Dissertations / Theses on the topic 'JNK'
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1
Rogge, Dorothea Elisabeth [Verfasser]. "JNK und Schlaganfall / Dorothea Elisabeth Rogge." Kiel : Universitätsbibliothek Kiel, 2012. http://d-nb.info/1023870363/34.
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Pietkiewicz, Sabine [Verfasser], Reiner [Akademischer Betreuer] Jänicke, and Matthias U. [Akademischer Betreuer] Kassack. "Die Bedeutung der JNK-Isoformen JNK1 und JNK2 für die Apoptose nach proteasomaler Inhibition / Sabine Pietkiewicz. Gutachter: Reiner Jänicke ; Matthias U. Kassack." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2012. http://d-nb.info/102435475X/34.
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Rogers, Jeffrey Scott. "Characterization of JNK Binding Proteins: A Dissertation." eScholarship@UMMS, 2005. https://escholarship.umassmed.edu/gsbs_diss/222.
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The JNK signal transduction pathway mediates a broad, complex biological process in response to inflammatory cytokines and environmental stress. These responses include cell survival and apoptosis, proliferation, tumorigenesis and the immune response. The divergent cellular responses caused by the JNK signal transduction pathway are often regulated by spatial and cell type contexts, as well as the interaction with other cellular processes. The discovery of additional components of the JNK signal transduction pathway are critical to elucidate the stress response mechanisms in cells.
This thesis first discusses the cloning and characterization of two novel members of the JNK signal transduction pathway. JIP1 and JMP1 were initially identified from a murine embryo library through a yeast Two-Hybrid screen to identify novel JNK interacting proteins. Full length cDNAs of both genes were cloned and analyzed. JIP1 represents the first member of the JIP group of JNK scaffold proteins which were characterized. The JNK binding domain (JBD) of JIP1 matches the D-domain consensus of other JNK binding proteins, and it demonstrates JNK binding both in vitro and in vivo. This JNK binding was demonstrated to inhibit JNK signal transduction and over-expression of JIP1 inhibits the JNK mediated pre-B cell transformation by bcr-abl. Over-expressed JIP1 also sequesters JNK in the cytoplasm, which may be a mechanism of the inhibition of JNK signaling. A new, high-resolution digital imaging microscopy technique using deconvolution demonstrated the absence of JNK1 in the nucleus of co-transfected JIP1 and JNK1 cells.
The other protein discussed in this thesis is JMP1, a novel JNK binding, microtubule co-localized protein. There is a JBD in the JMP1 carboxyl end and a consensus D-domain within this region. The JMP1 JBD demonstrates an increased association with phospho-JNK from UV irradiated cells compared to un-irradiated cells in vivo. JMP1 also has 12 WD-repeat motifs in its amino terminal end which are required for microtubule co-localization. JMP1 demonstrates a cell cycle specific localization at the mitotic spindle poles. This co-localization is dependent on intact microtubules and the amino-terminal WD-repeats are required for this localization. JMP1 mRNA is highly expressed in testis tissues. Immunocytochemistry on murine testis sections using an affinity purified anti-JMP1 antibody demonstrates JMP1 protein in the lumenal compartment of the seminiferous tubules. JMP1 protein is expressed in primary and secondary spermatocytes, cells which are actively undergoing meiosis.
The results obtained from the localization of JMP1 in meiotic spermatocytes led to an investigation of the roles of JNK signal transduction in the testis. The testis is an active region of cellular proliferation, apoptosis and differentiation, which make it an appealing model for studying JNK signal transduction. However, the roles JNK signaling have in the testis are poorly understood. I investigated the reproduction capability of Jnk3-/- male mice and discovered older Jnk3-/- males had a reduced capacity to impregnate females compared to younger animals and age-matched wild type controls. The testis morphology and sperm motility of these animals were similar to wild-type animals, and there was no alteration of apoptosis in the testis. The final section of this thesis involves the study of this breeding defect and investigating for cellular defects that might account for this age-related Jnk3-/- phenotype.
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Cosolo, Andrea [Verfasser], and Anne-Kathrin [Akademischer Betreuer] Classen. "Patterning of tissue stress responses by JNK and JAK/STAT / Andrea Cosolo ; Betreuer: Anne-Kathrin Classen." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1202011772/34.
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Collura, Kaitlin Marie. "Palmitoylation-Dependent Regulation of the DLK/JNK/cJun and the GP130/JAK/STAT Retrograde Signaling Pathways." Diss., Temple University Libraries, 2015. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/426710.
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Biomedical SciencesPh.D.
Palmitoylation is the post-translational addition of the 16-carbon fatty acid palmitate to protein cysteine residues. This process is best known for its roles in targeting proteins to lipid membranes, including both the plasma membrane and vesicles. Palmitoylation occurs in all eukaryotic cells, but appears to be particularly important in neurons, because genetic mutation or loss of several palmitoyl acyltransferases (PATs, the enzymes that catalyze palmitoylation), leads to predominantly neuropathological defects. In addition, a growing number of recent studies have revealed key roles for palmitoylation of specific proteins in neuronal regulation. However, most of these studies have focused on how palmitoylation regulates postsynaptic protein targeting. In contrast, it is far less clear how palmitoylation might regulate the specialized subcellular processes that are important in axons. One particularly important process in axons is retrograde signaling, in which information is conveyed from distal locations back to the cell body. Following injury to axons of the peripheral nervous system (PNS), retrograde signals are critical to activate transcription of pro-regenerative genes. Key retrograde signaling pathways include the DLK/JNK/c-Jun (Dual Leucine Zipper Kinase/c-Jun N-terminal Kinase/c-Jun) signaling pathway and the GP130/JAK/STAT (Glycoprotein 130/Janus Kinase/Signal Transducer and Activator of Transcription) signaling pathway, both of which are activated following nerve injury and are vital to promote regeneration. Though both of these pathways are critical for conveying distal information from the periphery to the cell body, many of their component proteins are predicted to be soluble and diffusible. This raises the question of how these proteins can directionally signal over the long distances that axons extend. Interestingly, bio-informatic and proteomic studies suggested that DLK, GP130, JAK and STAT may be palmitoylated. We hypothesized that palmitoylation could be important for the roles of these proteins in retrograde signaling. Because retrograde signals are initiated in distal axons, a considerable distance from the cell body, we further hypothesized axonally localized PATs might play key roles in the control of retrograde signaling. We find that the retrograde signaling protein DLK is palmitoylated at a highly conserved cysteine residue. This modification is necessary for its localization to motile vesicles and for its interaction with the retrograde signaling protein JIP3. Notably, we also describe a novel role for palmitoylation in regulating DLK’s kinase activity. In addition, our study identifies the first axonally enriched PATs in sensory neurons; DHHC5 and DHHC8. shRNA knockdown experiments in sensory neurons reveal that these axonal PATs control both palmitoylation and surface expression of GP130 and are essential for GP130/JAK/STAT3-dependent retrograde signaling. These findings reveal a novel role for palmitoylation in the control of axonal retrograde signaling, provide key insights into the molecular roles of this modification and identify new potential targets for therapy to improve nerve regeneration post-injury.
Temple University--Theses
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Willoughby, Emma Alexandra. "Interaction between dual specificity phosphatases and JNK scaffolds." Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1446531/.
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The c-Jun N-terminal kinase (JNK) group of mitogen-activated protein kinases (MAPKs) are activated by signals including environmental stresses, growth factors and hormones. In some pathways, scaffold proteins bind JNK and upstream kinases in order to activate subsets of JNK and localise them to specific subcellular sites. For example, the JNK-interacting protein (JIP) scaffold binds JNK, MKK7 and MLKs. The G protein coupled receptor (GPCR) adaptor protein ?-arrestin 2 has also recently been identified as a JNK scaffold, binding JNK3, ASK1 and indirectly MKK4. The work presented here shows that JNK specific dual specificity phosphatases MKP-7 and M3/6 bind to JIP-1 and -2 and that MKP-7 can also bind ?-arrestin 2. In both cases the phosphatases bind to the scaffolds independently of JNK, using the same region within their extended C terminal domains. MKP-7 can specifically dephosphorylate the ?-arrestin 2 bound subset of JNK3 either activated by ASK1 or in response to activation of the GPCR, angiotensin type 1a receptor (AT1aR). MKP-7 transiently dissociates from ?-arrestin 2 following AT1aR activation and over expression of ASK1. These results indicate that JIP-1 and ?-arrestin 2 modulate JNK signalling by binding JNK-specific kinases and phosphatases. The dynamic interaction between MKP-7 and ?-arrestin 2 suggests a possible mechanism by which a positive signal can be passed through a scaffold which binds both activating and inhibitory components.
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Girardin, Stephen. "Régulation de la voie de signalisation intracellulaire JNK/SAPK." Université Louis Pasteur (Strasbourg) (1971-2008), 2001. http://www.theses.fr/2001STR13179.
