You searched for subject:(GSK3 ).
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University of Vermont
1.
Bauman, Brittany Nicole.
Role of p38 MAPK inhibitor in conditioned fear.
Degree: Biology, 2015, University of Vermont
URL: https://scholarworks.uvm.edu/hcoltheses/186 
► <h1>p38 mitogen activated protein kinase (p38) is a kinase that has been implicated in cellular plasticity, stress, and psychiatric disorders and recently in the process…
(more)
▼ <h1>p38 mitogen activated protein kinase (p38) is a kinase that has been implicated in cellular plasticity, stress, and psychiatric disorders and recently in the process of DNA repair. Recently, we have shown that p38 is responsible for inhibiting Glycogen Synthase Kinase 3β (GSK3β), which has also been shown to be involved in the same processes and recently in the process of DNA repair. We have also shown that GSK3β is regulated by stress and that its inhibition produces exaggerated conditioned fear. The goal of this study is to examine whether inhibiting p38 will result in a similar exaggeration of conditioned fear. To this end, mice were injected systemically with the potent and selective inhibitor of p38, SB203580 or vehicle prior to tone and footshock fear conditioning and tested for freezing to the tone one day later. Mice injected with SB203580 showed greater tone freezing than mice injected with vehicle. In contrast to tone freezing, SB203580 injections did not affect freezing to the context. Injections of SB203580 prior to 24 hours after fear conditioning, but before fear testing, also did not affect freezing. These data suggest that p38 plays a role in regulating the strength of conditioned fear. The fact that p38 regulates GSK3β and that inhibition of GSK3β also produces exaggerated conditioned fear raises the possibility that a p38 to GSK3β pathway may be regulating the strength of conditioned fear.</h1>
Advisors/Committee Members: Dr. William Falls.
Subjects/Keywords: p38; conditioned fear; GSK3; inhibition; freezing
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APA (6th Edition):
Bauman, B. N. (2015). Role of p38 MAPK inhibitor in conditioned fear. (Thesis). University of Vermont. Retrieved from https://scholarworks.uvm.edu/hcoltheses/186
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Bauman, Brittany Nicole. “Role of p38 MAPK inhibitor in conditioned fear.” 2015. Thesis, University of Vermont. Accessed April 11, 2021.
https://scholarworks.uvm.edu/hcoltheses/186.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Bauman, Brittany Nicole. “Role of p38 MAPK inhibitor in conditioned fear.” 2015. Web. 11 Apr 2021.
Vancouver:
Bauman BN. Role of p38 MAPK inhibitor in conditioned fear. [Internet] [Thesis]. University of Vermont; 2015. [cited 2021 Apr 11].
Available from: https://scholarworks.uvm.edu/hcoltheses/186.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Bauman BN. Role of p38 MAPK inhibitor in conditioned fear. [Thesis]. University of Vermont; 2015. Available from: https://scholarworks.uvm.edu/hcoltheses/186
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Georgia
2.
Dowd, Christopher Colin.
Dosage suppression of mutations in casein kinase II by RIM11, a glycogen synthase kinase-3 homolog.
Degree: 2014, University of Georgia
URL: http://hdl.handle.net/10724/20314
► In this report, a glycogen synthase kinase-3 homolog, RIM11, was isolated in a multicopy screen for suppressors of the salt-sensitive phenotype of casein kinase II…
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▼ In this report, a glycogen synthase kinase-3 homolog, RIM11, was isolated in a multicopy screen for suppressors of the salt-sensitive phenotype of casein kinase II (CKII) regulatory subunit mutants. Previously known as a gene involved in
regulating the initiation of meiosis, RIM11 is now characterized as a determinant of salt-tolerance in cells growing on media containing galactose as the primary carbon source. Consistent with this, rim11 .mutants are shown to be salt-sensitive on
galactose media, but not on glucose media. The salt-sensitivity of rim11 .mutants is found to be additive with that of CKII mutants, suggesting that the Rim11 and CKII kinases do not operate in the same biochemical pathway. RIM11 overexpression is found
to improve the salt-tolerance of the wild-type strain, as well as CKII and calcineurin mutants, and the catalytic activity of Rim11 is determined to be necessary for this effect. Finally, Rim11 protein levels are shown to be higher when cells are grown
on galactose-containing compared to glucose-containing media, and also to be induced upon exposure to NaCl. RIM11 is proposed to be a galactose-specific determinant of salt-tolerance in Saccharomyces cerevisiae.
Subjects/Keywords: S. cerevisiae; CKII; RIM11; GSK3; salt sensitivity
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APA (6th Edition):
Dowd, C. C. (2014). Dosage suppression of mutations in casein kinase II by RIM11, a glycogen synthase kinase-3 homolog. (Thesis). University of Georgia. Retrieved from http://hdl.handle.net/10724/20314
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Dowd, Christopher Colin. “Dosage suppression of mutations in casein kinase II by RIM11, a glycogen synthase kinase-3 homolog.” 2014. Thesis, University of Georgia. Accessed April 11, 2021.
http://hdl.handle.net/10724/20314.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Dowd, Christopher Colin. “Dosage suppression of mutations in casein kinase II by RIM11, a glycogen synthase kinase-3 homolog.” 2014. Web. 11 Apr 2021.
Vancouver:
Dowd CC. Dosage suppression of mutations in casein kinase II by RIM11, a glycogen synthase kinase-3 homolog. [Internet] [Thesis]. University of Georgia; 2014. [cited 2021 Apr 11].
Available from: http://hdl.handle.net/10724/20314.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Dowd CC. Dosage suppression of mutations in casein kinase II by RIM11, a glycogen synthase kinase-3 homolog. [Thesis]. University of Georgia; 2014. Available from: http://hdl.handle.net/10724/20314
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Université Paris-Sud – Paris XI
3.
Martel, Cécile.
Rôle de la perméabilité membranaire mitochondriale, de la phosphorylation de VDAC et de la signalisation de l’apoptose dans la pathogenèse de la stéatose hépatique : Role of mitochondrial membrane permeability, VDAC phosphorylation and signaling pathway of apoptosis in the pathogenesis of steatosis.
Degree: Docteur es, Cancérologie - Biochimie, Biologie cellulaire et moléculaire, 2011, Université Paris-Sud – Paris XI
URL: http://www.theses.fr/2011PA11T075
► La stéatose hépatique non-alcoolique consiste en une accumulation de lipides dans le cytoplasme des hépatocytes. Longtemps considérée comme une pathologie bénigne, elle peut être à…
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▼ La stéatose hépatique non-alcoolique consiste en une accumulation de lipides dans le cytoplasme des hépatocytes. Longtemps considérée comme une pathologie bénigne, elle peut être à l’origine du développement d’un stade plus sévère : la stéatohépatite non alcoolique (NASH). La NASH s’accompagne de lésions sévères du foie liées à la genèse d’un stress oxydant, d’une inflammation et de la mort cellulaire. Le rôle de la mitochondrie est au centre de cette maladie, bien que les connaissances sur la dysfonction mitochondriale et ses conséquences sur l’apoptose soient encore insuffisantes. En effet, la mitochondrie est responsable de la dégradation des lipides par -oxydation et elle agit comme un centre intégrateur des signaux apoptotiques en déclenchant une perméabilisation des membranes mitochondriales (PMM) aboutissant à la libération de facteurs apoptogènes. Ce processus est considéré comme le point de non-retour de la voie mitochondriale de l’apoptose. Nos travaux ont porté sur la compréhension des mécanismes moléculaires liant l’apoptose hépatocytaire mitochondriale et la stéatose. La combinaison de quatre modèles expérimentaux de stéatose (biopsies de patients, mitochondries isolées de souris obèses ob/ob ou recevant un régime hypercalorique, et lignées cellulaires) a permis de montrer, dans le foie stéatosique, une sensibilité accrue à l’induction de la PMM et une augmentation de la perméabilité de VDAC (voltage-dependent anion channel), protéine formant un canal dans la membrane externe mitochondriale. Ces observations sont associées à une diminution de la phosphorylation de VDAC sur un résidu thréonine et sa perte d’interaction avec la protéine anti-apoptotique Bcl-XL et la kinase GSK3, révélant ainsi une nouvelle voie de signalisation par les lipides. Cette découverte s’est notamment appuyée sur l’utilisation de tests fonctionnels en mitochondries isolées que nous avions développés et validés dans plusieurs études aux stratégies expérimentales variées. En conclusion, notre étude permet de mieux comprendre la fragilité mitochondriale lipo-induite, stade précédant l’apoptose hépatocytaire, et ouvre des perspectives à visée biomédicale.
Non-alcoholic steatosis is a liver disease characterized by lipid accumulation in the cytoplasm of hepatocytes. For a long time, it has been considered as a benign condition. Now it is known that it can precede the development of a severe stage, non-alcoholic steatohepatitis (NASH). NASH is accompanied by severe dammages of the liver linked to the genesis of oxidative stress, inflammation and cell death. Mitochondrion is a central player of this disease; however, the knowledge of mitochondrial dysfunction and its consequences on apoptosis is still insufficient. Indeed, mitochondria are responsible for lipid degradation by -oxidation. Mitochondria act as a central integrator of apoptotic signals by triggering the mitochondrial membrane permeabilization (MMP) leading to the release of apoptogenic factors. This process is considered as the point of no return of the mitochondrial…
Advisors/Committee Members: Lemoine, Antoinette (thesis director).
Subjects/Keywords: Stéatose; Mitochondrie; Apoptose; VDAC; GSK3; Lipotoxicité; Stéatosis; Mitochondria; Apoptosis; VDAC; GSK3; Lipotoxicity
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APA (6th Edition):
Martel, C. (2011). Rôle de la perméabilité membranaire mitochondriale, de la phosphorylation de VDAC et de la signalisation de l’apoptose dans la pathogenèse de la stéatose hépatique : Role of mitochondrial membrane permeability, VDAC phosphorylation and signaling pathway of apoptosis in the pathogenesis of steatosis. (Doctoral Dissertation). Université Paris-Sud – Paris XI. Retrieved from http://www.theses.fr/2011PA11T075
Chicago Manual of Style (16th Edition):
Martel, Cécile. “Rôle de la perméabilité membranaire mitochondriale, de la phosphorylation de VDAC et de la signalisation de l’apoptose dans la pathogenèse de la stéatose hépatique : Role of mitochondrial membrane permeability, VDAC phosphorylation and signaling pathway of apoptosis in the pathogenesis of steatosis.” 2011. Doctoral Dissertation, Université Paris-Sud – Paris XI. Accessed April 11, 2021.
http://www.theses.fr/2011PA11T075.
MLA Handbook (7th Edition):
Martel, Cécile. “Rôle de la perméabilité membranaire mitochondriale, de la phosphorylation de VDAC et de la signalisation de l’apoptose dans la pathogenèse de la stéatose hépatique : Role of mitochondrial membrane permeability, VDAC phosphorylation and signaling pathway of apoptosis in the pathogenesis of steatosis.” 2011. Web. 11 Apr 2021.
Vancouver:
Martel C. Rôle de la perméabilité membranaire mitochondriale, de la phosphorylation de VDAC et de la signalisation de l’apoptose dans la pathogenèse de la stéatose hépatique : Role of mitochondrial membrane permeability, VDAC phosphorylation and signaling pathway of apoptosis in the pathogenesis of steatosis. [Internet] [Doctoral dissertation]. Université Paris-Sud – Paris XI; 2011. [cited 2021 Apr 11].
Available from: http://www.theses.fr/2011PA11T075.
Council of Science Editors:
Martel C. Rôle de la perméabilité membranaire mitochondriale, de la phosphorylation de VDAC et de la signalisation de l’apoptose dans la pathogenèse de la stéatose hépatique : Role of mitochondrial membrane permeability, VDAC phosphorylation and signaling pathway of apoptosis in the pathogenesis of steatosis. [Doctoral Dissertation]. Université Paris-Sud – Paris XI; 2011. Available from: http://www.theses.fr/2011PA11T075
4.
Benajiba, Lina.
Identification and Characterization of New Therapeutic Targets in Acute Myeloid Leukemia : Identification et caractérisation de nouvelles cibles thérapeutiques dans les LAM.
Degree: Docteur es, Aspects moléculaires et cellulaires de la biologie, 2018, Université Paris-Saclay (ComUE)
URL: http://www.theses.fr/2018SACLS173
► La leucémie aiguë myéloïde (LAM) est une pathologie hématologique dont le pronostic reste très défavorable, malgré les progrès réalisés dans la compréhension des mécanismes physiopathologiques…
(more)
▼ La leucémie aiguë myéloïde (LAM) est une pathologie hématologique dont le pronostic reste très défavorable, malgré les progrès réalisés dans la compréhension des mécanismes physiopathologiques sous-tendant son développement. Identifier de nouvelles stratégies anti-leucémiques représente donc une étape clé dans la concrétisation des avancées thérapeutiques. Grâce à la combinaison de plusieurs approches de criblage génétiques et pharmacologiques, l’objectif de ma thèse a été de définir et valider de nouvelles cibles thérapeutiques dans les LAM. La première partie de ma thèse a eu pour but de transposer en clinique l’inhibition de la Glycogen Synthase Kinase 3 (GSK3). La stabilisation de la β-caténine secondaire à l'inhibition concomitante des deux paralogues de GSK3, représente un obstacle à l’utilisation clinique de cette classe thérapeutique. Mettant à profit la présence d'un «switch» Asp133 à Glu196 dans les domaines de liaison ATP de GSK3, nous avons identifié un inhibiteur sélectif du paralogue GSK3α et mené des études précliniques validant le BRD0705 comme nouveau traitement pro-différenciant dans les LAM. De plus, une combinaison de profilage métabolomique et d'approches de criblage haut débit à l’aide d’une banque de shRNA a permis d'identifier un nouveau lien entre EVI-1, la voie de la créatine kinase et la voie de signalisation GSK3. La deuxième partie de ma thèse a porté sur l'identification de nouvelles cibles thérapeutiques en utilisant une approche de criblage par banque de shRNA dans le modèle murin de LAM porteur de la translocation MLL-AF9. VCP, une AAA-ATPase, a ainsi été identifiée puis validée comme cible thérapeutique. Nous avons montré que VCP orchestre la génération d'une plateforme à ADN simple brin recouverte de RPA, ce qui entraîne l'activation de la kinase ATM et la HR. Dans leur ensemble, nos découvertes permettent une meilleure compréhension de la biologie des LAM et participeront ainsi à l’amélioration des traitements futurs de cette pathologie.
Despite the significant progress made in understanding Acute Myeloid Leukemia oncogenesis over the last decades, this disease remains devastating and the overall five-year survival does not exceed 17%. Developing new translational research strategies focused on the identification of druggable oncogenic targets is critical to continued progress in AML treatment. The goal of this work was to define and validate novel leukemia-specific dependencies using small-molecule inhibitors and RNA-interference-based high-throughput screening methods.The first part of my thesis work aimed at translating Glycogen synthase kinase 3 (GSK3) inhibition into the clinic. Mechanism-based toxicities, driven in part by the inhibition of both GSK3 paralogs and subsequent β-catenin stabilization, were a concern in the clinical translation of this target candidate. Specific knock-down of GSK3α or GSK3β alone does not increase β-catenin, thereby offering a conceptual resolution to GSK3 targeting. The design of selective ATP-competitive inhibitors posed a drug discovery…
Advisors/Committee Members: Hermine, Olivier (thesis director), Stegmaier, Kimberly (thesis director).
Subjects/Keywords: LAM; Cibles thérapeutiques; GSK3; CKMT1; VCP; AML; Therapeutic targets; GSK3; CKMT1; VCP
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APA ·
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APA (6th Edition):
Benajiba, L. (2018). Identification and Characterization of New Therapeutic Targets in Acute Myeloid Leukemia : Identification et caractérisation de nouvelles cibles thérapeutiques dans les LAM. (Doctoral Dissertation). Université Paris-Saclay (ComUE). Retrieved from http://www.theses.fr/2018SACLS173
Chicago Manual of Style (16th Edition):
Benajiba, Lina. “Identification and Characterization of New Therapeutic Targets in Acute Myeloid Leukemia : Identification et caractérisation de nouvelles cibles thérapeutiques dans les LAM.” 2018. Doctoral Dissertation, Université Paris-Saclay (ComUE). Accessed April 11, 2021.
http://www.theses.fr/2018SACLS173.
