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1
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.
2
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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Lanuza, Masdeu Jordi. "Regulation and actions mediated by C-jun N-terminal kinase pathaway." Doctoral thesis, Universitat de Barcelona, 2013. http://hdl.handle.net/10803/110348.
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Es va generar un ratolí transgènic amb la capacitat d'activar JNK específicament al pàncrees. Tot i que aquests ratolins no tenen cap afectació morfoestructural en els seus illots pancreàtics ni diferències en el contingut total d'insulina però presenten intolerància a la glucosa i no secreten insulina en resposta a hiperglucèmia. A nivell molecular, les cèl•lules β pancreàtiques amb JNK activa, tenen un bloqueig a la via de senyalització d'insulina que fa que es redueixi la secreció d'insulina i l'expressió de gens diana de la insulina. El tractament amb rossiglitazona, un fàrmac del grup de les TZDs, aconsegueix revertir el fenotip in vivo. Tots aquests resultats indiquen que l'activació de JNK és suficient per promoure la resistència a insulina central però no n'hi ha prou per induir hiperplàsia dels illots o induir l'apoptosi de les cèl•lules β. A més a més, aquests ratolins estan protegits de la hiperinsulinèmia, la hiperglucèmia i l'obesitat induïdes per la dieta grassa o l'envelliment.
També s'ha estudiat la interacció entre les vies de senyalització de JNK i NF-κB. Fins ara, s'ha va publicat que JNK pot induir l'activació de NF-κB mitjançant l'estabilització del mRNA de la βTrCP, responsable de la degradació d'IκBα. JNK va resultar fosforilar a CRD-BP, una proteïna que s'uneix al mRNA de βTrCP per protegir-li de l'atac per part del miR-183. A més, un mutant de βTrCP perquè no s'hi unís el miRNA, es seguia estabilitzant en resposta a l'activació de JNK a nivel de proteïna però no de mRNA. A part d'aquest efecte, JNK també aconsegueix estabilitzar SKP1 però la interacció SKP1-βTrCP és necessària per a una màxima estabilització. A més a més, aquest efecte podria ser extensiu a altres dianes de βTrCP com β-catenina i també estan afectades els nivells d'altres F-Box com la SKP2, i el dels seus substrats.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 is focused on studying the effects of the activation of JNK in a mouse model and evaluating the capacity of those ligands to recover the homeostasis. In parallel, there is a second project about the characterization of the crosstalk between the JNK pathway and NF-κB, another major pathway in inflammation. The relevance of the activation of JNK in a wide range of pathologies with an inflammatory component, lead the group to the generation of a transgenic mouse carrying a a constitutively active form of the MAP2K of JNK, MKK7, with a conditional expression upon the regulation of the Cre recombinase. Despite these mice have no morphostructural affectation of the pancreatic islets or differences in the total insulin content, they have defective glucose homeostasis showing glucose intolerance and decreased insulin secretion in response to hyperglycemia. This reduction in glucoseinduced insulin release is β cell autonomous, as it is reproduced in isolated islets, and JNK activity dependent, as it is reverted by the specific inhibitor of JNK, TAT-JIPi. At molecular level, β-cells with activated JNK have a blockage in the insulin-signaling pathway that reduces the secretion of insulin and the expression of insulin target genes. The treatment with rosiglitazone, an insulin-sensitizing drug of the thiazolidinedione family that inhibits JNK activation, restored insulin secretion in response to glucose in isolated islets and in vivo. All these data indicate that the activation of JNK is sufficient to promote central insulin resistance but is not sufficient to induce islet hyperplasia or β-cell death. Moreover, these mice are protected from basal plasma hiperinsulinemia caused by aging or high fat diet challenge. Regarding the second project, the interaction between NF-κB.and JNK pathways, both signaling pathways are essential for the regulation of the immune and inflammatory response as well as other fundamental processes such as cell proliferation and survival. It was published that JNK was activating NF-κB. pathway by inducing the mRNA stabilization of the E3 ubiquitin ligase βTrcP. We have further reported that JNK is targeting the miRNA183/CRD-BP system to stabilize βTrCP mRNA. At a protein level we have shown that SPK1-βTrCP complex formation is required for JNKdependent SKP1 and βTrCP protein stabilization. Not only this but the βTrCP substrate β‐catenin is down regulated by the JNK-dependent increase of βTrCP and the protein levels of SKP2 and its substrate p27 are oppositely regulated by JNK
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Gourmaud, Sarah. "Expression de c-Jun N-terminal kinase (JNK) dans la maladie d'Alzheimer : intérêts diagnostiques et thérapeutiques." Paris 7, 2014. http://www.theses.fr/2014PA077106.
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La maladie d'Alzheimer (MA) se caractérise par l'accumulation de peptides d'amyloïde-β42 (Aß₄₂), de protéine tau hyperphosphorylée (ptau) et une perte neuronale. Les niveaux d'Aß₄₂ et de tau au niveau du liquide céphalo-rachidien (LCR) des patients sont utilisés comme biomarqueurs diagnostique. Les protéines PKR et JNK sont des kinases impliquées dans la production d'AE342, la phosphorylation de tau et la mort neuronale. L'accumulation de leur forme active a été mise en évidence dans le cerveau de patients MA. Il existe trois isoformes de JNK. JNK1 et JNK2 sont ubiquitaires et JNK3 est presque exclusivement exprimée au niveau du cerveau. Aucune étude n'a étudié à ce jour les variations de JNK3 dans la MA. L'objectif de notre étude était d'analyser in vitro le lien entre PKR et JNK puis de mesurer l'expression des différents isoformes de JNK dans la MA chez l'homme. Nos résultats montrent que la protéine PKR intervient à la fois dans la voie d'activation et celle de désactivation de JNK en fonction des conditions de stress. Nous mettons également en évidence la diminution de l'apoptose neuronale due à l'Aß₄₂ grâce à un peptide inhibiteur de JNK. Nous avons mesuré une augmentation de la forme totale de JNK3 dans le cortex frontal et le LCR de patients Alzheimer. Le signal de JNK3 colocalise avec celui d'Ar342 au niveau des plaques séniles. Grâce au suivi clinique des patients nous avons montré que le niveau de JNK3 mesuré dans le LCR est corrélé au déclin cognitif chez les patients. JNK3 pourrait devenir un nouveau biomarqueur diagnostique et pronostique de la MA. Ces résultats, associés à ceux de la littérature, font de JNK3 et PKR d'intéressantes cibles thérapeutiquesAlzheimer's disease (AD) is characterized by the accumulation of amyloid-β42 peptide (Aß₄₂), hyperphosphorylated tau (ptau) proteins and neuronal loss. Cerebrospinal fluid (CSF) Aß₄₂and tau levels in patients are used as diagnostic biomarkers. PKR and JNK are kinases involved in the production of Ar342, tau phosphorylation and neuronal death. The accumulation of their active form was demonstrated in AD brains. There are three isoforms of JNK. JNK1 and JNK2 are ubiquitous and JNK3 is almost exclusively expressed in brain. No studies have examined changes in JNK3 in AD. The aim of our study was to analyze in vitro the relationship between PKR and JNK and then to measure the expression of JNK isoforms in AD patients. Our results showed that PKR is involved in both JNK activation and deactivation, according to stress conditions. We also showed a decrease of neuronal apoptosis due to Aß₄₂ with a JNK inhibitor peptide. We measured an increase of the total form of JNK3 in AD frontal cortex and CSF. JNK3 signal colocalizes with Aß₄₂ in senile plaques. Thanks to the clinical monitoring of patients we have shown that the CSF level of JNK3 correlates with the cognitive decline. JNK3 could become a new diagnostic and prognostic biomarker for AD. These results, together with those of the literature, make JNK3 and PKR interesting therapeutic targets
5
Smith, Abigail O. "Defining the Role of c-Jun N-terminal Kinase (JNK) Signaling in Autosomal Dominant Polycystic Kidney Disease." eScholarship@UMMS, 2021. https://escholarship.umassmed.edu/gsbs_diss/1141.
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Polycystic kidney disease is an inherited degenerative disease in which the uriniferous tubules are replaced by expanding fluid-filled cysts that ultimately destroy organ function. Autosomal dominant polycystic kidney disease (ADPKD) is the most common form, afflicting approximately 1 in 1,000 people. It primarily is caused by mutations in the transmembrane proteins Polycystin-1 (PKD1) and Polycystin-2 (PKD2). The most proximal effects of polycystin mutations leading to cyst formation are not known, but pro-proliferative signaling must be involved for the tubule epithelial cells to increase in number over time. The stress-activated mitogen-activated protein kinase (MAPK) pathway c-Jun N-terminal kinase (JNK) promotes proliferation in specific contexts and is activated in acute and chronic kidney disease. Previous work found evidence of JNK activation in cystic tissues (Le et al., 2005) and others showed that JNK signaling is activated by aberrant expression of PKD1 and PKD2 in cell culture (Arnould et al., 1998; Arnould et al., 1999; Parnell et al., 2002; Yu et al., 2010) but the contribution of JNK signaling to cystic disease in vivo has not been investigated.
This body of work describes the use of conditional and germline deletion of Pkd2, Jnk1 and Jnk2 to model ADPKD and JNK signaling inhibition in juvenile and adult mice. Immunoblots and histological staining were used to measure JNK activation and evaluate the effect of JNK deletion on cystic disease. Results show that Pkd2 deletion activated JNK signaling in juvenile and adult mice. Reduction of JNK activity significantly reduced cystic burden in kidneys of juvenile Pkd2 mutant mice. This correlated with reduced tubule cell proliferation and reduced kidney fibrosis. The improvement in cystic phenotype was driven primarily by Jnk1 deletion rather than Jnk2. JNK signaling inhibition in adult Pkd2 mutants significantly reduced liver cysts when mice were aged six months. JNK inhibition reduces the severity of cystic disease caused by the loss of Pkd2 suggesting that the JNK pathway should be explored as a potential therapeutic target for ADPKD.
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Santos, Fernando Reyes, Maggie K. Diamond-Stanic, Mujalin Prasannarong, and Erik J. Henriksen. "The Serine Kinase C-Jun N-Terminal Kinase (JNK) Contributes to Oxidant-Induced Insulin Resistance in Isolated Rat Skeletal Muscle." Thesis, The University of Arizona, 2012. http://hdl.handle.net/10150/244754.
