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GSK3β Interactions with Amyloid Genes: An Autopsy Verification and Extension.
Hohman TJ, Chibnik L, Bush WS, Jefferson AL, De Jaeger PL, Thornton-Wells TA, Bennett DA, Schneider JA
(2015) Neurotox Res 28: 232-8
MeSH Terms: Adaptor Proteins, Signal Transducing, Aged, 80 and over, Aging, Alzheimer Disease, Amyloid, Brain, Cognitive Dysfunction, Cohort Studies, Educational Status, Female, Follow-Up Studies, Gene Expression, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Humans, Male, Polymorphism, Single Nucleotide, Sex Characteristics, United States
Show Abstract · Added February 22, 2016
Glyocogen synthase kinase 3 (GSK3) plays an important role in the pathophysiology of Alzheimer's disease (AD) through the phosphorylation of tau. Recent work has suggested that GSK3β also plays a role in the amyloid pathway of AD through genetic interactions with APP and APBB2 on in vivo measures of amyloid. This project extends the previously identified genotype interactions to an autopsy measure of amyloid, while also testing the same interactions leveraging gene expression data quantified in the prefrontal cortex. 797 participants (251 cognitively normal, 196 mild cognitive impairment, and 350 Alzheimer's disease) were drawn from the Religious Orders Study and Rush Memory and Aging Project. A mean score of amyloid load was calculated across eight brain regions, gene expression levels from frozen sections of the dorsolateral prefrontal cortex were quantified using RNA amplification, and expression signals were generated using Beadstudio. Three SNPs previously identified in genetic interactions were genotyped using the Illumina 1M genotyping chip. Covariates included age, sex, education, and diagnosis. We were able to evaluate 2 of the 3 previously identified interactions, of which the interaction between GSK3β (rs334543) and APBB2 (rs2585590) was found in this autopsy sample (p = 0.04). We observed a comparable interaction between GSK3β and APBB2 when comparing the highest tertile of gene expression to the lowest tertile, t(1) = -2.03, p = 0.043. These results provide additional evidence of a genetic interaction between GSK3β and APBB2 and further suggest that GSK3β is involved in the pathophysiology of both of the primary neuropathologies of Alzheimer's disease.
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19 MeSH Terms
Activation of β-catenin signalling by TFF1 loss promotes cell proliferation and gastric tumorigenesis.
Soutto M, Peng D, Katsha A, Chen Z, Piazuelo MB, Washington MK, Belkhiri A, Correa P, El-Rifai W
(2015) Gut 64: 1028-39
MeSH Terms: Animals, Cell Line, Tumor, Cell Proliferation, Down-Regulation, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Growth Inhibitors, Immunohistochemistry, Mice, Mice, Knockout, Peptides, Protein Phosphatase 2, Proto-Oncogene Proteins c-akt, Stomach Neoplasms, Transcriptional Activation, Trefoil Factor-1, beta Catenin
Show Abstract · Added February 19, 2015
OBJECTIVE - In this study, we investigated the role of Trefoil factor 1 (TFF1) in regulating cell proliferation and tumour development through β-catenin signalling using in vivo and in vitro models of gastric tumorigenesis.
DESIGN - Tff1-knockout (Tff1-KO) mice, immunohistochemistry, luciferase reporter, qRT-PCR, immunoblot, and phosphatase assays were used to examine the role of TFF1 on β-catenin signalling pathway.
RESULTS - Nuclear localisation of β-catenin with transcriptional upregulation of its target genes, c-Myc and Ccnd1, was detected in hyperplastic tissue at an early age of 4-6 weeks and maintained during all stages of gastric tumorigenesis in the Tff1-KO mice. The reconstitution of TFF1 or TFF1 conditioned media significantly inhibited the β-catenin/T-cell factor (TCF) transcription activity in MKN28 gastric cancer cells. In agreement with these results, we detected a reduction in the levels of nuclear β-catenin with downregulation of c-MYC and CCND1 mRNA. Analysis of signalling molecules upstream of β-catenin revealed a decrease in phosphorylated glycogen synthase kinase 3β (p-GSK3β) (Ser9) and p-AKT (Ser473) protein levels following the reconstitution of TFF1 expression; this was consistent with the increase of p-β-catenin (Ser33/37/Thr41) and decrease of p-β-catenin (Ser552). This TFF1-induced reduction in phosphorylation of GSK3β, and AKT was dependent on protein phosphatase 2A (PP2A) activity. The treatment with okadaic acid or knockdown of PP2A abrogated these effects. Consistent with the mouse data, we observed loss of TFF1 and an increase in nuclear localisation of β-catenin in stages of human gastric tumorigenesis.