MLA Handbook (7th Edition):
Benajiba, Lina. “Identification and Characterization of New Therapeutic Targets in Acute Myeloid Leukemia : Identification et caractérisation de nouvelles cibles thérapeutiques dans les LAM.” 2018. Web. 11 Apr 2021.
Vancouver:
Benajiba L. Identification and Characterization of New Therapeutic Targets in Acute Myeloid Leukemia : Identification et caractérisation de nouvelles cibles thérapeutiques dans les LAM. [Internet] [Doctoral dissertation]. Université Paris-Saclay (ComUE); 2018. [cited 2021 Apr 11].
Available from: http://www.theses.fr/2018SACLS173.
Council of Science Editors:
Benajiba L. Identification and Characterization of New Therapeutic Targets in Acute Myeloid Leukemia : Identification et caractérisation de nouvelles cibles thérapeutiques dans les LAM. [Doctoral Dissertation]. Université Paris-Saclay (ComUE); 2018. Available from: http://www.theses.fr/2018SACLS173
University of Vienna
5.
Ukowitz, Michaela.
Homology Modelling of Shaggy-like Kinase α in Arabidopsis thaliana (ASKα).
Degree: 2019, University of Vienna
URL: http://othes.univie.ac.at/57692/
► Pflanzen sind kontinuierlich Stress ausgesetzt. Auf der einen Seite ist es biotischer Stress, der unter anderem von Bakterien, Viren, Pilzen oder Insekten ausgelöst wird und…
(more)
▼ Pflanzen sind kontinuierlich Stress ausgesetzt. Auf der einen Seite ist es biotischer Stress, der unter anderem von Bakterien, Viren, Pilzen oder Insekten ausgelöst wird und auf der anderen Seite abiotischer Stress, der durch wechselnde Umweltbedingungen wie Trockenheit, Hitze, Frost oder hohen Salzgehalt der Böden verursacht wird. Diese Stressfaktoren führen jährlich zu enormen Ernteverlusten, weshalb die Wissenschaft gefragt ist, die Mechanismen, die durch Stress in Pflanzen ausgelöst werden, genauer zu erforschen. Das Ziel ist es, neue Methoden zu entwickeln, welche die Stresstoleranz in Pflanzen verbessern, was sowohl wirtschaftliche Vorteile bringen, als auch die ausreichende Versorgung der Bevölkerung mit Nahrung gewährleisten würde.
Mehrere Studien sprechen der Kinase ASKα eine wichtige Rolle bei der Stressmodulation zu. Die aktivierte Kinase erhöht die Stresstoleranz von Pflanzen, weshalb es wichtig ist, mehr über dieses Protein herauszufinden. Dafür ist eine dreidimensionale Struktur dieser Kinase von Bedeutung, die bis dato aber noch nicht experimentell ermittelt wurde.
Das Ziel dieser Arbeit war es, die 3D Struktur von ASKα zu modellieren und diese auf mögliche Bindetaschen für niedermolekulare Verbindungen zu untersuchen. Zuerst wurde eine geeignete Vorlage benötigt, als welche GSK3β aufgrund der hohen Sequenzidentität identifiziert wurde. Die PDB wurde nach der geeignetsten Struktur von GSK3β durchsucht. Mit dieser Vorlage wurden dann Homologiemodelle mit der Software Modeller berechnet. Die kalkulierten Modelle wurden mittels verschiedener Validierungskriterien (molpdf, DOPE-score) gefiltert und von den passendsten wurden mittels Procheck Ramachandran Plots erstellt. Die Plots wurden analysiert und ein finales Modell ausgewählt. Dieses Modell wurde mit Fpocket auf mögliche Bindungstaschen untersucht.
Plants are often exposed to stress. On the one hand, there is biotic stress caused by bacteria, viruses, fungi or insects. On the other hand, abiotic stress is caused by changing environmental conditions such as drought, heat, frost or high salinity of the soil. These stress factors lead to enormous annual yield losses, which is why research into the mechanisms triggered by stress in plants is of high interest.
Therefore, there is interest to develop new methods to improve stress tolerance in plants, which would bring both, economic benefits and ensure sufficient food supply to the population.
Several studies attribute the kinase ASKα an important role in stress modulation. The activated kinase increases stress tolerance of plants, which is why it is important to find out more about this protein. A three-dimensional structure of this kinase, which has not yet been determined experimentally, is important.
The aim of this work is to model the 3D structure of ASKα and to examine it for possible binding pockets for small molecules. First, a good template was needed, which was identified as GSK3β due to the high sequence identity. The PDB was searched for the most suitable structure of GSK3β. With…
Subjects/Keywords: 35.76 Aminosäuren, Peptide, Eiweiße; Homology modelling / ASK / GSK3; Homology modelling / ASK / GSK3
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APA ·
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APA (6th Edition):
Ukowitz, M. (2019). Homology Modelling of Shaggy-like Kinase α in Arabidopsis thaliana (ASKα). (Thesis). University of Vienna. Retrieved from http://othes.univie.ac.at/57692/
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Ukowitz, Michaela. “Homology Modelling of Shaggy-like Kinase α in Arabidopsis thaliana (ASKα).” 2019. Thesis, University of Vienna. Accessed April 11, 2021.
http://othes.univie.ac.at/57692/.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Ukowitz, Michaela. “Homology Modelling of Shaggy-like Kinase α in Arabidopsis thaliana (ASKα).” 2019. Web. 11 Apr 2021.
Vancouver:
Ukowitz M. Homology Modelling of Shaggy-like Kinase α in Arabidopsis thaliana (ASKα). [Internet] [Thesis]. University of Vienna; 2019. [cited 2021 Apr 11].
Available from: http://othes.univie.ac.at/57692/.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Ukowitz M. Homology Modelling of Shaggy-like Kinase α in Arabidopsis thaliana (ASKα). [Thesis]. University of Vienna; 2019. Available from: http://othes.univie.ac.at/57692/
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
6.
Lucas Kuhn Pereira Prado.
Exercício físico em idosos: efeito nos biomarcadores periféricos de neuroproteção.
Degree: 2012, University of São Paulo
URL: http://www.teses.usp.br/teses/disponiveis/5/5140/tde-09082012-141507/
► A atividade física (AF) demonstrou um efeito protetor contra a doença de Alzheimer (DA), mas não se sabe qual a influência da AF sobre o…
(more)
▼ A atividade física (AF) demonstrou um efeito protetor contra a doença de Alzheimer (DA), mas não se sabe qual a influência da AF sobre o biomarcador de neuroproteção, a glicogênio sintase-quinase 3 (GSK3). O Objetivo do nosso estudo é avaliar o efeito do exercício físico sobre os níveis séricos da GSK3. Foi realizado um estudo observacional de corte transversal, no qual 72 idosos saudáveis e sem demência foram selecionados e divido em dois grupos de acordo com o nível de atividade física. A atividade da GSK3 foi semelhante entre os grupos estudados, houve uma tendência a maior inativação da GSK3 (fator neuroprotetor) entre os ativos e maior ativação entre os sedentários e muito ativos, porém sem significância estatística. É possível que a atividade física de baixa intensidade já tenha um efeito protetor. Uma maior população de idosos e métodos mais precisos de mensurar AF serão necessários para demonstrar efeito da AF sobre a GSK3
The physical
activity (PA) was demonstrated to have a protective effect against Alzheimers disease, but the influence of exercising on the biomarker of neuroprotection such as Glycogen synthase kinase 3 (GSK-3) are hitherto imprecise. This study aims at assessing the effect of PA on the serum levels of GSK3. We have performed a cross-sectional observational study with 72 healthy elders, without dementia, selected and classified into two groups according to the level of PA. The GSK3 activity resulted similar in both groups; there was a tendency of inactivation of GSK3 (neuroprotective factor) among active elders and a higher activation among sedentary and highly active elders, although without statistical significance. Its possible that low-intensity physical activity may already have a protective effect. Further studies with higher number of participants and methods more accurate to measure PA will be needed to demonstrate effect of PA on the GSK3
Advisors/Committee Members: Luiz Eugenio Garcez Leme, Luiz Roberto Ramos, Maria do Carmo Sitta.
Subjects/Keywords: Alzheimer; Atividade física; Exercício; GSK3; Idosos; Aged; Alzheimer; Exercise; GSK3; Physical activity
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APA (6th Edition):
Prado, L. K. P. (2012). Exercício físico em idosos: efeito nos biomarcadores periféricos de neuroproteção. (Masters Thesis). University of São Paulo. Retrieved from http://www.teses.usp.br/teses/disponiveis/5/5140/tde-09082012-141507/
Chicago Manual of Style (16th Edition):
Prado, Lucas Kuhn Pereira. “Exercício físico em idosos: efeito nos biomarcadores periféricos de neuroproteção.” 2012. Masters Thesis, University of São Paulo. Accessed April 11, 2021.
http://www.teses.usp.br/teses/disponiveis/5/5140/tde-09082012-141507/.
MLA Handbook (7th Edition):
Prado, Lucas Kuhn Pereira. “Exercício físico em idosos: efeito nos biomarcadores periféricos de neuroproteção.” 2012. Web. 11 Apr 2021.
Vancouver:
Prado LKP. Exercício físico em idosos: efeito nos biomarcadores periféricos de neuroproteção. [Internet] [Masters thesis]. University of São Paulo; 2012. [cited 2021 Apr 11].
Available from: http://www.teses.usp.br/teses/disponiveis/5/5140/tde-09082012-141507/.
Council of Science Editors:
Prado LKP. Exercício físico em idosos: efeito nos biomarcadores periféricos de neuroproteção. [Masters Thesis]. University of São Paulo; 2012. Available from: http://www.teses.usp.br/teses/disponiveis/5/5140/tde-09082012-141507/
7.
Rahal, Pamela.
Role of GSK3β - MLK3 - p38γ MAPK Signalling in Satellite Cell Proliferation Regulation : Le rôle de la voie de signalisation GSK3β-MLK3-p38γ MAPK dans la régulation de la prolifération des cellules satellites.
Degree: Docteur es, Sciences de la Vie, 2015, Lyon, École normale supérieure
URL: http://www.theses.fr/2015ENSL1000
► MLK3 est une ser/thr MAP3K qui active la voie de signalisation des MAPKs dans différents types cellulaires. GSK3β interagit et active MLK3 en la phosphorylant…
(more)
▼ MLK3 est une ser/thr MAP3K qui active la voie de signalisation des MAPKs dans différents types cellulaires. GSK3β interagit et active MLK3 en la phosphorylant sur le residue ser 792. Cependant, le rôle de MLK3 ainsi que l’interaction entre MLK3 et GSK3β n’ont pas été précédemment étudiés dans le muscle squelettique. La croissance post-natale du muscle et la régénération musculaire chez l’adulte sont dépendantes de l’accrétion de myonoyaux, un processus médié par les cellules satellites qui prolifèrent, se différencient puis fusionnent aux fibres préexistantes. Durant ma thèse, j’ai démontré que GSK3β agit en amont de MLK3 pour induire la prolifération des cellules satellites, et cela par l’activation de la voie de signalisation MLK3-p38γ MAPK. In vivo, les muscles de souris déficientes injectés par la CTX montrent une diminution du nombre de cellules satellites prolifératrices Pax7+/ki67+, ainsi qu’une accélération du processus de régénération. En conclusion, mes résultats évoquent un nouveau rôle de MLK3 dans le muscle squelettique pouvant servir pour vaincre les dystrophies musculaire.
MLK3 is a Ser/Thr MAP3K, which activates MAPKs signalling pathways in different cell types. The Ser/Thr kinase GSK3-β directly phosphorylate Ser 792 residue and activate MLK3. Since neither the role of MLK3, nor GSK3-β -MLK3 interaction have been previously investigated in muscle, the aim of my thesis was to elucidate their contribution in the regulation of muscle mass and physiology.Skeletal muscle post-natal growth and adult regeneration relies on satellite cell-mediated myonuclear accretion, during which, activated satellite cells, proliferate, differentiate and fuse with preexisting myotubes.I have demonstrated that in skeletal muscle, GSK3-β acts upstream of MLK3 to induce satellite cells proliferation through the induction of MLK3-p38γ MAPK signalling. Similarly, in vivo CTX-induced TA damage in MLK3 KO mice resulted in decreased number of proliferating Pax7+/ki67+ satellite cells, with a rapid muscle regeneration ability.These data suggest provide a yet unknown role of MLK3 in skeletal muscle tissue that could help in curing age-related muscle dystrophies.
Advisors/Committee Members: Goillot, Evelyne (thesis director).
Subjects/Keywords: GSK3; MLK3; P38 MAPK; Régénération musculaire; Cellules satellites; Pax7; GSK3; MLK3; P38 MAPK; Muscle regeneration; Satellite cells; Pax7
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APA (6th Edition):
Rahal, P. (2015). Role of GSK3β - MLK3 - p38γ MAPK Signalling in Satellite Cell Proliferation Regulation : Le rôle de la voie de signalisation GSK3β-MLK3-p38γ MAPK dans la régulation de la prolifération des cellules satellites. (Doctoral Dissertation). Lyon, École normale supérieure. Retrieved from http://www.theses.fr/2015ENSL1000
Chicago Manual of Style (16th Edition):
Rahal, Pamela. “Role of GSK3β - MLK3 - p38γ MAPK Signalling in Satellite Cell Proliferation Regulation : Le rôle de la voie de signalisation GSK3β-MLK3-p38γ MAPK dans la régulation de la prolifération des cellules satellites.” 2015. Doctoral Dissertation, Lyon, École normale supérieure. Accessed April 11, 2021.
http://www.theses.fr/2015ENSL1000.
MLA Handbook (7th Edition):
Rahal, Pamela. “Role of GSK3β - MLK3 - p38γ MAPK Signalling in Satellite Cell Proliferation Regulation : Le rôle de la voie de signalisation GSK3β-MLK3-p38γ MAPK dans la régulation de la prolifération des cellules satellites.” 2015. Web. 11 Apr 2021.
Vancouver:
Rahal P. Role of GSK3β - MLK3 - p38γ MAPK Signalling in Satellite Cell Proliferation Regulation : Le rôle de la voie de signalisation GSK3β-MLK3-p38γ MAPK dans la régulation de la prolifération des cellules satellites. [Internet] [Doctoral dissertation]. Lyon, École normale supérieure; 2015. [cited 2021 Apr 11].
Available from: http://www.theses.fr/2015ENSL1000.
Council of Science Editors:
Rahal P. Role of GSK3β - MLK3 - p38γ MAPK Signalling in Satellite Cell Proliferation Regulation : Le rôle de la voie de signalisation GSK3β-MLK3-p38γ MAPK dans la régulation de la prolifération des cellules satellites. [Doctoral Dissertation]. Lyon, École normale supérieure; 2015. Available from: http://www.theses.fr/2015ENSL1000
NSYSU
8.
Ko, Chiung-Yuan.
Phosphorylation and Functional Regulation of Alzheimer's Tau by GSK3-beta and Prolyl Isomerase Pin1.
Degree: Master, Institute of Biomedical Sciences, 2003, NSYSU
URL: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0617103-232420
► Alzheimerâs disease (AD), one of the most common dementia, is characterized by the formation two types of aggregation in the brain: senile plaques and neurofibrillary…
(more)
▼ Alzheimerâs disease (AD), one of the most common dementia, is characterized by the formation two types of aggregation in the brain: senile plaques and neurofibrillary tangles (NFTs). NFTs are composed of hyperphosphorylated Tau. Tau protein mainly expressed in brain and was identified as one of the microtubule-associated proteins (MAPs). Hyperphophorylation on Tau affects its binding to tubulin and capacity to promote microtubule assembly. A number of proline-directed kinase capable of phosphorylating PHF-Tau have been identified, including Glycogen Synthase Kinase-3β (GSK-3β). Here we demonstrated that GSK3β can co-purify with PHFs and can co-localize with Tau in vitro in N18 cells. To examine the phosphorylation mechanism of Tau by GSK-3β, N-terminal, C-terminal, T231A, T231E, 154~441, S396A, S400A, S404A, S413A and S396A S400A mutants of Tau were used, respectively. We were able to demonstrate that phosphorylation on Thr231 and Ser404 in Tau may play important roles for GSK3β phosphorylation and its functional regulation. Most importantly, we have proved that T231P motif is necessary and critical for Tau phosphorylation by GSK3β.