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Insulin resistance of the mammalian skeletal muscle glucose transport system, one cause of which is oxidative stress, leads to the development of type 2 diabetes. While the direct contributions to insulin resistance of certain stress-activated serine kinases have been described previously, the specific contribution of c-Jun N-terminal kinase (JNK) is not fully understood. Therefore, we assessed the role of JNK in insulin resistance caused by in vitro exposure to the oxidant hydrogen peroxide (H₂O₂). Soleus muscles from lean Zucker rats were incubated in low levels (~30 μM) of H₂O₂ in the absence or presence of insulin for up to 6 hr. Decreases in insulin-stimulated glucose transport activity (ISGTA) were observed at all time points and were associated with similar diminutions in insulin stimulation of Akt Ser⁴⁶⁷ phosphorylation. Phosphorylation (Thr¹⁸³/Tyr¹⁸⁵) of JNK isoforms (JNK1 and JNK2/3) was increased by H₂O₂ in the absence and presence of insulin at all time points. To determine the specific contribution of JNK to oxidant-induced insulin resistance, the JNK inhibitor SP600125 was used. ISGTA in the presence of H₂O₂ was improved when the inhibitor was added during the 6-hr incubation. These results indicate that JNK contributes to oxidative stress-induced insulin resistance in mammalian skeletal muscle.
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Wang, Fang St George Clinical school UNSW. "Oxidative stress induced C-Jun N-terminal Kinase (JNK) activation in tendon cells upregulates MMP1 mRNA and protein expression." Awarded by:University of New South Wales. St George Clinical school, 2006. http://handle.unsw.edu.au/1959.4/28815.
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To explore the potential mechanisms of tendon degeneration, we investigated the role of c-Jun N-terminal Kinase (JNK) activation and the regulation of matrix metalloproteinase 1 (MMP1) in tendon matrix degradation under oxidative stress. JNK and MMP1 activity in samples from normal and ruptured human supraspinatus tendons were evaluated by immunohistochemistry. Real-time quantitative PCR was utilized to evaluate MMP1 mRNA expression and western blotting for MMP1 and JNK protein detection. JNK activation and increased MMP1 activity were found in the torn human supraspinatus tendon tissue, as well as in human tendon cells under in vitro oxidative stress. Inhibition of JNK prevented MMP1 over-expression in oxidative stressed human tendon cells. Results from the current study indicated that stress activated JNK plays an important role in tendon matrix degradation, possibly through upregulating of MMP1.
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Yu, Lola. "Investigating the role of the c-Jun NH2-terminal kinase pathway in ErbB2-driven breast cancer and macrophage polarization." eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1094.
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Breast cancer is the second most common malignancy in the world, accounting for over 1.7 million new diagnoses and an estimated 500,000 deaths per year (1). Overexpression of the receptor tyrosine kinase ErbB2, also known as Her2 or Neu, occurs in over 30% of breast cancers and correlates with metastasis, poor prognosis, and decreased survival (1, 2). Although therapeutics targeting ErbB2 show clinical efficacy, many patients display no initial response or develop drug resistance over time (2). A deeper understanding of the molecular basis of ErbB2-driven tumorigenesis is thus required for the development of improved therapeutic strategies.
In vitro experiments suggest that activation of the c-Jun NH2-terminal kinase (JNK) pathway, a mitogen-activated protein kinase pathway, promotes proliferation, cellular invasion, and stem cell expansion in ErbB2-driven breast cancer (3, 4). Furthermore, unpublished data from our lab using mammary epithelial cells expressing activated ErbB2 show that JNK is required for acinus formation in in vitro 3D cultures. In contrast to these studies showing a tumorigenic role for the JNK pathway, other data from our lab show that JNK loss results in accelerated breast tumor growth, suggesting a tumor suppressive role (5, 6). However, these studies were performed in p53 knockout mice with or without a Kras mutation, where the latter required extensive aging and genomic instability to occur before differences in tumor growth were observable. To date, limited in vivo studies exist to confirm the role of JNK in more biologically relevant breast tumor models, such as in ErbB2-mediated cancer, which accounts for over 30% of all human breast cancers. In addition, the molecular mechanisms by which JNK signaling promotes ErbB2-driven tumorigenesis remains poorly understood.
To address the discrepancy in JNK function between the in vitro ErbB2-driven breast cancer data and the in vivo p53 knockout tumor data, I began the development of an in vivo murine model to confirm the role of JNK in ErbB2-driven breast cancer. This mouse model will also allow us to test a potential mechanism by which JNK regulates tumorigenesis. Studies show that ErbB2-mediated secretion of the inflammatory cytokine IL6 promotes transformation and tumor growth by activation of the STAT3 transcription factor, triggering an IL6/STAT3 autocrine signaling loop (7,8). A major regulator of Il6 gene expression includes activator protein 1 (AP-1), a transcription factor composed of downstream JNK targets in the Jun protein family (9). In vitro experiments using ErbB2-overexpressing mammary epithelial cell lines show that chemical inhibition of JNK suppresses secreted IL6 protein levels, supporting a role for the JNK pathway in IL6 regulation (7). Thus, I hypothesize that JNK drives ErbB2-driven breast cancer by promoting IL6-mediated tumor progression. Addressing this will increase our understanding of the role of JNK in ErbB2-driven breast cancer and reveal a potentially new mechanism by which JNK functions in tumor progression.
Additionally, I began the development of a mouse model that will allow us to investigate the role of JNK in macrophage polarization as an alternative mechanism by which JNK regulates ErbB2-driven breast cancer. In addition to promoting STAT3-dependent tumor growth, IL6 can indirectly drive tumorigenesis by promoting expression of the IL4 receptor in macrophages, triggering STAT6-mediated macrophage polarization towards the pro-tumorigenic M2 phenotype (10, 11). Unlike classically activated M1 macrophages, which promote inflammation and anti-tumor immunity, alternatively activated M2 macrophages function in immunosuppression and metastasis and correlate with advanced stages of breast cancer (12, 13). Further evidence supporting a role for the JNK pathway in macrophage polarization includes a recent study suggesting that JunB, a downstream JNK target and component of the AP-1 complex, plays a crucial role in the induction of M2 macrophage polarization in human alveolar macrophages (13). I hypothesize that activation of the JNK signaling pathway induces IL6-dependent macrophage polarization towards the pro-tumorigenic M2 phenotype. Addressing this hypothesis will determine for the first time whether JNK functions in regulating macrophage polarization within the tumor microenvironment, offering a potentially new mechanism by which JNK can promote ErbB2-driven breast cancer.
Determining the role of JNK in ErbB2-mediated breast cancer will have direct therapeutic relevance, as targeting JNK has the potential to inhibit ErbB2-driven breast cancer and other IL6-mediated diseases. Investigating the underlying mechanisms by which JNK functions in ErbB2-positive breast cancer can also offer new molecular targets and further contribute to effective drug design.
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Joy, Jery 1992. "Chromosomal instability : interplay between proteotoxic and metabolic stress." Doctoral thesis, Universitat Pompeu Fabra, 2020. http://hdl.handle.net/10803/668516.
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Chromosomal Instability (CIN) and associated aneuploidy are salient
features of the majority of human solid tumors. In the Drosophila
epithelial model of CIN, the generation of highly aneuploid
karyotypes drive cell delamination and c-Jun N-terminal Kinase
(JNK) dependent cell death. Aneuploidy associated generation of
Reactive Oxygen Species (ROS) plays a key role in the activation of
JNK. When delaminating cells are maintained in the tissue by
apoptosis inhibition, aberrant karyotypes promote a cell-autonomous
malignant behavior. Here we have dissected the molecular
mechanisms underlying aneuploidy-induced ROS production and
cell delamination. On one hand, we have shown that aneuploidy
associated proteotoxic stress is being sensed and activates the major
protein quality control mechanisms in a cell. On the other hand,
mitochondria act as signaling centers as well as major sensors of the
unbalanced proteome in CIN tissues. Aneuploidy associated
proteotoxic stress leads to mitochondrial dysfunction and ROS
production, which further drives cell delamination as well as JNK
activation in CIN tissues.La inestabilidad cromosómica y la aneuploidía son características destacadas de la mayoría de los tumores sólidos en humanos. En el modelo epitelial de Drosophila, la generación de cariotipos altamente aneuploides promueve la delaminación y la muerte celular dependiente de c-Jun N-terminal Kinase (JNK). La producción de especies reactivas de oxígeno (ROS) juega un papel clave en la activación de JNK bajo dichas condiciones. Cuando las células delaminadas se mantienen en el tejido gracias a la inhibición de la apoptosis, los cariotipos aberrantes promueven un comportamiento maligno tumoral. En esta tesis hemos analizado los mecanismos moleculares subyacentes a la producción de ROS como consecuencia de la aneuploidía. Hemos demostrado que bajo una situación de inestablidad cromosómica se genera un estrés proteotóxico, detectado por la célula que activa los principales mecanismos de control de calidad de las proteínas. Además, dicho estrés, promueve la disfuncionalidad de las mitocondrias, favoreciendo la generación de ROS, que a su vez contribuye a la activación de JNK y a la delaminación celular al afectar el citoesqueleto de actina-miosina en los tejidos CIN.
10
Le, Aurore. "Deciphering the role of c-Jun N-Terminal Kinase (JNK1) in an in vivo model of skin inflammation." Doctoral thesis, Universite Libre de Bruxelles, 2020. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/314810.
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JNK1 (c-Jun N-terminal kinase 1) has been studied in numerous biological phenomena, but its role in skin inflammation diseases has not been fully defined yet. We therefore evaluated the role of JNK1 in imiquimod-induced dermatitis, a classical model that shares many features with human psoriasis. We showed that JNK1 was necessary for the expression of inflammatory markers and for acanthosis induced by imiquimod. We demonstrated that the loss of JNK1 in dendritic cells or myeloid cells reduced inflammatory markers but did not affect acanthosis induced by imiquimod. In vitro experiments in bone marrow-derived macrophages (BMMs) supported the role of JNK1 in the activation of the inflammasome pathway by the Aldara® cream. Next, we observed that the loss of JNK1 in keratinocytes did not reduce imiquimod-induced expression of most inflammatory markers but acanthosis and proliferation of epidermal cells was decreased. To better understand the role of JNK1 in keratinocytes, we evaluated the transcriptome and the epigenomic landscape of JNK1-deficient epidermal cells from mice treated with imiquimod. These data highlighted the potential role of JNK1 downstream of the EGFR pathway. We further observed that the inhibition of the EGFR pathway decreased imiquimod-induced acanthosis. Our work shows the dual role of JNK1 in skin inflammation induced by imiquimod. On one hand, JNK1 influences the expression of inflammatory mediators by myeloid cells, probably through the inflammasome pathway. On the other hand, JNK1 modulates the response of keratinocytes to EGFR ligands. Taken together, these data suggest that JNK1 could represent a valuable therapeutic target for the management of psoriasis.Doctorat en Sciences médicales (Médecine)
info:eu-repo/semantics/nonPublished
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Sluss, Hayla Karen. "The c-Jun NH₂-Terminal Kinase Regulates Jun in vitro and in vivo during the Process of Dorsal Closure: A Dissertation." eScholarship@UMMS, 1997. https://escholarship.umassmed.edu/gsbs_diss/264.