CONCLUSIONS - Our data indicate that loss of TFF1 promotes β-catenin activation and gastric tumorigenesis through regulation of PP2A, a major regulator of AKT-GSK3β signalling.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
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17 MeSH Terms
Interactions between GSK3β and amyloid genes explain variance in amyloid burden.
Hohman TJ, Koran ME, Thornton-Wells TA, Alzheimer's Neuroimaging Initiative
(2014) Neurobiol Aging 35: 460-5
MeSH Terms: Aged, Aged, 80 and over, Alzheimer Disease, Amyloid beta-Peptides, Female, Gene Expression Regulation, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Humans, Linear Models, Male, Middle Aged, Plaque, Amyloid, Polymorphism, Single Nucleotide, Risk, tau Proteins
Show Abstract · Added December 10, 2014
The driving theoretical framework of Alzheimer's disease (AD) has been built around the amyloid-β (Aβ) cascade in which amyloid pathology precedes and drives tau pathology. Other evidence has suggested that tau and amyloid pathology may arise independently. Both lines of research suggest that there may be epistatic relationships between genes involved in amyloid and tau pathophysiology. In the current study, we hypothesized that genes coding glycogen synthase kinase 3 (GSK-3) and comparable tau kinases would modify genetic risk for amyloid plaque pathology. Quantitative amyloid positron emission tomography data from the Alzheimer's Disease Neuroimaging Initiative served as the quantitative outcome in regression analyses, covarying for age, gender, and diagnosis. Three interactions reached statistical significance, all involving the GSK3β single nucleotide polymorphism rs334543-2 with APBB2 (rs2585590, rs3098914) and 1 with APP (rs457581). These interactions explained 1.2%, 1.5%, and 1.5% of the variance in amyloid deposition respectively. Our results add to a growing literature on the role of GSK-3 activity in amyloid processing and suggest that combined variation in GSK3β and APP-related genes may result in increased amyloid burden.
Copyright © 2014 Elsevier Inc. All rights reserved.
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16 MeSH Terms
AS160 deficiency causes whole-body insulin resistance via composite effects in multiple tissues.
Wang HY, Ducommun S, Quan C, Xie B, Li M, Wasserman DH, Sakamoto K, Mackintosh C, Chen S
(2013) Biochem J 449: 479-89
MeSH Terms: Adipocytes, Adipose Tissue, Animals, Blood Glucose, Blotting, Western, Cells, Cultured, Female, GTPase-Activating Proteins, Glucose, Glucose Tolerance Test, Glucose Transporter Type 4, Glycogen Synthase Kinase 3, Humans, Hypoglycemic Agents, In Vitro Techniques, Insulin, Insulin Resistance, Liver, Male, Mice, Mice, Knockout, Muscle, Skeletal, Phosphoenolpyruvate Carboxykinase (GTP), Phosphorylation
Show Abstract · Added July 21, 2014
AS160 (Akt substrate of 160 kDa) is a Rab GTPase-activating protein implicated in insulin control of GLUT4 (glucose transporter 4) trafficking. In humans, a truncation mutation (R363X) in one allele of AS160 decreased the expression of the protein and caused severe postprandial hyperinsulinaemia during puberty. To complement the limited studies possible in humans, we generated an AS160-knockout mouse. In wild-type mice, AS160 expression is relatively high in adipose tissue and soleus muscle, low in EDL (extensor digitorum longus) muscle and detectable in liver only after enrichment. Despite having lower blood glucose levels under both fasted and random-fed conditions, the AS160-knockout mice exhibited insulin resistance in both muscle and liver in a euglycaemic clamp study. Consistent with this paradoxical phenotype, basal glucose uptake was higher in AS160-knockout primary adipocytes and normal in isolated soleus muscle, but their insulin-stimulated glucose uptake and overall GLUT4 levels were markedly decreased. In contrast, insulin-stimulated glucose uptake and GLUT4 levels were normal in EDL muscle. The liver also contributes to the AS160-knockout phenotype via hepatic insulin resistance, elevated hepatic expression of phosphoenolpyruvate carboxykinase isoforms and pyruvate intolerance, which are indicative of increased gluconeogenesis. Overall, as well as its catalytic function, AS160 influences expression of other proteins, and its loss deregulates basal and insulin-regulated glucose homoeostasis, not only in tissues that normally express AS160, but also by influencing liver function.