Moreover, we used T231E, S396E and S400E mutants of Tau to understand the functional regulation of Tau by GSK3β phosphorylation by tubulin assembly assay. Surprisingly, we observed all of these Tau mutants can promote tubulin assembly and form tubulin bundles in N18 cells.
It has been proved that Pin1 WW domain can bind to Cdc2-phosphorylated Thr-231-Pro motif of Tau and restore the ability of Tau to promote tubulin assembly. In this study, we also studied whether Pin1 can regulate GSK3β- phosphorylated Tau. The results show that Pin1 WW domain can bind to phosphorylated Thr-231 of Tau by GSK3β and restore the ability of Tau to promote tubulin assembly.
Advisors/Committee Members: Pei-Jung Lu (committee member), Ming-Hong Tai (chair), Yi-Ren Hong (chair).
Subjects/Keywords: phosphorylation; Tau; GSK3-beta; Pin1
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Chicago ·
MLA ·
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CSE |
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to Zotero / EndNote / Reference
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APA (6th Edition):
Ko, C. (2003). Phosphorylation and Functional Regulation of Alzheimer's Tau by GSK3-beta and Prolyl Isomerase Pin1. (Thesis). NSYSU. Retrieved from http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0617103-232420
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Ko, Chiung-Yuan. “Phosphorylation and Functional Regulation of Alzheimer's Tau by GSK3-beta and Prolyl Isomerase Pin1.” 2003. Thesis, NSYSU. Accessed April 11, 2021.
http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0617103-232420.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Ko, Chiung-Yuan. “Phosphorylation and Functional Regulation of Alzheimer's Tau by GSK3-beta and Prolyl Isomerase Pin1.” 2003. Web. 11 Apr 2021.
Vancouver:
Ko C. Phosphorylation and Functional Regulation of Alzheimer's Tau by GSK3-beta and Prolyl Isomerase Pin1. [Internet] [Thesis]. NSYSU; 2003. [cited 2021 Apr 11].
Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0617103-232420.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Ko C. Phosphorylation and Functional Regulation of Alzheimer's Tau by GSK3-beta and Prolyl Isomerase Pin1. [Thesis]. NSYSU; 2003. Available from: http://etd.lib.nsysu.edu.tw/ETD-db/ETD-search/view_etd?URN=etd-0617103-232420
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
9.
Marchand, Benoît.
Rôle des Glycogène synthase kinases 3 (GSK3) dans la
régulation de l’autophagie et du facteur de transcription EB (TFEB)
dans les cellules pancréatiques tumorales humaines.
Degree: PhD, Biologie cellulaire, 2016, Université de Sherbrooke
URL: http://www.collectionscanada.gc.ca/obj/thesescanada/vol2/QSHERU/TC-QSHERU-11143_8185.pdf
;
http://savoirs.usherbrooke.ca/bitstream/11143/8185/1/Marchand_Benoit_PhD_2016.pdf
► Plusieurs études ont suggéré une implication des glycogène synthase kinases 3 (GSK3) dans la carcinogenèse, notamment du pancréas. Des études ont rapporté des résultats contradictoires…
(more)
▼ Plusieurs études ont suggéré une implication des
glycogène synthase
kinases 3 (
GSK3) dans la carcinogenèse,
notamment du pancréas. Des études ont
rapporté des résultats
contradictoires quant à l’impact des
GSK3 sur la survie
cellulaire. Au niveau du pancréas, il a été observé que
l’inhibition des
GSK3 inhibe
la croissance entre autres via la
régulation de la voie JNK ou NFkB. Les inhibiteurs
des
GSK3 sont
présentement à l’étude comme traitement de différentes
pathologies, notamment pour le cancer pancréatique. Une meilleure
compréhension des voies de signalisation régulées par les
GSK3 sera
donc
nécessaire. Nous avons entrepris ces travaux afin de mieux
comprendre les
mécanismes impliqués dans la régulation de la
survie des cellules pancréatiques
tumorales par les
GSK3.
Nous
avons démontré que l’inhibition des
GSK3 induit l’apoptose et
l’autophagie dans les cellules pancréatiques tumorales humaines.
L’inhibition des
GSK3 stimule l’autophagie autant dans les
cellules pancréatiques tumorales que
non tumorales, alors que
l’apoptose est induite spécifiquement dans les cellules
tumorales.
Contrairement à l’apoptose, l’autophagie est induite
indépendamment
de la voie JNK-cJUN suite à l’inhibition des
GSK3.
Nos résultats démontrent que
l’inhibition des
GSK3 mène à
l’inactivation de la voie mTORC1 qui pourrait
contribuer à
l’induction de l’autophagie. D’autre part, nos travaux ont
démontré
pour la première fois que les
GSK3 régulent le facteur de
transcription EB (TFEB)
dans les cellules pancréatiques tumorales.
En effet, l’inhibition des
GSK3 entraîne
la déphosphorylation de
TFEB, notamment sur la Ser211, la dissociation des 14-3-
3 et sa
translocation nucléaire. Nos résultats suggèrent que la régulation
de TFEB
par les
GSK3 impliquerait des Ser/Thr phosphatases et
pourrait être indépendante
de l’activité mTORC1. L’inhibition de
l’autophagie ou la déplétion de l’expression
de TFEB sensibilise
les cellules pancréatiques tumorales à l’apoptose induite suite
à
l’inhibition des
GSK3 suggérant un rôle pro-survie de l’autophagie
et de TFEB
dans ces cellules. Enfin, l’inhibition des
GSK3 semble
mener à l’inhibition de la
glycolyse qui contribuerait à
l’induction de l’apoptose. En résumé, nos résultats
démontrent que
l’inhibition des
GSK3 induit à la fois des signaux
pro-apoptotiques
et pro-survie suggérant que l’équilibre entre ces
signaux dicterait l’impact des
GSK3 sur la survie des cellules
pancréatiques tumorales humaines.
Advisors/Committee Members: Boucher, Marie-Josée.
Subjects/Keywords: GSK3; Cancer pancréatique; Autophagie; TFEB; mTOR; 14-3-3; JNK
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Marchand, B. (2016). Rôle des Glycogène synthase kinases 3 (GSK3) dans la
régulation de l’autophagie et du facteur de transcription EB (TFEB)
dans les cellules pancréatiques tumorales humaines. (Doctoral Dissertation). Université de Sherbrooke. Retrieved from http://www.collectionscanada.gc.ca/obj/thesescanada/vol2/QSHERU/TC-QSHERU-11143_8185.pdf ; http://savoirs.usherbrooke.ca/bitstream/11143/8185/1/Marchand_Benoit_PhD_2016.pdf
Chicago Manual of Style (16th Edition):
Marchand, Benoît. “Rôle des Glycogène synthase kinases 3 (GSK3) dans la
régulation de l’autophagie et du facteur de transcription EB (TFEB)
dans les cellules pancréatiques tumorales humaines.” 2016. Doctoral Dissertation, Université de Sherbrooke. Accessed April 11, 2021.
http://www.collectionscanada.gc.ca/obj/thesescanada/vol2/QSHERU/TC-QSHERU-11143_8185.pdf ; http://savoirs.usherbrooke.ca/bitstream/11143/8185/1/Marchand_Benoit_PhD_2016.pdf.
MLA Handbook (7th Edition):
Marchand, Benoît. “Rôle des Glycogène synthase kinases 3 (GSK3) dans la
régulation de l’autophagie et du facteur de transcription EB (TFEB)
dans les cellules pancréatiques tumorales humaines.” 2016. Web. 11 Apr 2021.
Vancouver:
Marchand B. Rôle des Glycogène synthase kinases 3 (GSK3) dans la
régulation de l’autophagie et du facteur de transcription EB (TFEB)
dans les cellules pancréatiques tumorales humaines. [Internet] [Doctoral dissertation]. Université de Sherbrooke; 2016. [cited 2021 Apr 11].
Available from: http://www.collectionscanada.gc.ca/obj/thesescanada/vol2/QSHERU/TC-QSHERU-11143_8185.pdf ; http://savoirs.usherbrooke.ca/bitstream/11143/8185/1/Marchand_Benoit_PhD_2016.pdf.
Council of Science Editors:
Marchand B. Rôle des Glycogène synthase kinases 3 (GSK3) dans la
régulation de l’autophagie et du facteur de transcription EB (TFEB)
dans les cellules pancréatiques tumorales humaines. [Doctoral Dissertation]. Université de Sherbrooke; 2016. Available from: http://www.collectionscanada.gc.ca/obj/thesescanada/vol2/QSHERU/TC-QSHERU-11143_8185.pdf ; http://savoirs.usherbrooke.ca/bitstream/11143/8185/1/Marchand_Benoit_PhD_2016.pdf
Penn State University
10.
Burns, Katherine Anne.
REGULATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA ACTIVITY VIA CROSS-TALK WITH GLYCOGEN SYNTHASE KINASE 3
.
Degree: 2008, Penn State University
URL: https://submit-etda.libraries.psu.edu/catalog/7598
► Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a nuclear receptor involved in the maintenance of fatty acid homeostasis and is important for mediating the adaptive…
(more)
▼ Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a nuclear receptor involved in the maintenance of fatty acid homeostasis and is important for mediating the adaptive response to fasting. PPAR alpha is phosphorylated by multiple kinases which differentially regulate its activity. Computational analysis of PPAR alpha revealed 5 potential glycogen synthase kinase 3 (
GSK3) phosphorylation sites.
GSK3 is a key enzyme involved in glycogen metabolism, and is important for signaling by insulin, growth factors, and nutrients. It was hypothesized that PPAR alpha is a substrate for
GSK3 phosphorylation and this association is involved in fasting mediated homeostasis. PPAR alpha is phosphorylated by
GSK3 beta, primarily at serine-73 in the A/B domain of rat PPAR alpha. This residue is conserved across PPAR alpha species including humans. The regulation of PPAR alpha target gene expression was affected by manipulating
GSK3 activity via chemical inhibitors and specific RNA inhibitors (RNAis). We also demonstrated an increased turnover and ubiquitination of PPAR alpha with the over-expression of
GSK3 beta, presumably the result of increased PPAR alpha phosphorylation. In addition to
GSK3 affecting PPAR alpha activity, it has been noted that ligands for this nuclear receptor, the peroxisome proliferators, influence
GSK3 alpha and
GSK3 beta expression and activity. The adaptive response in the liver to fasting involves both PPAR alpha and
GSK3. Thus, mice subjected to fasting represents an ideal, physiologically-relevant model system to explore PPAR alpha and
GSK3 activity and their confluence. Fatty acid metabolism genes, such as Acyl CoA Oxidase (ACO), the bifunctional enzyme (BIEN), and 3-ketoacyl-CoA thiolase (thiolase) were increased during fasting in wild-type (PPAR alpha +/+) but not in PPAR alpha knockout (PPAR alpha -/-) mice.
GSK3 alpha was increased at the mRNA and protein level, while
GSK3 beta was decreased at the phosphospecific level by fasting in wild-type mice. Two potential mechanistic links between PPAR alpha activation upon fasting and
GSK3 expression and activity were examined, Tribbles 3 (TRB3) and Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha). TRB3 is a fasting inducible inhibitor of the serine-threonine kinase AKT/PKB and PGC-1 alpha is a ligand inducible coactivator for PPAR alpha involved in the control of cellular energy metabolic pathways. In contrast to previously published results, TRB3 was not differentially regulated by fasting in wild-type or PPAR alpha -/- mice at the mRNA or protein level. However, PGC-1 alpha mRNA levels were increased upon fasting, and unexpectedly, the levels were increased in a PPAR alpha-dependent manner. This establishes a novel regulation of PGC-1 alpha that is dependent on the expression of PPAR alpha during fasting. This thesis has demonstrated that PPAR alpha is a substrate for
GSK3 beta phosphorylation that causes increased ubiquitination and turnover of PPAR alpha, and that PPAR alpha,
GSK3 alpha/beta, and PGC-1 alpha…
Advisors/Committee Members: John Patrick Vanden Heuvel, Committee Chair/Co-Chair, Pamela Hankey Giblin, Committee Member, Donna Hope Korzick, Committee Member, Gary H Perdew, Committee Member, Jeffrey Maurice Peters, Committee Member.
Subjects/Keywords: fasting; phosphorylation; GSK3; PPARalpha
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Burns, K. A. (2008). REGULATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA ACTIVITY VIA CROSS-TALK WITH GLYCOGEN SYNTHASE KINASE 3
. (Thesis). Penn State University. Retrieved from https://submit-etda.libraries.psu.edu/catalog/7598
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Burns, Katherine Anne. “REGULATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA ACTIVITY VIA CROSS-TALK WITH GLYCOGEN SYNTHASE KINASE 3
.” 2008. Thesis, Penn State University. Accessed April 11, 2021.
https://submit-etda.libraries.psu.edu/catalog/7598.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Burns, Katherine Anne. “REGULATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA ACTIVITY VIA CROSS-TALK WITH GLYCOGEN SYNTHASE KINASE 3
.” 2008. Web. 11 Apr 2021.
Vancouver:
Burns KA. REGULATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA ACTIVITY VIA CROSS-TALK WITH GLYCOGEN SYNTHASE KINASE 3
. [Internet] [Thesis]. Penn State University; 2008. [cited 2021 Apr 11].
Available from: https://submit-etda.libraries.psu.edu/catalog/7598.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Burns KA. REGULATION OF PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR ALPHA ACTIVITY VIA CROSS-TALK WITH GLYCOGEN SYNTHASE KINASE 3
. [Thesis]. Penn State University; 2008. Available from: https://submit-etda.libraries.psu.edu/catalog/7598
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Washington
11.
Fagnan, Erin.
Mechanisms for Scaffold-Mediated Regulation of Kinase Activity in the Wnt Signaling Pathway.
Degree: PhD, 2019, University of Washington
URL: http://hdl.handle.net/1773/44746
► Cellular signaling is a complex process involving numerous pathways. Many of these pathways are connected through shared proteins, creating branch points that may result in…
(more)
▼ Cellular signaling is a complex process involving numerous pathways. Many of these pathways are connected through shared proteins, creating branch points that may result in crosstalk between pathways. It is not fully understood how protein activity can be regulated by a variety of different upstream signals and still maintain specificity. Scaffold proteins may act as a solution to this specificity issue by physically assembling signaling proteins within a specific pathway, such as a MAPK cascade. There are many models for how scaffold proteins regulate protein activity, all of which are based on the idea that scaffold proteins increase specificity by increasing reaction rates for the proteins they bring together. Even though this idea has laid the foundation for many studies in the signaling field, we still lack a thorough kinetic analysis of scaffold function and its effect on specificity. In order to determine if scaffold proteins actually increase reaction rates as a mechanism for specificity, we measured GSK3β reaction rates with several substrates in a minimal, biochemically reconstituted system of the Wnt signaling network. We found that the Wnt scaffold Axin produces a modest, 2-fold enhancement of the rate of phosphorylation of the Wnt substrate β-catenin. Surprisingly, we found that Axin significantly slows the rate of phosphorylation of a non-Wnt substrate. Together, these data suggest that Axin alone is not sufficient to accelerate a specific kinase-substrate reaction. Instead, Axin can promote signaling specificity by suppressing kinase reactions with competing, non-Wnt pathway targets. Further, these newly identified properties of Axin reinforce an emerging trend that scaffold proteins can regulate kinase activity through a diverse set of mechanisms.
Advisors/Committee Members: Zalatan, Jesse (advisor).
Subjects/Keywords: Axin; Cell Signaling; GSK3; Scaffold Proteins; Wnt pathway; Chemistry; Biochemistry; Chemistry
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APA ·
Chicago ·
MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Fagnan, E. (2019). Mechanisms for Scaffold-Mediated Regulation of Kinase Activity in the Wnt Signaling Pathway. (Doctoral Dissertation). University of Washington. Retrieved from http://hdl.handle.net/1773/44746
Chicago Manual of Style (16th Edition):
Fagnan, Erin. “Mechanisms for Scaffold-Mediated Regulation of Kinase Activity in the Wnt Signaling Pathway.” 2019. Doctoral Dissertation, University of Washington. Accessed April 11, 2021.
http://hdl.handle.net/1773/44746.
MLA Handbook (7th Edition):
Fagnan, Erin. “Mechanisms for Scaffold-Mediated Regulation of Kinase Activity in the Wnt Signaling Pathway.” 2019. Web. 11 Apr 2021.
