Academic literature on the topic 'GSK-3beta'
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Journal articles on the topic "GSK-3beta"
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Sun, Yi, Lu Yang, and Qiang Wei. "Protection of prostate cancer cells from GSK-3β-induced oxidative stress by Il-8 through activating the mTOR signaling pathway." Journal of Clinical Oncology 37, no. 7_suppl (March 1, 2019): 311. http://dx.doi.org/10.1200/jco.2019.37.7_suppl.311.
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311 Background: Both oxidative stress and inflammation play important roles in prostate cancer cell apoptosis or proliferation. However, the mechanisms underlying these processes remain unclear. Thus, we chose IL-8 as the bridge between inflammation and cancer cell oxidative stress-induced death and confirmed its connection with mTOR and GSK-3beta. Methods: We overexpressed GSK-3beta and observed the effect of GSK-3beta on reactive oxygen species (ROS) and cell death induced by oxidative stress. Then, IL-8 was upregulated or downregulated to determine its impact on preventing cells from damage by GSK-3beta-induced oxidative stress. In addition, we confirmed the role of mTOR in this process through its overexpression or knockdown. Real-time PCR, Western blotting, transcription, Cell Counting Kit 8, flow cytometry and other techniques were used. Results: IL-8 promotes prostate cancer cell proliferation and decreases apoptosis, while GSK-3beta induces cell death by oxidative stress through the activation of the caspase-3 signaling pathway by increasing ROS. In addition, mTOR can also decrease the activation of the caspase-3 signaling pathway by inhibiting GSK--3beta and thus decreasing ROS production. Moreover, the inhibitory effect of IL-8 on GSK-3beta occurs through the regulation of mTOR. Conclusions: The results of this study highlight the importance of GSK-3beta, which increases the production of ROS and then induces oxidative stress in tumor cells, while IL-8 and mTOR attenuate the oxidative stress to protect prostate cancer cells through the inhibitor GSK-3beta.
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Lucas, F. R., R. G. Goold, P. R. Gordon-Weeks, and P. C. Salinas. "Inhibition of GSK-3beta leading to the loss of phosphorylated MAP-1B is an early event in axonal remodelling induced by WNT-7a or lithium." Journal of Cell Science 111, no. 10 (May 15, 1998): 1351–61. http://dx.doi.org/10.1242/jcs.111.10.1351.
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WNT-7a induces axonal spreading and branching in developing cerebellar granule neurons. This effect is mediated through the inhibition of GSK-3beta, a serine/threonine kinase and a component of the WNT pathway. Lithium, an inhibitor of GSK-3beta, mimics WNT-7a in granule cells. Here we examined further the effect of GSK-3beta inhibition on cytoskeletal re-organisation. Lithium induces axonal spreading and increases growth cone area and perimeter. This effect is associated with the absence or reduction of stable microtubules in spread areas. Lithium induces the loss of a phosphorylated form of MAP-1B, a microtubule associated protein involved in axonal outgrowth. Down-regulation of the phosphorylated MAP-1B, MAP-1B-P, from axonal processes occurs before axonal remodelling is evident. In vitro phosphorylation assays show that MAP-1B-P is generated by direct phosphorylation of MAP-1B by GSK-3beta. WNT-7a, like lithium, also leads to loss of MAP-1B-P from spread axons and growth cones. Our data suggest that WNT-7a and lithium induce changes in microtubule dynamics by inhibiting GSK-3beta which in turn lead to changes in the phosphorylation of MAP-1B. These findings suggest a novel role for GSK-3beta and WNTs in axonal remodelling and identify MAP-1B as a new target for GSK-3beta and WNT.
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Fisher, D. L., N. Morin, and M. Doree. "A novel role for glycogen synthase kinase-3 in Xenopus development: maintenance of oocyte cell cycle arrest by a beta-catenin-independent mechanism." Development 126, no. 3 (February 1, 1999): 567–76. http://dx.doi.org/10.1242/dev.126.3.567.
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We have examined the expression of glycogen synthase kinase-3beta in oocytes and early embryos of Xenopus and found that the protein is developmentally regulated. In resting oocytes, GSK-3beta is active and it is inactivated on maturation in response to progesterone. GSK-3beta inactivation is necessary and rate limiting for the cell cycle response to this hormone and the subsequent accumulation of beta-catenin. Overexpression of a dominant negative form of the kinase accelerates maturation, as does inactivation by expression of Xenopus Dishevelled or microinjection of an inactivating antibody. Cell cycle inhibition by GSK-3beta is not mediated by the level of beta-catenin or by a direct effect on either the MAP kinase pathway or translation of mos and cyclin B1. These data indicate a novel role for GSK-3beta in Xenopus development: in addition to controlling specification of the dorsoventral axis in embryos, it mediates cell cycle arrest in oocytes.