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Shirakawa, Takashi. "Deactivation of STAT6 through serine 707 phosphorylation by JNK." Kyoto University, 2011. http://hdl.handle.net/2433/142114.
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Le-Niculescu, Helen. "Characterization of the biological roles of the JNK MAPK pathways in mammalian cells : specific and stringent activation of the JNKK2-JNK signaling module /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2000. http://wwwlib.umi.com/cr/ucsd/fullcit?p9984810.
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Fujikawa, Risako. "EP4 Receptor-Associated Protein in Microglia Promotes Inflammation in the Brain." 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225462.
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Morbach, Anne. "The Role of Cdep in the Embryonic Morphogenesis of Drosophila melanogaster." Doctoral thesis, Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2016. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-203534.
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Many organs and structures formed during the embryonic morphogenesis of animals derive from epithelia. Epithelia are made up of apicobasally polarized cells which adhere to and communicate with each other, allowing for epithelial integrity and plasticity. During embryonic morphogenesis, epithelia change their shape and migrate in a coordinated manner. How these epithelial processes are regulated is still not fully understood. In a forward genetic screen using the embryo of the fruit fly Drosophila melanogaster, candidate genes influencing the morphogenesis of epithelial structures were identified. Three genes, CG17364, CG17362 and CG9040 were identified as possible regulators of lumen stability in the salivary glands, tubular organs deriving from the embryonic epithelium. Furthermore, the gene Cdep was found to play a crucial role in epithelial sheet migration during dorsal closure of the embryo. Embryos carrying genomic insertions that could affect the expression of CG17364, CG17362 and CG9040 show a luminal penotype of the embryonic salivary glands characterized by alternating bloated and seemingly closed sections. Therefore, one of these genes or a combination of them likely plays a role in stabilizing the salivary gland lumen. However, neither CG17364 nor CG17362 or CG9040 contain any known protein domains, hence their molecular roles remain unknown. Cdep (Chondrocyte-derived ezrin-like protein) is a member of the FERM-FA subclass of proteins. Proteins of the FERM family have been shown to interact with the plasma membrane and membrane-bound proteins as well as cytoskeleton components.
Accordingly, they have been implicated in stabilizing the cell cortex, and some of them are involved in signal transduction mechanisms. In addition to a FERM domain, Cdep also contains a RhoGEF domain, although is still not clear whether it actually exerts GEF activity. Genomic insertions in the Cdep locus cause defects in embryonic dorsal closure and atypical migratory behaviour in epithelial tubes. In order to study the molecular role of Cdep, the CRISPR/Cas9 system was employed to establish loss-of-function mutants of Cdep. The mutants show aberrations in germ band retraction, dorsal closure and head involution. Moreover, I found that two mutants carrying a premature STOP codon in the Cdep ORF, CdepE16X and CdepG17X, rescue the defects observed in embryonic cuticles mutant for two other FERM-FA members yurt (yrt) and coracle (cora). A deletion of the full Cdep ORF did not rescue those defects. I hypothesize that CdepE16X and CdepG17X encode Cdep variants with increased activity, which compensates for the loss of yrt or cora function, respectively. In conclusion, this leads to a model in which Cdep acts in parallel to Yrt and Cora during Drosophila embryonic morphogenesis. Many of the defects described in this study are reminiscent of phenotypes found in embryos mutant for components and downstream effectors of the Jun-N-terminal Kinase (JNK) pathway. Hence, my work supports an earlier hypothesis according to which a mouse homologue of Cdep, Farp2, acts as an upstream activator of the JNK pathway during epithelial cell migration in vitro (Miyamoto et al., 2003) The data provided here shows that Cdep plays a role in the morphogenesis of a great number of epithelia-derived organs and structures in vivo. My study therefore elucidates a missing link between cell migration cues and JNK pathway activation.
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Çavusoglu, Kader 1982. "The Crosstalk between LXR and JNK pathways : mechanisms and mediators." Doctoral thesis, Universitat Pompeu Fabra, 2013. http://hdl.handle.net/10803/116934.
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This project was carried out in the Cell Signaling Research Group headed by Dr. Carme Caelles
at IRB Barcelona. As a part of the research-line that deals with physiological and
pharmacological (anti-inflammatory and/or anti-diabetic) actions conducted by some nuclear
receptor (NR) ligands through negative interference with the c-Jun N-terminal kinase (JNK)
signaling pathway, this project was focused on studying the mechanism of cross-talk between
those pathways.
The results of the study show the ligand-dependent LXR inhibition of the LPS-activated SAPK
(JNK and p38MAPK) pathways. Moreover, PP5, a serine/threonine phosphatase previously
shown to regulate MAPK pathways, is suggested as a novel target of LXR that negatively
regulates LPS-induced activation of SAPK pathways. Furthermore, it is proposed that through
the inhibition of SAPK activity, and thereby cJun/AP-1 activity, PP5 is mediating negative
regulation of LPS-induced Mmp13 gene expression by LXR in murine primary macrophages.Este proyecto se llevó a cabo en el Grupo de Investigación en Señalización Celular del IRB Barcelona y fue dirigido por la Dra. Carme Caelles. El trabajo se centra en el estudio del mecanismo de interferencia entre las vías de los receptores nucleares (NR) y la señalización de la quinasa c-Jun N-terminal Kinase (JNK). Esta inhibición forma parte de la línea investigación sobre las acciones fisiológicas y farmacológicas (anti-inflamatorias y / o anti-diabéticas) realizadas por los ligandos de algunos NR. El estudio demuestra la inhibición de las vías SAPK (JNK y p38MAPK) en respuesta a LPS a través de la activación dependiente de ligando de LXR. Además, PP5, una fosfatasa serina/treonina que previamente se demostró que regula las vías de las MAPKs, se sugiere como el mediador de esta inhibición. Esta interacción estaría inhibiendo la expresión en respuesta a LPS del gen Mmp13 en macrófagos de ratón.
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Klingler, Barbara [Verfasser], and Harald [Gutachter] Wajant. "Mechanismen der Todesrezeptorinduzierten JNK-Aktivierung / Barbara Klingler. Gutachter: Harald Wajant." Würzburg : Universität Würzburg, 2015. http://d-nb.info/1110984898/34.
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Gazin, Vincent. "Etude cellulaire et moléculaire de la toxicité chimique de l'uranium au niveau pulmonaire." Paris 7, 2004. http://www.theses.fr/2004PA077079.
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Mateos, Stéphanie. "Interférence de la voie de signalisation Notch avec les mécanismes de transformation des cellules de neurorétine aviaires par v-Src." Paris 7, 2004. http://www.theses.fr/2004PA077126.
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Barutcu, Seda. "Role of JIP1-JNK Signaling in Beta-Cell Function and Autophagy." eScholarship@UMMS, 2018. https://escholarship.umassmed.edu/gsbs_diss/954.
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Proper functioning of endocrine cells is crucial for organismal homeostasis. The underlying mechanisms that fine-tune the amount, and the timing of hormone secretion are not clear. JIP1 / MAPK8IP1 (JNK interacting protein 1) is a scaffold protein that mediates cellular stress response, and is highly expressed in endocrine cells, including insulin secreting b-cells in pancreas islets. However, the role of JIP1 in b-cells is unclear. This study demonstrates that b-cell specific Jip1 ablation results in decreased glucose-induced insulin secretion, without a change in Insulin1 and Insulin2 gene expression. Inhibition of both JIP1-kinesin interaction, and JIP1-JNK interaction by genetic mutations also resulted in decreased insulin secretion, suggesting that JIP1 may mediate insulin vesicle trafficking through interacting with kinesin and JNK. Autophagy is a cellular recycling mechanism and implicated in the b-cell function. Both JIP1 and JNK are proposed to regulate autophagy pathway. However, it is unclear whether JNK plays a role in the promotion or suppression of autophagy. The findings of this study show that JNK is not essential for autophagy induction, but can regulate autophagy in a cell and context specific manner. The results in this thesis implies a mechanism that link cellular trafficking and stress signaling pathways in the regulated hormone secretion. In addition to the known role of JIP1 in metabolism and insulin resistance, this finding may also be relevant to endocrine pathologies.
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Wylie, Paul. "Muscarinic acetylcholine receptor regulation of ERK and JNK in CHO cells." Thesis, University of Leicester, 2000. http://hdl.handle.net/2381/29924.