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Tyrosine phosphorylation of proteins by protein tyrosine kinases is an important step in initiating mitogenic signal transduction pathways. The receptor tyrosine kinases represent a class of protein kinases that employ phosphorylation cascades to transmit a signal generated at the cell surface. The AP-1 transcription factor is a common target of receptor tyrosine kinase activation, transformation by Ras-like proteins and activation of the MAP kinase pathway. The AP-1 complex contains a dimer of Jun proteins or a heterodimer of Jun and Fos or other bZip proteins. The transcriptional activation of Jun is enhanced by phosphorylation on residues Ser-63 and Ser-73. Therefore, identifying the regulatory proteins kinases of Jun would be an important link in signaling from the upstream cell surface events to downstream events, such as gene expression. The JNK1 protein kinase was identified and phosphorylates c-Jun at these sites. The JNK1 protein is a member of the JNK group of protein kinases, which are activated in response to UV treatment. JNK1 is the 46 kDa isoform, and the isolation of the 55 kDa isoform is described in this thesis. Furthermore, a role for JNK was established in Drosophila. Drosphila JNK (DJNK) is essential for the process of dorsal closure. The JNK protein kinases are involved in cytokine signaling, response to environmental stress and development.
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Kenney, Justin Ward. "Nicotine and learning interact to alter transcription factor activity at the c-jun N-terminal kinase 1 gene promoter in the hippocampus." Diss., Temple University Libraries, 2010. http://cdm16002.contentdm.oclc.org/cdm/ref/collection/p245801coll10/id/112533.
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PsychologyPh.D.
Approximately 1 in 5 Americans smoke despite the widely known negative health consequences of the habit. One factor that contributes to the high rates of nicotine addiction and its continued use is the ability of the drug to alter long-term memory. Learning in the presence of nicotine results in changes to the cellular and molecular processes that support the formation and storage of long-term memories. The consolidation of long-term memory requires a number of mechanisms, such as gene transcription. Previous work has found that learning a contextual fear conditioning task in the presence of nicotine results in the upregulation of the c-jun N-terminal kinase (JNK1) gene in the hippocampus and that JNK protein activation is necessary for the nicotine induced enhancement of contextual conditioning. The present study examines the transcription factors involved in the transcriptional regulation of jnk1 in the hippocampi of mice following learning in the presence of nicotine. The hypothesis that cAMP response element binding protein (CREB) regulates jnk1 transcription was examined. Further, a protein/DNA transcription factor array was used as an unbiased examination of changes in transcription factor activity following learning in the presence of nicotine. Using chromatin immunoprecipitation (ChIP), transcription factors identified from the array and CREB were examined for changes in their binding to the jnk1 promoter following fear conditioning in the presence of nicotine. An increase in the binding of phosphorylated CREB was found in the jnk1 promoter of mice trained in the presence of nicotine. This implicates CREB activation in the increase of jnk1 transcription following learning in the presence of nicotine. Additionally, data from the transcription factor array suggest other factors such as PARP, TR, USF-1 and E2F-1 as potentially playing a role in the cognitive effects of nicotine. These findings are discussed with respect to how they inform our understanding of the signaling cascades and genetics involved in the memory enhancing effects of this addictive drug.
Temple University--Theses
13
Pang, Wei Wei. "The role of mitochondria in regulating MAPK signalling pathways during oxidative stress." University of Western Australia. School of Biomedical, Biomolecular and Chemical Sciences, 2006. http://theses.library.uwa.edu.au/adt-WU2007.0026.
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[Truncated abstract] Reactive oxygen species (ROS) have been implicated to play a major role in many pathological conditions including heart attack and stroke. Their ability to modulate the extracellular signal-regulated protein kinase (ERK) and c-Jun Nterminal kinase (JNK) signalling pathways, thereby influencing cellular response has been well-documented. Recent studies implicate a central role for mitochondria in ERK and JNK activation by ROS although the mechanisms remained unresolved. Using Jurkat T-lymphocyte as a cell model, this study demonstrated increased mitochondrial ROS production as a result of decreased mitochondrial complex activities mediated by hydrogen peroxide treatment. This is the first study to show that mitochondria are not essential for activating ERKs, however damaged mitochondria producing ROS can be expected to cause sustained ERK activation . . . This study revealed that JNK and its upstream kinases MKK4, MKK7 and ASK1 are associated with the mitochondria. Furthermore, findings from this study imply that JNK resides in the mitochondrial matrix. This study is the first to demonstrate that mitochondrial JNK can be activated in a cell-free environment by signals originating from the mitochondria. Experimental work using isolated mitochondria demonstrated that mitochondrial JNK can be activated by ROS generated from the mitochondria themselves. Flavin-containing proteins appear to be the main sources of mitochondrial-ROS which signal through redoxsensitive proteins to activate mitochondrial JNK.
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Henrie, Hélène. "Régulation de la dynamique des microtubules par la kinase de stress JNK dans les cellules épithéliales : caractérisation de CLIP-170 comme un nouveau substrat." Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS461/document.
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Les microtubules sont des éléments dynamiques du cytosquelette qui contrôlent à la fois l’organisation du cytoplasme, la polarité, la migration et la division cellulaire. Notre laboratoire a précédemment montré que la kinase de stress JNK (c-Jun NH2-terminal Kinase) régule la dynamique des microtubules dans les cellules épithéliales de mammifères, en augmentant les vitesses de polymérisation, ainsi que les fréquences de sauvetage (transition vers une phase de repolymérisation). Alors que certaines protéines neuronales capables de réguler la dynamique des microtubules ont été identifiées comme des substrats de JNK, leurs équivalents dans les cellules épithéliales sont largement méconnus. Dans le but de comprendre comment JNK module la dynamique des microtubules dans les cellules épithéliales de mammifère, nous avons étudié deux substrats potentiels de JNK : la -tubuline et le facteur de sauvetage CLIP-170. Nous avons bien mis en évidence in vitro, une phosphorylation de la -tubuline par JNK sur une thréonine non-consensus, mais cette phosphorylation n’a pas été retrouvée dans les cellules HeLa, suggérant que la -tubuline n’est pas un substrat naturel de JNK in vivo. Nous avons mis en évidence par ailleurs que CLIP-170 est un nouveau substrat de JNK. Dans les cellules épithéliales, JNK activée phosphoryle trois résidus (Thr25, Thr45 et Ser147) situés dans la partie N-terminale de CLIP-170 de part et d’autre du premier domaine CAP-Gly qui est nécessaire pour l’interaction avec les microtubules. Ces acides aminés présentent des différences aussi bien dans leur phosphorylation basale que dans leurs cinétiques de phosphorylation par JNK sous divers stress. De plus, nous avons trouvé que dans différentes cellules épithéliales, la phosphorylation de ces sites est conservée. In vitro, ces résidus sont directement phosphorylés par JNK, préférentiellement quand le domaine N-terminal de CLIP-170 lie la tubuline. De plus, l’expression de mutants de CLIP-170 phospho-mimétiques et non-phosphorylables a montré que la phosphorylation de chaque site augmente la fréquence des sauvetages microtubulaires. Cette modulation n’est pas corrélée à une augmentation de la capacité de CLIP-170 à former des comètes aux extrémités plus en croissance ou à être retenue aux croissements microtubulaires, qui sont des sites de sauvetage potentiels.Ce travail a permis de décrire les premières phosphorylations de CLIP-170 qui stimulent sa fonction de sauvetage in vivo. Il souligne par ailleurs la complexité des mécanismes de sauvetage, qui demeurent un aspect encore énigmatique de l’instabilité dynamique des microtubules. L’activité de JNK sur CLIP-170 ne permet d’expliquer qu’une partie des effets de la kinase sur la dynamique des microtubules, aussi la recherche d’autres protéines cibles de JNK pouvant réguler notamment leur vitesse de polymérisation, reste à entreprendreMicrotubules are dynamic cytoskeleton elements, which control cytoplasm organization, cell polarity, migration and division. Our laboratory has previously shown that the stress kinase JNK (c-Jun NH2-terminal Kinase) regulates microtubule dynamics in mammalian epithelial cells, by increasing their growth rates, and their rescue frequencies (transition towards phases of repolymerization). While several neuronal proteins regulating microtubule dynamics have been identified as JNK substrates, their counterparts in epithelial cells are largely unknown. With the aim to understand how JNK modulates microtubule dynamics in mammalian epithelial cells, we studied two putative substrates of JNK: -tubulin and the rescue factor CLIP-170. Regarding -tubulin, using an in vitro kinase assay, we found that a non-consensus threonine is actually phosphorylated by JNK, but we were not able to find this phosphorylation in HeLa cells, suggesting that -tubulin is not a natural JNK substrate. In parallel, we found that CLIP-170 is a new substrate of JNK in epithelial cells. Activated JNK phosphorylates three residues (Thr25, Thr45 and Ser147) located in the N-terminal part of CLIP-170, on each side of the first CAP-Gly domain, which is required for CLIP-170 interaction with microtubules. These residues exhibit differences in their level of basal phosphorylation and their kinetics of phosphorylation by JNK under various stresses. Moreover, we found that in different epithelial cells, the phosphorylation of these sites is conserved. Using an in vitro kinase assay, we found that all these residues are directly phosphorylated by JNK, preferentially when the N-terminal domain of CLIP-170 binds tubulin. Furthermore, using phospho-mimetic and non-phosphorylatable CLIP-170 mutants in epithelial cells, we revealed that the phosphorylation of each site increases microtubule rescues. Such modulation operates without increasing CLIP-170 capability to form comets at the microtubule growing plus ends or to accumulate at microtubule crossings, which are potential rescue sites.This work described the first phosphorylations that enhance CLIP-170 rescue factor function in vivo. It also points out to which extent rescue mechanisms are complex and remain an elusive aspect of dynamic instability. JNK-mediated phosphorylation of CLIP-170 only partly explains the kinase effects on microtubule dynamics. Therefore, identifying other JNK targets that may regulate microtubule polymerization rate, remains to be addressed
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Manganaro, Lara. "Concerted action of cellular JNK and Pin-1 restricts HIV-1 genome integration to activated CD4+T lymphocytes." Doctoral thesis, Scuola Normale Superiore, 2009. http://hdl.handle.net/11384/85950.
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Prunier, Céline. "Étude de mécanismes de répression de l'activité des protéines Smad." Paris 6, 2002. http://www.theses.fr/2002PA066303.
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Zamani, Marzieh. "The role of the JNK/AP-1 pathway in the induction of iNOS and CATs in vascular cells." Thesis, University of Hertfordshire, 2013. http://hdl.handle.net/2299/10626.
