axin Protein, Cell Line, Tumor, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Humans, Lithium Chloride, Molecular Sequence Data, Neoplasm Proteins, Phosphorylation, Protein Binding, Protein Structure, Tertiary, RNA Interference, RNA, Small Interfering, Receptor, Notch3, Receptors, Notch, Repressor Proteins, Sequence Alignment, Ubiquitination
Show Abstract · Added March 5, 2014
Glycogen synthase kinase 3β (GSK3β) can regulate a broad range of cellular processes in a variety of cell types and tissues through its ability to phosphorylate its substrates in a cell- and time-specific manner. Although it is known that Axin and presenilin help to recruit β-catenin/Smad3 and tau protein to GSK3β, respectively, it is not clear how many of the other GSK3β substrates are recruited to it. Here, we have established the binding of GSK3β with a novel scaffold protein, STRAP, through its WD40 domains. In a new finding, we have observed that STRAP, GSK3β and Axin form a ternary complex together. We show for the first time that intracellular fragment of Notch3 (ICN3) binds with GSK3β through the ankyrin repeat domain. This binding between STRAP and GSK3β is reduced by small-molecule inhibitors of GSK3β. Further studies revealed that STRAP also binds ICN3 through the ankyrin repeat region, and this binding is enhanced in a proteasomal inhibition-dependent manner. In vivo ubiquitination studies indicate that STRAP reduces ubiquitination of ICN3, suggesting a role of STRAP in stabilizing ICN3. This is supported by the fact that STRAP and Notch3 are co-upregulated and co-localized in 59% of non-small cell lung cancers, as observed in an immunohistochemical staining of tissue microarrays. These results provide a potential mechanism by which STRAP regulates GSK3β function and Notch3 stabilization and further support the oncogenic functions of STRAP.
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21 MeSH Terms
Regulation of β-catenin by t-DARPP in upper gastrointestinal cancer cells.
Vangamudi B, Zhu S, Soutto M, Belkhiri A, El-Rifai W
(2011) Mol Cancer 10: 32
MeSH Terms: Binding Sites, Blotting, Western, Cell Line, Tumor, Cell Nucleus, Cell Proliferation, Chromones, Dopamine and cAMP-Regulated Phosphoprotein 32, Enzyme Inhibitors, Gastrointestinal Neoplasms, Gene Expression Regulation, Neoplastic, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Humans, Luciferases, Microscopy, Fluorescence, Morpholines, Mutation, Phosphatidylinositol 3-Kinases, Phosphorylation, Protein Isoforms, Proto-Oncogene Proteins c-akt, RNA Interference, Signal Transduction, TCF Transcription Factors, Upper Gastrointestinal Tract, beta Catenin
Show Abstract · Added July 26, 2012
BACKGROUND - Truncated dopamine and cyclic-AMP-regulated phosphoprotein (t-DARPP) is frequently overexpressed in gastrointestinal malignancies. In this study, we examined the role of t-DARPP in regulating β-catenin.
RESULTS - The pTopFlash construct that contains multiple TCF/LEF-binding sites was used as a measure of β-catenin/TCF transcription activity. Gastric (AGS, MKN28) and esophageal (FLO-1) adenocarcinoma cancer cell lines that lack t-DARPP expression were utilized to establish stable and transient in vitro expression models of t-DARPP. The expression of t-DARPP led to a significant induction of the pTOP reporter activity, indicative of activation of β-catenin/TCF nuclear signaling. Immunofluorescence assays supported this finding and showed accumulation and nuclear translocation of β-catenin in cells expressing t-DARPP. These cells had a significant increase in their proliferative capacity and demonstrated up-regulation of two transcription targets of β-catenin/TCF: Cyclin D1 and c-MYC. Because phosphorylated GSK-3β is inactive and loses its ability to phosphorylate β-catenin and target it towards degradation by the proteasome, we next examined the levels of phospho-GSK-3β. These results demonstrated an increase in phospho-GSK-3β and phospho-AKT. The knockdown of endogenous t-DARPP in MKN45 cancer cells demonstrated a reversal of the signaling events. To examine whether t-DARPP mediated GSK-3β phosphorylation in an AKT-dependent manner, we used a pharmacologic inhibitor of PI3K/AKT, LY294002, in cancer cells expressing t-DARPP. This treatment abolished the phosphorylation of AKT and GSK-3β leading to a reduction in β-catenin, Cyclin D1, and c-MYC protein levels.