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Extracellular signal-regulated kinases (ERKs) and the c-Jun N-terminal kinases/stress- activated protein kinases (JNKs/SAPKs) are activated by an array of extracellular signals to mediate a variety of cellular responses e.g. mitogenesis, differentiation, hypertrophy and apoptosis. The study investigated the regulation of ERK and JNK by agonist-mediated stimulation of the human m2-AChR or m3-AChR stably expressed in CHO cells. Stimulation of both receptors dramatically activated ERK, although stimulation by the m3-AChR was more sustained. The m3-AChR is efficiently coupled to JNK activation, whereas the m2-AChR is not. Activation of JNK in CHO-m3 cells was delayed and more sustained relative to that of ERK in either CHO-m2 or CHO-m3 cells. The dose-dependence for methacholine (MCh)-stimulated JNK activation by m3-AChR and ERK activation by both receptor subtypes were similar. Although pertussis toxin (PTX) had no effect on Ins(1,4,5)P3 accumulation in CHO-m3 cells, there was significant inhibition of agonist-induced ERK and JNK activation in CHO-m3 cells, suggesting that the m3-AChR was able to couple to Gi/o in addition to Gq. ERK activation was entirely PTX-sensitive in CHO-m2 cells. ERK activation in both cell types was shown to be independent of Ca2+. However, JNK activation by m3 receptors was shown to have both a Ca2+-depdnent and a Ca2+-independent component. PKC inhibition studies demonstrated a novel PKC- and an atypical PKC-component, but not a classical PKC-component in ERK activation in CHO-m2 cells, whereas, there appears to be a cPKC and an aPKC-component in CHO-m3 cells. In contrast to this, PKC appears to have an inhibitory role in m3-AChR-mediated JNK activation. The results presented demonstrate that the m2-AChR activate ERK and JNK via divergent mechanisms.
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Murai, Norihiko. "Activation of JNK in the Inner Ear Following Impulse Noise Exposure." Kyoto University, 2008. http://hdl.handle.net/2433/124329.
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Jacinto, Estela. "Signal integration in T lymphocytes : the role of JNK and ERK /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 1997. http://wwwlib.umi.com/cr/ucsd/fullcit?p9814546.
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Eminel, Sevgi [Verfasser]. "Functions of JNK stresskinases in neuronal apoptosis and differentiation / Sevgi Eminel." Kiel : Universitätsbibliothek Kiel, 2008. http://d-nb.info/1019542004/34.
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Diouani, Sara. "Implication de PiT1 dans l’apoptose induite par le TNF-α dans des modèles in vivo et in vitro." Thesis, Paris 5, 2013. http://www.theses.fr/2013PA05T036.
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PiT1/SLC20A1 a été identifiée pour la première fois comme récepteur rétroviral, puis de nombreuses autres études réalisées in vitro ont permis de révéler ces différentes fonctions. PiT1 est notamment un transporteur de phosphate-sodium dépendant. Par le biais de cette activité de transporteur de phosphate inorganique (Pi), PiT1 est impliqué dans plusieurs processus cellulaires comme la minéralisation osseuse, la calcification vasculaire (dans certaines pathologies), et la réabsorption rénale et intestinale de Pi. Dans notre laboratoire, afin de mieux caractériser les fonctions physiologiques de PiT1, un Knock Out (KO) total pour cette protéine a été généré. Les souris présentent un phénotype létal embryonnaire et une atteinte hépatique. Au vu de ces résultats, d’autres études, réalisées dans le laboratoire, ont mis en évidence l’implication de PiT1 dans la prolifération et l’apoptose cellulaire. Ces fonctions nouvellement décrites sont spécifiques à PiT1 et indépendantes de sa fonction de transporteur de Pi.Les objectifs majeurs de mon travail de thèse ont consisté à mieux comprendre le rôle de PiT1 dans les mécanismes apoptotiques déclenchés par le TNF-α. Pour cela, j’ai étudié la cascade d’activation du TNF-α dans les cellules Hela exprimant de manière stable un shPiT1 ou un shScramble. En effet, mes résultats suggèrent que l’association de TRAF2 ; un élément clé de l’activation de la voie des MAPKs ; à PiT1 par le bisais de sa large boucle intracellulaire, permettrait la dissociation des kinases en amont de la voie des MAPKs, GCK (MAP4K) et MLK3 (MAP3K), induisant leur désactivation et ainsi la régulation négative de JNK. La désactivation de JNK induit à son tour à l’inhibition des caspases et donc la signalisation apoptotique. Par ailleurs, j’ai montré que la suractivation de JNK dans les cellules invalidées pour PiT1 corrèle avec la dissocition antérieur du complexe TRAF2-cellular Inhibitor of Apoptosis Proteins (cIAPs). Ainsi, le complexe pro-apoptotique formé de la caspase-8, la protéine FAS-Associated via Death Domaine (FADD) et du Receptor Interactinf Protein 1 (RIP1) était plus actif.Par ailleurs, la boucle PiT1 et la boucle PiT2 ; son homologue ; ont été échangées, permettant ainsi l’obtention des protéines chimères P2-BclP1 et P1-BclP2. Celles-ci représenteraient des outils intéressants pour mieux comprendre les mécanismes cellulaires engagés dans cette voie apoptotique. Enfin, le rôle de PiT1 dans l’apoptose induite par le TNF-α étudié dans des modèles cellulaires a été confirmé dans deux modèles murins faisant ainsi et pour la première fois un lien entre PiT1 et une pathologie inflammatoire, l’hépatite fulminante. Ces résultats montrent que l’absence de PiT1 sensibilise le foie à l’apoptose; à l’appui d’autres résultats ; PiT1 pourrait être considéré comme une cible thérapeutique dans des pathologies inflammatoires et cancéreusesPiT1/SLC20A1 was identified for the first time as retroviral receptor then phosphate inorganic-dependent sodium transporter activity. Through this more a function of phosphate inorganic (Pi) transporter, PiT1 is involved in multiple cellular processes such as bone mineralization, vascular calcification, renal and intestinal reabsorption of Pi. In our laboratory, a total mice Knock Out (KO) for this gene encoding for PiT1 was generated to characterize its physiological functions. The embryonic mice PiT1 KO have a lethal phenotype through liver damage. We have previously found that additional transport-independent functions. PiT1 is involeved in proliferation and in the regulation of tumour necrosis factor (TNF)-induced apoptosis. Modulated cells was mediated by an increased activation of c-Jun N-terminal Kinase (JNK).The aim of my study was to define the role of PiT1 in apoptotic mechanisms of TNF-α signaling. For that, I have studied the regulation cascade of TNF-α pathway in Hela cells expressing shPiT1 or shScramble. My results suggest that intra-cytoplasmic loop domain of PiT1 was interact with TRAF2 ; a key element in the MAPK pathway activation. Furthermore, we also have shown that TNF-induced association of two JNK upstream kinases (Germinal Centre Kinase (GCK or MAP4K) and Mixed Lineage Kinase 3 (MLK3 or MAP3K) to PiT1 suggesting that PiT1 inducing their deactivation and thus down-regulation of JNK. Furthermore, we have shown that JNK increased signalling in PiT1-depleted cells correlates with the earlier dissociation of TRAF2 – cellular Inhibitor of Apoptosis Proteins (cIAPs) complexes. Thus, the apoptotic complex formed by caspase-8, Fas-Associated protein via Death Domain (FADD) and Receptor Interacting Protein 1 (RIP1) was more effectively activated. Moreover, PiT1 and PiT2 loops, were exchanged, thus allowing obtaining chimeric proteins BclP1-P2 and P1-BclP2. These proteins represent valuable tools to explore the mechanisms involved in the apoptotic pathway. Finally, we confirmed the relevance of these observations in vitro and showed that PiT1 gene conditional deletion in the liver of adult mice increases their sensitivity to fulminant hepatitis TNF-induced. These results are the first report of the involvement of PiT1 in a fatal pathology
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Vonkavaara, Malin. "Host-pathogen interactions between Francisella tularensis and Drosophila melanogaster." Doctoral thesis, Umeå universitet, Institutionen för klinisk mikrobiologi, 2012. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-54604.