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24 MeSH Terms
Thr 163 phosphorylation causes Mcl-1 stabilization when degradation is independent of the adjacent GSK3-targeted phosphodegron, promoting drug resistance in cancer.
Nifoussi SK, Vrana JA, Domina AM, De Biasio A, Gui J, Gregory MA, Hann SR, Craig RW
(2012) PLoS One 7: e47060
MeSH Terms: Animals, Antineoplastic Agents, Apoptosis, Blotting, Western, CHO Cells, Cell Line, Tumor, Cisplatin, Cricetinae, Cytarabine, Drug Resistance, Neoplasm, Etoposide, Flow Cytometry, Glycogen Synthase Kinase 3, Humans, Myeloid Cell Leukemia Sequence 1 Protein, Phosphorylation, Protein Stability, Proto-Oncogene Proteins c-bcl-2, Threonine, Vinblastine
Show Abstract · Added March 20, 2014
The antiapoptotic Bcl-2 family member Mcl-1 is a PEST protein (containing sequences enriched in proline, glutamic acid, serine, and threonine) and is subject to rapid degradation via multiple pathways. Impaired degradation leading to the maintenance of Mcl-1 expression is an important determinant of drug resistance in cancer. Phosphorylation at Thr 163 in the PEST region, stimulated by 12-O-tetradecanoylphorbol acetic acid (TPA)-induced activation of extracellular signal-regulated kinase (ERK), is associated with Mcl-1 stabilization in BL41-3 Burkitt lymphoma cells. This contrasts with the observation that Thr 163 phosphorylation in normal fibroblasts primes glycogen synthase kinase (GSK3)-induced phosphorylation at Ser 159, producing a phosphodegron that targets Mcl-1 for degradation. In the present follow-up studies in BL41-3 cells, Mcl-1 degradation was found to be independent of the GSK3-mediated pathway, providing a parallel to emerging findings showing that Mcl-1 degradation through this pathway is lost in many different types of cancer. Findings in Mcl-1-transfected CHO cells corroborated those in BL41-3 cells in that the GSK3-targeted phosphodegron did not play a major role in Mcl-1 degradation, and a phosphomimetic T163E mutation resulted in marked Mcl-1 stabilization. TPA-treated BL41-3 cells, in addition to exhibiting Thr 163 phosphorylation and Mcl-1 stabilization, exhibited an ∼10-fold increase in resistance to multiple chemotherapeutic agents, including Ara-C, etoposide, vinblastine, or cisplatin. In these cancer cells in which Mcl-1 degradation is not dependent on the GSK3/phosphodegron-targeted pathway, ERK activation and Thr 163 phosphorylation are associated with pronounced Mcl-1 stabilization and drug resistance - effects that can be suppressed by inhibition of ERK activation.
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20 MeSH Terms
Interaction between the central and peripheral effects of insulin in controlling hepatic glucose metabolism in the conscious dog.
Ramnanan CJ, Kraft G, Smith MS, Farmer B, Neal D, Williams PE, Lautz M, Farmer T, Donahue EP, Cherrington AD, Edgerton DS
(2013) Diabetes 62: 74-84
MeSH Terms: Animals, Brain, Dogs, Female, Glucokinase, Glucose, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Glycogenolysis, Hypothalamus, Insulin, Liver, Male, Phosphorylation, STAT3 Transcription Factor
Show Abstract · Added February 13, 2015
The importance of hypothalamic insulin action to the regulation of hepatic glucose metabolism in the presence of a normal liver/brain insulin ratio (3:1) is unknown. Thus, we assessed the role of central insulin action in the response of the liver to normal physiologic hyperinsulinemia over 4 h. Using a pancreatic clamp, hepatic portal vein insulin delivery was increased three- or eightfold in the conscious dog. Insulin action was studied in the presence or absence of intracerebroventricularly mediated blockade of hypothalamic insulin action. Euglycemia was maintained, and glucagon was clamped at basal. Both the molecular and metabolic aspects of insulin action were assessed. Blockade of hypothalamic insulin signaling did not alter the insulin-mediated suppression of hepatic gluconeogenic gene transcription but blunted the induction of glucokinase gene transcription and completely blocked the inhibition of glycogen synthase kinase-3β gene transcription. Thus, central and peripheral insulin action combined to control some, but not other, hepatic enzyme programs. Nevertheless, inhibition of hypothalamic insulin action did not alter the effects of the hormone on hepatic glucose flux (production or uptake). These data indicate that brain insulin action is not a determinant of the rapid (<4 h) inhibition of hepatic glucose metabolism caused by normal physiologic hyperinsulinemia in this large animal model.