CONCLUSIONS - Our findings demonstrate, for the first time, that t-DARPP regulates β-catenin/TCF activity, thereby implicating a novel oncogenic signaling in upper gastrointestinal cancers.
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26 MeSH Terms
Neuregulin-1β regulation of embryonic endothelial progenitor cell survival.
Safa RN, Peng XY, Pentassuglia L, Lim CC, Lamparter M, Silverstein C, Walker J, Chen B, Geisberg C, Hatzopoulos AK, Sawyer DB
(2011) Am J Physiol Heart Circ Physiol 300: H1311-9
MeSH Terms: Animals, Bone Marrow Cells, Cell Survival, Cells, Cultured, Embryonic Stem Cells, Extracellular Signal-Regulated MAP Kinases, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Humans, Leukocytes, Mononuclear, Mice, Neuregulin-1, Phosphorylation, Proto-Oncogene Proteins c-akt, Rats, Rats, Sprague-Dawley, Receptor, ErbB-2, Receptor, ErbB-3, beta Catenin
Show Abstract · Added November 13, 2012
Endothelial progenitor cells (EPCs) are mobilized into the vascular space and home to damaged tissues, where they promote repair in part through a process of angiogenesis. Neuregulins (NRGs) are ligands in the epidermal growth factor family that signal through type I receptor tyrosine kinases in the erbB family (erbB2, erbB3, and erbB4) and regulate endothelial cell biology, promoting angiogenesis. Stimuli such as ischemia and exercise that promote EPC mobilization also induce cleavage and release of transmembrane NRG from cardiac microvascular endothelial cells (CMECs). We hypothesized that NRG/erbB signaling may regulate EPC biology. Using an embryonic (e)EPC cell line that homes to and repairs injured myocardium, we were able to detect erbB2 and erbB3 transcripts. Identical receptor expression was found in EPCs isolated from rat bone marrow and human whole blood. NRG treatment of eEPCs induces phosphorylation of kinases including Akt, GSK-3β, and Erk1/2 and the nuclear accumulation and transcriptional activation of β-catenin. NRG does not induce eEPC proliferation or migration but does protect eEPCs against serum deprivation-induced apoptosis. These results suggest a role for tissue-derived NRG in the regulation of EPC survival.
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19 MeSH Terms
Gbetagamma activates GSK3 to promote LRP6-mediated beta-catenin transcriptional activity.
Jernigan KK, Cselenyi CS, Thorne CA, Hanson AJ, Tahinci E, Hajicek N, Oldham WM, Lee LA, Hamm HE, Hepler JR, Kozasa T, Linder ME, Lee E
(2010) Sci Signal 3: ra37
MeSH Terms: Animals, Drosophila melanogaster, GTP-Binding Protein beta Subunits, GTP-Binding Protein gamma Subunits, Glycogen Synthase Kinase 3, HeLa Cells, Humans, LDL-Receptor Related Proteins, Low Density Lipoprotein Receptor-Related Protein-6, Signal Transduction, Transcription, Genetic, Wnt Proteins, Xenopus laevis, beta Catenin, beta-Adrenergic Receptor Kinases
Show Abstract · Added December 10, 2013
Evidence from Drosophila and cultured cell studies supports a role for heterotrimeric guanosine triphosphate-binding proteins (G proteins) in Wnt signaling. Wnt inhibits the degradation of the transcriptional regulator beta-catenin. We screened the alpha and betagamma subunits of major families of G proteins in a Xenopus egg extract system that reconstitutes beta-catenin degradation. We found that Galpha(o), Galpha(q), Galpha(i2), and Gbetagamma inhibited beta-catenin degradation. Gbeta(1)gamma(2) promoted the phosphorylation and activation of the Wnt co-receptor low-density lipoprotein receptor-related protein 6 (LRP6) by recruiting glycogen synthase kinase 3 (GSK3) to the membrane and enhancing its kinase activity. In both a reporter gene assay and an in vivo assay, c-betaARK (C-terminal domain of beta-adrenergic receptor kinase), an inhibitor of Gbetagamma, blocked LRP6 activity. Several components of the Wnt-beta-catenin pathway formed a complex: Gbeta(1)gamma(2), LRP6, GSK3, axin, and dishevelled. We propose that free Gbetagamma and Galpha subunits, released from activated G proteins, act cooperatively to inhibit beta-catenin degradation and activate beta-catenin-mediated transcription.
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15 MeSH Terms
A new class of molecular targeted radioprotectors: GSK-3beta inhibitors.