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Nitric oxide (NO) is an important biological molecule within the body, which over production of this molecule in response to different stimulations can cause various inflammatory diseases. Over production of this molecule is caused by the induction of the inducible nitric oxide synthase (iNOS) enzyme. This enzyme uses L-arginine as a substrate and therefore the presence and transport of this amino acid into the cells can be a key factor in regulating NO over production. Different signalling mechanisms have been implicated in the regulation of this pathway and one of which involves the Mitogen Activated Protein Kinases (MAPK). This family of proteins respond to inflammatory conditions and may mediate effects induced by inflammatory mediators. Of the MAPKs, the role of the c-Jun-N-terminal kinase (JNK) pathway in the induction of iNOS is still controversial. JNK and its downstream target, the transcription factor Activator Protein-1 (AP-1), have shown contradictory effects on iNOS induction leading to controversies over their role in regulating iNOS expression in different cell systems or with various stimuli. The studies described in this thesis have determined the role of JNK/AP-1 on iNOS expression, NO production, L-arginine uptake and also on the transporters responsible for L-arginine transport into the cells. The studies were carried out in two different cell types: rat aortic smooth muscle cells (RASMCs) and J774 macrophages which are both critically associated with the over production of NO in vascular inflammatory disease states. The first approach was to block the expression of the inducible L-arginine-NO pathway using SP600125 and JNK Inhibitor VIII which are both pharmacological inhibitors of JNK. The results from these studies showed that the pharmacological intervention was without effect in RASMCs, but inhibited iNOS, NO and L-arginine transport in J774 macrophages. In contrast, the molecular approach employed using two dominant negative constructs of AP-1 (TAM-67 and a-Fos) revealed a different profile of effects in RASMCs, where a-Fos caused an induction in iNOS and NO while TAM-67 had an inhibitory effect on iNOS, NO, L-arginine transport and CAT-2B mRNA expression. The latter was unaffected in RASMCs but suppressed in J774 macrophages by SP600125. Examination of JNK isoforms expression showed the presence of JNK1 and 2 in both cell systems. Moreover, stimulation with LPS/IFN- or LPS alone resulted in JNK phosphorylation which did not reveal any difference between smooth muscle cells and macrophages. In contrast, expression and activation of AP-1 subunits revealed differences between the two cell systems. Activation of cells with LPS and IFN- (RASMCs) or LPS alone (J774 macrophages) resulted in changes in the activated status of the different AP-1 subunit which was different for the two cell systems. In both cell types c-Jun, JunD and Fra-1 were increased and in macrophages, FosB activity was also enhanced. Inhibition of JNK with SP600125 caused down-regulation in c-Jun in both cell types. Interestingly this down-regulation was in parallel with increases in the subunits JunB, JunD, c-Fos and Fra-1 in RASMCs or JunB and Fra-1 in J774 macrophages. Since, SP600125 was able to exert inhibitory effects in the latter cell type but not in RASMCs, it is possible that the compensatory up-regulation of certain AP-1 subunits in the smooth muscle cells may compensate for c-Jun inhibition thereby preventing suppression of iNOS expression. This notion clearly needs to be confirmed but it is potentially likely that hetero-dimers formed between JunB, JunD, c-Fos and Fra-1 could sustain gene transcription in the absence of c-Jun. The precise dimer required has not been addressed but unlikely to exclusively involve JunB and Fra-1 as these are up-regulated in macrophages but did not sustain iNOS, NO or induced L-arginine transport in the presence of SP600125. To further support the argument above, the dominant negatives caused varied effects on the activation of the different subunits. a-Fos down-regulated c-Jun, c-Fos, FosB, Fra-1 whereas TAM-67 reduced c-Jun and c-Fos but marginally induced Fra-1 activity. Associated with these changes was an up-regulation of iNOS-NO by a-Fos and inhibition by TAM-67. Taken together, the data proposes a complex mechanism(s) that regulate the expression of the inducible L-arginine-NO pathway in different cell systems and the complexity may reflect diverse intracellular changes that may be different in each cell type and not always be apparent using one experimental approach especially where this is pharmacological. Moreover, these findings strongly suggest exercising caution when interpreting pure pharmacological findings in cell-based systems particularly where these are inconsistent or contradictory.
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Tonner, Juliane [Verfasser]. "Spezifische Expression von c-Jun N-terminalen Kinasen (JNK) im Nervensystem : eine immunhistochemische Analyse / Juliane Tonner." Kiel : Universitätsbibliothek Kiel, 2009. http://d-nb.info/1019871245/34.
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Chaudhury, Hera Ashraf. "c-Jun N-terminal kinase primes endothelial cells at atheroprone sites for apoptosis." Thesis, Imperial College London, 2010. http://hdl.handle.net/10044/1/6136.
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Atherosclerosis can be initiated by pro-inflammatory activation of endothelial cells (EC) which leads to the recruitment of leukocytes to the vessel wall, and also by endothelial apoptosis which elevates the permeability of arteries to lipoproteins. The greater curvature of the aorta is exposed to high shear and is protected from EC apoptosis, inflammation and atherosclerosis, whereas the lesser curvature is exposed to low shear and is susceptible to atherosclerosis. Pro-inflammatory mediators (e.g. TNFα, LPS) trigger phosphorylation of c-Jun N-terminal kinase (JNK) and p38 MAP kinases to positively regulate these process and influence atherosclerosis. I examined the effects of JNK activation on EC physiology at atherosusceptible sites. En face staining revealed that phosphorylation of JNK in EC occurs constitutively at the susceptible site of the murine aortic arch and can be enhanced by LPS treatment. In contrast, JNK activation was suppressed at the protected site by mitogen-activated protein kinase phosphatase-1 (MKP-1), a negative regulator of JNK and p38 MAP kinases. To study the function of JNK and p38 in vascular endothelium, I identified the transcriptional programs that they regulate by applying specific pharmacological inhibitors to cultured EC and assessing the transcriptome using microarrays. Functional annotation revealed that JNK and p38 positively regulate the expression of numerous pro-inflammatory and pro-apoptotic molecules. Subsequent gene silencing studies demonstrated that JNK1 positively regulates pro-apoptotic molecule expression in EC. I validated my findings in vivo by analyzing EC in aortae of wild-type, JNK1-/- and MKP-1-/- mice. I observed that EC at an atherosusceptible site express pro-apoptotic proteins and are primed for apoptosis and proliferation in response to LPS through a JNK1-dependent mechanism, whereas EC at a protected site expressed lower levels of pro-apoptotic molecules and was protected from injury by MKP-1. These findings indicate that the spatial variation of JNK1 activity delineates the spatial distribution of apoptosis and turnover of EC in arteries, and may influence the punctuate development of atherosclerotic lesions.
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Helbig, Lars [Verfasser]. "Aktivierung von c-Jun-N-terminalen Kinasen (SAPK,JNK) als Teil der späten Cisplatin abhängigen DNA-Schadensantwort / Lars Helbig." Mainz : Universitätsbibliothek Mainz, 2013. http://d-nb.info/1034965247/34.
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Sclip, Alessandra. "C-Jun-N-terminal kinase regulates Aβ oligomers production, synapthopathy and cognitive deficits in Alzheimer's disease." Thesis, Open University, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.594746.
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Alzheimer's disease (AD) is a debilitating neurodegenerative disorder characterized by Amyloid-B CAP) and tau deposition in the brain. The number of patients suffering AD is estimated at 36 million worldwide, making AD the most common fonn of dementia. There is no efficient therapy for AD, thus efforts to develop new pharmacological strategies to treat AD need to be intensified. Increasing evidence establishes a central role of soluble and oligomeric form of AP peptide in the pathogenesis of AD. AP accumulates in the synaptic compartment and disrupts the synaptic functionality, leading at least to synaptic loss and neurodegeneration. These events strongly correlate with cognitive deficits characteristic of the pathology. The mechanisms promoting AP production as well as the intracellular pathways responsible for synaptic degeneration are not well known. Objective of this study was thus to decipher the signaling pathways involved in A~ oligorners toxicity, focusing on cj Jun N-terminal kinase (JNK). JNK has been extensively studied for its role in stress stimuli and AD. Here we found that JNK participates to the production of AP oiigomers, promoting phosphorylation of APP at Thr668 residue. Moreover we reported a strong activation of the JNK pathway in the synaptic compartment in both in vitro and in vivo models of synaptopathy. This correlates with the reduction of dendritic spines density and a decrease of postsynaptic markers (AMP AR and NMDAR subunits, PSD-95 and drebrin). To confirm the involvement of JNK in synaptic degeneration induced by AP oligomers we phannacologically inhibited JNK action, using the specific cell permeable peptide, D-JNKll. Treatment with D-JNKII reduces the amyloidogenic cleavage of APP, and thus the production of AP oiigomers. Moreover, D-JNKll reverts synaptic degeneration preventing loss of dendritic spines and proteins from the postsynaptic membrane. Finally, the peptide prevents long term potentiation and long term depression alterations and completely reverts cognitive deficits. These results provide essential new infotmation about the molecular changes that ultimately lead to the disruption of synaptic functionality and validate JNK inhibition as a new pharmacological strategy for the treatment of AD.
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Camardo, Andrew T. "C-JUN N-TERMINAL KINASE INHIBITORY NANOTHERAPEUTICS FOR REGENERATIVE ELASTIC MATRIX REPAIR IN ABDOMINAL AORTIC ANEURYSMS." Cleveland State University / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=csu1499868307678719.
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He, Hua, and 何華. "Anti-tumor mechanisms of cyclooxygenase inhibitors and a c-Jun-N-terminal kinase inhibitor in gastrointestinal cancers." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2004. http://hub.hku.hk/bib/B30075245.
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Orton, Christopher R. "Analysis of Protein Adduction Kinetics and the Effects of Protein Adduction on C-Jun N-Terminal Kinase Signaling." Diss., The University of Arizona, 2006. http://hdl.handle.net/10150/194247.
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Defining the mechanics and consequences of protein adduction is crucial to understanding the toxicity of reactive electrophiles. Application of tandem mass spectrometry and data analysis algorithms enables detection and mapping of chemical adducts at the level of amino acid sequence. Nevertheless, detection of adducts does not indicate relative reactivity of different sites. In this dissertation I describe a method to measure the kinetics of competing adduction reactions at different sites on the same protein using quantitative mass spectrometry. Adducts are formed by electrophiles at Cys-14 and Cys-47 on the metabolic enzyme glutathione-S-transferase P1-1 and accompanied by a loss of enzymatic activity. Relative quantitation of protein adducts was done by tagging N-termini of peptide digests with isotopically labeled phenyl isocyanate and tracking the ratio of light-tagged peptide adducts to heavy-tagged reference samples. This method was used to measure rate constants for adduction at both positions with two different model electrophiles, IAB and BMCC. The results indicate that Cys-47 was approximately 2-3-fold more reactive toward both electrophiles than was Cys-14. This result was consistent with the relative reactivity of these electrophiles in a complex proteome system. Quantitative analyses of protein modifications provide a means of determining the reactivity and selectivity of damaging protein modifications in chemical toxicity.Another area of study explored in this dissertation is looking at the effects of protein alkylation on activating cellular signaling pathways, specifically the JNK signaling pathway. Protein adduction has been shown to be selective between different alkylating agents. It would then be reasonable to think this selectivity of adduction translates to selectivity of downstream consequences or cellular events directly tied to specific adductions. My work will show how treatment of HEK293 cells with either IAB or BMCC leads to differences in activation of JNK signaling. In addition, I've been able to show a difference in selectivity of a number of adducted targets by each alkylating agent, which are directly involved in regulation of the JNK signaling pathway. These studies illustrate not only the significance of protein adduction, but the importance for continual research to better understand their behavior in living systems.