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Strekalova, Tatyana, Nataliia Markova, Elena Shevtsova, Olga Zubareva, Anastassia Bakhmet, Harry M. Steinbusch, Sergey Bachurin, and Klaus-Peter Lesch. "Individual Differences in Behavioural Despair Predict Brain GSK-3beta Expression in Mice: The Power of a Modified Swim Test." Neural Plasticity 2016 (2016): 1–17. http://dx.doi.org/10.1155/2016/5098591.
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While deficient brain plasticity is a well-established pathophysiologic feature of depression, little is known about disorder-associated enhanced cognitive processing. Here, we studied a novel mouse paradigm that potentially models augmented learning of adverse memories during development of a depressive-like state. We used a modification of the classic two-day protocol of a mouse Porsolt test with an additional session occurring on Day 5 following the initial exposure. Unexpectedly, floating behaviour and brain glycogen synthase kinase-3 beta (GSK-3beta) mRNA levels, a factor of synaptic plasticity as well as a marker of distress and depression, were increased during the additional swimming session that was prevented by imipramine. Observed increases of GSK-3beta mRNA in prefrontal cortex during delayed testing session correlated with individual parameters of behavioural despair that was not found in the classic Porsolt test. Repeated swim exposure was accompanied by a lower pGSK-3beta/GSK-3beta ratio. A replacement of the second or the final swim sessions with exposure to the context of testing resulted in increased GSK-3beta mRNA level similar to the effects of swimming, while exclusion of the second testing prevented these changes. Together, our findings implicate the activation of brain GSK-3beta expression in enhanced contextual conditioning of adverse memories, which is associated with an individual susceptibility to a depressive syndrome.
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Dao, Kim-Hien T., Michael D. Rotelli, Jane E. Yates, Brieanna Brown, Juha Rantala, Keaney Rathbun, Jeffrey W. Tyner, Brian J. Druker, and Grover C. Bagby. "Regulation of FANCL by Glycogen Synthase Kinase-3beta Links the Fanconi anemia pathway to Self Renewal and Survival Signals." Blood 120, no. 21 (November 16, 2012): 1263. http://dx.doi.org/10.1182/blood.v120.21.1263.1263.
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Abstract Abstract 1263 The molecular basis for how a Fanconi anemia (FA) genetic background contributes to hematopoietic stem cell defects and hypoplastic organ development remains poorly understood. Protein modification by ubiquitination is a mechanism that diversifies the function and regulation of proteins. In light of this, we focus on the dysfunction of FANCL, the E3 ubiquitin ligase of the FA pathway, as a key molecular defect in Fanconi anemia. Here we report our studies investigating mechanisms of post-translational regulation of FANCL. We view these mechanisms as potential targets to augment the function of the FA core complex and correct hematopoietic stem cell defects. We provide evidence that FANCL is exquisitely regulated by ubiquitin-proteosome degradation. Ligase-inactive mutants (FANCL-C307A and -W341G) are less sensitive to this regulation, suggesting a role for auto-ubiquitination in directing lysine-48 polyubiquitination. This constitutive negative regulation of FANCL is partially reversed with an ATP-competitive glycogen synthase kinase-3beta (GSK-3beta) inhibitor. GSK-3beta is a serine/threonine kinase that phosphorylates proteins and marks them for ubiquitin-mediated proteolysis. Mitogenic and survival pathways, including Ras/MAPK and PI3K/Akt, negatively regulate GSK-3beta by serine-9 phosphorylation. We show that the regulation of FANCL by GSK-3beta is likely direct because FANCL and GSK-3beta co-immunoprecipitate in cell lysates and as GST-fusion proteins. To define the biochemical mechanisms of FANCL regulation, we generated N-terminal deletion mutants of FANCL and we show that the regulation of FANCL is dictated by a region at the N-terminus (aa1-78). Mutational analysis of FANCL (lysine to arginine) in this N-terminus region does not affect the overall protein level or ubiquitination of FANCL, suggesting that FANCL may be targeted for degradation by phosphorylation and/or in a complex with other proteins. The potential biological relevance of our findings, that FANCL is regulated by GSK-3beta is revealed in studies overexpressing constitutively active, myristoylated-Akt. This experimental condition increases FANCL protein levels and suggests a role for FANCL as a downstream effector of PI3K/Akt signaling. In turn, FANCL likely regulates non-canonical targets that alter the transcriptome profile favoring self-renewal and survival of hematopoietic stem cells. We recently published our studies identifying beta-catenin as one such downstream target (Blood 2012 Jul 12;120:323). Suppression of FANCL expression severely disrupts Wnt/beta-catenin signaling and expression of downstream Wnt-responsive targets MYC and CCND1. We also identified that GSK3B gene expression is approximately 5-fold higher in Fancc-deficient hematopoietic stem cells exposed to TNF-alpha compared to untreated cells or to wildtype cells with or without TNF-alpha. Our current studies show that inhibition of GSK-3beta preserves the number of murine Fancc-deficient hematopoietic stem cells exposed to TNF-alpha compared with no GSK-3beta inhibition. Taken together, we have accumulated evidence suggesting that GSK-3beta is a promising molecular target to improve the self-renewal and survival of FA hematopoietic stem cells. Disclosures: No relevant conflicts of interest to declare.