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4 Members
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15 MeSH Terms
Reconciling the different roles of Gsk3β in "naïve" and "primed" pluripotent stem cells.
Singh AM, Bechard M, Smith K, Dalton S
(2012) Cell Cycle 11: 2991-6
MeSH Terms: Animals, Cell Differentiation, Enzyme Activation, Furans, Gene Expression Regulation, Enzymologic, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Homeodomain Proteins, Humans, Immunoenzyme Techniques, Mice, Nanog Homeobox Protein, Phosphatidylinositol 3-Kinases, Phosphorylation, Pluripotent Stem Cells, Proto-Oncogene Proteins c-myc, Pyridines, Pyrimidines, Species Specificity, Wnt Signaling Pathway
Show Abstract · Added August 25, 2016
Signaling pathways orchestrated by PI3K/Akt, Raf/Mek/Erk and Wnt/β-catenin are known to play key roles in the self-renewal and differentiation of pluripotent stem cells. The serine/threonine protein kinase Gsk3β has roles in all three pathways, making its exact function difficult to decipher. Consequently, conflicting reports have implicated Gsk3β in promoting self-renewal, while others suggest that it performs roles in the activation of differentiation pathways. Different thresholds of Gsk3β activity also have different biological effects on pluripotent cells, making this situation even more complex. Here, we describe a further level of complexity that is most apparent when comparing "naïve" murine and "primed" human pluripotent stem cells. In naïve cells, Gsk3β activity is restrained by PI3K/Akt, but when released from inhibitory signals it antagonizes self-renewal pathways by targeting pluripotency factors such as Myc and Nanog. This situation also applies in primed cells, but, in addition, a separate pool of Gsk3β is required to suppress canonical Wnt signaling. These observations suggest that different Gsk3β-protein complexes shift the balance between naïve and primed pluripotent cells and identify fundamental differences in their cell signaling. Altogether, these findings have important implications for the mechanisms underpinning the establishment of different pluripotent cell states and for the control of self-renewal and differentiation.
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20 MeSH Terms
Specific deletion of glycogen synthase kinase-3β in the renal proximal tubule protects against acute nephrotoxic injury in mice.
Howard C, Tao S, Yang HC, Fogo AB, Woodgett JR, Harris RC, Rao R
(2012) Kidney Int 82: 1000-9
MeSH Terms: Acute Disease, Acute Kidney Injury, Animals, Anti-Infective Agents, Local, Apoptosis, Cell Proliferation, Disease Models, Animal, Female, Gene Deletion, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Kaplan-Meier Estimate, Kidney Tubules, Proximal, Mercuric Chloride, Mice, Mice, Inbred C57BL, Mice, Knockout, Thiadiazoles
Show Abstract · Added August 19, 2013
Renal proximal tubular damage and repair are hallmarks of acute kidney injury. As glycogen synthase kinase-3β (GSK3β) is an important cellular regulator of survival and proliferation, we determined its role during injury and recovery of proximal tubules in a mercuric chloride-induced nephrotoxic model of acute kidney injury. Renal proximal tubule-specific GSK3β knockout mice exposed to mercuric chloride had improved survival and renal function compared to wild-type mice. Apoptosis, measured by TUNEL staining, Bax activation, and caspase 3 cleavage, was reduced in the knockout mice. The restoration of renal structure, function, and cell proliferation was also accelerated in the GSK3β knockout mice. This enhanced repair, evidenced by increased Ki-67 and BRDU staining, along with increased cyclin D1 and c-myc levels, was recapitulated by treatment of wild-type mice with the small-molecule GSK3 inhibitor TDZD-8 following injury. This confirmed that hastened repair in the knockout mice was not merely due to lower initial injury levels. Thus, inhibition of GSK3β prior to nephrotoxic insult protects from renal injury. Such treatment after acute kidney injury may accelerate repair and regeneration.