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Garcia, Marta. "Rôle des voies de transduction intracellulaire c-Jun N-terminal Kinase dans la neurodégénérescence striatale : application à la maladie de Huntington." Paris 11, 2003. http://www.theses.fr/2003PA112066.
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La maladie de Huntington (MH) est une affection génétique neurodégénérative héréditaire, létale causée par l'expansion d'un motif polyglutamine dans la huntingtine. Cette maladie résulte d'une mort neuronale dans une région cérébrale, le striatum. Une approche expérimentale utilisée pour étudier ce point, consiste à reproduire chez l'animal, les caractéristiques phénotypiques de la maladie par administration systémique d'une neurotoxine: l'acide 3-Nitropropionique (3-NP). Notre travail de recherche a concerné l'élucidation des mécanismes intracellulaires qui gouverne la mort des neurones striataux dans la maladie de Huntington. Une première approche était un modèle in vivo, chez le rat, utilisant l'administration chronique de 3-NP. Nous avons montré dans ce modèle l'activation d'une voie de transduction intracellulaire, la voie des c-Jun N-terminal Kinase (JNK) in vivo, en réponse au 3-NP. Cette activation est sélective du striatum, associée à la régulation du facteur de transcription c-Jun, qui joue un rôle important dans l'expression de gènes pro-apoptotiques. Pour pouvoir caractériser la fonction du module JNK/c-Jun dans la mort induite par le 3-NP, nous avons utilisé des cultures primaires de striatum traitées au 3-NP. Grâce à ce modèle, nous avons pu montrer que l'inhibition de c-Jun protégeait les neurones striataux de l'apoptose induite par le 3-NP. La suite logique de ce travail est d'appliquer ces résultats à la neurodégénérescence observée dans la MH. Dans des cultures primaires de striatum exprimant l'exon 1 de la huntingtine mutée, nous avons pu reproduire la dégénérescence striatale et observé une activation du facteur de transcription c-Jun. L'invalidation des fonctions de c-Jun montre une protection vis à vis de la mort neuronale induite par la huntingtine mutée. L'ensemble de ces études, nous a permis de mettre en évidence, l'implication de la voie JNK ciblant c-Jun dans la neurodégénérescence striatale dans deux modèles de MHHuntington's disease (HD) is an autosomal dominant neurodegenerative disorder, caused by an expansion of a polyglutamine repeat in the huntingtin protein, the function of which is still unknown. Although huntingtin is expressed throughout the body, HD pathology is characterized by extensive loss of neurons in the striatum. The mechanism of this neuronal degeneration is unknown. The JNK (c-Jun N-terminal Kinase) belongs to the group of Mitogen-activated protein (MAP) kinases and is activated in response to cellular stress, including high doses of dopamine or glutamate, in striatal neurons. Ln this manner, JNK participates to the apoptotic response in various systems. The apoptotic functions of JNK critically depend of its major substrate the nuclear transcription factor c-Jun. We showed that the JNK/c- Jun module was activated by 3-nitropropionic acid (3-NP), a mitochondrial toxin that reproduces, in vivo, in the rat, some major characteristics of HD, including behavioural and morphological alterations (including selective degeneration of striatal neurons). Of interest, systemic and chronic administration of 3-NP, induced, JNK and c-Jun phosphorylation specifically within the striatum. Application of 3-NP on primary striatal cultures in vitro, reproduced both JNK and c-Jun activation, and overexpression of a dominant negative version of c-Jun inhibited 3-NP-induced striatal death. We then washed in an in vitro model of HD, primary striatal neurons transfected with the mutated huntingtin, with an expanded polyglutamine tract. Our data indicate that a significant percentage of striatal neurons expressing expanded- but not normal-huntingtin, present phosphorylation of c-Jun. Moreover, co-expression of a dominant negative version of c-Jun, together with mutated huntingtin significantly impairs striatal neuron death induced by mutated huntingtin. These data suggest that a pro-apoptotic gene program, involving the JNK pathway, can be an early event in the pathogenesis of HD
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Chan, Anthony Siu Lung. "Activation of c-jun N-terminal kinase by G protein-coupled receptors and the cross-communication with epidermal growth factor signaling /." View Abstract or Full-Text, 2002. http://library.ust.hk/cgi/db/thesis.pl?BICH%202002%20CHAN.
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Thesis (Ph. D.)--Hong Kong University of Science and Technology, 2002.Includes bibliographical references (leaves 201-236). Also available in electronic version. Access restricted to campus users.
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Tavares, Macedo Joana [Verfasser], and Bärbel [Akademischer Betreuer] Blaum. "Production and glycan binding characterization of human properdin and structural elucidation of c-Jun N-terminal kinase 3 inhibitors / Joana Tavares Macedo ; Betreuer: Bärbel Blaum." Tübingen : Universitätsbibliothek Tübingen, 2019. http://d-nb.info/1201644925/34.
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Amin, Shahreen. "Regulation of the tyrosine phosphatase SHP-1 expression by C-jun-N-terminal kinase and RFX-1 and AP-4 transcription factors in insulin-like growth factor-1 (IGF-1) stimulated breast adenocarcinoma MCF-7 cells." Thesis, University of Ottawa (Canada), 2005. http://hdl.handle.net/10393/26837.
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This thesis is devoted to reveal the negative regulators in IGF-1 (Insulin like growth factor 1) stimulated growth of a human breast adenocarcinoma cell line. It is a well established fact that increased circulating levels of IGF-1 correlate with increased risk of breast cancer. IGF-1 activation of its receptor, IGF-1R, is implicated in the progression of breast cancer, where IGF-1 stimulation leads to proliferative and anti-apoptotic responses by stimulating MAPK Erk and PI3K, respectively. In this study, IGF-1 stimulated MCF-7 cells proliferated more in the absence of MAPK JNK, implicating the involvement of MAPK JNK in the negative regulation of IGF-1 stimulated cell growth.
In this research study, we show for the first time that IGF-1 stimulation of breast cancer cells induces SHP-1-expression by activating JNK, which in turn, activates RFX-1 and AP-4 transcription factors to allow them to bind to the high-expression region of the SHP-1 P-1 promoter in breast adenocarcinoma MCF-7 cells. (Abstract shortened by UMI.)
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He, Tiantian. "Studying the Role of Peroxiredoxin 1 in ROS Modulation and Drug Resistance." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA112139.
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Les peroxyrédoxines sont des enzymes essentielles de la cellule. Outre leur rôle d’antioxydant, elles sont aussi des régulateurs de la signalisation cellulaire et des suppresseurs de tumeurs. La péroxiredoxine 1 (Prx1) est la plus abondante parmi les six isoformes de peroxyrédoxines humaines. Elle est fréquemment surexprimée dans plusieurs types de cellules cancéreuses, et on a pu associer Prx1 aux processus de carcinogenèse et de métastase, ainsi qu’à la résistance à la radiothérapie ou la chimiothérapie. Ainsi, Prx1 pourrait donc être une cible anticancéreuse intéressante. Au cours de ce travail de thèse, nous avons d’abord évalué l'impact d’une diminution de Prx1 (Prx1 knockdown (Prx1–)) sur la sensibilité cellulaire à des dizaines de médicaments anticancéreux dont la vinblastine, le taxol, la doxorubicine, la daunorubicine, l’actinomycine D, et le 5-fluorouracile, et d’agents connus pour provoquer la production d’espèces réactives de l’oxygène (ROS), dont le peroxyde d'hydrogène, le 2-phényléthyle isothiocyanate, le β-lapachone (β-lap) et la ménadione. Nous avons mis en évidence qu’une diminution de Prx1 augmente significativement la sensibilité des cellules à l'effet cytotoxique de la β-lap et de la ménadione, deux naphtoquinones possédant une activité anti-tumorale.Nous avons étudié les mécanismes responsables de l'augmentation de la cytotoxicité de la β-lap dans un contexte Prx1–. Nous montrons que la toxicité accrue de la β-lap dans des cellules Prx1– est due à une accumulation intracellulaire de ROS. Cet effet est dépendant de l’activité NADPH quinone oxydoréductase (NQO1) et s’accompagne d’une phosphorylation de c-Jun N-terminal kinases (JNK), protein 38 (p38), extracellular signal-regulated kinases (Erk) et des mitogen-activated protein kinases (MAPK), mais aussi d’une diminution des niveaux protéiques de la thiorédoxine 1. En se basant sur le fait que Prx1 est une enzyme antioxydante et un partenaire d'au moins ASK1 et JNK, deux éléments clés de la voie MAPK, nous proposons que la sensibilisation à la β-lap, observée après diminution de Prx1, est provoquée par une action synergique entre l'accumulation de ROS et l'induction de la voie MAPK, conduisant ainsi à l'apoptose.Nous avons ensuite étudié les mécanismes responsables de l'augmentation de la cytotoxicité de la ménadione dans le contexte Prx1–. La sensibilité accrue des cellules à l'effet cytotoxique de la ménadione et également associée à l'accumulation rapide et massive des ROS intracellulaire et à une mort cellulaire ressemblant à la nécrose programmée (necroptosis). L’accumulation de ROS induite par la ménadione et très rapidement détectée dans le cytosol, le noyau, et de façon encore plus importante, dans la matrice mitochondriale. Ce phénomène est en corrélation avec l'oxydation importante des thiorédoxine 2 et peroxiredoxine 3, deux protéines antioxydantes localisées dans la mitochondrie. La diminution de l’expression de Prx1 s’accompagne d’une augmentation des quantités tant de l’ARNm que de la protéine NRH: quinone oxydoréductase 2 (NQO2). Cette augmentation de l'activité de NQO2 est en grande partie responsable de l'accumulation intracellulaire de ROS et de la mort cellulaire après le traitement à la ménadione. Nos données révèlent que l’accumulation de ROS dans les cellules Prx1– provient de la résultante entre l’augmentation de leur production par NQO2 au cours du métabolisme de la ménadione et la diminution de leur élimination par Prx1. Enfin et de façon surprenante, selon la nature des naptoquinones (β-lap ou ménadione), les voies métaboliques qui conduisent à l'accumulation des ROS, ou les voies de signalisation et les mécanismes de mort cellulaire impliqués semblent être distinctsPeroxiredoxins have multiple cellular functions as major antioxidants, signaling regulators, molecular chaperones and tumor suppressors. Peroxiredoxin 1 (Prx1) is the most abundant among the six isoforms of human peroxiredoxins. It is frequently over-expressed in various cancer cells, which is known associated with carcinogenesis, metastasis and resistance to radiotherapy or chemotherapy. Prx1 could thus be an interesting anticancer target. In this study, we first evaluated the impact of Prx1 knockdown (Prx1–) on cellular sensitivity to dozens of anticancer drugs including vinblastine, taxol, doxorubicin, daunorubicin, actinomycin D, and 5-fluorouracil, and of reactive oxygen species (ROS)-generating agents, including hydrogen peroxide, 2-phenylethyl isothiocyanate, β-lapachone (β-lap) and menadione. We observed that Prx1 knockdown significantly enhanced cancer cell sensitivity to β-lap and menadione, two naphthoquinones with anti-cancer activity.We first investigated the underlying mechanisms responsible for the specifically enhanced cytotoxicity to β-lap in a Prx1 knockdown context. Prx1 knockdown markedly potentiated β-lap-induced cytotoxicity through ROS accumulation. This effect was largely NAD(P)H:quinone oxidoreductase 1 (NQO1)-dependent and associated with the phosphorylation of c-Jun N-terminal kinases (JNK), protein 38 (p38) and extracellular signal-regulated kinases (Erk) proteins in mitogen-activated protein kinase (MAPK) pathways, and a decrease in thioredoxin 1 protein levels. Based on the fact that Prx1 is a major ROS scavenger and a partner of apoptosis signaling kinase 1 (ASK1) and JNK, two key components of MAPK pathways, we propose that Prx1 knockdown-induced sensitization to β-lap is achieved through the combined action of ROS accumulation and MAPK pathway activation, leading to cell apoptosis.We then investigated the underlying mechanisms responsible for the specifically enhanced cytotoxicity to menadione in Prx1– cells. Enhanced sensitivity to menadione was associated with a rapid and significant intracellular ROS accumulation and necroptotic-like cell death. Menadione-induced ROS accumulation occurred immediately in the cytosol, the nucleus, and even more noticeably in the mitochondrial matrix, correlated with significant oxidation of both mitochondria-localized thioredoxin 2 and peroxiredoxin 3. Prx1 knockdown significantly up-regulated mRNA and protein levels of NRH: quinone oxidoreductase 2 (NQO2). Increased activity of NQO2 was largely responsible for menadione-induced ROS accumulation and consequent cell death. Our data indicate that massive ROS accumulation results from the combined effect of increased ROS generation by higher NQO2 activity during menadione metabolism, and diminished Prx1 scavenging activity. Finally and noteworthy, the metabolic pathways that lead to ROS accumulation, downstream signaling pathways and cell death mechanisms appear to be distinct for β-lap and menadione
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Chan, Yushin, and 詹育欣. "The role of c-Jun N-terminal kinase (JNK)." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/60142941903169660454.