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Francisella tularensis is a highly virulent Gram-negative bacterium causing the zoonotic disease tularemia. Arthropod-borne transmission plays an important role in transferring the disease to humans. F. tularensis induces very low amounts of pro-inflammatory cytokines during infection, due to inhibition of immune signaling pathways and an unusual structure of its lipopolysaccharide (LPS). To date, there is no vaccine available that is approved for public use, although an attenuated live vaccine strain (LVS) is commonly used as a model of the more infectious Francisella strains. To produce an effective vaccine it is important to understand the lifecycle of F. tularensis, including the interaction with the arthropod hosts. Drosophila melanogaster is a widely used model organism, which is increasingly being used in host-pathogen interaction studies as the immune pathways in flies are evolutionary conserved to the immune pathways in humans. An important part of the immune defense of D. melanogaster as well as of arthropods in general is the production of antimicrobial peptides. These peptides primarily target the bacterial membrane, inhibiting bacterial proliferation or directly killing the bacteria. The aim of this thesis was to establish D. melanogaster as a model for F. tularensis infection and as a model for arthropod vectors of F. tularensis. Also, to use D. melanogaster to further study the interaction between F. tularensis and arthropod vectors, with specific regard to the host immune signaling and arthropod antimicrobial peptides. F. tularensis LVS infects and kills D. melanogaster in a dose-dependent manner. During an infection, bacteria are found inside fly hemocytes, phagocytic blood cells, similar as in human infections. In mammals genes of the intracellular growth locus (igl) are important for virulence. In this work it is shown that the igl genes are also important for virulence in flies. These results demonstrate that D. melanogaster can be used as a model to study F. tularensis-host interactions. LVS induces a prolonged activation of several immune signaling pathways in the fly, but seem to interfere with the JNK signaling pathway, similarly as in mammals. Overexpression of the JNK pathway in flies has a protective effect on fly survival. Relish mutant flies, essentially lacking a production of antimicrobial peptides, succumb quickly to a F. tularensis infection, however, F. tularensis is relatively resistant to individual D. melanogaster antimicrobial peptides. Overexpressing antimicrobial peptide genes in wildtype flies has a protective effect on F. tularensis infection, suggesting that a combination of several antimicrobial peptides is necessary to control F. tularensis. The production of numerous antimicrobial peptides might be why D. melanogaster survives relatively long after infection. An intact structure of the lipid A and of the Kdo core of Francisella LPS is necessary for resistance to antimicrobial peptides and full virulence in flies. These results are similar to previous studies in mammals. In contrast to studies in mammals, genes affecting the O-antigen of F. tularensis LPS are not necessary for virulence in flies. In conclusion, this thesis work shows that D. melanogaster can be used as a model for studying F. tularensis-host interactions. LVS activates several immune pathways during infection, but interfere with the JNK pathway. Overexpressing the JNK pathway results in increased survival of flies infected with LVS. Despite rather high resistance to individual antimicrobial peptides, exposure to a combination of several D. melanogaster antimicrobial peptides reduces the virulence of F. tularensis.
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Guo, Qianyu. "Skeletal muscle JNK activity after acute resistive exercise in elder adults with T2D: Metabolic and clinical correlates." Thesis, The University of Sydney, 2011. http://hdl.handle.net/2123/7207.
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Objective This study describes the results of the baseline sub-study of a randomized double-blind, sham-exercise controlled trial designed to assess the efficacy of power training in older adults with type 2 diabetes. The primary purpose of this sub-study was to define the state of total and activated JNK in skeletal muscle which had been exposed to an acute resistive bout of exercise. In addition, metabolic and clinical characteristics were investigated in an attempt to explain the variance and the metabolic relevance of the JNK expression (total JNK, tJNK) and activation (ratio of phosphorylated/total JNK, p/tJNK) observed. We hypothsized that greater JNK expression and activation would be related to impaired health status, chronic inflammation, metabolic disturbance and insulin resistance in our cohort. We hypothsized that greater JNK expression and activation would be related to impaired health status (decreasing habitual exercise amount and burdens of diseases), chronic inflammation (increasing pro-inflammatory cytokines and decreasing anti-inflammatory cytokines), metabolic disturbance (disturbance of blood glucose and lipid regulation) and insulin resistance in our cohort. Methods Our cohort consisted of sedentary adults over 60 years of age with type 2 diabetes. The study recruited 103 participants from Aug 2006 to Dec 2009. Since the 50th participant completed theirassessments in Apr 2009 and this thesis was to be submitted in Aug 2010, it only included analysis of baseline data from the first 50 participants which were available at the time of submission. Insulin resistance was measured by homeostasis model assessment 2 (HOMA 2) computerized model; body composition was measured by computed tomography (CT) scan, bioelectric impedance analysis (BIA) and anthropometrics; glucose, insulin and serum cytokines (adiponectin, c-reactive protein (CRP) were measured by serum assays, factors related to the insulin signalling pathway obtained from skeletal muscle and subcutaneous adipose tissue biopsies (Insulin-like Growth Factor-1 (IGF-1), Tumour Necrosis Factor-α (TNFα), Interleukin 6 (IL-6), Heat Shock Protein 72 (HSP72), phospho-Jun N-terminal Kinase (pJNK) and total JNK (tJNK) in muscle, and Adiponetin, TNFα, IL-6 in adipose tissue) were measured by cytokine assays and Western Blot. The secondary outcomes, including health status, medications, physical performance and quality of life, were assessed by validated questionnaires. Results 35 of the 50 subjects had baseline measures of skeletal muscle JNK. As hypothesized, higher JNK was related or had the tendency to related to potentially poorer health status: number of medications/day(r=0.304, 0.081) and lower habitual physical activity (r=-0.333, p=0.055). Similarly, the relationships we found between total and activated JNK and anti-inflammatory/metabolic factors supported our hypotheses: higher tJNK was related to lower serum (r=-0.364, p=0.057) and adipose tissue (r=-0.465, p=0.060) HMW/adiponectin ratios, and higher p/tJNK was related to higher skeletal muscle IL-6 (rho=0.644, p<0.001), lower serum total (r=-0.336, p=0.081) and HMW adiponectin (r=-0.504, p=0.006), and lower HOMA β cell function (r=-0.332, p=0.055). By contrast, the relationships we found between JNK and systemic pro-inflammatory and local anabolic factors were inconsistent with our hypothesis. Specifically, higher tJNK was related to lower serum CRP (r=-0.457,p=0.015) and higher skeletal muscle IGF-1(r=0.641, p<0.001). Also contrary to our expectations, higher p/tJNK was related to lower serum total cholesterol (r=-0.059, p<0.001) and LDL (r=-0.401, p=0.016). Conclusion This was the first study to describe activated and total skeletal muscle JNK expression after acute resistive exercise in older adults with type 2 diabetes, and the first study to analyze potential correlations between skeletal muscle JNK and other aspects of health status, metabolism, and inflammation in this cohort. As hypothesized, higher JNK was related to more impaired health status (age, inactivity) and inversely related to anti-inflammatory adiponectin and HOMA2 β cell function. Unexpectedly, however, higher JNK was related to higher skeletal muscle IGF-1 and inversely related to CRP, serum total cholesterol and LDL. Additional studies are warranted to investigate whether chronic exercise training in type 2 diabetes alters the expression and activation of JNK, and to determine whether beneficial adaptations in JNK may explain a portion of the variance in exercise-related metabolic benefits in this cohort.
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Vaisnav, Mahesh. "The role of JIP-1 in JNK signalling during stress and apoptosis." Thesis, University of Leicester, 2002. http://hdl.handle.net/2381/29675.
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Recently, the JIP group of proteins was shown to organise the JNK pathway components into scaffolds. Transient transfection studies have shown that JIP-1 binds to JNK, MKK7, MLK3 and HPK1 and organises the JNK pathway in the form of a scaffold to selectively mediate JNK activation in response to stressful stimuli. An examination of the interaction of endogenous JIP-1 with JNK, MLK3 and HPK1 in vivo demonstrated that JIP-1 interacted with MLK3 and HPK1 in resting N1E-115 cells. In stressed N1E-115 cells, the activation of JNK coincided with the JIP-1-JNK1 interaction while the JIP-1-MLK3 interaction was lost. In the rat brain extracts JIP-1-JNK and MLK3-HPK1 interactions were detected. These data suggest that the JIP-1 scaffold complex is dynamic and the differential interaction of JIP-1 with the JNK pathway kinases may regulate JNK activity in vivo. The exchange of the JNK pathway components with the JIP-1 scaffold during stress and the ability of JIP-1 to oligomerise also suggests a possibility of signal amplification. The presence of putative caspase-3 and -8 cleavage sites in JIP-1 led us to investigate whether JIP-1 was caspase substrate during apoptosis in vivo. The results showed that JIP-1 was cleaved by caspase-3 in vivo during both receptor- and chemical-induced apoptosis of HeLa cells. An analysis of caspase-3 cleavage-resistant JIP-1b mutants in vitro mapped the caspase-3 cleavage sites as being DLID98/A and DESD405/S. An examination of JIP-1 cleavage and JNK activity in HeLa cells during apoptosis demonstrated that intact JIP-1 was associated with high levels of JNK activity and the cleavage of JIP-1 was coincident with a decrease in JNK activity. Furthermore, during TRAIL-induced apoptosis, the co-immunoprecipitation of JIP-1 and JJNK1 was coincident with JNK activation, whereas a decrease in JNK activity correlated with a reduced ability of JIP-1 to interact with JNK1. These results suggest that the interaction of JIP-1 with JNK may be required for JNK activation, and that the cleavage of JIP-1 may attenuate JNK signalling, in vivo during apoptosis. Overall, the results suggests that the interaction of JIP-1 with the JNK pathway components may be necessary for JNK activation in vivo during stress and apoptosis.
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Lamb, Jennifer A. "Role of the JNK Signal Transduction Pathway in Cell Survival: a Dissertation." eScholarship@UMMS, 2004. http://escholarship.umassmed.edu/gsbs_diss/232.