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Lemoine, Sandrine, Lan Zhu, Gallic Beauchef, Olivier Lepage, Gérard Babatasi, Caline Ivascau, Massimo Massetti, Philippe Galera, Jean-Louis Gérard, and Jean-Luc Hanouz. "Role of 70-kDa Ribosomal Protein S6 Kinase, Nitric Oxide Synthase, Glycogen Synthase Kinase-3β, and Mitochondrial Permeability Transition Pore in Desflurane-induced Postconditioning in Isolated Human Right Atria." Anesthesiology 112, no. 6 (June 1, 2010): 1355–63. http://dx.doi.org/10.1097/aln.0b013e3181d74f39.
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Background Desflurane during early reperfusion has been shown to postcondition human myocardium. Whether it involves "reperfusion injury salvage kinase" pathway remains incompletely studied. The authors tested the involvement of 70-kDa ribosomal protein S6 kinase, nitric oxide synthase, glycogen synthase kinase (GSK)-3beta, and mitochondrial permeability transition pore in desflurane-induced postconditioning. Methods The authors recorded isometric contraction of human right atrial trabeculae suspended in an oxygenated Tyrode's solution (34 degrees C, stimulation frequency 1 Hz). After a 30-min hypoxic period, desflurane 6% was administered during the first 5 min of reoxygenation. Desflurane was administered alone or with pretreatment of rapamycin, a 70-kDa ribosomal protein S6 kinase inhibitor, NG-nitro-L-arginine methyl ester, a nitric oxide synthase inhibitor, and atractyloside, the mitochondrial permeability transition pore opener. GSK-3beta inhibitor VII was administered during the first few minutes of reoxygenation alone or in the presence of desflurane 6%, rapamycin, NG-nitro-L-arginine methyl ester, and atractyloside. Developed force at the end of a 60-min reoxygenation period was compared (mean +/- SD). Phosphorylation of GSK-3beta was measured using blotting. Results Desflurane 6% (84 +/- 4% of baseline) enhanced the recovery of force after 60 min of reoxygenation when compared with the control group (54 +/- 4%, P < 0.0001). Rapamycin (68 +/- 8% of baseline), NG-nitro-L-arginine methyl ester (57 +/- 8%), atractyloside (52 +/- 7%) abolished desflurane-induced postconditioning (P < 0.001). GSK-3beta inhibitor-induced postconditioning (84 +/- 5%, P < 0.0001 vs. control) was not modified by desflurane (78 +/- 6%), rapamycin (81 +/- 6%), and NG-nitro-L-arginine methyl ester (82 +/- 10%), but it was abolished by atractyloside (49 +/- 6%). Desflurane increased the phosphorylation of GSK-3beta (3.30 +/- 0.57-fold increase in desflurane vs. control; P < 0.0001). Conclusions In vitro, desflurane-induced postconditioning protects human myocardium through the activation of 70-kDa ribosomal protein S6 kinase, nitric oxide synthase, inhibition, and phosphorylation of GSK-3beta, and preventing mitochondrial permeability transition pore opening.
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Lin, Xiao, and Yu Li. "Mechanisms of Plant Polyphenol Genistein on Regulation of EMT in Ovarian Carcinoma." Advanced Materials Research 1120-1121 (July 2015): 803–6. http://dx.doi.org/10.4028/www.scientific.net/amr.1120-1121.803.