Thotala DK, Geng L, Dickey AK, Hallahan DE, Yazlovitskaya EM
(2010) Int J Radiat Oncol Biol Phys 76: 557-65
MeSH Terms: Aminophenols, Animals, Apoptosis, Caspase 3, Cell Line, Cell Survival, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, In Situ Nick-End Labeling, Indoles, Intestines, Maleimides, Mice, Mice, Inbred C57BL, Radiation Injuries, Experimental, Radiation-Protective Agents, Rats, bcl-2-Associated X Protein, beta Catenin
Show Abstract · Added August 21, 2013
PURPOSE - Development of new treatments is critical to effective protection against radiation-induced injury. We investigate the potential of developing small-molecule inhibitors of glycogen synthase kinase 3beta (GSK-3beta)-SB216763 or SB415286-as radioprotective agents to attenuate intestinal injury.
METHODS AND MATERIALS - A survival study was done by use of C57BL/6J mice to evaluate the radioprotective effect of GSK-3beta inhibitors. Terminal deoxynucleotidyl transferase dUTP nick end labelling (TUNEL) assay and immunohistochemical staining for Bax and Bcl-2 were used to assess apoptosis in the small intestines of the treated mice. A clonogenic survival study, apoptosis assays (staining with annexin V or 4',6-diamidino-2-phenylindole), and immunoblot analysis of beta-catenin, Bcl-2, Bax, and caspase 3 were done by use of Rat intestinal epithelial cell line IEC-6 cells.
RESULTS - Pretreatment with SB415286 significantly improved survival of mice irradiated with 8 and 12 Gy. Mice pretreated with SB216763 or SB415286 showed a significant reduction in TUNEL- and Bax-positive cells and an increase in Bcl-2-positive cells in intestinal crypts at 4 and/or 12 h after radiation with 4 and/or 8 Gy compared with radiation alone. Pretreatment of irradiated IEC-6 cells with GSK-3beta inhibitors significantly increased clonogenic survival compared with cells treated with radiation alone. This increase was due to the attenuation of radiation-induced apoptosis, as shown by annexin V and 4',6-diamidino-2-phenylindole assays, as well as immunoblot analysis of Bcl-2, Bax, and caspase 3.
CONCLUSIONS - Glycogen synthase kinase 3beta small-molecule inhibitors protect mouse intestine from radiation-induced damage in cell culture and in vivo and improve survival of mice. Molecular mechanisms of this protection involve attenuated radiation-induced apoptosis regulated by Bcl-2, Bax, and caspase 3. Therefore GSK-3beta inhibitors reduce deleterious consequences of intestinal irradiation and thereby improve quality of life during radiation therapy.
Copyright 2010 Elsevier Inc. All rights reserved.
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19 MeSH Terms
GSK3beta mediates renal response to vasopressin by modulating adenylate cyclase activity.
Rao R, Patel S, Hao C, Woodgett J, Harris R
(2010) J Am Soc Nephrol 21: 428-37
MeSH Terms: Adenylyl Cyclases, Animals, Antidiuretic Agents, Aquaporin 2, Cells, Cultured, Colforsin, Cyclic AMP, Deamino Arginine Vasopressin, Female, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Kidney Concentrating Ability, Kidney Tubules, Collecting, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, RNA, Messenger, Water Deprivation, Water-Electrolyte Balance
Show Abstract · Added August 19, 2013
Glycogen synthase kinase 3beta (GSK3beta), a serine/threonine protein kinase, is a key target of drug discovery in several diseases, including diabetes and Alzheimer disease. Because lithium, a potent inhibitor of GSK3beta, causes nephrogenic diabetes insipidus, GSK3beta may play a crucial role in regulating water homeostasis. We developed renal collecting duct-specific GSK3beta knockout mice to determine whether deletion of GSK3beta affects arginine vasopressin-dependent renal water reabsorption. Although only mildly polyuric under normal conditions, knockout mice exhibited an impaired urinary concentrating ability in response to water deprivation or treatment with a vasopressin analogue. The knockout mice had reduced levels of mRNA, protein, and membrane localization of the vasopressin-responsive water channel aquaporin 2 compared with wild-type mice. The knockout mice also expressed lower levels of pS256-AQP2, a phosphorylated form crucial for membrane trafficking. Levels of cAMP, a major regulator of aquaporin 2 expression and trafficking, were also lower in the knockout mice. Both GSK3beta gene deletion and pharmacologic inhibition of GSK3beta reduced adenylate cyclase activity. In summary, GSK3beta inactivation or deletion reduces aquaporin 2 expression by modulating adenylate cyclase activity and cAMP generation, thereby impairing responses to vasopressin in the renal collecting duct.