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The c-Jun NH2-terminal kinases (JNK) are evolutionarily conserved serine/threonine protein kinases that are activated by proinflammatory cytokines, environmental stress, and genotoxic agents. These kinases play key regulatory roles within a cell by coordinating signals from the cell surface to nuclear transcription factors. JNK phosphorylates the amino terminal domain of all three Jun transcription factors (JunB, c-Jun and JunD) all members of the AP-1 family. The activated transcription factors modulate gene expression to generate appropriate biological responses, including cell migration, proliferation, differentiation and cell death.
The role of the JNK signaling pathway in cell death/apoptosis is controversial, both pro-apoptotic and pro-survival roles have been attributed to JNK. The mechanism that enables the JNK signaling pathway to mediate both apoptosis and survival is unclear. The aim of this study is to examine the role of TNF-stimulated JNK activation on cell survival.
The proinflammatory cytokine TNF, is known to activate JNK and induce apoptosis. To test whether the JNK signaling pathway contributes to TNF-induced apoptosis, the response of wild type and Jnk1-/- Jnk2-/- (JNK deficient fibroblasts) fibroblasts to TNF was examined. JNK deficient fibroblasts are more sensitive to TNF-induced apoptosis than wild-type fibroblasts. The TNF-sensitivity cannot be attributed to altered expression of TNF receptors or defects in the NF-кB or AKT pathways, known anti-apoptotic signal transduction pathways. (In fact, TNF stimulated NF-кB activation provides a major mechanism to account for survival in both wild-type and JNK deficient cells.) However this increased TNF-sensitivity can be attributed to JNK deficiency. Apoptosis is suppressed in JNK deficient cells when transduced with JNK1 retrovirus. These data implicate the JNK signaling pathway in cell survival.
The AP-1 family of transcription factors is a target of the JNK signal transduction pathway. In addition JNK is required for the normal expression of the AP-1 family member, JunD. Previous studies have indicated that JunD can mediate survival. Interestingly, JNK deficient and JunD null cells display similar phenotypes: premature senescence and increased sensitivity to TNF induced apoptosis. In fact, the TNF-sensitivity is also suppressed in JNK deficient fibroblasts transduced with JunD retrovirus. Although JunD can replace the survival signaling role of JNK, phosphorylation of JunD is essential to inhibit TNF induced apoptosis. JNK deficient cells transduced with phosphomutant JunD retrovirus maintain TNF-sensitivity.
Activated transcription factors modulate gene expression. It is most likely that JunD functions by regulating the expression of key molecules that act to inhibit TNF-stimulated apoptosis. Microarray analysis comparing wild-type with JNK deficient fibroblasts revealed that the expression of the survival gene, cIAP-2, was induced by TNF in only wild-type fibroblasts. Furthermore, protein expression of cIAP-2 was induced by TNF in only wild-type fibroblasts. Analysis of the cIAP-2 promoter revealed two critical NF-кB binding sites and one AP-1 binding site. Luciferase reporter assays indicated key roles for both NF-кB and the AP-1 component, JunD in TNF-induced cIAP-2 gene expression. These experiments establish that the JNK/JunD pathway collaborates with NF-кB pathway to increase the expression of the anti-apoptotic protein cIAP-2 in TNF treated cells. Without this collaboration, the JNK pathway mediates apoptosis.
The integration of JNK signaling with other signaling pathways represents a mechanism to account for the dual ability of the JNK pathway to mediate either survival or apoptosis. The dynamic coordination of signals within and between pathways is critical. The future challenge will be to fit the details of individual signaling pathways into the context of signaling networks.
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Römer, Lutz [Verfasser]. "Pro- and antidegenerative effects of JNK stresskinases in neuronal cells / Lutz Römer." Kiel : Universitätsbibliothek Kiel, 2008. http://d-nb.info/1019541253/34.
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Cellurale, Cristina Arrigo. "Role of the cJun NH2-Terminal Kinase (JNK) in Cancer: A Dissertation." eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/478.
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cJun NH2-terminal kinase (JNK) is a member of the MAPK (mitogen- activated protein kinase) signaling family that responds to various extracellular stimuli, such as stress, growth factors, cytokines, or UV radiation. JNK activation can lead to cellular responses including gene expression, growth, survival, and apoptosis. JNK has been implicated in normal developmental processes, including tissue morphogenesis, as well as pathological processes, such as cellular transformation and cancer. JNK exists in three isoforms, and knockout mice have been generated for each isoform; the ubiquitously expressed Jnk1 and Jnk2 have been studied independently, however, the two isoforms are partially functionally redundant. Jnk1-/- Jnk2-/-mice are nonviable, therefore studies of compound JNK-deficiency have been limited to mouse embryonic fibroblasts (MEF). Understanding the role of JNK in epithelial cells is now possible with the creation of conditional JNK knockout animals.
I sought to elucidate the role of JNK in cellular transformation, cancer, and normal development. I employed both in vitro and in vivo approaches. First, I evaluated the role of JNK in cellular transformation using p53-/- Jnk1-/- Jnk2-/- MEF transduced with oncogenic Ras. To extend this study, I examined JNK-deficiency in a Kras-induced model of lung tumorigenesis. Second, I investigated JNK1- and JNK2-deficiency in a p53-mediated model of mammary tumorigenesis. Finally, I examined the role of JNK in mouse mammary gland development by establishing JNK-deficient primary mouse mammary epithelial cells and evaluating JNK-deficient mammary gland transplants. Taken together, this work provides evidence of context-dependent roles for JNK in both normal and pathological cell biology.
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Loudhaief, Rihab. "Effets des bioinsecticides à base de Bacillus thuringiensis sur la physiologie intestinale de la Drosophile." Thesis, Université Côte d'Azur (ComUE), 2016. http://www.theses.fr/2016AZUR4054/document.
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Le tube digestif est la première barrière contre les agresseurs présents dans la nourriture (virus, bactéries, produits chimiques, pesticides etc...). Il doit donc maintenir au mieux son intégrité structurale et fonctionnelle tout au long de la vie de l'individu. Bien que l'impact délétère d'une intoxication aiguë puisse être surmonté par la capacité de défense et de régénération de la muqueuse digestive, une agression prolongée ou répétée peut compromettre l'équilibre physiologique (l'homéostasie) du tube digestif. Parmi les agresseurs pouvant être ingérés avec la nourriture, on trouve la bactérie Bacillus thuringiensis (Bt) et représente 70% des ventes de bioinsecticides. Bt est une bactérie Gram+ sporulante qui produit, pendant la sporulation, des toxines nommées Cry. Parmi les différentes souches de Bt, certaines ont été sélectionnées pour la spécificité d'action de leurs toxines Cry contre des nuisibles et sont commercialisées sous forme de sporanges. Certaines de ces souches sont utilisées en agriculture biologique en France et l'accroissement de leur utilisation fait qu'elles sont de plus en plus présentes dans la nourriture, source de contamination potentielle pour l'homme et l’environnement. La question qui se pose maintenant est de savoir si un tel accroissement de l’utilisation de Bt peut avoir des impacts sur des espèces non cibles. Mon projet de thèse a consisté en l’étude des conséquences de l'ingestion de Bt (sous forme végétative ou de sporanges) sur la physiologie intestinale de la drosophile (animal non sensible à Bt en termes de toxicité aigüeThe digestive tract is continuously subjected to multiple aggressions through virus, bacteria, toxins and chemicals mixed in the feed. Therefore the gut lining has established a mechanism of replenishment in order to maintain the physiological function of the organ called the gut homeostasis. Although the deleterious impact of acute poisoning can be overcome by the defense capacity and regeneration of the gut mucosa, prolonged or repeated intoxication can impair its homeostasis. Among the aggressors hidden in the feed, there is the bacterium Bacillus thuringiensis (Bt). Bt is worldwide used as bioinsecticide. Indeed the multitude of Bt strains produces a broad range of crystalline toxins, named Cry toxins, which certain have been selected in organic farming owing to their lethal properties against specific pests. Because of incentive programs for sustainable development, the use of Bt bioinsecticides as an alternative to chemical pesticides will further increase in the next decades. Although the specificity of the acute toxicity of Cry toxins has been proved since many years, data are scarce on adverse effects that could result from chronic exposure. The question now is how far non-target organisms will be potentially impacted by the resulting augmentation of the Bt bacterium and its Cry toxins in the environment. To answer this challenge, I used Drosophila (a non-target organism) to study the impacts of Bt bioinsecticides on the gut physiology because 1/ the digestive tract is the main entrance for feed contaminated by Bt bioinsecticides and 2/ Bt and its toxins are known to impair the gut epithelium of sensitive pests
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Etter, Paul, Radhakrishnan Narayanan, Zaneta Navratilova, Chirag Patel, Dirk Bohmann, Heinrich Jasper, and Mani Ramaswami. "Synaptic and genomic responses to JNK and AP-1 signaling in Drosophila neurons." BioMed Central, 2005. http://hdl.handle.net/10150/610070.