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碩士長庚大學
基礎醫學研究所
92
Paclitaxel is one of the microtubule-active agents. It interacts with β-tubulin, stabilzes the microtubule structure and thus alters the microtubule dynamics, resulting in the G2/M phase arrest. After a prolonged G2/M arrest, cells undergo apoptosis. Paclitaxel also activates JNK/SAPK (c-Jun N-terminal kinases/stress-activated protein kinases) and the activated JNK further phosphorylates c-Jun, a transcription factor, regulating downstream genes expression. JNK activation is required for the early phase of paclitaxel-induced apoptosis. However, the exact role of JNK in paclitaxel-induced apoptosis is not completely clear, and genes that are involved in paclitaxel-induced apoptosis remain to be clarified. SP600125, a JNK inhibitor, can inhibit the phosphorylation of c-Jun by JNK. Although the cytotoxicity of SP600125 was low, we found that, at high concentration of SP600125, cells arrest at the G2/M phase. Pretreatment of SP600125 inhibited the activation of c-Jun and reduced the paclitaxel-induced apoptosis. Using cDNA microarrays, I also analyzed the downstream target genes of c-Jun upon JNK activation. Twenty genes were selected and 14 among them were upregulated by paclitaxel and could be downregulated by SP600125; and the other 6 were downregulated by paclitaxel and could be upregulated by SP600125. Most of the genes were involved in the regulation of cytoskeleton, cell growth, apoptosis and other signal transduction pathways. Results of my study have detected some interesting genes that are worth further studies to characterize their roles in paclitaxel-induced apoptosis.
31
Melino, Michelle. "The role of c-jun N-terminal kinase (JNK) in human T cell function." 2009. http://hdl.handle.net/2440/56209.
Full textAbstract:
T cells are involved in cellular pathways which enable the immune system to protect us against infection and cancer. However, the same mechanisms also allow T cells to generate chronic inflammatory conditions, including autoimmunity and allergy. Thus a concerted effort has been made to try to understand how the immune system functions in order to inhibit responses which may have harmful effects on tissues and organs. There is a continued search for new immunosuppressants which can only be accomplished through a better understanding of the pathways that regulate T cell function. This includes the intracellular signalling pathways which modulate T cell proliferation and cytokine production. While the Mitogen-Activated Protein Kinases (MAPK), extracellular signal-regulated protein kinases (ERK) and p38 have received attention, the role of the stress-activated protein kinases or c-jun N-terminal kinases (JNK) remains controversial. To overcome some of the limitations in studying the role of JNK, a new approach was taken in this thesis. The investigations used recently described peptides (TAT-JIP[subscript]153-163 and TAT-JIP[subscript]153-172) derived from the scaffold protein, JIP-1, which have previously been demonstrated to act as JNK pathway inhibitors. The research characterised the specificity of these inhibitors to enable the appropriate interpretation of data. Using these inhibitors, we were able to show that JNK regulated human T cell proliferation and cytokine production in T cell responses induced independently of TCR ligation (PHAPMA) or via the TCR (anti-CD3-anti-CD28 antibodies, Mixed Lymphocyte Reaction (MLR), Tetanus Toxoid and Der p 2). The data demonstrated that JNK primarily regulated the Th1 cytokine patterns (IFNγ, IL2 and LT) with minimal effect on Th2 cytokine production (IL4, IL10) in response to all stimulatory models. However, while the JNK signalling pathway promoted T cell proliferation and cytokine production in response to PHA-PMA, the pathway depressed these responses following stimulation with anti-CD3-anti-CD28 antibodies and Tetanus Toxoid. Thus activation of JNK with microbial pathogens such as Pseudomonas aeruginosa (PA), which non-specifically activate T cells, may promote lymphocyte proliferation and the release of Th1 cytokines, such as IFNγ. In contrast, JNK activation resulting from engagement of the T cell receptor (TCR) (i.e. Tetanus Toxoid), down-regulates Th1 cytokine production. Therefore, it is likely that the JNK signalling pathway may dampen the development of chronic inflammatory conditions resulting from infection with intracellular parasites and autoimmune diseases. In contrast to Tetanus Toxoid, responses to the recombinant house dust mite allergen, Dermatophagoides pteronyssinus (Der p 2) were promoted by JNK, leading to an increase in Th1 cytokine production. Thus the results suggest that the use of JNK inhibitors could exacerbate both inflammatory conditions (autoimmunity and allergy) and this may also apply to p38 but not the ERK signalling pathway.http://proxy.library.adelaide.edu.au/login?url= http://library.adelaide.edu.au/cgi-bin/Pwebrecon.cgi?BBID=1374669
Thesis (Ph.D.) - University of Adelaide, School of Molecular and Biomedical Science, 2009
32
Melino, Michelle. "The role of c-jun N-terminal kinase (JNK) in human T cell function." Thesis, 2009. http://hdl.handle.net/2440/56209.
Full textAbstract:
T cells are involved in cellular pathways which enable the immune system to protect us against infection and cancer. However, the same mechanisms also allow T cells to generate
chronic inflammatory conditions, including autoimmunity and allergy. Thus a concerted effort has been made to try to understand how the immune system functions in order to inhibit
responses which may have harmful effects on tissues and organs. There is a continued search for new immunosuppressants which can only be accomplished through a better understanding of the pathways that regulate T cell function. This includes the intracellular signalling pathways which modulate T cell proliferation and cytokine production.
While the Mitogen-Activated Protein Kinases (MAPK), extracellular signal-regulated protein kinases (ERK) and p38 have received attention, the role of the stress-activated protein kinases or c-jun N-terminal kinases (JNK) remains controversial. To overcome some of the limitations in studying the role of JNK, a new approach was taken in this thesis. The
investigations used recently described peptides (TAT-JIP[subscript]153-163 and TAT-JIP[subscript]153-172) derived from the scaffold protein, JIP-1, which have previously been demonstrated to act as JNK pathway inhibitors. The research characterised the specificity of these inhibitors to enable the appropriate interpretation of data.
Using these inhibitors, we were able to show that JNK regulated human T cell proliferation and cytokine production in T cell responses induced independently of TCR ligation (PHAPMA) or via the TCR (anti-CD3-anti-CD28 antibodies, Mixed Lymphocyte Reaction (MLR), Tetanus Toxoid and Der p 2). The data demonstrated that JNK primarily regulated the Th1 cytokine patterns (IFNγ, IL2 and LT) with minimal effect on Th2 cytokine production (IL4, IL10) in response to all stimulatory models. However, while the JNK signalling pathway promoted T cell proliferation and cytokine production in response to PHA-PMA, the pathway depressed these responses following stimulation with anti-CD3-anti-CD28 antibodies and Tetanus Toxoid. Thus activation of JNK with microbial pathogens such as Pseudomonas
aeruginosa (PA), which non-specifically activate T cells, may promote lymphocyte proliferation and the release of Th1 cytokines, such as IFNγ. In contrast, JNK activation resulting from engagement of the T cell receptor (TCR) (i.e. Tetanus Toxoid), down-regulates Th1 cytokine production. Therefore, it is likely that the JNK signalling pathway may dampen the development of chronic inflammatory conditions resulting from infection with intracellular parasites and autoimmune diseases. In contrast to Tetanus Toxoid, responses to the recombinant house dust mite allergen, Dermatophagoides pteronyssinus (Der p 2) were promoted by JNK, leading to an increase in Th1 cytokine production. Thus the results suggest that the use of JNK inhibitors could exacerbate both inflammatory conditions (autoimmunity and allergy) and this may also apply to p38 but not the ERK signalling pathway.Thesis (Ph.D.) - University of Adelaide, School of Molecular and Biomedical Science, 2009
33
Mitra, Shreya. "Role of c-Jun N-terminal kinase (JNK) in mediating mammary cancer cell migration and metastasis." 2009. http://hdl.handle.net/2152/18422.