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20 MeSH Terms
Subcellular localization of glycogen synthase kinase 3beta controls embryonic stem cell self-renewal.
Bechard M, Dalton S
(2009) Mol Cell Biol 29: 2092-104
MeSH Terms: Active Transport, Cell Nucleus, Animals, Cell Differentiation, Embryonic Stem Cells, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Mice, Phosphorylation, Proto-Oncogene Proteins c-akt, Proto-Oncogene Proteins c-myc, Signal Transduction
Show Abstract · Added February 3, 2011
Phosphatidylinositol 3-kinase (PI3K), protein kinase B (AKT1), and c-myc have well-established roles in promoting the maintenance of murine embryonic stem cells (mESCs). In contrast, the activity of glycogen synthase kinase 3beta (GSK3beta), a negatively regulated target of AKT1 signaling, antagonizes self-renewal. Here, we show that PI3K/AKT1 signaling promotes self-renewal by suppressing GSK3beta activity and restricting its access to nuclear substrates such as c-myc. GSK3beta shuttles between the cytoplasm and nucleus in mESCs but accumulates in the cytoplasm in an inactive form due to AKT1-dependent nuclear export and inhibitory phosphorylation. When PI3K/AKT1 signaling declines following leukemia inhibitory factor withdrawal, active GSK3beta accumulates in the nucleus, where it targets c-myc through phosphorylation on threonine 58 (T58), promoting its degradation. Ectopic nuclear localization of active GSK3beta promotes differentiation, but this process is blocked by a mutant form of c-myc (T58A) that evades phosphorylation by GSK3beta. This novel mechanism explains how AKT1 promotes self-renewal by regulating the activity and localization of GSK3beta. This pathway converges on c-myc, a key regulator of mESC self-renewal.
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11 MeSH Terms
The aurora kinase A regulates GSK-3beta in gastric cancer cells.
Dar AA, Belkhiri A, El-Rifai W
(2009) Oncogene 28: 866-75
MeSH Terms: Active Transport, Cell Nucleus, Aurora Kinase A, Aurora Kinases, Cell Line, Tumor, Cell Separation, Flow Cytometry, Gene Expression Regulation, Neoplastic, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Humans, Microscopy, Fluorescence, Models, Biological, Phosphorylation, Protein-Serine-Threonine Kinases, RNA, Small Interfering, Recombinant Proteins, Stomach Neoplasms, beta Catenin
Show Abstract · Added March 20, 2014
Aurora kinase A (AURKA) is located at 20q13, a region that is frequently amplified in gastric cancer. In this study, we have investigated the role of AURKA in regulating glycogen synthase kinase (GSK)-3beta and beta-catenin/TCF complex in gastric cancer cells. Our results demonstrate a significant increase in the phosphorylation of GSK-3beta at Ser 9 following the overexpression of AURKA in AGS cells. The immunoprecipitation with antibodies specific for AURKA and GSK-3beta indicated that the two proteins coexist in the same protein complex. The recombinant human AURKA protein phosphorylated the GSK-3beta protein at Ser 9 in a concentration-dependent manner, in vitro. The phosphorylation of beta-catenin (Ser33/37/Thr41) by GSK-3beta is known to target beta-catenin towards degradation. In line with our findings, the increase in phospho-GSK-3beta level was accompanied by a significant decrease in beta-catenin phosphorylation (Ser33/37/Thr41) and accumulation of beta-catenin protein. The knockdown of AURKA reversed the phosphorylation of GSK-3beta and the beta-catenin protein levels. The immunofluorescence analysis demonstrated colocalization of AURKA and GSK-3beta proteins and a significant increase in the nuclear beta-catenin levels in cells overexpressing AURKA. The beta-catenin/TCF transcription activity was measured using the pTopFlash and its mutant pFopFlash luciferase reporter vectors. Indeed, AURKA overexpression led to a significant increase in the pTopFlash reporter activity, whereas kinase dead AURKA mutant (D274A) had no effect. Consistent with these findings, we detected a significant mRNA up-regulation of several direct targets of the beta-catenin/TCF transcription complex (cyclin D1, c-MYC, c-MYC-binding protein, CLDN1, FGF18 and vascular endothelial growth factor), and a two-fold increase in the proliferation rate in AURKA overexpressing cells. We conclude that the AURKA/GSK-3beta interaction is important in regulating beta-catenin, underscoring a novel oncogenic potential for AURKA in gastric tumorigenesis.
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18 MeSH Terms