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More and more studies have reported that epithelial-mesenchymal translation (EMT) plays key roles not only on genesis, development and metastasis, but also on drug-resistance of chemotherapy of tumor. Meanwhile, the fact that beta-catenin transfer from membrance and cytoplasm to nucleus is major steps in process of EMT [1]. Research found that Genistein would suppress Wnt/beta-catenin signal pathway though inhibiting beta-catenin translation [2]. Furthermore, our research showed that Genistein could decrease the expression of GSK-3beta in ovarian carcinoma cell SKOV3. Beta-catenin and GSK-3beta are important factors of EMT, which indicated that Genistein would regulate EMT signal pathway through beta-catenin and GSK-3beta, but the mechanism is not clear. So, there has been great interest in understanding the molecular mechanisms on the effect of Genistein.
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Ray, L. B. "Hsp90 Controls GSK-3beta Kinase Specificity." Science's STKE 2006, no. 362 (November 14, 2006): tw395. http://dx.doi.org/10.1126/stke.3622006tw395.
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Lin, Fei-xiang, Gui-zhou Zheng, Bo Chang, Rong-chun Chen, Qi-hao Zhang, Peng Xie, Da Xie, et al. "Connexin 43 Modulates Osteogenic Differentiation of Bone Marrow Stromal Cells Through GSK-3beta/Beta-Catenin Signaling Pathways." Cellular Physiology and Biochemistry 47, no. 1 (2018): 161–75. http://dx.doi.org/10.1159/000489763.
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Background/Aims: Bone marrow stromal cells (BMSCs) are multipotent precursors that give rise to osteoblasts, and contribute directly to bone formation. Connexin 43 (Cx43) is the most ubiquitous gap junction protein expressed in bone cell types, and plays crucial roles in regulating intercellular signal transmission for bone development, differentiation and pathology. However, the precise role and mechanism of Cx43 in BMSCs are less known. Here, we investigate the function of Cx43 in osteogenic differentiation of BMSCs in vitro. Methods: BMSCs were isolated by whole bone marrow adherent culture. Knock down of Cx43 was performed by using lentiviral transduction of Cx43 shRNA. BMSCs were induced to differentiate by culturing in a-MEM, 10% FBS, 50 µM ascorbic acid, 10 mM beta-glycerophosphate, and 100 nM dexamethasone. Alkaline phosphatase (ALP) activity and alizarin red S staining were used to evaluate osteogenic differentiation in calcium nodules. Target mRNAs and proteins were analyzed by using real-time quantitative PCR (qPCR) and western blotting. Results: Cx43 expression markedly increased during osteogenic differentiation. Osteogenic differentiation was suppressed following lentiviral-mediated knockdown of Cx43 expression, as judged by decreased levels of Runt-related transcription factor 2 (Runx2), bone sialoprotein (BSP), osteocalcin (Bglap), Osterix (Osx), alkaline phosphatase (ALP) activity and the number of calcium nodules in response to osteogenic differentiation stimuli. Knock down of Cx43 reduced the level of phosphorylation of GSK-3beta at Ser9 (p-GSK-3beta), resulting in decreased beta-catenin expression and activation. Furthermore, treatment of Cx43-knockdown cells with lithium chloride (LiCl), a GSK-3beta inhibitor, reduced osteogenic differentiation and decreased GSK-3beta levels, as well as partially rescued levels of both total and activated beta-catenin. Conclusion: These findings indicate that Cx43 positively modulates osteogenic differentiation of BMSCs by up-regulating GSK-3beta/beta-catenin signaling pathways, suggesting a potential role for Cx43 in determining bone mass and bone mineral density by modulating osteogenesis.
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Cui, Dehua, Y. Yoshiike, J. M. Park, Y. L. Jin, M. Murayama, E. Planel, Y. Tatebayashi, and A. Takashima. "P3-245 Participation of GSK-3beta in neurodegeneration." Neurobiology of Aging 25 (July 2004): S424. http://dx.doi.org/10.1016/s0197-4580(04)81395-2.
Full textDissertations / Theses on the topic "GSK-3beta"
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Hsin, Honor. "Roles of GSK-3beta and PYK2 signaling pathways in synaptic plasticity." Thesis, Massachusetts Institute of Technology, 2010. http://hdl.handle.net/1721.1/57798.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2010.Cataloged from PDF version of thesis.
Includes bibliographical references.