Full textAbstract:
The c-Jun N-terminal kinases (JNKs) are MAPK family members and are activated by stress, growth factors and cytokines. They are encoded by three separate genes (jnk 1, 2, and 3), spliced alternately creating 10 isoforms. JNK signaling promotes both cell death and cell survival in a stimuli and tissue specic manner and is also implicated in tumorigenesis. Using the Polyoma Virus Middle T Antigen (PyVMT) transgenic mouse model where jnk2 was either expressed or deleted, we found that the PyVMTjnk2-/- tumors expressed higher Epidermal Growth Factor Receptor Substrate 8 (EPS8) mRNA and protein. EPS8 regulates EGFR signaling from Ras to Rac and EGFR tracking via Rab5 and RN-Tre. EPS8 is a prime candidate for connecting the EGFR signaling to actin cytoskeleton remodeling, thus mediating cell migration, a critical step in metastasis. In migration assays, PyVMTjnk2+/+ cells migrated ve fold more than the PyVMTjnk2-/- cells. Re-expression of JNK2[alpha] in the PyVMTjnk2-/- cells rescued this phenotype. Expression of shRNA EPS8 in the PyVMTjnk2-/- cell increased migration in vitro. EPS8 localization at dorsal rues and internalization of EGF-EGFR complexes coincided with JNK2 expression. Expression of shEPS8 in the PyVMTjnk2-/- cells increased EGF internalization suggesting that in absence of JNK2, EPS8 participates in Rab5-RN-Tre complex that inhibits EGFR internalization. Finally, we report that in absence of JNK2, EPS8 protein stability is greatly increased, suggesting that JNK2 is essential for endosomal sorting and degradation of EGFR associated cargo, of which EPS8 is a critical part. In contrast, silencing JNK1 (p46) in 4T1.2 mammary tumor cells, consistently enhanced cell invasion and tumor growth. Tumors derived from orthotopic injection of the 4T1.2shJNK1 expressing cells into the mammary fat pad reached target volume signicantly earlier than non-silencing vector expressing tumors. When injected intravenously, signicantly higher lung metastasis was observed in the 4T1.2shJNK1 group. The more aggressive behavior of 4T1.2shJNK1 tumors was associated with an increase in CCR5 and pAkt as detected by microarray analysis. Taken together, our data suggest that JNK1 suppresses the expression of proteins associated with tumor growth and invasive phenotype, contributing to tumor progression.text
34
Kaschwich, Mark. "Die Rolle der C-jun N-terminalen Kinase (JNK) im neuronalen Zelltod nach Schädigung des Cytoskeletts." 2006. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=015430602&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
Full text
35
Shine-Gwo, Shiah, and 夏興國. "Mechanism of c-Jun NH2-terminal Kinase (JNK) Signal Transduction Pathway in Anticancer Drugs-induced Apoptosis." Thesis, 1999. http://ndltd.ncl.edu.tw/handle/17640492931482607622.
Full textAbstract:
博士國立臺灣大學
毒理學研究所
87
ABSTRACT B-Lapachone (B-Lap) has been found to inhibit DNA topoisomerases (Topo) by a mechanism distinct from that of other commonly known Topo inhibitors. In the present study, we demonstrated a pronounced elevation of H2O2 and O2- in human leukemia HL-60 cells treated with b-Lap. Treatment with other Topo poisons, such as camptothecin (CPT), VP-16, and GL331, did not have the same effect. On the other hand, antioxidant vitamin C (Vit. C) treatment effectively antagonized b-Lap-induced apoptosis. This suggested that a reactive oxygen species (ROS)-related pathway was involved in b-Lap-induced apoptosis program. We also found that c-Jun NH2-terminal kinase (JNK), but not p38-mitogen-activated protein kinase (MAPK) or extracellular signal-regulated kinase 1/2 (ERK1/2) was persistently activated in apoptosis induced by b-Lap. Overexpression of a dominant-negative mutant MAPK kinase kinase 1 (MEKK1-DN) or treatment with JNK-specific antisense oligonucleotide or Vit. C all prevented b-Lap-induced JNK activation and the subsequent apoptosis. Only the expression of MEKK1-DN, but not Vit. C treatment, blocked the JNK activity induced by CPT, VP-16 or GL331. These results confirm again that ROS acts as a mediator for JNK activation during b-Lap-induced apoptosis. Furthermore, we found that b-Lap can stimulate CPP32/Yama activity, which was, however, markedly inhibited by the MEKK1-DN expression or Vit. C treatment. Again, CPT-induced CPP32/Yama activation can be abolished by MEKK1-DN but not by Vit. C treatment. Taken together, these results indicate that b-Lap, but not other Topo inhibitors, triggers apoptosis signaling, i.e., JNK and subsequent CPP32/Yama activation are mediated by the generation of ROS.
36
Huang, Yi-Feng, and 黃怡鳳. "The Role of c-Jun N-terminal kinase 1 (JNK1) in BMP2 induced osteoblastic differentiation." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/25726381910909510774.
Full textAbstract:
博士國立陽明大學
生物藥學研究所
100
Runx2 plays a crucial role in osteoblastic differentiation, which can be upregulated by bone morphogenetic protein 2 (BMP2). Mitogen-activated protein kinase (MAPK) cascades, such as extracellular signal-regulated kinase (ERK) and p38, have been reported to be activated by BMP2 to increase Runx2 activity. The role of cjun-N-terminal kinase (JNK), the other member of MAPK, in osteoblastic differentiation has not been well elucidated. In this study, we first demonstrated that JNK1 is activated by BMP2 in multipotent C2C12 and preosteoblastic MC3T3-E1 cell lines. We then demonstrated that early and late osteoblastic differentiation, represented by ALP expression and mineralization, respectively, are significantly enhanced by JNK1 loss-of-function, such as treatment of JNK inhibitor, knockdown of JNK1 and ectopic expression of a dominant negative JNK1 (DN-JNK1). Consistently, BMP2-induced osteoblastic differentiation is reduced by JNK1 gain-of-function, such as enforced expression of a constitutively active JNK1 (CA-JNK1). Most importantly, we demonstrated that Runx2 is required for JNK1-mediated inhibition of osteoblastic differentiation, and identified Ser104 of Runx2 is the site phosphorylated by JNK1 upon BMP2 stimulation. Finally, we found that overexpression of the mutant Runx2 (Ser104Ala) stimulates osteoblastic differentiation of C2C12 and MC3T3-E1 cells to the extent similar to that achieved by overexpression of wild-type Runx2 plus JNK inhibitor treatment. Taken together, these data indicate that JNK1 negatively regulates BMP2-induced osteoblastic differentiation through phosphorylation of Runx2 at Ser104. In addition, unraveling these mechanisms may help to develop new strategies in enhancing osteoblastic differentiation and bone formation.
37
Ganduri, Ramesh. "Cocrystallization Studies Extending from Small Molecules to Proteins: a) Cocrystals, Salts and Eutectics, b) Chemical, Structural and Biological Evaluation of Anthrapyrazolones as Inhibitors of JNK proteins." Thesis, 2018. https://etd.iisc.ac.in/handle/2005/5363.
Full textAbstract:
In summary, we have designed and synthesized three halogenated derivatives of 1,9-
pyrazoloanthrone. The involvement of halogen bonding provides highly directional
interactions in the binding pocket and hence demonstrates improved inhibitory activity.
Among the three halogenated derivatives of 1,9-pyrazoloanthrone, R3 exhibits the most
specific inhibition of JNKs activity at significantly lower concentrations (1M) compared
to R1, R2 and SP600125 with no off-target effects on other kinases such as p38 and
ERK1/2. Further, R3 being a potent and specific inhibitor of JNKs, regulates LPStriggered
expressions of chemokines in macrophages. R3 appears as the best designed
inhibitor and hence may facilitate the development of novel therapeutics to treat JNKs
associated disorders. Therefore, current study proposes R3 as a better alternative for
SP600125 to inhibit JNKs activity and may act as a promising tool to comprehend the
physiological role of JNKs for therapeutic benefits
38
Chen, Ya-Hui, and 陳雅惠. "The Roles of FasL/Fas Apoptotic System and C-Jun N-terminal Kinase (JNK) Activation in the Outgrowth of Cultured Trophoblast Spheroids on Monolayers of Endometrial Epithelial Cells." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/45106666235537619033.
Full textAbstract:
碩士國立陽明大學
解剖暨細胞生物學研究所
92
During embryo implantation in mammals, trophoblast cells of the attached blastocyst penetrate the endometrial epithelium of the uterus before invasion into the endometrial stroma. Signaling of apoptosis was demonstrated in endometrial epithelial cells (EEC) surrounding the trophoblast cells; however, the signaling mechanisms leading to apoptosis in EEC remain unclear. Since mitogen-activated protein kinases (MAPKs) were shown to mediate apoptosis in several model systems and found to be activated in the uterus during decidualization, and then evidenced the important role of induction of p38 MAPK-mediated apoptosis involved in outgrowth of trophoblast cells on EEC in a model of human trophoblast-endometrial interactions, rather not ERK. The Fas-Fas Ligand (FasL) system is one of the major for the induction of apoptosis in cells and tissues. However, the Fas/FasL death system was found to be active at the embryo-endometrial interface, and in various cell models, activation of members of the MAPK superfamily was demonstrated to either mediate Fas-induced apoptosis or enhance FasL expression. The objective of this study were to investigate the roles of JNK activation and Fas/FasL system during embryo implantation using a co-culture model by co-culturing BeWo human trophoblast spheroids with RL95-2 human EEC monolayers to mimic the blastocyst-endometrial interaction. First, immunoblotting analysis showed that JNK were activated in EEC after co-culture. However, SP600125 (a JNK inhibitor) inhibited trophoblast outgrowth on EEC monolayers through the suppression of JNK activation in EEC and trophoblast cells. Second, MTT assay showed that Fas and FasL expressed on RL95-2 cells were functional to Fas-mediated apoptosis by using anti-Fas activating Ab, but BeWo cells was not observed. Then, trophoblast spheroid outgrowth on EEC monolayers was not significantly inhibited by anti-Fas neutralizing Ab, but spheroid outgrowth on EEC was notably increased by anti-Fas activating Ab. Furthermore, trophoblast expansion on EEC in the presence of anti-Fas activating Ab caused prominent EEC apoptosis at the spheroid-EEC interface compare with in the absence of anti-Fas activating Ab, as detected by annexin V labeling and valyl-alanyl-aspartyl-[O-methyl]-fluoromethylketone (VAD-FMK, which binds activated caspases) staining. Then, Z-VAD (pan-caspase inhibitor) appeared to have minimal effect on spheroid outgrowth, whereas Z-VAD significantly inhibited spheroid expansion on EEC monolayers that anti-Fas activating Ab was existed. In addition, SB203580 and SP600125 inhibited spheroid outgrowth enhanced by anti-Fas activating Ab on EEC monolayers, respectively, and p38 MAPK and JNK were both activated in EEC exposed to anti-Fas activating Ab. Then, using VAD-FMK staining technique for detecting caspase activation, marked activated caspase-positive cells along the spheroid-EEC interface in the presence of anti-Fas activating Ab that could be significantly suppressed by SB203580 and SP600125, respectively. Our results based on a model of human trophoblast-EEC interactions establish that trophoblast cells cause activation of JNK in EEC and trophoblast cells. In addition, our results also suggests that Fas/FasL system was not one of major for the mechanism of attachment between trophoblast cells and EEC, but may play an important role in trophoblast invasion, such as using anti-Fas activating Ab in our study. The signal was transferred by activating p38 MAPK and JNK in EEC, respectively, and then inducing apoptosis in EEC at the inter-implantation site and implantation site through the caspase-dependent pathway and caspase-independent pathway, therefore EEC were easy to be displaced and trophoblast spheroids outgrowth were easy successful.