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BACKGROUND:The transcription factor AP-1 positively controls synaptic plasticity at the Drosophila neuromuscular junction. Although in motor neurons, JNK has been shown to activate AP-1, a positive regulator of growth and strength at the larval NMJ, the consequences of JNK activation are poorly studied. In addition, the downstream transcriptional targets of JNK and AP-1 signaling in the Drosophila nervous system have yet to be identified. Here, we further investigated the role of JNK signaling at this model synapse employing an activated form of JNK-kinaseand using Serial Analysis of Gene Expression and oligonucleotide microarrays, searched for candidate early targets of JNK or AP-1 dependent transcription in neurons.RESULTS:Temporally-controlled JNK induction in postembryonic motor neurons triggers synaptic growth at the NMJ indicating a role in developmental plasticity rather than synaptogenesis. An unexpected observation that JNK activation also causes a reduction in transmitter release is inconsistent with JNK functioning solely through AP-1 and suggests an additional, yet-unidentified pathway for JNK signaling in motor neurons. SAGE profiling of mRNA expression helps define the neural transcriptome in Drosophila. Though many putative AP-1 and JNK target genes arose from the genomic screens, few were confirmed in subsequent validation experiments. One potentially important neuronal AP-1 target discovered, CG6044, was previously implicated in olfactory associative memory. In addition, 5 mRNAs regulated by RU486, a steroid used to trigger conditional gene expression were identified.CONCLUSION:This study demonstrates a novel role for JNK signaling at the larval neuromuscular junction and provides a quantitative profile of gene transcription in Drosophila neurons. While identifying potential JNK/AP-1 targets it reveals the limitations of genome-wide analyses using complex tissues like the whole brain.
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Caswell, Patrick Tomas. "Subcellular distribution and function of the neuronal JNK signalling pathway scaffold protein JIP3." Thesis, University of Leicester, 2004. http://hdl.handle.net/2381/29689.
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The JNKs have been shown to regulate cellular processes ranging from apoptosis to differentiation and survival, depending on cell-tissue type and cell context. JIP3 was identified as a putative scaffold protein functioning in the JNK signalling pathway. JIP3 is predominantly expressed in neurons, and is thought to have a role in neuronal vesicular transport. The function of JIP3 in the context of JNK signalling has, however, not been established.;A polyclonal JIP3 antiserum was generated in the course of this study, which was suitable for western blotting, immunprecipitation and indirect immunofluorescence microscopy experiments. This antiserum showed greater efficacy than any other available antisera, and was essential in subsequent experiments.;Biochemical fractionation and immunofluorescence microscopy experiments identified the association of endogenous JIP3 with an unconventional vesicular species. The majority of JIP3 was found to localise predominantly in growth cone regions of differentiated N1E-115 and PC-12 cells. In these growth cone regions, significant co-localisation was identified between JIP3 and JNK pathway components, but was not apparent in other subcellular compartments. Immunoprecipitation experiments showed increased association of JIP3 with JNK pathway components upon differentiation of PC-12 cells.;The proposed function of the JNK pathway in neurite outgrowth led to the investigation of the potential for JIP3 regulation of this neuronal differentiation process. Overexpression of JIP3, which acts as a partial inhibitor of JNK pathway signalling, was found to significantly suppress neurite outgrowth in N1E-115 and PC-12 cells. Moreover, re-constitution of a JIP3 mediated JNK signalling module was sufficient to induce neurite outgrowth in PC-12 cells.;Finally, JIP3 co-localised with the cytoskeletal regulator paxillin specifically within growth cone regions of differentiated PC-12 cells. This suggests that JIP3 may direct JNK pathway signalling towards a growth cone associated substrate, paxillin, and thus regulate neurite outgrowth.
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Rui, Hongliang. "Regulation of MAPK/JNK signaling pathway and TGF-beta signaling pathway by axin /." View abstract or full-text, 2004. http://library.ust.hk/cgi/db/thesis.pl?BICH%202004%20RUI.
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Thesis (Ph.D.)--Hong Kong University of Science and Technology, 2004.CD-ROM contains electronic versons of the thesis in pdf and word format. Includes bibliographical references (leaves 129-151). Also available in electronic version. Access restricted to campus users.
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Lessel, Wiebke [Verfasser]. "Die Rolle des JNK-Signalwegs in der Colitis ulcerosa-assoziierten Karzinogenese / Wiebke Lessel." Magdeburg : Universitätsbibliothek, 2017. http://d-nb.info/1141230631/34.
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Dumont, Adélie. "L'action ambivalente de l'agent anti-cancéreux 5-Fluorouracile sur les cellules myéloïdes immunosuppressives sous contrôle de l'acide docosahexaénoïque : Rôle de l'inflammasome NLRP3 et de la voie JNK dans la sécrétion de l'IL-1beta." Thesis, Bourgogne Franche-Comté, 2018. http://www.theses.fr/2018UBFCI013/document.
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Selon une étude précédente, une limitation à l'efficacité anticancéreuse du 5-Fluorouracile (5-FU) repose sur la sécrétion d'IL-1β par des cellules myéloïdes immunosuppressives (MDSC). La libération d'IL-1β mature provient de l'activation de NLRP3 induite par le 5- FU et de l’augmentation de l’activité de la caspase-1 dans les MDSC, qui favorise la reprise de la croissance tumorale chez des souris traitées avec 5-FU. L'acide docosahexaénoïque (DHA) appartient à la famille des acides gras oméga-3 et possède des propriétés anticancéreuses et anti-inflammatoires qui pourraient améliorer la chimiothérapie à base de 5-FU. Dans ces travaux, nous démontrons que le DHA inhibe la sécrétion d'IL 1β induite par le 5 FU dans une lignée cellulaire de MDSC (MSC-2). Chez des souris porteuses de tumeurs traitées par 5 FU, nous avons montré qu'un régime alimentaire enrichi en DHA réduit la concentration d'IL 1β circulante et la récidive tumorale après une injection de 5 FU. Le traitement par 5 FU conduit à l'activation de JNK dans les MDSC et l'inhibiteur de JNK SP600125 diminue la sécrétion d’IL-1β. De plus, le DHA est capable de contrecarrer l'activation de JNK induite par 5-FU dans les MDSC, entraînant la chute de la libération de l’IL 1β. De plus, nous avons montré que la supplémentation en DHA dans les MDSC exposées au 5 FU diminuait l’activité de la caspase-1 ainsi que la modification des interactions entre NLRP3 et la caspase-1, ASC ou β-arrestine-2. De manière inattendue, la régulation de l'activité de la caspase-1 par le DHA était indépendante de JNK, ce qui suggère que le DHA pourrait contrôler la sécrétion de l’IL 1β par le biais de l'inflammasome NLRP3 et de la voie JNK. Enfin, nous avons trouvé une corrélation négative entre la teneur en DHA dans le plasma et l'induction du niveau d'IL 1β ou de la caspase-1 dans le sang de patients traités par chimiothérapie à base de 5-FU.L’ensemble de ces données fournissent de nouvelles informations sur la régulation de la sécrétion de l’IL-1β par le DHA et son bénéfice potentiel dans la chimiothérapie à base de 5-FUA limitation to 5-Fluorouracil (5-FU) anti-cancer efficacy relies on the secretion of IL-1β by myeloid-derived suppressor cells (MDSC) according to a previous pre-clinical report. The release of mature IL-1β originates from 5 FU mediated NLRP3 activation with increased caspase-1 activity in MDSC and sustains tumor growth recovery in 5 FU treated mice. Docosahexaenoic acid (DHA) belongs to omega-3 fatty acid family and harbors both anti cancer and anti inflammatory properties which might could improve 5 FU chemotherapy. Here, we demonstrate that DHA inhibits 5 FU induced IL 1β secretion produced by a MDSC cell line (MSC-2). In tumor-bearing mice treated with 5 FU, we showed that a DHA enriched diet reduces circulating IL 1β concentration and tumor recurrence after 5 FU injection. 5 FU treatment led to JNK activation in MDSC and JNK inhibitor SP600125 decreased IL 1β secretion. Moreover, DHA was able to counteract 5 FU mediated JNK activation in MDSC leading to the drop of IL 1β release. In addition, we showed that DHA supplementation in 5 FU exposed MDSC decreases caspase-1 activity along with a modification of the interactions between NLRP3 and caspase-1, ASC or β arrestin-2. Unexpectedly, the regulation of caspase-1 activity by DHA was independent of JNK which suggests that DHA could control IL 1β secretion through both NLRP3 inflammasome and JNK pathway. Interestingly, we found a negative correlation between DHA content in plasma and the induction of circulating IL 1β level or caspase-1 activity in patients treated with 5 FU based chemotherapy.Together, these data provide new insights on the regulation of IL 1β secretion by DHA and its potential benefit in 5-FU based chemotherapy
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Willaime-Morawek, Sandrine. "Apoptose neuronale et second messager céramide : étude des voies de signalisation intracellulaires." Paris 6, 2003. http://www.theses.fr/2003PA066339.