Activity-dependent modification of synapses, as in long term potentiation (LTP) or long term depression (LTD), is widely believed to be a crucial mechanism for learning and memory. Molecular perturbations in these processes may underlie certain neuropsychiatric conditions. This thesis examines the role of two signaling pathways, glycogen synthase kinase 3 beta (GSK- 3beta) and proline-rich tyrosine kinase 2 (PYK2), in LTD at rat hippocampal synapses. GSK-3beta, a serine/threonine kinase implicated in the pathophysiology of schizophrenia, mood disorders, and Alzheimer's disease, is known to play a critical role in LTD. Here we report that GSK-3beta phosphorylates the postsynaptic scaffold protein PSD-95, a major determinant of synaptic strength, at the Thr- 19 residue. In hippocampal neurons, this promotes the activity-dependent dispersal of synaptic PSD-95 clusters. We found that overexpression of a phospho-null mutant (Ti 9A-PSD-95), but not a phospho-mimic mutant, blocks LTD without affecting basal synaptic function relative to wild type PSD-95 overexpression. Thus PSD-95 phosphorylation by GSK-3beta is a necessary step in LTD. [This project is a collaboration with Myung Jong Kim, and I am second author of the manuscript.] PYK2 is a calcium-dependent tyrosine kinase that is activated in cerebral ischemia and seizures. PYK2 is also known to bind PSD-95 at a region implicated in LTD signaling. Here we report a novel role for PYK2 in LTD. Chemical LTD treatment induces PYK2 phosphorylation at Tyr-402, and small hairpin RNA-mediated knockdown of PYK2 blocks LTD, but not LTP. We identify both enzymatic and non-enzymatic (scaffolding) roles for PYK2 in LTD, and find that PYK2 is required to suppress activity-dependent phosphorylation of the mitogen activated protein kinase ERK. ERK activity is believed to promote glutamate receptor insertion at synapses. Overexpression of WT-PYK2 further depresses activity-dependent ERK phosphorylation, and inhibits LTP, but not LTD. Our studies support a model whereby PYK2 antagonizes ERK signaling to promote LTD, at the expense of LTP, in hippocampal neurons. [This project is a collaboration with Myung Jong Kim and Chi-Fong Wang, and I am first author of the manuscript.]
by Honor Hsin.
Ph.D.
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Whitcomb, Daniel. "Alpha-beta1-42 of LTP is mediated by a signaling pathway involving caspase-3, Akt1 GSK-3beta." Thesis, University of Bristol, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.550333.
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Amyloid-f31--42 (Af3) is considered a major mediator of the cognitive impairments that are seen in Alzheimer's disease, the leading form of dementia and a growing world-wide health problem. In vitro, Af3 treatment of hippocampal brain slices impairs long-term potentiation and enhances long- term depression, forms of synaptic plasticity, and as such serve to provide cellular correlates of this action. However, the mechanisms underlying these effects are not fully understood. In this thesis the mechanisms underlying the Aj3-mediated dysregulation of synaptic plasticity are therefore explored. Exogenously applied Aj3 was first confirmed to inhibit an NMOAR-dependent form of L TP in the hippocampus (in both acute hippocampal slices and cultured hippocampal slices) and the characteristics of the inhibition of L TP by Aj3 were examined. Next, the inhibition of L TP was found to be reliant on the activation and function of caspases, which themselves have recently been implicated in a newly characterised mechanism of L TO. Finally, evidence is provided showing that this mechanism forms part of a signalling cascade that likely reflects the cleavage and inactivation of Akt-1 by caspases, liberating GSK-3j3 from inhibition - a key L TO-signalling mechanism. These results are best explained by a mechanism whereby the exogenous application of Aj3 causes the induction of L TO signalling. The consequence of which is to inhibit LTP.
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Wagner, Claudia Karin. "Kardioprotektion durch Postkonditionierung gesunder Rattenherzen sowie von Herzen mit kardiovaskulären Risikofaktoren: Charakterisierung der Signaltransduktion unter besonderer Betrachtung von PI3-K/Akt, mTOR, ERK1/2 und GSK-3ß." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2008. http://nbn-resolving.de/urn:nbn:de:bsz:14-ds-1226858602601-68237.