Vancouver:
Fagnan E. Mechanisms for Scaffold-Mediated Regulation of Kinase Activity in the Wnt Signaling Pathway. [Internet] [Doctoral dissertation]. University of Washington; 2019. [cited 2021 Apr 11].
Available from: http://hdl.handle.net/1773/44746.
Council of Science Editors:
Fagnan E. Mechanisms for Scaffold-Mediated Regulation of Kinase Activity in the Wnt Signaling Pathway. [Doctoral Dissertation]. University of Washington; 2019. Available from: http://hdl.handle.net/1773/44746
University of Kansas
12.
Venugopal, Anand.
IDENTIFICATION OF THE RNA BINDING PROTEIN RBM3 AS A NOVEL EFFECTOR OF β-CATENIN SIGNALING AND COLON CANCER STEM CELLS.
Degree: PhD, Molecular & Integrative Physiology, 2014, University of Kansas
URL: http://hdl.handle.net/1808/22535
► The intestinal epithelium is one of the fastest renewing tissues within the adult. This renewal is primarily driven by the intestinal epithelial stem cell compartment…
(more)
▼ The intestinal epithelium is one of the fastest renewing tissues within the adult. This renewal is primarily driven by the intestinal epithelial stem cell compartment and homeostasis of this compartment needs to be strictly maintained. Loss of regulation can lead to hyperplasia and subsequent malignant transformation. Moreover, cancers are also thought to contain a stem cell population which maintains long term tumor viability and recurrence following therapy. Therefore, a thorough understanding of the molecular machinery that governs stem cell homeostasis can further our understanding of colon cancer initiation and progression. The RNA binding protein RBM3 is upregulated in many solid tumors including colon, prostate and breast. It also serves as a proto-oncogene inducing the malignant transformation of normal cells when overexpressed. To further characterize the mechanism, we overexpressed RBM3 in DLD-1 and HCT 116 colon cancer cell lines. We show that RBM3 overexpression is capable of increasing the cancer stem cell phenotype as measured by side population assay, spheroid formation and expression of the putative stem cell markers DCLK1, LGR5 and CD44. Interestingly, RBM3 also increases chemoresistance through increased multidrug efflux and quiescence, both characteristics commonly attributed to cancer stem cells. Moreover, RBM3 overexpression appears to increase activity of the β-catenin signaling cascade, a pathway critical for the maintenance of stem cell self-renewal and implicated in the pathogenesis of colon cancer. We also show that RBM3 overexpression decreases the activity of
GSK3β, a member of the destruction complex known to suppress β-catenin levels within the cell. Consistent with this, pharmacologic inhibition of
GSK3β similarly phenocopies RBM3 induced β-catenin transcriptional activity. Taken together, we conclude that RBM3 overexpression is capable of increasing the cancer stem cell population. We also show a novel role for RBM3 in increasing β-catenin signaling activity. Based on these data, we infer that the overexpression of RBM3 observed within solid tumors may be critical for maintaining self-renewal within the cancer stem cells and necessary for long term viability of tumor formation.
Advisors/Committee Members: Anant, Shrikant (advisor), Jensen, Roy (cmtemember), Godwin, Andrew (cmtemember), Welch, Danny (cmtemember), Wood, John (cmtemember).
Subjects/Keywords: Molecular biology; Oncology; DCLK1; GSK3β
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Venugopal, A. (2014). IDENTIFICATION OF THE RNA BINDING PROTEIN RBM3 AS A NOVEL EFFECTOR OF β-CATENIN SIGNALING AND COLON CANCER STEM CELLS. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/22535
Chicago Manual of Style (16th Edition):
Venugopal, Anand. “IDENTIFICATION OF THE RNA BINDING PROTEIN RBM3 AS A NOVEL EFFECTOR OF β-CATENIN SIGNALING AND COLON CANCER STEM CELLS.” 2014. Doctoral Dissertation, University of Kansas. Accessed April 11, 2021.
http://hdl.handle.net/1808/22535.
MLA Handbook (7th Edition):
Venugopal, Anand. “IDENTIFICATION OF THE RNA BINDING PROTEIN RBM3 AS A NOVEL EFFECTOR OF β-CATENIN SIGNALING AND COLON CANCER STEM CELLS.” 2014. Web. 11 Apr 2021.
Vancouver:
Venugopal A. IDENTIFICATION OF THE RNA BINDING PROTEIN RBM3 AS A NOVEL EFFECTOR OF β-CATENIN SIGNALING AND COLON CANCER STEM CELLS. [Internet] [Doctoral dissertation]. University of Kansas; 2014. [cited 2021 Apr 11].
Available from: http://hdl.handle.net/1808/22535.
Council of Science Editors:
Venugopal A. IDENTIFICATION OF THE RNA BINDING PROTEIN RBM3 AS A NOVEL EFFECTOR OF β-CATENIN SIGNALING AND COLON CANCER STEM CELLS. [Doctoral Dissertation]. University of Kansas; 2014. Available from: http://hdl.handle.net/1808/22535
University of Sydney
13.
Duan, Xiaowen.
Characterization of Trafficking Regulator of GLUT4-1 (TRARG1)
.
Degree: 2020, University of Sydney
URL: http://hdl.handle.net/2123/23722
► Insulin resistance is a precursor of most metabolic diseases including Type 2 diabetes, and is largely recapitulated by impaired insulin-stimulated glucose transport mediated by the…
(more)
▼ Insulin resistance is a precursor of most metabolic diseases including Type 2 diabetes, and is largely recapitulated by impaired insulin-stimulated glucose transport mediated by the glucose transporter, GLUT4. However, understanding precisely how insulin orchestrates regulation of GLUT4 traffic at the various transport steps, has been a longstanding puzzle. GLUT4 storage vesicles (GSVs) are specialized intracellular storage compartment of GLUT4 and translocate to the plasma membrane (PM) in response to insulin stimulation. In pursuit of novel proteins regulating GLUT4 traffic, our laboratory performed proteomic studies of GSVs purified from adipocytes and uncovered TRARG1 as a novel positive regulator of insulin-stimulated GLUT4 trafficking. To elucidate the mechanism(s) by which TRARG1 functions, I began with demonstrating that TRARG1 contains a single transmembrane domain (TMD) and one re-entrant loop, with a cytosolic N-terminus, contrary to the consensus predicted topology. Mass spectrometry (MS) analysis revealed a range of post-translational modifications (PTMs) on TRARG1, including phosphorylation. Examination of MS analysis of insulin-regulated protein phosphorylation in 3T3-L1 adipocytes and biochemical validation suggested that TRARG1 dephosphorylation by insulin is PI3K/Akt-dependent. Furthermore, TRARG1 is a novel substrate of the protein kinase GSK3. TRARG1 protein-protein interaction analysis revealed that insulin-mediated TRARG1 dephosphorylation regulates its binding to a range of proteins including Bcl9l. These findings have elucidated novel functions of TRARG1 in that it is predicted to function at multiple steps along the GLUT4 trafficking pathway as well as other functions thought to interact with GLUT4 trafficking. These latter include the Wnt-β-catenin signalling pathway which may regulate insulin sensitivity. My studies have revealed many novel functions of TRARG1 and highlighted this to be a key mediator of GLUT4 trafficking in fat cells.
Subjects/Keywords: GSK3; GLUT4; TRARG1; Protein phosphorylation; insulin signaling; BCL9L
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APA (6th Edition):
Duan, X. (2020). Characterization of Trafficking Regulator of GLUT4-1 (TRARG1)
. (Thesis). University of Sydney. Retrieved from http://hdl.handle.net/2123/23722
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Duan, Xiaowen. “Characterization of Trafficking Regulator of GLUT4-1 (TRARG1)
.” 2020. Thesis, University of Sydney. Accessed April 11, 2021.
http://hdl.handle.net/2123/23722.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Duan, Xiaowen. “Characterization of Trafficking Regulator of GLUT4-1 (TRARG1)
.” 2020. Web. 11 Apr 2021.
Vancouver:
Duan X. Characterization of Trafficking Regulator of GLUT4-1 (TRARG1)
. [Internet] [Thesis]. University of Sydney; 2020. [cited 2021 Apr 11].
Available from: http://hdl.handle.net/2123/23722.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Duan X. Characterization of Trafficking Regulator of GLUT4-1 (TRARG1)
. [Thesis]. University of Sydney; 2020. Available from: http://hdl.handle.net/2123/23722
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
14.
Ribeiro, Marco Saleh.
Modulação da AKT/GSK3-B e SNAP-25 pela administração de curcumina em modelo de mania induzido por cetamina.
Degree: 2015, Universidade Catolica de Pelotas; Programa de Pos-Graduacao em Saude Comportamento#;-1990782970254042025#; #600; UCPel; Brasil; Centro de Ciencias da Saude#; #-7432574962795991241#; #600
URL: http://tede.ucpel.edu.br:8080/jspui/handle/tede/536
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Made available in DSpace on 2016-11-11T11:14:08Z…
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▼ Submitted by Cristiane Chim ([email protected]) on 2016-11-11T11:14:08Z No. of bitstreams: 1 MARCO SALEH RIBEIRO.pdf: 1233321 bytes, checksum: aebd2e7f49d852825cab51345cf5eebc (MD5)
Made available in DSpace on 2016-11-11T11:14:08Z (GMT). No. of bitstreams: 1 MARCO SALEH RIBEIRO.pdf: 1233321 bytes, checksum: aebd2e7f49d852825cab51345cf5eebc (MD5) Previous issue date: 2015-08-31
Bipolar disorder is a psychiatric illness associated with alternate states of depression and mania/hypomania episodes. Glycogen synthase kinase 3β (GSK-3β) and synaptosomal-associated protein 25 (SNAP-25) are associated respectively, with the modulation of gene expression and neural plasticity in the pathogenesis of mood disorders. Curcumin, active compound extracted from Curcuma longa, has been described as a neuroprotective agent in neurodegenerative disorders, although their mechanisms of action are not completely elucidated. In this study we investigate
the impact of ketamine-induced model of mania on GSK-3β and SNAP-25 immunocontent, and assess in this model the neuroprotective effect of Curcumin pretreatment. Rats received peanut oil (vehicle), curcumin 20 or 50 mg/kg (p.o.), once a day for 14 days. From the 8th to the 14th day the animals also received saline or ketamine (25 mg/kg i.p.), once a day. On the 15th day of treatment, the animals received a single injection of ketamine or saline and the locomotor activity was assessed in the open-field apparatus after 30 min. Immunodetection of the proteins pGSK-3β and SNAP-25 were evaluated by Western Blotting in the prefrontal cortex (PFC) and the hippocampus (HP). The administration of Curcumin in doses of 20 and 50 mg/kg prevented the hyperlocomotion induced by ketamine in the open-field test. In addition, both doses of Curcumin prevented the decrease in density of pGSK-3β and SNAP-25 ketamine-induced in PFC and HP. In conclusion, our results show that Curcumin prevents
hyperlocomotion and presents a neuroprotective effect by restoring SNAP-25 density probably via modulation of GSK-3β.
O transtorno bipolar é uma doença psiquiátrica associada a estados alternados de episódios de depressão e mania / hipomania. O glicogênio sintase quinase 3β (GSK-3β) e proteína associada a sinaptossomas de 25 (SNAP-25) estão associados, respectivamente, com a modulação da expressão gênica e a plasticidade neural na patogênese de perturbações do humor. A curcumina, composto ativo extraído de Curcuma longa, tem sido descrito como um agente neuroprotetor em desordens neurodegenerativas, embora o seu mecanismo de ação não está completamente elucidado. Neste estudo foi investigado o impacto do modelo induzida por cetamina de mania em GSK-3β e SNAP-25, e avaliado neste modelo, o efeito neuroprotetor da curcumina pré-tratamento. Os ratos receberam óleo de amendoim (veículo), curcumina 20 ou 50 mg / kg (p.o.), uma vez por dia durante 14 dias. A partir do dia 8 ao dia 14 os
animais também receberam solução salina ou cetamina (25 mg / kg i.p.), uma vez por dia. No 15º dia de tratamento, os animais…
Advisors/Committee Members: Ghisleni, Gabriele Cordenonzi, Pochmann, Daniela, Spanevello, Rosélia Maria, Bast, Rachel Krolow Santos Silva.
Subjects/Keywords: transtorno bipolar; cetamina; GSK3; SNAP-25; FARMACOLOGIA::NEUROPSICOFARMACOLOGIA#; 3291013325247130665#; #600
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APA (6th Edition):
Ribeiro, M. S. (2015). Modulação da AKT/GSK3-B e SNAP-25 pela administração de curcumina em modelo de mania induzido por cetamina. (Masters Thesis). Universidade Catolica de Pelotas; Programa de Pos-Graduacao em Saude Comportamento#;-1990782970254042025#; #600; UCPel; Brasil; Centro de Ciencias da Saude#; #-7432574962795991241#; #600. Retrieved from http://tede.ucpel.edu.br:8080/jspui/handle/tede/536
Chicago Manual of Style (16th Edition):
Ribeiro, Marco Saleh. “Modulação da AKT/GSK3-B e SNAP-25 pela administração de curcumina em modelo de mania induzido por cetamina.” 2015. Masters Thesis, Universidade Catolica de Pelotas; Programa de Pos-Graduacao em Saude Comportamento#;-1990782970254042025#; #600; UCPel; Brasil; Centro de Ciencias da Saude#; #-7432574962795991241#; #600. Accessed April 11, 2021.
http://tede.ucpel.edu.br:8080/jspui/handle/tede/536.
MLA Handbook (7th Edition):
Ribeiro, Marco Saleh. “Modulação da AKT/GSK3-B e SNAP-25 pela administração de curcumina em modelo de mania induzido por cetamina.” 2015. Web. 11 Apr 2021.
Vancouver:
Ribeiro MS. Modulação da AKT/GSK3-B e SNAP-25 pela administração de curcumina em modelo de mania induzido por cetamina. [Internet] [Masters thesis]. Universidade Catolica de Pelotas; Programa de Pos-Graduacao em Saude Comportamento#;-1990782970254042025#; #600; UCPel; Brasil; Centro de Ciencias da Saude#; #-7432574962795991241#; #600; 2015. [cited 2021 Apr 11].
Available from: http://tede.ucpel.edu.br:8080/jspui/handle/tede/536.
Council of Science Editors:
Ribeiro MS. Modulação da AKT/GSK3-B e SNAP-25 pela administração de curcumina em modelo de mania induzido por cetamina. [Masters Thesis]. Universidade Catolica de Pelotas; Programa de Pos-Graduacao em Saude Comportamento#;-1990782970254042025#; #600; UCPel; Brasil; Centro de Ciencias da Saude#; #-7432574962795991241#; #600; 2015. Available from: http://tede.ucpel.edu.br:8080/jspui/handle/tede/536
15.
Briant, Rémi.
Développement de nouvelles séries d’inhibiteurs hétérocycliques des protéines kinases : synthèse, relations structure-activité et optimisation de leur sélectivité au sein du groupe CMGC : Development of new series of heterocyclic inhibitors of protein kinases : synthesis, structure-activity relationships and optimization of their selectivity within the CMGC group.