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18 MeSH Terms
Frat is a phosphatidylinositol 3-kinase/Akt-regulated determinant of glycogen synthase kinase 3β subcellular localization in pluripotent cells.
Bechard M, Trost R, Singh AM, Dalton S
(2012) Mol Cell Biol 32: 288-96
MeSH Terms: Active Transport, Cell Nucleus, Animals, Carrier Proteins, Cell Differentiation, Cell Nucleus, Embryonic Stem Cells, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Mice, Mutation, Neoplasm Proteins, Phosphatidylinositol 3-Kinase, Pluripotent Stem Cells, Protein Binding, Proto-Oncogene Proteins c-akt
Show Abstract · Added December 5, 2011
Suppressing the activity of Gsk3β is critical for maintenance of murine pluripotent stem cells. In murine embryonic stem cells (mESCs), Gsk3β is inhibited by multiple mechanisms, including its inhibitory phosphorylation on serine 9 by protein kinase B (Akt), a major effector of the canonical phosphatidylinositol 3-kinase (PI3K) pathway. A second PI3K/Akt-regulated mechanism promotes the nuclear export of Gsk3β, thereby restricting its access to nuclear substrates such as c-myc and β-catenin. Although Gsk3β shuttles between the nucleus and cytoplasm under self-renewing conditions, its localization is primarily cytoplasmic because its rate of nuclear export exceeds its rate of nuclear import. In this report, we show that Gsk3β is exported from the nucleus in a complex with Frat. Loss of PI3K/Akt activity results in dissociation of this complex and retention of Gsk3β in the nucleus. Frat continues to shuttle between the nucleus and cytoplasm under these conditions and remains predominantly in the cytoplasm. These results indicate that Frat carries Gsk3β out of the nucleus under self-renewing conditions and that PI3K regulates this by promoting its association with Frat. These findings provide new links between PI3K/Akt signaling and regulation of Gsk3β activity by Frat, an oncogene previously shown to cooperate with Myc in tumorigenesis.
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15 MeSH Terms
GSK3-mediated instability of tubulin polymers is responsible for the failure of immature CD4+CD8+ thymocytes to polarize their MTOC in response to TCR stimulation.
Cunningham NR, Hinchcliff EM, Kutyavin VI, Beck T, Reid WA, Punt JA
(2011) Int Immunol 23: 693-700
MeSH Terms: Aminophenols, Animals, Blotting, Western, CD4 Antigens, CD8 Antigens, Cell Differentiation, Enzyme Inhibitors, Female, Flow Cytometry, Gene Expression Regulation, Developmental, Glycogen Synthase Kinase 3, Lymphocyte Activation, Maleimides, Mice, Mice, Inbred C57BL, Microtubule-Organizing Center, Microtubules, Polymerization, Receptors, Antigen, T-Cell, Signal Transduction, T-Lymphocytes, Thymocytes, Tubulin
Show Abstract · Added January 11, 2016
Although mature T cells divide and differentiate when they receive strong TCR stimulation, most immature CD4+CD8+ thymocytes die. The molecular basis for this marked difference in response is not known. Observations that TCR-stimulated CD4+CD8+ thymocytes fail to polarize their microtubule-organizing center (MTOC), one of the first events that occurs upon antigen activation of mature T cells, suggests that TCR signaling routes in immature and mature T cells diverge early and upstream of MTOC polarization. To better understand the source of the divergence, we examined the molecular basis for the difference in TCR-mediated MTOC polarization. We show that unstable microtubules are a feature of immature murine CD4+CD8+ thymocytes, which also exhibit higher levels of glycogen synthase kinase 3 (GSK3) activity, a known inhibitor of microtubule stability. Importantly, CD4+CD8+ thymocytes gained the ability to polarize their MTOC in response to TCR signals when GSK3 activity was inhibited. GSK3 inhibition also abrogated TCR-mediated apoptosis of immature thymocytes. Together, our results suggest that a developmentally regulated difference in GSK3 activity has a major influence on immature CD4+CD8+ thymocyte versus mature T-cell responses to TCR stimulation.
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23 MeSH Terms