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In den ersten Versuchsreihen der hier vorliegenden Arbeit bestätigte sich, dass im in vitro Modell die klassische ischämische Präkonditionierung kardioprotektiv wirkt. Die Präkonditionierung bewirkte eine Infarktgrößenreduktion um 54 %; dies wird durch Literaturangaben bestätigt. Die Postkonditionierung dagegen, trotz drei verschiedener Postkonditionierungsprotokolle, ist am isoliert perfundierten Rattenherzen nicht protektiv. Im in vivo Rattenherz-Modell wurden die Präkonditionierung und die klinisch relevantere Postkonditionierung gegenüberstellend untersucht. Hier zeigte sich, dass die 3 Reperfusions-/Ischämiezyklen für jeweils 30 Sekunden der Postkonditionierung genauso protektiv wie die Präkonditionierung wirken. Infarktgrößen- und biochemische Untersuchungen belegen, dass hierbei die PI3-Kinase ein wichtiges Signaltransduktionselement ist, da einerseits durch die Inhibition der PI3-Kinase mittels Wortmannin die Infarktgrößenreduktion vollständig aufgehoben war und andererseits nach einer 1,5-minütigen Reperfusion eine vermehrte Phosphorylierung der Akt im Western-Blot auftrat. Des Weiteren konnte erstmals die Inaktivierung der GSK-3ß durch eine verstärkte Phosphorylierung über einen PI3-Kinase-vermittelten Signaltransduktionsweg nachgewiesen werden. Die Zugabe des spezifischen Inhibitors TDZD-8 der GSK-3ß verringert ebenfalls die Infarktgröße signifikant. Auch konnte zum ersten Mal gezeigt werden, dass das mammalian target of Rapamycin in der Postkonditionierung des in vivo Rattenherzens eine wichtige Rolle zu spielen scheint. Außerdem konnte neben dem PI3-Kinase/Akt-Signaltransduktionsweg auch die Beteiligung des MEK1/2-ERK1/2–Wegs als Signaltransduktionsweg der Postkonditionierung im in vivo Rattenherzen nachgewiesen werden. Erstmals wurde die Apoptose in einem in vivo Herzen nach regionaler Ischämie untersucht. Die Ergebnisse des TUNEL-Tests und der Western-Blot-Analysen zeigen eine unterdrückte Apoptose durch die Postkonditionierung. Ein weiterer Teil der vorliegenden Arbeit widmete sich der Untersuchung der Postkonditionierung in pathologischen Rattenherzen. Im Gegensatz zu gesunden Herzen schlug die Postkonditionierung in hypertrophiertem Myokardium von spontan-hypertensiven Ratten mit einer signifikant arteriellen Hypertension fehl. Diese Blockierung der Kardioprotektion zeigte sich durch die fehlende Reduzierung der Infarktgröße trotz unterschiedlicher Postkonditionierungsprotokolle (3x30’’ und 6x10’’ R/I) und unterschiedlich langer Ischämiedauern (20 und 30 Minuten). Gleichfalls war auch die Phosphorylierung der GSK-3ß aufgehoben. Als Modell des metabolischen Syndroms wurde die WOKW-Ratte untersucht. Diese Ratten entwickeln in sehr jungem Alter klassische Symptome wie Dyslipidämie, Hyperinsulinämie und Fettsucht. Wie bei der Herzhypertrophie war auch beim Modell des metabolischen Syndroms die Postkonditionierung - mit 3 Reperfusions-/ Ischämiezyklen für jeweils 30 Sekunden - blockiert. Dabei konnte weder eine Infarktgrößenreduktion noch eine vermehrte Phosphorylierung der GSK-3ß nachgewiesen werden. Die Ergebnisse der vorliegenden Arbeit erlauben die Schlußfolgerung, dass das Substrat der GSK-3ß, die mPTP des Mitochondriums, eine „Schlüsselrolle“ in der Apoptose innehat - die Postkonditionierung vermindert nicht nur die Nekrose, sondern reduziert auch die Apoptose. Bemerkenswert und potentiell von klinischer Bedeutung ist die Beobachtung, dass bei Vorliegen von Risikofaktoren, wie arterielle Hypertonie und metabolischem Syndrom, solche Schutzmechanismen des Herzens aufgehoben sind. Diese Erkenntnisse sind im Hinblick auf die Therapie am Menschen von großer Bedeutung. Ob langfristig einzelne Komponenten der Signaltransduktionswege, wie PI3-Kinase, Akt, mTOR, ERK1/2 oder GSK-3ß, Angriffspunkte einer pharmakologischen Therapie sein könnten, muß in weiteren Untersuchungen geklärt werden.