Degree: Docteur es, Chimie, 2011, Université Claude Bernard – Lyon I
URL: http://www.theses.fr/2011LYO10256
► Depuis la mise sur le marché de l'imatinib (ou Gleevec®), les protéines kinases sont devenues des cibles thérapeutiques privilégiées dans le traitement de multiples pathologies.…
(more)
▼ Depuis la mise sur le marché de l'imatinib (ou Gleevec®), les protéines kinases sont devenues des cibles thérapeutiques privilégiées dans le traitement de multiples pathologies. Parmi les huit groupes de protéines kinases, le groupe CMGC contient 61 kinases sérine-thréonine, dont les CDKs (cyclin-dependent kinases), les GSK3 (glycogen synthase kinase 3), les CLKs (Cdc2-like kinases) ou encore les DYRKs (dual specificity,tyrosine phosphorylation-regulated kinases). Néanmoins, l'un des défis majeurs dans le développement d'inhibiteurs de kinases reste la sélectivité vis-à-vis des autres protéines kinases car la majorité de ces composés se place dans la poche ATP, site commun à toutes ces protéines. L'objectif de notre équipe est de synthétiser de nouveaux inhibiteurs sélectifs des protéines kinases du groupe CMGC. Dans cette présentation, nous décrirons la synthèse, l'évaluation des relations structure-activité et l'optimisation de la sélectivité de trois séries d'inhibiteurs hétérocycliques. A partir de l'inhibiteur N-&-N1 (GP0210) développé dans notre laboratoire et actuellement en phase préclinique, la synthèse et l'évaluation biologique d'une nouvelle chimiothèque de pyrazolo[1,5-a]triazines ont permis d'identifier deux séries de composés responsables de l'inhibition d'une part de CDKs et d'autre part de GSK3. Sur la base du composé AT7519, inhibiteur de CDKs et GSK3 actuellement en phase clinique en oncologie, nous avons découvert de nouveaux pyrazole-3-carboxamides, inhibiteurs sélectifs de GSK3 avec de nouvelles indications thérapeutiques. Enfin, nous avons préparé des dérivés de la famille des mériolines, inhibiteurs non sélectifs de protéines kinases, présentant des activités d'inhibition nanomolaires sur les kinases CLKs et une sélectivité vis-à-vis des autres protéines kinases du groupe CMGC, en particulier les DYRKs. Ce dernier résultat n'avait jamais été observé jusqu'à ce jour
Since the approval of imatinib (or Gleevec®), protein kinases have become major targets for the treatment of several pathologies (cancer, neurodegenerative diseases,…). Among the eight existing groups of protein kinases, the CMGC group consists of 61 serine-threonine kinases classified as CDKs (cyclin-dependent kinases), GSK3 (glycogen synthase kinases), CLKs (Cdc2-like kinases), DYRKs (dual specificity, tyrosine phosphorylationregulated kinases) or other sub-families. Nevertheless a major challenge remains concerning the development of kinase-modulating small molecules: the selectivity of these new inhibitors, which generally bind in the ATPbinding pocket, a common site for all protein kinases. Our team aims at synthesizing original and selective inhibitors of CMGC kinases. In this presentation, we are introducing the synthesis, the evaluation of the structure-activity relationships and the optimization of the selectivity of three series of heterocyclic inhibitors, targeting CMGC protein kinases. Based on N-&-N1 (GP0210), an inhibitor developed in the laboratory and currently in preclinical trials, the synthesis and the…
Advisors/Committee Members: Joseph, Benoît (thesis director).
Subjects/Keywords: Inhibiteurs; CMGC; CDK; GSK3; CLK; DYRK; Pyrazolo[1,5-a]triazines; N-&-N1; Inhibitors; CMGC; CDK; GSK3; CLK; DYRK; Pyrazolo[1,5-a]triazines; N-&-N1; 540
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APA ·
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MLA ·
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Export
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APA (6th Edition):
Briant, R. (2011). Développement de nouvelles séries d’inhibiteurs hétérocycliques des protéines kinases : synthèse, relations structure-activité et optimisation de leur sélectivité au sein du groupe CMGC : Development of new series of heterocyclic inhibitors of protein kinases : synthesis, structure-activity relationships and optimization of their selectivity within the CMGC group. (Doctoral Dissertation). Université Claude Bernard – Lyon I. Retrieved from http://www.theses.fr/2011LYO10256
Chicago Manual of Style (16th Edition):
Briant, Rémi. “Développement de nouvelles séries d’inhibiteurs hétérocycliques des protéines kinases : synthèse, relations structure-activité et optimisation de leur sélectivité au sein du groupe CMGC : Development of new series of heterocyclic inhibitors of protein kinases : synthesis, structure-activity relationships and optimization of their selectivity within the CMGC group.” 2011. Doctoral Dissertation, Université Claude Bernard – Lyon I. Accessed April 11, 2021.
http://www.theses.fr/2011LYO10256.
MLA Handbook (7th Edition):
Briant, Rémi. “Développement de nouvelles séries d’inhibiteurs hétérocycliques des protéines kinases : synthèse, relations structure-activité et optimisation de leur sélectivité au sein du groupe CMGC : Development of new series of heterocyclic inhibitors of protein kinases : synthesis, structure-activity relationships and optimization of their selectivity within the CMGC group.” 2011. Web. 11 Apr 2021.
Vancouver:
Briant R. Développement de nouvelles séries d’inhibiteurs hétérocycliques des protéines kinases : synthèse, relations structure-activité et optimisation de leur sélectivité au sein du groupe CMGC : Development of new series of heterocyclic inhibitors of protein kinases : synthesis, structure-activity relationships and optimization of their selectivity within the CMGC group. [Internet] [Doctoral dissertation]. Université Claude Bernard – Lyon I; 2011. [cited 2021 Apr 11].
Available from: http://www.theses.fr/2011LYO10256.
Council of Science Editors:
Briant R. Développement de nouvelles séries d’inhibiteurs hétérocycliques des protéines kinases : synthèse, relations structure-activité et optimisation de leur sélectivité au sein du groupe CMGC : Development of new series of heterocyclic inhibitors of protein kinases : synthesis, structure-activity relationships and optimization of their selectivity within the CMGC group. [Doctoral Dissertation]. Université Claude Bernard – Lyon I; 2011. Available from: http://www.theses.fr/2011LYO10256
Temple University
16.
Nwaneshiudu, Chinwe A.
Characterization of a functional role of the neurokinin-3 receptor in behavioral effects of cocaine.
Degree: PhD, 2011, Temple University
URL: http://digital.library.temple.edu/u?/p245801coll10,62614
► Pharmacology
The tachykinin NK-3 receptor is a G-protein coupled receptor activated by mammalian tachykinin neuropeptides, which can modulate dopaminergic neurotransmission, and alter dopamine-mediated behaviors. The…
(more)
▼ Pharmacology
The tachykinin NK-3 receptor is a G-protein coupled receptor activated by mammalian tachykinin neuropeptides, which can modulate dopaminergic neurotransmission, and alter dopamine-mediated behaviors. The NK-3 receptor is currently under investigation as a novel therapeutic target for cocaine addiction. Our studies, as outlined in this dissertation, sought to determine if NK-3 receptors have a functional role in the acute as well as long-term behavioral effects of cocaine.
Administration of NK-3 receptor agonists or antagonists potentiates or attenuates dopamine-mediated behaviors, respectively. Based on these findings, we hypothesized that blockade of neurokinin-3 receptors would alter acute and long-term behavioral responses to cocaine. We investigated whether acute and repeated administration of the NK-3 receptor antagonist SB 222200 altered hyperactivity induced by cocaine, and determined a possible mechanism involving dopamine D1 receptors in the striatum. We also determined whether NK-3 receptor blockade altered the development and expression of behavioral sensitization after repeated cocaine administration. Lastly, we investigated whether modulation of behavioral effects of acute and repeated cocaine by NK-3 receptors involved GSK3 phosphorylation in the nucleus accumbens.
As described in this dissertation, we show that acute administration of the NK-3 receptor antagonist SB 222200 before a cocaine injection attenuated stereotypic responses produced by cocaine. Repeated administration of SB 222200 enhanced stereotypic activity produced by either cocaine or a low dose of SKF 82958 (0.125 mg/kg, i.p.) when administered seven days later. Dopamine receptor binding studies were performed to determine the mechanism of enhanced stereotypic responses. Binding studies showed a 19.7% increase in dopamine D1 receptor density in the striatum seven days later after repeated SB 222200 administration. These findings demonstrate that acute blockade of NK-3 receptors attenuated cocaine-induced behaviors in agreement with previous studies. Furthermore, these studies also show novel effects of repeated blockade of NK-3 receptors, which causes subsequent enhancement of cocaine and dopamine D1 receptor-mediated behaviors, possibly resulting from dopamine D1 receptor up-regulation in the striatum.
In order to determine a role of NK-3 receptors in the development of cocaine-induced behavioral sensitization, the NK-3 receptor antagonist SB 222200 (2.5 or 5 mg/kg, s.c.) was administered prior to daily cocaine injections for 5 days. After a 7-day drug-free period, behavioral responses to a cocaine challenge were measured. Repeated administration of cocaine for 5 days induced a sensitized response upon a cocaine challenge 7 days later. Administration of SB 222200 prior to daily cocaine attenuated the development of behavioral sensitization. Moreover, administration of SB 222200 prior to the cocaine challenge blocked the expression of behavioral sensitization. These findings demonstrate that NK-3…
Advisors/Committee Members: Unterwald, Ellen M., Ashby, Barrie, Dun, Nae J., Cowan, Alan, Walker, Ellen A., Simmons, Mark A..
Subjects/Keywords: Health Sciences, Pharmacology; Behavioral Sciences; Biology, Neuroscience; CD-1; cocaine; dopamine; GSK3; NK-3; striatum
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APA (6th Edition):
Nwaneshiudu, C. A. (2011). Characterization of a functional role of the neurokinin-3 receptor in behavioral effects of cocaine. (Doctoral Dissertation). Temple University. Retrieved from http://digital.library.temple.edu/u?/p245801coll10,62614
Chicago Manual of Style (16th Edition):
Nwaneshiudu, Chinwe A. “Characterization of a functional role of the neurokinin-3 receptor in behavioral effects of cocaine.” 2011. Doctoral Dissertation, Temple University. Accessed April 11, 2021.
http://digital.library.temple.edu/u?/p245801coll10,62614.
MLA Handbook (7th Edition):
Nwaneshiudu, Chinwe A. “Characterization of a functional role of the neurokinin-3 receptor in behavioral effects of cocaine.” 2011. Web. 11 Apr 2021.
Vancouver:
Nwaneshiudu CA. Characterization of a functional role of the neurokinin-3 receptor in behavioral effects of cocaine. [Internet] [Doctoral dissertation]. Temple University; 2011. [cited 2021 Apr 11].
Available from: http://digital.library.temple.edu/u?/p245801coll10,62614.
Council of Science Editors:
Nwaneshiudu CA. Characterization of a functional role of the neurokinin-3 receptor in behavioral effects of cocaine. [Doctoral Dissertation]. Temple University; 2011. Available from: http://digital.library.temple.edu/u?/p245801coll10,62614
Wayne State University
17.
Yu, Wenxi.
Novel Regulatory Mechanisms Of Inositol Biosynthesis In Saccharomyces Cerevisiae And Mammalian Cells, And Implications For The Mechanism Underlying Vpa-Induced Glucose 6-Phosphate Depletion.
Degree: PhD, Biological Sciences, 2016, Wayne State University
URL: https://digitalcommons.wayne.edu/oa_dissertations/1610
► Myo-inositol is the precursor of all inositol containing molecules, including inositol phosphates, phosphoinositides and glycosylphosphatidylinositols, which are signaling molecules involved in many critical cellular…
(more)
▼ Myo-inositol is the precursor of all inositol containing molecules, including inositol phosphates, phosphoinositides and glycosylphosphatidylinositols, which are signaling molecules involved in many critical cellular functions. Perturbation of inositol metabolism has been linked to neurological disorders. Although several widely-used anticonvulsants and mood-stabilizing drugs have been shown to exert inositol depletion effects, the mechanisms of action of the drugs and the role of inositol in these diseases are not understood. Elucidation of the molecular control of inositol synthesis will shed light on the pathologies of inositol related illnesses.
In Saccharomyces cerevisiae, deletion of the four glycogen synthase kinase-3 genes, MCK1, MRK1, MDS1, and YGK3, resulted in multiple features of inositol depletion. My studies demonstrated that the MCK1 gene is required for normal inositol homeostasis. mck1∆ and gsk3∆ (mck1∆mrk1∆mds1∆ygk3∆) cells exhibited similar features of inositol depletion. MCK1 ablation led to decreased myo-inositol-3-phosphate synthase (MIPS) activity and a decreased rate of inositol de novo synthesis. This is the first demonstration that Mck1 controls inositol synthesis by regulating MIPS activity.
While elegant studies have revealed several inositol-regulating mechanisms in yeast, very little is known about regulation of inositol synthesis in mammals. My studies discovered that IP6K1, an inositol hexakisphosphate kinase that catalyzes the synthesis of inositol pyrophosphate, negatively regulates inositol synthesis in mammalian cells. Interestingly, IP6K1 preferentially bound to the phospholipid phosphatidic acid, and this binding was required for IP6K1 nuclear localization and the transcriptional regulation of Isyna1, which encodes mammalian MIPS. This is the first demonstration of the molecular control of de novo synthesis of inositol in mammalian cells.
VPA depletes intracellular glucose 6-phosphate in yeast cells by an unidentified mechanism. My studies discovered that VPA inhibits expression of hexose transporter genes HXT2, HXT4, HXT6, and HXT7. Mig1, a DNA-binding transcription repressor that translocates to the nucleus to repress gene expression under high glucose conditions, is required to inhibit HXT2 and HXT4 expression. Interestingly, VPA triggered Mig1 nuclear localization under non-repressive conditions. Furthermore, ablation of REG1, which regulates Mig1 translocation, reversed VPA-induced inhibition of HXT4 expression. These findings suggest that VPA may inhibit glucose uptake by activating Mig1-mediated repression of hexose transporter genes.
Advisors/Committee Members: Miriam L. Greenberg.
Subjects/Keywords: GSK3; inositol biosynthesis; inositol pyrophosphate; IP6K1; valproic acid; Biochemistry; Genetics; Molecular Biology
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APA ·
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APA (6th Edition):
Yu, W. (2016). Novel Regulatory Mechanisms Of Inositol Biosynthesis In Saccharomyces Cerevisiae And Mammalian Cells, And Implications For The Mechanism Underlying Vpa-Induced Glucose 6-Phosphate Depletion. (Doctoral Dissertation). Wayne State University. Retrieved from https://digitalcommons.wayne.edu/oa_dissertations/1610
Chicago Manual of Style (16th Edition):
Yu, Wenxi. “Novel Regulatory Mechanisms Of Inositol Biosynthesis In Saccharomyces Cerevisiae And Mammalian Cells, And Implications For The Mechanism Underlying Vpa-Induced Glucose 6-Phosphate Depletion.” 2016. Doctoral Dissertation, Wayne State University. Accessed April 11, 2021.
https://digitalcommons.wayne.edu/oa_dissertations/1610.
MLA Handbook (7th Edition):
Yu, Wenxi. “Novel Regulatory Mechanisms Of Inositol Biosynthesis In Saccharomyces Cerevisiae And Mammalian Cells, And Implications For The Mechanism Underlying Vpa-Induced Glucose 6-Phosphate Depletion.” 2016. Web. 11 Apr 2021.
Vancouver:
Yu W. Novel Regulatory Mechanisms Of Inositol Biosynthesis In Saccharomyces Cerevisiae And Mammalian Cells, And Implications For The Mechanism Underlying Vpa-Induced Glucose 6-Phosphate Depletion. [Internet] [Doctoral dissertation]. Wayne State University; 2016. [cited 2021 Apr 11].
Available from: https://digitalcommons.wayne.edu/oa_dissertations/1610.
Council of Science Editors:
Yu W. Novel Regulatory Mechanisms Of Inositol Biosynthesis In Saccharomyces Cerevisiae And Mammalian Cells, And Implications For The Mechanism Underlying Vpa-Induced Glucose 6-Phosphate Depletion. [Doctoral Dissertation]. Wayne State University; 2016. Available from: https://digitalcommons.wayne.edu/oa_dissertations/1610
Texas Medical Center
18.
Bruno, Debora S.
Glycogen Synthase Kinase 3 is Required for Optimal AKT Activation.
Degree: MS, 2011, Texas Medical Center
URL: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/200
► The phosphatidylinositol 3-kinase (PI3K) pathway, through its major effector node AKT, is critical for the promotion of cell growth, division, motility and apoptosis evasion.…
(more)
▼ The phosphatidylinositol 3-kinase (PI3K) pathway, through its major effector node AKT, is critical for the promotion of cell growth, division, motility and apoptosis evasion. This signaling axis is therefore commonly targeted in the form of mutations and amplifications in a myriad of malignancies. Glycogen synthase kinase 3 (
GSK3) was first discovered as the kinase responsible for phosphorylating and inhibiting the activity of glycogen synthase, ultimately antagonizing the storage of glucose as glycogen. Its activity counteracts the effects of insulin in glucose metabolism and AKT has long been recognized as one of the key molecules capable of phosphorylating
GSK3 and inhibiting its activity. However, here we demonstrate that
GSK3 is required for optimal phosphorylation and activation of AKT in different malignant cell lines, and that this effect is independent of the type of growth factor stimulation and can happen even in basal states. Both
GSK3 alpha and
GSK3 beta isoforms are necessary for AKT to become fully active, displaying a redundant role in the setting. We also demonstrate that this effect of
GSK3 on AKT phosphorylation and full activation is dependent on its kinase activity, since highly specific inhibitors targeting
GSK3 catalytic activity also promote a reduction in phosphorylated AKT. Analysis of reverse phase protein array screening of MDA-MB-231 breast cancer cells treated with RNA interference targeting
GSK3 unexpectedly revealed an increase in levels of phosphorylated MAPK14 (p38). Treatment with the selective p38 inhibitor SB 202190 rescued AKT activation in that cell line, corroborating the importance of unbiased proteomic analysis in exposing cross-talks between signaling networks and demonstrating a critical role for p38 in the regulation of AKT phosphorylation.