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Feoktistov, Alexander. "Setting the Limit on Axon Growth: Multiple Overlapping Mechanisms Repress the MAP3K Wnd/DLK So That Growth Cones Can Remodel into Stationary Synaptic Boutons." Thesis, University of Oregon, 2016. http://hdl.handle.net/1794/20403.
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The development of a stereotyped pattern of neural connectivity depends upon the behavior of growth cones, motile structures at the tips of axons that propel axon growth and steer the axon to its targets. When growth cones reach their appropriate target cells, they halt and ultimately remodel into stationary presynaptic boutons. The influence of extracellular cues in directing growth cones to their targets is well studied, but cell-intrinsic factors are also increasingly appreciated for their role in driving much of growth cone behavior.
Dual leucine zipper kinases (DLKs) promote growth cone motility and must be kept in check to ensure normal development. PHR (Pam/Highwire/RPM-1) ubiquitin ligases therefore target DLK for proteosomal degradation unless axon injury occurs. Overall DLK levels decrease during development, but how DLK levels are regulated within a developing growth cone has not been examined. We analyzed the expression of the fly DLK Wallenda (Wnd) in R7 photoreceptor growth cones as they halt at their targets and as they remodel into presynaptic boutons. We found that Wnd protein levels are repressed by the PHR protein Highwire (Hiw) during R7 growth cone halting, as has been observed in other systems. However, during remodeling, Wnd levels are further repressed by a temporally-expressed transcription factor, Tramtrack69 (Ttk69). Previously unobserved negative feedback from JNK also contributes to Wnd repression. We conclude that maturing neurons progressively deploy additional mechanisms to keep DLK off and thereby protect their connectivity. We use live imaging to directly probe the effects of Wnd and Ttk69 on remodeling R7 growth cones and conclude that Ttk69 coordinates multiple regulators of this process.
Preliminary results indicate that excess Wnd signaling requires the transcription factor Fos to disrupt growth cone remodeling in R7s. This opens up new strategies to identify how Wnd exerts its motility-promoting effects on growth cone cytoskeletons. Additional findings point to a later requirement for Wnd in normal R7 synapse development, suggesting that Wnd expression is not fully silenced in R7s. Further investigation into these findings would greatly advance our understanding of how the neuronal cytoskeleton is regulated as neurons undergo profound morphological and functional changes while developing.
This dissertation includes both unpublished and published co-authored material. This dissertation also includes supplemental movie files, which can be found online and are described in Appendix B.
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Busquets, Figueras Oriol. "Estudi del paper de les proteïnes JNK en el desenvolupament de trastorns metabòlics i cognitius = Study on the role of the JNK proteins in the development of metabolic and cognitive disruptions." Doctoral thesis, Universitat de Barcelona, 2019. http://hdl.handle.net/10803/668381.
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Molts estudis previs sobre el paper de les cinases c-JUN N-terminal (JNK) no tenien en compte les diferències existents en l’activitat de cadascuna de les isoformes. Això va provocar que les propostes terapèutiques que regulaven les JNK de manera inespecífica es trobessin amb problemes importants. L’objectiu de la present tesi doctoral era ampliar els coneixements que es tenen actualment sobre el paper individual de les isoformes de les JNK i, avaluar qualsevol interès terapèutic que pugui derivar de la seva modulació per a l’epilèpsia del lòbul temporal i afectacions cognitives derivades del metabolisme.
Estudis previs van demostrar que la inactivació genètica de la JNK1 tenia efectes neuroprotectors davant el dany citotòxic derivat de l’administració d’àcid kainic, un model d’epilèpsia del lòbul temporal. Per tant, es va posar a prova el potencial terapèutic de la Licochalcona A (LIC- A), un inhibidor de la JNK1. Els resultats van confirmar que quan els animals eren pretractats amb LIC-A, aquests quedaven protegits dels efectes de l’àcid kainic, tal i com ho demostrava l’absència de cèl·lules en degeneració ni de teixit escleròtic, així com una menor resposta neuroinflamatòria en astròcits i micròglia.
A més a més, es van estudiar les conseqüències metabòliques d’una alimentació crònica amb una dieta rica en greixos (HFD). Els resultats demostraven que la dieta provocava l’aparició de resistència la insulina a escala central i perifèrica com a resultat d’estrès en les mitocòndries i el reticle endoplasmàtic, desregulacions de l’autofàgia, entre altres. Al final, això portava a l’aparició d’afectacions cognitives. Paral·lelament, es van avaluar els efectes de la inactivació genètica de la JNK2 i, es va determinar
que afavoria l’aparició d’aquestes mateixes alteracions, especialment quan es combinava amb HFD. Per contra, la inactivació de JNK1 protegia de les conseqüències metabòliques d’una ingesta crònica de HFD, afavorint una major sensibilitat a la insulina, un menor pes corporal i una activitat mitocondrial més eficient. A més a més, aquests animals estaven protegits davant l’aparició de dèficits cognitius derivats d’alteracions metabòliques.Many past reports on the c-JUN N-terminal Kinases (JNKs) did not take into account the existing differences in the activity of each of the isoforms. And so, therapeutic proposals that regulated the JNKs unspecifically encountered setbacks of import. The aim of the present thesis was to contribute to current understanding of the role of individual JNK isoforms in the development of pathology and, to appraise any therapeutic interest derived of their modulation for temporal lobe epilepsy and the metabolic- cognitive syndrome. Reported results demonstrated that the knock-out JNK1 had neuroprotective effects against excitotoxic damage derived of the administration of kainic acid, a model of temporal lobe epilepsy. Thus, Licochalcone A (LIC-A), a JNK1 inhibitor, was tested for its potential as a therapeutic agent. Results confirmed that when animals were pre-treated with LIC-A they were protected from the effects of kainic acid, as demonstrated by the absence of degenerating cells and sclerotic tissue, as well as lower neuroinflammatory responses in astrocytes and microglia. Additionally, the metabolic consequences of a chronic feeding of a fat- enriched diet (High fat diet; HFD) were also assessed. Data demonstrated that HFD caused the appearance of peripheral and central insulin resistance as a result of mitochondrial and endoplasmic stress, dysregulation of autophagy and other alterations. In the end, it led to the appearance of cognitive impairments. Parallelly, the effects of the ablation of JNK2 were evaluated and, it was determined that it favoured the appearance of these same alterations, especially when combined with HFD. On the contrary, the knockout of JNK1 protected against the metabolic consequences of a chronic feeding with HFD, showing improved sensibility to insulin, reduced body weight and more efficient mitochondrial activity. Moreover, these animals were protected against the appearance of metabolic-derived cognitive dysfunctions.
Muchos estudios previos sobre el papel de las quinasas c-JUN N- terminal (JNK) no tenían en cuenta las diferencias existentes en la actividad de cada una de las isoformas. Esto provocó que las propuestas terapéuticas que regulaban las JNK de forma inespecífica se encontraran con problemas importantes. El objetivo de la presente tesis doctoral era ampliar los conocimientos que se tienen actualmente sobre el papel individual de las isoformas de las JNK y, evaluar cualquier interés terapéutico que pueda derivar de su modulación para la epilepsia del lóbulo temporal y afectaciones cognitivas derivadas del metabolismo. Estudios previos demostraron que la inactivación genética de la JNK1 tenía efectos neuroprotectores ante el daño citotóxico derivado de la administración de ácido kaínico, un modelo de epilepsia del lóbulo temporal. Por tanto, se puso a prueba el potencial terapéutico de la Licochalcona A (LIC-A), un inhibidor de la JNK1. Los resultados confirmaron que cuando los animales eran pretratados con LIC-A, estos quedaban protegidos de los efectos del ácido kaínico, tal y como lo demostraba la ausencia de células en degeneración ni de tejido esclerótico, así como una menor respuesta neuroinflamatoria en astrocitos y microglía. Además, se estudiaron las consecuencias metabólicas de una alimentación crónica con una dieta rica en grasas (HFD). Los resultados demostraban que la dieta provocaba la aparición de resistencia a la insulina a escala central y periférica como resultado de estrés en las mitocondrias y el retículo endoplasmático, desregulaciones de la autofagia, entre otros. Al final, esto llevaba a la aparición de afectaciones cognitivas. Paralelamente, se evaluaron los efectos de la inactivación genética de la JNK2 y, se determinó que favorecía la aparición de estas mismas alteraciones, especialmente cuando se combinaba con HFD. Por lo contrario, la inactivación de JNK1 protegía ante las consecuencias metabólicas de una ingesta crónica de HFD, favoreciendo una mayor sensibilidad a la insulina, un menor peso corporal y una actividad mitocondrial más eficiente. Además, estos animales quedaban protegidos ante la aparición de déficits cognitivos derivados de alteraciones metabólicas.