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Lin, Ching-chih, and 林敬智. "Multiple tasks of Glycogen synthase kinase-3beta (GSK-3β ) and its partners." Thesis, 2007. http://ndltd.ncl.edu.tw/handle/5a7s85.
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博士國立中山大學
生物科學系研究所
95
Glycogen synthase kinase-3 (GSK-3) is a serine/threonine protein kinase which plays a key role in several signaling pathways and its homologues have been identified in most eukaryotes. Since GSK3βis an essential protein kinase that regulates numerous functions within the cell, an effort to survey possible GSK3β- interacting proteins from a human testis cDNA library using the yeast two-hybrid system is made. Two interesting candidates are chosen to characterize their functions in this study. One is a centrosomal protein, hNinein, and the other is a novel inhibitor of GSK3β, designated as GSKIP (GSK3β interaction protein). In the first part of the present thesis we describe the identification of four diverse CCII-termini of human hNinein isoforms, including a novel isoform 6, by differential expression in a tissue-specific manner. In a kinase assay, the CCII region of hNinein isoforms provides a differential phosphorylation site by GSK3β. In addition, either N-terminal or CCIIZ domain disruption may cause hNinein conformational change which recruits γ-tubulin to centrosomal or non-centrosomal hNinein-containing sites. Further, depletion of all hNinein isoforms caused a significant decrease in the γ-tubulin signal in the centrosome. In domain swapping, it clearly shows that the CCIIX-CCIIY region provides docking sites for γ-tubulin. Moreover, nucleation of microtubules from the centrosome is significantly affected by the overexpression of either the full-length hNinein or CCIIX-CCIIY region. Taken together, these results show that the centrosomal targeting signals of hNinein have a role not only in regulating hNinein conformation, resulting in localization change, but also provide docking sites to recruit γ-tubulin at centrosomal and non-centrosomal sites. In the second part of the thesis we describe another candidate, GSK3βinteraction protein (GSKIP), to characterize its functions in neuron differentiation. We use human neuroblastoma SH-SY5Y cells as a model of neuronal cell differentiation. When overexpression of GSKIP prevents neurite outgrowth from RA-mediated differentiation, this result is similar to the presence of LiCl or SB415286, an inhibitor of GSK3β. Further, GSKIP regulates the activity of GSK3β through protein-protein interactions rather than post-modulation and GSKIP may affect GSK3β on neurite outgrowth via inhibiting the specific phosphorylation site of tau. In addition to inhibition of neurite outgrowth, GSKIP overexpressed in SH-SY5Y cells also promotes cell cycle progression by analyzing cell proliferation with cell growth and MTT assay. Furthermore, GSKIP raises the level of β-catenin and cyclin D1 through inhibition of GSK3β activity in RA-mediated differentiation SH-SY5Y cells. Taken together, the data suggest that GSKIP, a dual functional molecule, is able to inhibit neurite outgrowth and promote cell proliferation via negative regulation of GSK3β activity in RA-mediated differentiation of SH-SY5Y cells.
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Förster, Karina [Verfasser]. "Mechanismen des rezeptorvermittelten Myokardschutzes nach akutem Herzinfarkt: Beteiligung von Adenosin-, δ-Opioidrezeptoren [delta-Opioidrezeptoren] und GSK-3β [GSK-3beta] / vorgelegt von Karina Förster." 2009. http://d-nb.info/998998206/34.
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Liu, Chen-Wei, and 劉振偉. "Snail Regulate Nanog Status during Epithelial-Mesenchymal Transition via Smad1/Akt/GSK-3beta Signaling Pathway in Non-Small-Cell Lung Cancer." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/25526094801273573471.
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博士國防醫學院
醫學科學研究所
103
The epithelial-mesenchymal transition (EMT), a crucial step in cancer metastasis, is important in transformed cancer cells with stem cell-like properties. In this study, we established a Snail-overexpressing cell model in non-small-cell lung cancer (NSCLC) and investigated its underlying mechanism. We also identified the downstream molecular signaling pathway that contributed to the role of Snail to regulated Nanog expression. Our data shown that high level Snail expression correlate with metastasis and high Nanog expression in NSCLC. NSCLC cells expressing Snail are characterized by active EMT characteristics, and exhibit increased ability of migration, chemoresistance, sphere formation and stem cell-like properties. Then, the signals required for Snail-mediated Nanog expression was studied. Our data demonstrated that LY294002, SB431542, LDN193189 and Noggin pretreatment inhibited Snail-induced Nanog expression during EMT. This study shown a significant correlation between the Snail and phosphorylation Smad1, Akt or GSK-3β pretreatment with SB431542, LDN193189 and Noggin prevented Snail-induced Smad1 and Akt hyper-activation and reactivated GSK-3β. In addition, LY294002 pretreatment also prevented Akt hyper-activation and reactivated GSK-3β but without any changes in Smad1 activation. These findings demonstrated that the novel mechanistic insight into an important role of Snail in NSCLC during EMT, and suggest provide an useful therapeutic targets in NSCLC prognosis and treatment.