Advisors/Committee Members: Gordon B. Mills, M.D., Ph.D., Powel Brown, M.D., Ph.D, Peter Davies, M.D., Ph.D..
Subjects/Keywords: GSK3; AKT; p38; PI3K pathway; signaling; reverse phase protein array; Medicine and Health Sciences
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APA (6th Edition):
Bruno, D. S. (2011). Glycogen Synthase Kinase 3 is Required for Optimal AKT Activation. (Thesis). Texas Medical Center. Retrieved from https://digitalcommons.library.tmc.edu/utgsbs_dissertations/200
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Bruno, Debora S. “Glycogen Synthase Kinase 3 is Required for Optimal AKT Activation.” 2011. Thesis, Texas Medical Center. Accessed April 11, 2021.
https://digitalcommons.library.tmc.edu/utgsbs_dissertations/200.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Bruno, Debora S. “Glycogen Synthase Kinase 3 is Required for Optimal AKT Activation.” 2011. Web. 11 Apr 2021.
Vancouver:
Bruno DS. Glycogen Synthase Kinase 3 is Required for Optimal AKT Activation. [Internet] [Thesis]. Texas Medical Center; 2011. [cited 2021 Apr 11].
Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/200.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Bruno DS. Glycogen Synthase Kinase 3 is Required for Optimal AKT Activation. [Thesis]. Texas Medical Center; 2011. Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/200
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Texas Medical Center
19.
Ko, How-Wen.
GSK3BETA-MEDIATED EZH2 PHOSPHORYLATION SUPPRESSES METHYLATION OF H3K27 AND EZH2’S ONCOGENIC FUNCTIONS.
Degree: PhD, 2016, Texas Medical Center
URL: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/669
► During the process of tumorigenesis, inactivation of tumor suppressors is a critical step. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and the…
(more)
▼ During the process of tumorigenesis, inactivation of tumor suppressors is a critical step. Enhancer of zeste homolog 2 (EZH2), a histone methyltransferase and the enzymatic core subunit of polycomb repressive complex 2 (PRC2), promotes cell growth and migration through catalyzing trimethylation of histone H3 at Lys 27 (H3K27me3) and plays an important role in tumorigenesis. Its expression can be controlled by phosphorylation. However, the regulation of EZH2 activity by tumor suppressor kinase is not well understood. Glycogen synthase kinase 3 beta (GSK3b), a multifunctional serine/threonine kinase, is involved in many cellular processes. GSK3b also participates in neoplastic transformation, tumor development and regulate cancer cell metastasis. Inactivation of GSK3b contributes to tumor development in certain types of cancers, such as breast cancer. In this study, we found that GSK3b negatively regulates H3K27 trimethylation. We also validated that GSK3b physically interacts with EZH2 and their interaction mainly exists in the cytosol. GSK3b phosphorylates EZH2 at Ser363 and Thr367
in vitro, and activating GSK3b upregulates Thr367 phosphorylation
in vivo. Cells expressing mutant EZH2 to block phosphorylation by GSK3b have higher H3K27 trimethylation and enhanced ability of cell migration and anchorage-independent growth. Inactivation of GSK3b as measured by its phosphorylation at Ser9 is positively correlated with higher level of H3K27 trimethylation in breast cancer patients. Our study indicates that GSK3b has a critical role in regulating EZH2-mediated oncogenesis.
Advisors/Committee Members: Mien-Chie Hung, John Heymach, Zhen Fan.
Subjects/Keywords: EZH2; GSK3 beta; H3K27me3; Cancer; Phosphorylation; Cancer Biology; Medicine and Health Sciences
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APA ·
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MLA ·
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APA (6th Edition):
Ko, H. (2016). GSK3BETA-MEDIATED EZH2 PHOSPHORYLATION SUPPRESSES METHYLATION OF H3K27 AND EZH2’S ONCOGENIC FUNCTIONS. (Doctoral Dissertation). Texas Medical Center. Retrieved from https://digitalcommons.library.tmc.edu/utgsbs_dissertations/669
Chicago Manual of Style (16th Edition):
Ko, How-Wen. “GSK3BETA-MEDIATED EZH2 PHOSPHORYLATION SUPPRESSES METHYLATION OF H3K27 AND EZH2’S ONCOGENIC FUNCTIONS.” 2016. Doctoral Dissertation, Texas Medical Center. Accessed April 11, 2021.
https://digitalcommons.library.tmc.edu/utgsbs_dissertations/669.
MLA Handbook (7th Edition):
Ko, How-Wen. “GSK3BETA-MEDIATED EZH2 PHOSPHORYLATION SUPPRESSES METHYLATION OF H3K27 AND EZH2’S ONCOGENIC FUNCTIONS.” 2016. Web. 11 Apr 2021.
Vancouver:
Ko H. GSK3BETA-MEDIATED EZH2 PHOSPHORYLATION SUPPRESSES METHYLATION OF H3K27 AND EZH2’S ONCOGENIC FUNCTIONS. [Internet] [Doctoral dissertation]. Texas Medical Center; 2016. [cited 2021 Apr 11].
Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/669.
Council of Science Editors:
Ko H. GSK3BETA-MEDIATED EZH2 PHOSPHORYLATION SUPPRESSES METHYLATION OF H3K27 AND EZH2’S ONCOGENIC FUNCTIONS. [Doctoral Dissertation]. Texas Medical Center; 2016. Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/669
University of Southern California
20.
Shaw, Jillian Lee Satter.
Nebula/DSCR1 upregulation preserves axonal transport and
memory function in a Drosophila model for Alzheimer's
disease.
Degree: PhD, Neuroscience, 2015, University of Southern California
URL: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/538930/rec/4349
► The Down syndrome critical region 1 gene (also called regulator of calcineurin and Nebula) is located in the DSCR region of human chromosome 21 and…
(more)
▼ The Down syndrome critical region 1 gene (also called
regulator of calcineurin and Nebula) is located in the DSCR region
of human chromosome 21 and upregulated in post-mortem brains from
Down syndrome (DS) and Alzheimer’s disease (AD) patients. Questions
remain as to whether elevated expression of DSCR1 is exacerbating
disease pathology or delaying degeneration. The goal of this
dissertation is to gain insight into the role of DSCR1/Nebula in
Alzheimer’s disease. Over the course of my research, I explored the
functional interaction between DSCR1/Nebula and the amyloid
precursor protein (APP), which is known to cause AD when duplicated
or upregulated in DS. I find that the Drosophila homolog of DSCR1,
Nebula, delays neurodegeneration, ameliorates axonal transport
defects caused by APP overexpression, and preserves memory function
in young flies by regulating phosphatase and kinase activity. ❧ APP
upregulation results in the accumulation of pre-synaptic proteins
in the axons and increases in calcineurin and glycogen synthase
kinase 3 beta (GSK-3β) activity. Live-imaging experiments reveal
that nebula facilitates the transport of synaptic proteins and
mitochondria affected by APP upregulation. Impaired transport of
essential organelles caused by APP perturbation is thought to be an
underlying cause of synaptic failure and neurodegeneration in AD,
these findings imply that correcting calcineurin and GSK-3β can
prevent APP-induced pathologies. ❧ I further investigate the
effects of DSCR1/Nebula upregulation on amyloid precursor
protein-induced learning and memory deficits. I find that while
upregulation of nebula alone impairs memory, co-upregulation of APP
and nebula can effectively restore APP-induced memory defects, but
only in young Drosophila. Nebula/DSCR1 overexpression rescues
perturbations in calcineurin and cAMP signaling caused by APP
overexpression. Surprisingly, nebula accelerated age-dependent
memory impairments, increased reactive oxygen species, and enhanced
mitochondrial dysfunction in aged flies. This finding suggests that
upregulation of DSCR1 may delay APP-induced memory problems
initially but enhances memory decline at a later age. My data
further demonstrates that acute upregulation of Nebula/DSCR1 is
neuroprotective in the presence of APP upregulation; however,
chronic upregulation of nebula negatively affects memory. Finally,
I present evidence for calcineurin inhibition as a novel target for
therapeutic intervention in preventing axonal transport and memory
impairments associated with AD.
Advisors/Committee Members: Chang, Karen T. (Committee Chair), Sieburth, Derek (Committee Member), Miller, Carol Ann (Committee Member), Chen, Jeannie (Committee Member), Jakowec, Michael (Committee Member).
Subjects/Keywords: Drosophila; Nebula; DSCR1; Down syndrome; axonal transport; Alzheimer'; s disease; memory; calcineurin; GSK3
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Shaw, J. L. S. (2015). Nebula/DSCR1 upregulation preserves axonal transport and
memory function in a Drosophila model for Alzheimer's
disease. (Doctoral Dissertation). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/538930/rec/4349
Chicago Manual of Style (16th Edition):
Shaw, Jillian Lee Satter. “Nebula/DSCR1 upregulation preserves axonal transport and
memory function in a Drosophila model for Alzheimer's
disease.” 2015. Doctoral Dissertation, University of Southern California. Accessed April 11, 2021.
http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/538930/rec/4349.
MLA Handbook (7th Edition):
Shaw, Jillian Lee Satter. “Nebula/DSCR1 upregulation preserves axonal transport and
memory function in a Drosophila model for Alzheimer's
disease.” 2015. Web. 11 Apr 2021.
Vancouver:
Shaw JLS. Nebula/DSCR1 upregulation preserves axonal transport and
memory function in a Drosophila model for Alzheimer's
disease. [Internet] [Doctoral dissertation]. University of Southern California; 2015. [cited 2021 Apr 11].
Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/538930/rec/4349.
Council of Science Editors:
Shaw JLS. Nebula/DSCR1 upregulation preserves axonal transport and
memory function in a Drosophila model for Alzheimer's
disease. [Doctoral Dissertation]. University of Southern California; 2015. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/538930/rec/4349
University of Kansas
21.
Bhushan, Bharat.
MECHANISMS OF LIVER REGENERATION AFTER ACETAMINOPHEN-INDUCED HEPATOTOXICITY IN MICE.
Degree: PhD, Pharmacology, Toxicology & Therapeutics, 2016, University of Kansas
URL: http://hdl.handle.net/1808/25366
► Overdose of acetaminophen (APAP) is the major cause of acute liver failure (ALF) in the western world with very limited treatment options. Recent studies suggest…
(more)
▼ Overdose of acetaminophen (APAP) is the major cause of acute liver failure (ALF) in the western world with very limited treatment options. Recent studies suggest that liver regeneration is a critical determinant of final recovery and overall survival following APAP overdose. Stimulating liver regeneration in patients of APAP-induced ALF holds a great therapeutic potential. However, development of novel regenerative therapies for ALF is hampered because the mechanisms of liver regeneration after APAP-induced ALF are not completely known. The focus of this research was to investigate the mechanisms of liver regeneration after APAP-induced hepatotoxicity in mice. Firstly, we identified potential regulators of liver regeneration following APAP-induced hepatotoxicity using a novel incremental dose model. Liver injury and regeneration were studied in C57BL/6 mice treated with either 300 mg/kg (APAP300) or 600 mg/kg (APAP600) APAP. Mice treated with APAP300 developed extensive liver injury initially, followed by robust liver regeneration, resulting in resolution of the injury. In contrast, mice treated with APAP600 exhibited significant liver injury, but substantially delayed and attenuated liver regeneration resulting in sustained injury and decreased survival. The inhibition of liver regeneration in APAP600 group was associated with cell cycle arrest and decreased Cyclin D1 expression. Further analysis revealed that several known regenerative pathways including IL-6/STAT-3, growth factor signaling via EGFR/c-Met/MAPK pathways were activated even in APAP600 group where regeneration was inhibited. However, canonical Wnt/β-catenin and NF-κB pathways were activated only in APAP300 treated mice, where liver regeneration was stimulated. Next, we investigated role of Wnt/β-catenin in further detail. ChIP analysis revealed decreased binding of β-catenin to Cyclin D1 promoter in APAP600 group correlating with decreased cyclin D1 induction and impaired liver regeneration. Overexpression of a stable form of β-catenin (S45D) in mice resulted in improved liver regeneration following APAP overdose. Inactivation of
GSK3, an upstream negative regulator β-catenin, was found to be positively associated with β-catenin activation and liver regeneration.
GSK3 inactivation was remarkably reduced in APAP600 group, where liver regeneration was attenuated and delayed. Treatment with a selective
GSK3 inhibitor (L803-mts), as late as 4 hr after APAP600, resulted in early initiation of liver regeneration and improved survival in mice. Early hepatocyte proliferation after
GSK3 inhibition was due to rapid induction of cyclin D1 secondary to increased activation of β-catenin signaling. Finally, we investigated the role of EGFR signaling in liver regeneration, which was dose-dependently activated after APAP overdose. Surprisingly, early EGFR inhibition (1 hr post-APAP) by treatment with an irreversible EGFR inhibitor, canertinib, strikingly attenuated APAP hepatotoxicity suggesting role of EGFR in development of APAP hepatotoxicity. Delayed EGFR…
Advisors/Committee Members: Apte, Udayan (advisor), Jaeschke, Hartmut (cmtemember), Weinman, Steven A (cmtemember), Ding, Wen-Xing (cmtemember), DiTacchio, Luciano (cmtemember).
Subjects/Keywords: Toxicology; Pharmacology; Acetaminophen; EGF receptor; Liver; mice model; Regeneration; Wnt-Beta Catenin-GSK3 Beta pathway
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
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Manager
APA (6th Edition):
Bhushan, B. (2016). MECHANISMS OF LIVER REGENERATION AFTER ACETAMINOPHEN-INDUCED HEPATOTOXICITY IN MICE. (Doctoral Dissertation). University of Kansas. Retrieved from http://hdl.handle.net/1808/25366
Chicago Manual of Style (16th Edition):
Bhushan, Bharat. “MECHANISMS OF LIVER REGENERATION AFTER ACETAMINOPHEN-INDUCED HEPATOTOXICITY IN MICE.” 2016. Doctoral Dissertation, University of Kansas. Accessed April 11, 2021.
http://hdl.handle.net/1808/25366.
MLA Handbook (7th Edition):
Bhushan, Bharat. “MECHANISMS OF LIVER REGENERATION AFTER ACETAMINOPHEN-INDUCED HEPATOTOXICITY IN MICE.” 2016. Web. 11 Apr 2021.
Vancouver:
Bhushan B. MECHANISMS OF LIVER REGENERATION AFTER ACETAMINOPHEN-INDUCED HEPATOTOXICITY IN MICE. [Internet] [Doctoral dissertation]. University of Kansas; 2016. [cited 2021 Apr 11].
Available from: http://hdl.handle.net/1808/25366.
Council of Science Editors:
Bhushan B. MECHANISMS OF LIVER REGENERATION AFTER ACETAMINOPHEN-INDUCED HEPATOTOXICITY IN MICE. [Doctoral Dissertation]. University of Kansas; 2016. Available from: http://hdl.handle.net/1808/25366
University of Western Ontario
22.
Jassar, Harman.
The Role of GSK3 alpha and beta in Embryonic Craniofacial Development.
Degree: 2021, University of Western Ontario
URL: https://ir.lib.uwo.ca/etd/7612
► Background: The GSK-3 genes (Gsk3a and Gsk3b) have been known to affect many cellular processes and signaling pathways some of which are implicated in the…
(more)
▼ Background: The GSK-3 genes (Gsk3a and Gsk3b) have been known to affect many cellular processes and signaling pathways some of which are implicated in the growth and development of the craniofacial skeleton.
Aim: The purpose of this study was to assess the effect of chondrocyte-specific deletion of Gsk3a and Gsk3b on the size of the mandible and craniofacial skeleton in embryonic mice.