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Arnold, Richard Graham. "The role of c-Jun-N-Terminal Kinase (JNK) in hindlimb ischaemia-reperfusion injury." Thesis, Queen's University Belfast, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.579569.
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In spite of improvements in the care of the critically ill patient, both elective and emergency vascular surgical interventions are associated with significant morbidity and mortality. Successful reperfusion of the ischaemic limb often initiates a systemic inflammatory response syndrome (SIRS), which may be complicated by multiple organ failure, including Acute Lung Injury (All) and the Acute Respiratory Distress Syndrome (ARDS). An exaggerated inflammatory response has been shown to play an integral role in the development of ARDS following lower torso or limb ischaemia-reperfusion injury. JNK enzymes, part of the Mitogen Activated Protein Kinase (MAPK) group, have been implicated in neutrophil activation as part of this response. Furthermore the role of JNK in ischaemia reperfusion injury is well established .as well as its role in All as evidenced by the attenuation of such injury with inhibitors in a number of animal models of direct lung injury. This thesis tests the hypothesis that .hibition of JNK attenuates the neutrophil-based All and ARDS associated with lower limb ischaemia-reperfusion injury. A murine model of bilateral hindlimb ischaemia-reperfusion injury was established. Lung injury was confirmed by tissue oedema, neutrophil sequestration and microvascular permeability in association with increased expression of the JNK enzymes. In a genetic JNK knockout model subjected to ischaemia-reperfusion injury, there was an attenuated lung injury as evidenced by a reduction in histology injury scores and myeloperoxidase levels. In a therapeutic inhibitor model, using the JNK inhibitor SP600125, this attenuation was observed in the histology injury scores and bronchoalveolar lavage (BAL) protein levels. These results suggest that JNK may play a role in the pathogenesis of lung injury following ischaemia-reperfusion injury and its inhibition may provide a novel therapeutic approach.
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Zecchini, Vincent. "A novel function of Notch regulates JNK activity and apoptosis in the Drosophila embryo." Thesis, University of Cambridge, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621033.
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Kyula, Joan Nduku. "HSV-1 induced activation of C-JUN-N-Terminal Kinase (JNK) and P38 MAPK." Thesis, Glasgow Caledonian University, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.413914.
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Kawauchi, Takeshi. "The in vivo roles of STEF/Tiam1, Rac1 and JNK in cortical neuronal migration." Kyoto University, 2004. http://hdl.handle.net/2433/147523.
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Pocivavsek, Ana. "Microglial LRP1 modulates JNK activation a signaling cascade that also regulates apolipoprotein E levels /." Connect to Electronic Thesis (CONTENTdm), 2009. http://worldcat.org/oclc/457179623/viewonline.
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Marchand, Benoît. "L'activité des glycogènes synthase kinases 3 est essentielle à la survie et à la prolifération des cellules pancréatiques tumorales humaines." Mémoire, Université de Sherbrooke, 2009. http://savoirs.usherbrooke.ca/handle/11143/4047.
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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 cellulaire. Nous avons observé qu'en réponse au sérum les GSK3 sont inactivées de façon transitoire (0- 10h) avant d'être réactivées (10-16h). L'inhibition de l'activité des GSK3 lors de leur réactivation (10-16h) par le SB216763 prévient 1- l'hyperphosphorylation de pRb et de p130 et 2- l'augmentation d'E2F1 induites par le sérum et 3- diminue l'expression d'E2F4, suggérant un rôle des GSK3 dans la phase G1 tardive du cycle cellulaire. Également, nous avons observé la présence de complexes formés de GSK3-pRb et de GSK3?-E2F4 dans les cellules pancréatiques tumorales humaines. Ces observations suggèrent que l'activité des GSK3 pourrait contribuer à l'hyperphosphorylation de pRb et de p130 et pourrait également réguler directement l'activité des E2F. Bref, ces résultats suggèrent que l'activité des GSK3 est essentielle pour la survie et la prolifération des cellules pancréatiques tumorales humaines. Les auteurs suggèrent donc que l'inhibition des GSK3 pourrait s'avérer un traitement potentiel du cancer pancréatique, en ciblant les cellules cancéreuses. [Symboles non conformes]
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Zhao, Jing. "Protein Kinases can differentially regulate transactivation activities of hLRH-1 through the modulation of cofactors interactions." Kent State University / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=kent1271686070.
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Huang, Jie. "Depolarization-dependent pro-survival signaling in spiral ganglion neurons." Diss., University of Iowa, 2007. https://ir.uiowa.edu/etd/214.
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Membrane depolarization is an effective neurotrophic stimulus, with its trophic effect on spiral ganglion neurons (SGNs) even surpassing that of neurotrophins. Thus, SGN cultures are a favorable system to investigate pro-survival signal transduction downstream of depolarization.
Depolarization promotes SGN survival by recruiting three distinct kinase pathways: cyclic AMP-dependent protein kinase (PKA), Ca2+/calmodulin-dependent protein kinase II (CaMKII) and CaMKIV. CaMKIV mediates the pro-survival effect of depolarization by activating CREB in nucleus. However, the mechanisms by which PKA and CaMKII promote survival are still not clear. By targeting constitutively active PKA or a PKA inhibitor (PKI) to the outer mitochondrial membrane (OMM), we showed that PKA activity at the OMM is sufficient to support SGN survival in the absence of other trophic factors and necessary for cAMP-dependent SGN survival. It has been suggested that PKA can promote survival by inactivating pro-apoptotic protein Bad. By cotransfection of SGNs with OMM-PKA and wild-type Bad, we showed that this was the case. We further showed that Ser112 and Ser136 in Bad, but not Ser155, a hypothetical PKA target, were necessary for functional inactivation of Bad by PKA.
CaMKII mediates the third depolarization-dependent pro-survival pathway. A specific pro-survival target for CaMKII was identified through a separate investigation of the pro-apoptotic JNK-Jun signaling pathway, which we had identified as active in apoptotic SGNs in vivo. By measuring anti-phosphoJun immunofluorescence, we could quantify JNK-Jun activation in SGNs under different conditions. We showed that JNK inhibition or genetic deletion of JNK3 reduces SGN death after neurotrophic factor withdrawal. Neurotrophins have been shown to suppress JNK activation via their receptor protein tyrosine kinases (PTKs). By expressing constitutively active and dominant negative forms of candidate protein kinases, we identified a novel signaling pathway linking depolarization to JNK: Ca2+ entry - CaMKII - FAK/Pyk2 - PI-3-OH Kinase - Protein Kinase B - inhibition of MLKs (upstream activators of JNK). Thus, depolarization also recruits PTKs - the nonreceptor PTKs FAK and Pyk2 - to suppress JNK activation, implying a conserved PTK-PI3K-PKB pathway for suppression of pro-apoptotic JNK activation by neurotrophic stimuli.
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Herdman, Michelle L. "Thimerosal-induced neurotoxicity apoptosis occurs through a mitochondrial-mediated pathway via the JNK signaling pathway /." Huntington, WV : [Marshall University Libraries], 2006. http://www.marshall.edu/etd/descript.asp?ref=685.
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Rui, Yanning. "Elucidation of molecular mechanisms and biological functions of axin-mediated JNK pathway and p53 signaling /." View abstract or full-text, 2007. http://library.ust.hk/cgi/db/thesis.pl?BICH%202007%20RUI.
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Heywood, Darren J. "Investigating the involvement of the JNK and PKC signalling pathways in mediating neuronal cell death." Thesis, University of Bristol, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.288333.
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Yeun, Pei. "The role of purinergic receptors in the modulation of JNK signalling endothelial and cancer cells." Thesis, University of Strathclyde, 2012. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=18196.
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Wong, Chung Kai. "The DIX domain protein Ccd1 inhibits JNK activation by axin and dishevelled through distinct mechanisms /." View abstract or full-text, 2004. http://library.ust.hk/cgi/db/thesis.pl?BICH%202004%20WONG.
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Thesis (M. Phil.)--Hong Kong University of Science and Technology, 2004.Includes bibliographical references (leaves 60-68). Also available in electronic version. Access restricted to campus users.
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Wan, Jun. "Elucidation of the JNK pathway mediated by Epstein-Barr virus encoded latent membrane protein 1 /." View abstract or full-text, 2004. http://library.ust.hk/cgi/db/thesis.pl?BICH%202004%20WAN.
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Thesis (Ph. D.)--Hong Kong University of Science and Technology, 2004.Includes bibliographical references (leaves 105-128). Also available in electronic version. Access restricted to campus users.