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Wagner, Claudia Karin [Verfasser]. "Kardioprotektion durch Postkonditionierung gesunder Rattenherzen sowie von Herzen mit kardiovaskulären Risikofaktoren : Charakterisierung der Signaltransduktion unter besonderer Betrachtung von PI3-K/Akt, mTOR, ERK1,2 und GSK-3β [GSK-3beta] / vorgelegt von Claudia Karin Wagner, geb Reußner." 2008. http://d-nb.info/992401569/34.
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Tackenberg, Christian. "Effect of amyloid precursor protein and tau on dendritic spines and cell survival in an ex vivo model of Alzheimer s disease." Doctoral thesis, 2009. https://repositorium.ub.uni-osnabrueck.de/handle/urn:nbn:de:gbv:700-2009121414.
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Alzheimer s disease is characterized by synaptic alterations and neurodegeneration. Histopathological hallmarks represent amyloidplaques composed of amyloid-beta (Abeta) and neurofibrillary tangles containing hyperphosphorylated tau. To determine whether synaptic changes and neurodegeneration share common pathways we established an ex vivo model using organotypic hippocampal slicecultures from amyloid precursor protein transgenic mice combined with virus-mediated expression of EGFP-tagged tau constructs. Confocal high-resolution imaging, algorithm-based evaluation of spines and live imaging was employed to determine spine changes and neurodegeneration. We report that Abeta but not tau induces spine loss and shifts spine shape from mushroom to stubby through a mechanism involving NMDA receptor (NMDAR), calcineurin and GSK-3beta activation. In contrast, Abeta alone does not cause neurodegeneration but induces toxicity by phosphorylation of wt tau in a NMDAR-dependent pathway. We show thatGSK-3beta levels are elevated in APP transgenic cultures and that inhibiting GSK-3beta activity or use of phosphorylation-blocking tau mutations prevent Abeta-induced toxicity of tau. FTDP-17 tau mutants are differentially affected by Abeta. While R406W tau shows increased toxicity in the presence of Abeta, no change is observed with P301L tau. While blocking NMDAR activity abolishes toxicity of both wt and R406W tau, the inhibition of GSK-3beta only protects against toxicity of wt tau but not of R406W tau induced by Abeta. Tau aggregation does not correlate with toxicity. We propose that Abeta-induced spine pathology and tau-dependent neurodegeneration are mediated by divergent pathways downstream of NMDA receptor activation and suggest that Abeta affects wt and R406W tau toxicity by different pathways downstream of NMDAR activity.
Conference papers on the topic "GSK-3beta"
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Mishra, Prajna, Subramanian Senthivinayagam, Ajay Rana, and Basabi Rana. "Abstract 1724: Role of GSK-3beta in gastrin-induced migration of gastric cancer cells." In Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC. American Association for Cancer Research, 2010. http://dx.doi.org/10.1158/1538-7445.am10-1724.
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Matsangou, Maria, Andrey Ugolkov, Timothy J. Taxter, Sandeep Samant, Andrew P. Mazar, and Francis J. Giles. "Abstract 1127: Aberrant nuclear expression of GSK-3beta in human head and neck carcinoma." In Proceedings: AACR Annual Meeting 2017; April 1-5, 2017; Washington, DC. American Association for Cancer Research, 2017. http://dx.doi.org/10.1158/1538-7445.am2017-1127.
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Kuroki, Hiroo, Tsutomu Anraku, Vladimir Bilim, Masayuki Tasaki, Daniel Schmitt, Andrew Mazer, Francis J. Giles, Andrey Ugolkov, and Yoshihiko Tomita. "Abstract 4812: 9-ING-41, a novel inhibitor of glycogen synthase kinase-3beta (GSK-3β), is active as a single agent and within combination therapies in bladder cancer cell lines." In Proceedings: AACR Annual Meeting 2019; March 29-April 3, 2019; Atlanta, GA. American Association for Cancer Research, 2019. http://dx.doi.org/10.1158/1538-7445.am2019-4812.
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