Materials & Methods: Mice were bred to generate cartilage-specific Gsk3a and Gsk3b KO mice. On embryonic day 18.5 (E18.5) the offspring were gathered by caesarian section. Whole mount skeletal staining was completed on the specimens using Alcian blue and Alizarin red. The antero-posterior (AP) dimension of the entire craniofacial skeleton and the mandible was measured, along with the transverse dimension of the cranial vault and the intramandibular angle for each embryo. The investigator was blind to the genotype of embryos in each trial group. Immunohistochemistry was used to detect and localize three proteins, Sox9, Beta-catenin, and Osteocalcin, in the bone and cartilage of E16 mouse skulls.
Results: The specific removal of both Gsk3a and Gsk3b in prenatal cartilage of mice leads to a significant reduction in the antero-posterior length of the total craniofacial skeleton and mandible when compared to wildtype mice. Cartilage-specific Gsk3a/Gsk3b KO mouse embryo display no significant change in the transverse width of the cranial vault. A significant increase in the intramandibular angle is seen in the KO mice when compared to the wild type mice.
Conclusions: Loss of both GSK-3 isoforms in prenatal mice results in significant changes to the size and shape of the facial skeleton and cranium.
Subjects/Keywords: GSK3; craniofacial; mandible; cleft palate; embryonic; intramandibular angle; Genetics; Musculoskeletal System; Orthodontics and Orthodontology
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APA (6th Edition):
Jassar, H. (2021). The Role of GSK3 alpha and beta in Embryonic Craniofacial Development. (Thesis). University of Western Ontario. Retrieved from https://ir.lib.uwo.ca/etd/7612
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Jassar, Harman. “The Role of GSK3 alpha and beta in Embryonic Craniofacial Development.” 2021. Thesis, University of Western Ontario. Accessed April 11, 2021.
https://ir.lib.uwo.ca/etd/7612.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Jassar, Harman. “The Role of GSK3 alpha and beta in Embryonic Craniofacial Development.” 2021. Web. 11 Apr 2021.
Vancouver:
Jassar H. The Role of GSK3 alpha and beta in Embryonic Craniofacial Development. [Internet] [Thesis]. University of Western Ontario; 2021. [cited 2021 Apr 11].
Available from: https://ir.lib.uwo.ca/etd/7612.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Jassar H. The Role of GSK3 alpha and beta in Embryonic Craniofacial Development. [Thesis]. University of Western Ontario; 2021. Available from: https://ir.lib.uwo.ca/etd/7612
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Vanderbilt University
23.
Kashikar, Nilesh Digvijay.
Novel and diverse roles of STRAP in maintenance of mesenchymal morphology and GSK3Beta signaling.
Degree: PhD, Cancer Biology, 2010, Vanderbilt University
URL: http://hdl.handle.net/1803/12466
► STRAP inhibits transforming growth factor-Beta (TGF-Beta) signaling and enhances tumorigenicity. The aim of our current research project was to identify novel TGF-Beta independent functions of…
(more)
▼ STRAP inhibits transforming growth factor-Beta (TGF-Beta) signaling and enhances tumorigenicity. The aim of our current research project was to identify novel TGF-Beta independent functions of STRAP. STRAP acts as a scaffold for the assembly of multi-protein complexes and our study has uncovered two novel but independent functions of STRAP.
In the first part, we report, for the first time, that deletion of STRAP from Mouse Embryonic Fibroblasts (MEFs) results in a loss of mesenchymal morphology. These cells lose their spindle shape and exhibit cobloid epithelial morphology. Loss of STRAP leads to upregulation of WT1 that subsequently upregulates E-cadherin leading to the formation of adherens junctions, and sequesters Beta-catenin to the cell membrane and downregulation of the mesenchymal markers like LEF1. Finally, stable expression of STRAP in these cells results in a loss of WT1 and E-cadherin expressions, and a reversal from epithelial to the mesenchymal morphology.
In the second part, we validated that STRAP binds with
GSK3-Beta, an enzyme that plays multiple roles in a cell, including insulin and Wnt signaling. In a completely novel finding, we observed that STRAP,
GSK3-Beta and Axin form a ternary complex. We also, for the first time show that intracellular fragment of Notch3 (ICN3) binds with
GSK3-Beta, suggesting that Notch3 may be a novel substrate of
GSK3-Beta.
We show that STRAP binds ICN3 in a proteasomal inhibition-dependent manner. Further studies revealed that STRAP binds ICN3 through the same ankyrin repeat region. In-vivo ubiquitination studies indicate that STRAP is able to reduce ubiquitination of ICN3, raising a possibility that STRAP may stabilize ICN3 leading to a longer half life in the cells. STRAP and Notch3 are both known to be upregulated in lung cancers and we observed that STRAP and ICN3 are co-overexpressed in 59 % of lung cancers in a tissue microarray study. STRAP shows oncogenic activity and our results from the two independent studies provide additional insights into how STRAP may behave as an oncogene using diverse mechanisms.
Advisors/Committee Members: Dr. Utpal P. Davé (committee member), Dr. Anna L. Means (committee member), Dr. Sarki A. Abdulkadir (committee member), Dr. Pran K. Datta (committee member), Dr. Robert J. Matusik (Committee Chair).
Subjects/Keywords: STRAP; EMT; Notch3; Lung cancer; Ubiquitination; GSK3
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Kashikar, N. D. (2010). Novel and diverse roles of STRAP in maintenance of mesenchymal morphology and GSK3Beta signaling. (Doctoral Dissertation). Vanderbilt University. Retrieved from http://hdl.handle.net/1803/12466
Chicago Manual of Style (16th Edition):
Kashikar, Nilesh Digvijay. “Novel and diverse roles of STRAP in maintenance of mesenchymal morphology and GSK3Beta signaling.” 2010. Doctoral Dissertation, Vanderbilt University. Accessed April 11, 2021.
http://hdl.handle.net/1803/12466.
MLA Handbook (7th Edition):
Kashikar, Nilesh Digvijay. “Novel and diverse roles of STRAP in maintenance of mesenchymal morphology and GSK3Beta signaling.” 2010. Web. 11 Apr 2021.
Vancouver:
Kashikar ND. Novel and diverse roles of STRAP in maintenance of mesenchymal morphology and GSK3Beta signaling. [Internet] [Doctoral dissertation]. Vanderbilt University; 2010. [cited 2021 Apr 11].
Available from: http://hdl.handle.net/1803/12466.
Council of Science Editors:
Kashikar ND. Novel and diverse roles of STRAP in maintenance of mesenchymal morphology and GSK3Beta signaling. [Doctoral Dissertation]. Vanderbilt University; 2010. Available from: http://hdl.handle.net/1803/12466
Texas Medical Center
24.
Smith, Debra L.
GSK3 Mediates Signaling Upstream of Akt.
Degree: PhD, 2010, Texas Medical Center
URL: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/12
► The phosphatidylinositide 3 kinase (PI3K)/Akt signaling network plays a pivotal role in multiple cellular functions. PI3K links the extracellular growth factor receptors to the serine-threonine…
(more)
▼ The phosphatidylinositide 3 kinase (PI3K)/Akt signaling network plays a pivotal role in multiple cellular functions. PI3K links the extracellular growth factor receptors to the serine-threonine kinase Akt which, through phosphorylation of numerous intracellular proteins, mediates increased cell growth, survival, motility and proliferation. The significance of the PI3K/Akt signaling network to human malignancy is demonstrated by cancer-associated genetic aberrations at multiple levels in the PI3K/Akt pathway in many tumor lineages. These aberrations include mutation or amplification of Akt, catalytic and regulatory subunits of PI3K, and growth factor receptors upstream of PI3K. Inactivating mutations and decreased expression of the PTEN, a major antagonist of PI3K signaling, also lead to constitutive hyperactivity of Akt.
Multiple small molecule inhibitors targeting components of the PI3K/Akt signaling pathway including Akt catalytic domain inhibitors, significantly slow tumor growth in preclinical models. Strikingly, these Akt kinase inhibitors induce a paradoxical increase in phosphorylation of Akt activation sites. As Akt catalytic domain inhibitors are entering clinical trials, elucidation of the mechanism(s) underlying Akt inhibitor-induced Akt phosphorylation is needed to understand and anticipate drug effects.
In this study, we demonstrate an unexpected requirement of Glycogen Synthase Kinase 3 (
GSK3), a serine-threonine kinase that participates in multiple cell signaling pathways downstream of Akt, for Akt inhibitor-induced Akt phosphorylation. siRNA-mediated knockdown of
GSK3 in MDAMB231 breast cancer cells and in mouse embryonic fibroblasts (MEFs) abrogated induction of Akt phosphorylation by the Akt catalytic domain inhibitor A674563. Our discovery that
GSK3 can function upstream of Akt led us to explore the role of
GSK3 in mediating signaling from growth factors to Akt. Knockdown of
GSK3 expression in MDAMB231 cells and in MEFs blocked stimulation of Akt phosphorylation by epidermal growth factor (EGF) and insulin-like growth factor (IGF1).
The results, taken together, demonstrate a novel signaling role for
GSK3 upstream of Akt.
Advisors/Committee Members: Gordon B. Mills, M.D., Ph.D., Oliver Bogler, Ph.D., Ruth Heidelberger, M.D., Ph.D..
Subjects/Keywords: GSK3; Akt; PI3K; cancer cell signaling; signal transduction; Biology
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APA ·
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MLA ·
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CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Smith, D. L. (2010). GSK3 Mediates Signaling Upstream of Akt. (Doctoral Dissertation). Texas Medical Center. Retrieved from https://digitalcommons.library.tmc.edu/utgsbs_dissertations/12
Chicago Manual of Style (16th Edition):
Smith, Debra L. “GSK3 Mediates Signaling Upstream of Akt.” 2010. Doctoral Dissertation, Texas Medical Center. Accessed April 11, 2021.
https://digitalcommons.library.tmc.edu/utgsbs_dissertations/12.
MLA Handbook (7th Edition):
Smith, Debra L. “GSK3 Mediates Signaling Upstream of Akt.” 2010. Web. 11 Apr 2021.
Vancouver:
Smith DL. GSK3 Mediates Signaling Upstream of Akt. [Internet] [Doctoral dissertation]. Texas Medical Center; 2010. [cited 2021 Apr 11].
Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/12.
Council of Science Editors:
Smith DL. GSK3 Mediates Signaling Upstream of Akt. [Doctoral Dissertation]. Texas Medical Center; 2010. Available from: https://digitalcommons.library.tmc.edu/utgsbs_dissertations/12
25.
Downey, Kimberlee.
Antidepressant Interactions of Ketamine and Glycogen Synthase Kinase-3 (GSK3) in Mice.
Degree: MS, Biochemistry and Molecular Biology (Medicine), 2015, University of Miami
URL: https://scholarlyrepository.miami.edu/oa_theses/545
► Depression is a prevalent and debilitating mood disorder afflicting nearly one in five people in the United States. Current medications used for treatment of depression…
(more)
▼ Depression is a prevalent and debilitating mood disorder afflicting nearly one in five people in the United States. Current medications used for treatment of depression are inadequate because they have a delayed onset of therapeutic benefit, low efficacy, several side effects, and require chronic administration. This presents the need for improved antidepressant therapies. Ketamine, a general anesthetic, was recently shown to have rapid-acting antidepressant effects at a sub-anesthetic dose. It is unknown how ketamine elicits an antidepressant effect, but several mechanisms have been proposed, including glycogen synthase kinase-3 (
GSK3) inhibition and a-amino-3-hydroxy-5-methylospxazol-4-propionic acid (AMPA) receptor activation. This thesis focuses on the role of
GSK3 in the ketamine antidepressant effect by expanding previous findings to additional depressive-like behavior models in mice and examines the molecular role of
GSK3 and AMPA receptors in response to ketamine in order to further understand the signaling that leads to ketamine’s antidepressant effect. I provide evidence that the antidepressant effect of ketamine requires the inhibition of
GSK3 and the activation of AMPA receptors and support a mechanism involving interaction between
GSK3 and AMPA receptor trafficking that leads to the antidepressant effect of ketamine. This will provide possible strategies to develop much needed new antidepressant therapies.
Advisors/Committee Members: Eleonore Beurel, Richard Jope, Michal Toborek, Sylvia Daunert.
Subjects/Keywords: ketamine; GSK3; mice; depression; antidepressant effect
…4.
Ketamine’s Antidepressant Effect Involves Signaling
Between GSK3 and AMPA Receptors… …GSK3 regulation and GSK3 knockin mice ..
13
Figure 3.2.1- Ketamine increases… …inhibitory serine phosphorylation
of GSK3 …
24
Figure 3.2.2… …Experimental setup for investigating requirement of
GSK3 inhibition in ketamine antidepressant… …response …
25
Figure 3.2.3- GSK3 inhibition is required for the antidepressant
effect of…
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APA (6th Edition):
Downey, K. (2015). Antidepressant Interactions of Ketamine and Glycogen Synthase Kinase-3 (GSK3) in Mice. (Thesis). University of Miami. Retrieved from https://scholarlyrepository.miami.edu/oa_theses/545
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Downey, Kimberlee. “Antidepressant Interactions of Ketamine and Glycogen Synthase Kinase-3 (GSK3) in Mice.” 2015. Thesis, University of Miami. Accessed April 11, 2021.
https://scholarlyrepository.miami.edu/oa_theses/545.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Downey, Kimberlee. “Antidepressant Interactions of Ketamine and Glycogen Synthase Kinase-3 (GSK3) in Mice.” 2015. Web. 11 Apr 2021.
Vancouver:
Downey K. Antidepressant Interactions of Ketamine and Glycogen Synthase Kinase-3 (GSK3) in Mice. [Internet] [Thesis]. University of Miami; 2015. [cited 2021 Apr 11].
Available from: https://scholarlyrepository.miami.edu/oa_theses/545.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Downey K. Antidepressant Interactions of Ketamine and Glycogen Synthase Kinase-3 (GSK3) in Mice. [Thesis]. University of Miami; 2015. Available from: https://scholarlyrepository.miami.edu/oa_theses/545
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
26.
Lindenberg, J.J.
Targeting skin associated DC subsets and conferring resistance to tumor-related immune suppression
.
Degree: 2014, Vrije Universiteit Amsterdam
URL: http://hdl.handle.net/1871/52011
Subjects/Keywords: iimmune suppression;
Dendritic cells;
CD14;
STAT3;
GSK3-beta;
Targetting
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APA (6th Edition):
Lindenberg, J. J. (2014). Targeting skin associated DC subsets and conferring resistance to tumor-related immune suppression
. (Doctoral Dissertation). Vrije Universiteit Amsterdam. Retrieved from http://hdl.handle.net/1871/52011
Chicago Manual of Style (16th Edition):
Lindenberg, J J. “Targeting skin associated DC subsets and conferring resistance to tumor-related immune suppression
.” 2014. Doctoral Dissertation, Vrije Universiteit Amsterdam. Accessed April 11, 2021.
http://hdl.handle.net/1871/52011.
MLA Handbook (7th Edition):
Lindenberg, J J. “Targeting skin associated DC subsets and conferring resistance to tumor-related immune suppression
.” 2014. Web. 11 Apr 2021.
Vancouver:
Lindenberg JJ. Targeting skin associated DC subsets and conferring resistance to tumor-related immune suppression
. [Internet] [Doctoral dissertation]. Vrije Universiteit Amsterdam; 2014. [cited 2021 Apr 11].
Available from: http://hdl.handle.net/1871/52011.
Council of Science Editors:
Lindenberg JJ. Targeting skin associated DC subsets and conferring resistance to tumor-related immune suppression
. [Doctoral Dissertation]. Vrije Universiteit Amsterdam; 2014. Available from: http://hdl.handle.net/1871/52011
27.
Ali, Husnain.
Exploring the potential of glycogen synthase kinase-3 (GSK3) mediated therapy in castrate-resistant prostate cancer
.
Degree: 2016, National University of Ireland – Galway
URL: http://hdl.handle.net/10379/6387
► Glycogen Synthase Kinase 3 (GSK3) is involved in a myriad of signalling pathways and has recently received considerable interest due to its conflicting roles tumourigenesis.…
(more)
▼ Glycogen Synthase Kinase 3 (
GSK3) is involved in a myriad of signalling pathways and has recently received considerable interest due to its conflicting roles tumourigenesis. Though it has classically been regarded as a tumour suppressor, emerging evidence suggests that
GSK3 it is also a tumour promoter. One of GSK3’s tumour promoting properties has been linked to its ability to inhibit the death receptor mediated apoptosis (the extrinsic apoptotic pathway) by regulating NFκB signalling, which is constitutively active in castrate-resistant prostate cancer (CRPC). Targeting
GSK3 has been shown to reduce NFκB activity and the expression of some of its associated anti-apoptotic proteins, thus sensitising tumour cells to the cytotoxic effects of death receptor ligands such as TNFα, whose circulating levels are increased in CRPC. In this study we sought to determine if
GSK3 regulates NFκB signalling in CRPC and whether targeting it can sensitise CRPC cells to the cytotoxic effects of TNFα.
Our findings show that NFκB and
GSK3 are active and up-regulated in CRPC cell lines (DU145 and PC3) compared to normal prostate epithelial cells (RWPE-1) and androgen-dependent prostate cancer cell lines (LNCaP and MDA-PCa2b). Treatment of the CRPC cell lines with the pan-
GSK3 inhibitor CHIR99021 (CHIR) reduced NFκB activity, the expression anti-apoptotic proteins and IL-6 secretion. Furthermore, CHIR also sensitised the normally TNFα-apoptosis resistant CRPC cell lines to TNFα-induced apoptosis. Using an RNAi based approach, siRNA directed against each of the two
GSK3 isoforms, GSK3α and GSKβ, confirmed the effects of CHIR as being
GSK3 mediated and allowed us to identify the role of each isoform in relation to regulating NFκB signalling in CRPC. Although the knockdown of either
GSK3 isoform didn’t affect the phosphorylation or nuclear translocation of the NFκB RelA subunit, there was a marked reduction in NFκB activity and RelA-DNA binding, suggesting that both
GSK3 isoforms regulate NFκB signalling at a nuclear level in CRPC. In order to ascertain whether the reduction in both NFκB activity and RelA-DNA binding following the knockdown of either
GSK3 isoform was due to elevated β-catenin arising from reduced
GSK3, treatment with the β-catenin inhibitor JW67 restored NFκB activity in both CRPC cell lines. Although treatment with JW67 restored RelA-DNA binding in PC3 cells, it didn’t restore it in DU145 cells, suggesting that
GSK3 regulates NFκB signalling in CRPC in a β-dependent and independent manner.
Taxanes, the current standard of care for CRPC, are fraught with problems relating to chemo-resistance and selectivity. NFκB signalling is thought to be a key mediator of taxane-resistance in CRPC. Using paclitaxel-resistant variants of the CRPC cell lines, PC3-TX-R and DU145-TX-R, we showed that NFκB activity is increased in these cells compared to their respective parental cell lines. Whereas increasing NFκB activity by overexpressing RelA was shown to be insufficient to induce paclitaxel resistance in DU145 cells, targeting NFκB…
Advisors/Committee Members: Glynn, Sharon (advisor).
Subjects/Keywords: GSK3;
Cancer;
Apoptosis;
NFkB;
Medicine;
Prostate cancer
…Synthase Kinase 3 (GSK3) is involved in a myriad of signalling pathways and
has… …has classically been regarded as a tumour suppressor, emerging evidence
suggests that GSK3… …it is also a tumour promoter. One of GSK3’s tumour promoting
properties has been linked to… …resistant prostate cancer (CRPC). Targeting GSK3 has been shown to reduce
NFκB activity… …levels are increased in CRPC. In this study we sought to determine if
GSK3 regulates NFκB…
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APA ·
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MLA ·
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CSE |
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to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Ali, H. (2016). Exploring the potential of glycogen synthase kinase-3 (GSK3) mediated therapy in castrate-resistant prostate cancer
. (Thesis). National University of Ireland – Galway. Retrieved from http://hdl.handle.net/10379/6387
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
Ali, Husnain. “Exploring the potential of glycogen synthase kinase-3 (GSK3) mediated therapy in castrate-resistant prostate cancer
.” 2016. Thesis, National University of Ireland – Galway. Accessed April 11, 2021.
http://hdl.handle.net/10379/6387.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
Ali, Husnain. “Exploring the potential of glycogen synthase kinase-3 (GSK3) mediated therapy in castrate-resistant prostate cancer
.” 2016. Web. 11 Apr 2021.
Vancouver:
Ali H. Exploring the potential of glycogen synthase kinase-3 (GSK3) mediated therapy in castrate-resistant prostate cancer
. [Internet] [Thesis]. National University of Ireland – Galway; 2016. [cited 2021 Apr 11].
Available from: http://hdl.handle.net/10379/6387.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
Ali H. Exploring the potential of glycogen synthase kinase-3 (GSK3) mediated therapy in castrate-resistant prostate cancer
. [Thesis]. National University of Ireland – Galway; 2016. Available from: http://hdl.handle.net/10379/6387
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Université de Sherbrooke
28.
Marchand, Benoît.
L'activité des glycogènes synthase kinases 3 est essentielle à la survie et à la prolifération des cellules pancréatiques tumorales humaines.
Degree: 2009, Université de Sherbrooke
URL: http://savoirs.usherbrooke.ca/handle/11143/4047
► Depuis leur découverte, les glycogènes synthase kinases 3 (GSK3) ont été associées à de multiples fonctions cellulaires, incluant notamment la prolifération et la survie cellulaire.…
(more)
▼ Depuis leur découverte, les glycogènes synthase kinases 3 (
GSK3) ont été associées à de multiples fonctions cellulaires, incluant notamment la prolifération et la survie cellulaire. La délétion homozygote de
GSK3? chez les souris est létale au stade embryonnaire E13,5 et il a été démontré que l'apoptose massive des hépatocytes due à une hypersensibilité au TNF? serait la principale cause de la létalité suggérant que l'activité de
GSK3? est nécessaire pour la survie cellulaire. Plusieurs études suggèrent une activité des
GSK3 plus élevée dans certains types de cancers, particulièrement au niveau des adénocarcinomes pancréatiques. Différentes études proposent que les
GSK3 pourraient réguler la voie NF?B et influencer la prolifération et la survie des cellules pancréatiques tumorales. Mes travaux de maîtrise visaient à déterminer le rôle des
GSK3 dans la survie et la prolifération des cellules pancréatiques tumorales humaines. Dans un premier temps, l'inhibition prolongée (24 à 72h) de l'activité des
GSK3 a permis d'observer une diminution de l'activité métabolique des cellules pancréatiques tumorales humaines : MIA PaCa2 et PANC-1. Cette diminution semble être due en partie à une induction de l'apoptose et à une inhibition de la prolifération cellulaire. En effet, l'inhibition des
GSK3 induit l'apoptose chez les cellules pancréatiques tumorales humaines (MIA PaCa2, PANC-1 et BxPC3) après 48 et 72h, mais non chez les cellules d'origine non-tumorale (HPDE6 et HEK293T). L'étude plus approfondie du mécanisme moléculaire de l'apoptose induit suite à l'inhibition des
GSK3 par l'inhibiteur pharmacologique spécifique SB216763 démontre 1- l'activation des caspases 3 et 7, 2- l'augmentation de l'homologue BCL-2 pro-apoptotique BIM et 3- la diminution de l'homologue anti-apoptotique BCL-2. L'analyse des voies de signalisation associées à la survie cellulaire et à l'apoptose suite à l'inhibition des
GSK3 a permis d'observer l'activation de la voie JNK-c-Jun qui contribuerait potentiellement à l'induction de l'apoptose. À cet égard, nous avons observé que la voie JNK est nécessaire 1- au clivage de PARP, 2- à l'activation de la caspase 7 et 3- à l'augmentation de BIM induit par l'inhibition des
GSK3. De plus, la diminution de l'expression de c-Jun, une cible des JNK, à l'aide d'un siARN prévient la modulation de BIM par l'inhibition des
GSK3, alors que l'induction de l'apoptose n'est pas bloquée. Donc, l'activation de la voie JNK-c-Jun semble également nécessaire à la régulation de l'homologue BCL-2 proapoptotique BIM. Nous avons ensuite observé que la voie MEKK1-JNK-c-Jun semble insuffisante pour induire l'apoptose des cellules PANC-1, suggérant que l'activation de la voie JNK pourrait requérir la régulation de d'autres voies afin d'induire l'apoptose. Dans un deuxième temps, nous avons observé que l'inhibition des
GSK3 pendant 16h inhibe la prolifération des cellules pancréatiques tumorales humaines. En effet, nous avons observé que l'inhibition des
GSK3 pendant 16h empêche l'atteinte du point de restriction en phase G1 du cycle…
Advisors/Committee Members: Boucher, Marie-Josée (advisor).
Subjects/Keywords: Pancréas; BIM; Apoptose; Prolifération; JNK; GSK3; Cancer pancréatique
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APA ·
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to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Marchand, B. (2009). L'activité des glycogènes synthase kinases 3 est essentielle à la survie et à la prolifération des cellules pancréatiques tumorales humaines. (Masters Thesis). Université de Sherbrooke. Retrieved from http://savoirs.usherbrooke.ca/handle/11143/4047
Chicago Manual of Style (16th Edition):
Marchand, Benoît. “L'activité des glycogènes synthase kinases 3 est essentielle à la survie et à la prolifération des cellules pancréatiques tumorales humaines.” 2009. Masters Thesis, Université de Sherbrooke. Accessed April 11, 2021.
http://savoirs.usherbrooke.ca/handle/11143/4047.
MLA Handbook (7th Edition):
Marchand, Benoît. “L'activité des glycogènes synthase kinases 3 est essentielle à la survie et à la prolifération des cellules pancréatiques tumorales humaines.” 2009. Web. 11 Apr 2021.
Vancouver:
Marchand B. L'activité des glycogènes synthase kinases 3 est essentielle à la survie et à la prolifération des cellules pancréatiques tumorales humaines. [Internet] [Masters thesis]. Université de Sherbrooke; 2009. [cited 2021 Apr 11].
Available from: http://savoirs.usherbrooke.ca/handle/11143/4047.
Council of Science Editors:
Marchand B. L'activité des glycogènes synthase kinases 3 est essentielle à la survie et à la prolifération des cellules pancréatiques tumorales humaines. [Masters Thesis]. Université de Sherbrooke; 2009. Available from: http://savoirs.usherbrooke.ca/handle/11143/4047
29.
ANIRUDH GAUTAM MANNAVA.
WNT SIGNALLING AT THE MEMBRANE.
Degree: 2016, National University of Singapore
URL: http://scholarbank.nus.edu.sg/handle/10635/130175
Subjects/Keywords: Wnt signalling; GSK3; Disheveled; membrane activation complex; OTK; neuroblast
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APA (6th Edition):
MANNAVA, A. G. (2016). WNT SIGNALLING AT THE MEMBRANE. (Thesis). National University of Singapore. Retrieved from http://scholarbank.nus.edu.sg/handle/10635/130175
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Chicago Manual of Style (16th Edition):
MANNAVA, ANIRUDH GAUTAM. “WNT SIGNALLING AT THE MEMBRANE.” 2016. Thesis, National University of Singapore. Accessed April 11, 2021.
http://scholarbank.nus.edu.sg/handle/10635/130175.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
MLA Handbook (7th Edition):
MANNAVA, ANIRUDH GAUTAM. “WNT SIGNALLING AT THE MEMBRANE.” 2016. Web. 11 Apr 2021.
Vancouver:
MANNAVA AG. WNT SIGNALLING AT THE MEMBRANE. [Internet] [Thesis]. National University of Singapore; 2016. [cited 2021 Apr 11].
Available from: http://scholarbank.nus.edu.sg/handle/10635/130175.
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
Council of Science Editors:
MANNAVA AG. WNT SIGNALLING AT THE MEMBRANE. [Thesis]. National University of Singapore; 2016. Available from: http://scholarbank.nus.edu.sg/handle/10635/130175
Note: this citation may be lacking information needed for this citation format:
Not specified: Masters Thesis or Doctoral Dissertation
University of Southern California
30.
Li, Chen.
PI3K/AKT signaling and the regulation of the mitochondrial
energy-redox axis.
Degree: PhD, Molecular Pharmacology and Toxicology, 2012, University of Southern California
URL: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/23637/rec/5051
► The concept of the mitochondrial energy-redox axis integrates the mitochondrial energy-transduction and redox status as a concerted process with the two components inter-linked by the…
(more)
▼ The concept of the mitochondrial energy-redox axis
integrates the mitochondrial energy-transduction and redox status
as a concerted process with the two components inter-linked by the
reducing equivalents (i.e., NAD(P)⁺/NAD(P)H). Decrease of
mitochondrial energy transduction and pro-oxidant shift of cellular
redox status precede the pathological changes of several diseases
(i.e., diabetes) and are key features of aging. Mitochondria are
also recipients of cellular signaling regulations such as MAPKs and
PI3K/AKT pathway of insulin signaling. These studies are aimed at
assessing the effect of the PI3K/AKT signaling pathway in the
mitochondrial energy-redox axis and depicting the molecular
mechanisms inherent in the effect. A liver-specific Pten deletion
model that shows a robust insulin signaling was used to study how
the PI3K/AKT pathways affect the mitochondrial energy-redox axis.
The hypothesis to be tested is that liver-specific Pten deletion
up-regulates mitochondrial bioenergetics through modulation of
PI3K/AKT signaling pathways, which further affect mitochondrial and
cellular H₂O₂ homeostasis, redox status, and the intrinsic
apoptotic pathway. ❧ These studies revealed that mitochondrial
bioenergetics is regulated by PI3K/AKT signaling through three
mechanisms: 1) AKT increases glycolysis and thus, a higher
substrate (pyruvate) supply to mitochondria; 2) AKT, upon
activation, translocates to mitochondria and phosphorylates ATP
synthase subunits α/β leading to a higher ATP synthase activity; 3)
AKT phosphorylates / inactivates GSK3β, which is correlated with
the decrease of the phosphorylation (inactivation) of mitochondria
PDH-E1α at Ser²⁷³. ❧ These effects translate in a higher
bioenergetic capacity of mitochondria and, consequently, a lower
generation of H2O2 by these organelles. This is attributed to: 1)
the highly oxidized state of the mitochondrial respiratory
complexes; 2) the higher expression of mitochondrial and cellular
H₂O₂ removal enzymes; 3) through modulation of the expression of
mitochondrial isocitrate dehydrogenase-2 and consequently the
increased generation of reducing equivalents (NADPH), which are
critical for the mitochondrial H₂O₂ removal system. The study of
AKT activation on mitochondria as a function of age shows that
mitochondria of Pten⁻/⁻ liver have a significantly reduced H₂O₂
generation level than control at older age (9-12 month old) and AKT
activation antagonizes the increase of mitochondrial source of H₂O₂
production caused by aging.
Advisors/Committee Members: Cadenas, Enrique (Committee Chair), Stiles, Bangyan L. (Committee Member), Kaplowitz, Neil (Committee Member).
Subjects/Keywords: mitochondrial respiration; PI3K; AKT; PTEN; GSK3β
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APA ·
Chicago ·
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Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Li, C. (2012). PI3K/AKT signaling and the regulation of the mitochondrial
energy-redox axis. (Doctoral Dissertation). University of Southern California. Retrieved from http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/23637/rec/5051
Chicago Manual of Style (16th Edition):
Li, Chen. “PI3K/AKT signaling and the regulation of the mitochondrial
energy-redox axis.” 2012. Doctoral Dissertation, University of Southern California. Accessed April 11, 2021.
http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/23637/rec/5051.
MLA Handbook (7th Edition):
Li, Chen. “PI3K/AKT signaling and the regulation of the mitochondrial
energy-redox axis.” 2012. Web. 11 Apr 2021.
Vancouver:
Li C. PI3K/AKT signaling and the regulation of the mitochondrial
energy-redox axis. [Internet] [Doctoral dissertation]. University of Southern California; 2012. [cited 2021 Apr 11].
Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/23637/rec/5051.
Council of Science Editors:
Li C. PI3K/AKT signaling and the regulation of the mitochondrial
energy-redox axis. [Doctoral Dissertation]. University of Southern California; 2012. Available from: http://digitallibrary.usc.edu/cdm/compoundobject/collection/p15799coll3/id/23637/rec/5051
◁ [1] [2] ▶
. 
Open Access Theses and Dissertations