39
Prasad, Karothu Durga. "Exploration of 1,9-Pyrazoloanthrones as a Copious Reserve for Multifarious Chemical and Biological Applications." Thesis, 2014. http://etd.iisc.ac.in/handle/2005/2980.
Full textAbstract:
Pyrazoloanthrone and its analogues form the central core of the thesis and the work is focused on the evaluation of chemical and biological applications of pyrazoloanthrones. Selective and sensitive detection of biologically, environmentally and industrially important molecular species such as fluoride, cyanide and picric acid by using pyrazoloanthrones as sensors form the first part while the second part deals with selective and specific kinase inhibition by pyrazoloanthrones to moderate inflammation associated disorders like septic shock. All the investigations are based on extensive crystallographic studies of the participating molecules.
Chapter 1 provides a brief review on the history and biological importance of 1,9-pyrazoloanthrones. The potential of these molecules as probes in sensor chemistry and protein kinase inhibition is envisaged. A short account of the techniques employed for the investigations along with a preamble is presented.
Chapter 2 is divided into two parts. Part A deals with the design of a colorimetric and “turn-on” fluorescent chemosensor based on 1,9-pyrazoloanthrone specifically for cyanide and fluoride ion detection. A remarkable solid state reaction indicated by the development of intense red color occurs when crystals of tetrabutylammonium cyanide/fluoride are brought in physical contact with 1,9¬pyrazoloanthrone resulting in corresponding molecular complexes (Figure 1). X-ray crystal structures of these complexes and also of 1,9-pyrazoloanthrone have been determined and the ion sensing activity has been substantiated on the basis of spectroscopic (absorption, fluorescence and NMR) and structural analyses. The crystal structure of the parent compound exhibits a disorder as a consequence of tautomerism and the disorder gets carried on to the complexes as well with even the cyanide and the fluoride ions showing partial occupancy sites. The presence of the –NH group and associated intramolecular charge transfer upon complex formation is attributed to the extreme sensitivity of 1,9-pyrazoloanthrone for cyanide and fluoride (detection limits of
0.2 ppb and 2 ppb) ions respectively.
Figure 1. Development of intense red color during the solid state reaction (shown on left) and the turn on fluorescence behavior (shown to the right)
Part B demonstrates the utilization of electron rich N-alkyl substituted pyrazoloanthrones to design sensors for detecting explosive and electron deficient nitro aromatics such as picric acid (PA). The N-alkyl derivative of 1,9-pyrazoloanthrone has been synthesized, characterized by single crystal X-ray diffraction studies and evaluated as a potent sensor for picric acid. NMR and fluorescence lifetime measurements validate that the fluorescence quenching of sensor compound by PA (Figure 2) as due to the formation of excited state charge-transfer complex resulting in dynamic quenching.
Figure 2. Fluorescence quenching measurements demonstrating the dynamic quenching in the charge transfer complex.
Chapter 3 deals with the biological evaluation of 1,9-pyrazoloanthrone and its alkyl derivatives towards the inhibition of a decisive protein kinase called c-Jun N-terminal Kinase (JNK), an important member of MAP kinase family. JNK controls crucial cellular processes like apoptosis and cell proliferation and is implicated in disorders associated with inflammation such as septic shock, arthritis, inflammatory bowel disease, etc. Therapeutic inhibition of JNK activity by small molecules has proven to be advantageous in the treatment of diseases coupled with derailed inflammation. In this context, it is already established that 1,9-pyrazoloanthrone (SP600125) effectively
and selectively inhibits JNK at concentrations beyond 10 M. A series of alkyl isomers of pyrazoloanthrone derivatives have been synthesized to evaluate the structural implications of inhibition and to elevate both selectivity and sensitivity at lower concentrations. The crystal structures of these isomers have been characterized and their utility as inhibitors has been tested for their in vitro inhibitory activity over c-Jun N-terminal kinase (JNK). The minimum inhibitory concentrations required by these molecules to inhibit JNK was found to be lesser as compared to 1,9-pyrazoloanthrone (<5 µM; Figure 3). Critically, it turns out that among the various inhibitors synthesized, the lead candidates SPP1 and SPB1 display specific inhibition of JNK among other LPS activated MAP kinases like ERK1/2 and p38. These results suggest that N-alkyl (propyl and butyl) bearing pyrazoloanthrone scaffolds provide promising therapeutic inhibitors for JNK in regulating inflammation associated disorders.
Figure 3. Inhibition of JNK in macrophages by the SPP1 and SPB1 compared to the known SP600125.
Inspired by the results reported in the previous chapter, Chapter 4 is devoted to the generation of a library of compounds based on SPP1 and SPB1 with a purpose to design inhibitors of JNK which perform at the lowest possible concentrations and the consequent evaluation of their potential on endotoxin induced septic shock. Severe sepsis or septic shock is one of the rising causes for mortality worldwide representing nearly 10% of intensive care unit admissions. Susceptibility to sepsis is identified to be mediated by innate pattern recognition receptors and responsive signaling pathways of the host. The c-Jun N-terminal Kinase (JNK)-mediated signaling events play critical role in bacterial infection triggered multi-organ failure, cardiac dysfunction and mortality.
Figure 4. Two selected molecules for specific inhibition studies of JNK at lower concentrations.
It is demonstrated that alkyl and halogen substitution on the periphery of anthrapyrazolone increases the binding potency of the inhibitors specifically towards JNK. Based on the results from both in vitro with macrophages and in vivo with the mouse model of septicemia, the potential role of two selected molecules D1 and D2 (Figure 4) in regulating endotoxin induced inflammation is firmly established. Further, it is demonstrated that hydrophobic and hydrophilic interactions generated by these small molecules effectively block endotoxin-induced inflammatory genes expression in in vitro and septic shock in vivo, in a mouse model, with remarkable efficacies. Altogether, the in vitro as well as the in vivo data clearly potentiates the selective inhibitory capacity of small molecule inhibitors like D1 and D2 which can facilitate the treatment of current inflammatory disorders when used in combination with the available drugs having varied efficacies. The results rationalize the significance of the diversity oriented synthesis of small molecules for selective inhibition of JNK and their potential in the treatment of severe sepsis.
40
Prasad, Karothu Durga. "Exploration of 1,9-Pyrazoloanthrones as a Copious Reserve for Multifarious Chemical and Biological Applications." Thesis, 2014. http://etd.iisc.ernet.in/handle/2005/2980.
Full textAbstract:
Pyrazoloanthrone and its analogues form the central core of the thesis and the work is focused on the evaluation of chemical and biological applications of pyrazoloanthrones. Selective and sensitive detection of biologically, environmentally and industrially important molecular species such as fluoride, cyanide and picric acid by using pyrazoloanthrones as sensors form the first part while the second part deals with selective and specific kinase inhibition by pyrazoloanthrones to moderate inflammation associated disorders like septic shock. All the investigations are based on extensive crystallographic studies of the participating molecules.
Chapter 1 provides a brief review on the history and biological importance of 1,9-pyrazoloanthrones. The potential of these molecules as probes in sensor chemistry and protein kinase inhibition is envisaged. A short account of the techniques employed for the investigations along with a preamble is presented.
Chapter 2 is divided into two parts. Part A deals with the design of a colorimetric and “turn-on” fluorescent chemosensor based on 1,9-pyrazoloanthrone specifically for cyanide and fluoride ion detection. A remarkable solid state reaction indicated by the development of intense red color occurs when crystals of tetrabutylammonium cyanide/fluoride are brought in physical contact with 1,9¬pyrazoloanthrone resulting in corresponding molecular complexes (Figure 1). X-ray crystal structures of these complexes and also of 1,9-pyrazoloanthrone have been determined and the ion sensing activity has been substantiated on the basis of spectroscopic (absorption, fluorescence and NMR) and structural analyses. The crystal structure of the parent compound exhibits a disorder as a consequence of tautomerism and the disorder gets carried on to the complexes as well with even the cyanide and the fluoride ions showing partial occupancy sites. The presence of the –NH group and associated intramolecular charge transfer upon complex formation is attributed to the extreme sensitivity of 1,9-pyrazoloanthrone for cyanide and fluoride (detection limits of
0.2 ppb and 2 ppb) ions respectively.
Figure 1. Development of intense red color during the solid state reaction (shown on left) and the turn on fluorescence behavior (shown to the right)
Part B demonstrates the utilization of electron rich N-alkyl substituted pyrazoloanthrones to design sensors for detecting explosive and electron deficient nitro aromatics such as picric acid (PA). The N-alkyl derivative of 1,9-pyrazoloanthrone has been synthesized, characterized by single crystal X-ray diffraction studies and evaluated as a potent sensor for picric acid. NMR and fluorescence lifetime measurements validate that the fluorescence quenching of sensor compound by PA (Figure 2) as due to the formation of excited state charge-transfer complex resulting in dynamic quenching.
Figure 2. Fluorescence quenching measurements demonstrating the dynamic quenching in the charge transfer complex.
Chapter 3 deals with the biological evaluation of 1,9-pyrazoloanthrone and its alkyl derivatives towards the inhibition of a decisive protein kinase called c-Jun N-terminal Kinase (JNK), an important member of MAP kinase family. JNK controls crucial cellular processes like apoptosis and cell proliferation and is implicated in disorders associated with inflammation such as septic shock, arthritis, inflammatory bowel disease, etc. Therapeutic inhibition of JNK activity by small molecules has proven to be advantageous in the treatment of diseases coupled with derailed inflammation. In this context, it is already established that 1,9-pyrazoloanthrone (SP600125) effectively
and selectively inhibits JNK at concentrations beyond 10 M. A series of alkyl isomers of pyrazoloanthrone derivatives have been synthesized to evaluate the structural implications of inhibition and to elevate both selectivity and sensitivity at lower concentrations. The crystal structures of these isomers have been characterized and their utility as inhibitors has been tested for their in vitro inhibitory activity over c-Jun N-terminal kinase (JNK). The minimum inhibitory concentrations required by these molecules to inhibit JNK was found to be lesser as compared to 1,9-pyrazoloanthrone (<5 µM; Figure 3). Critically, it turns out that among the various inhibitors synthesized, the lead candidates SPP1 and SPB1 display specific inhibition of JNK among other LPS activated MAP kinases like ERK1/2 and p38. These results suggest that N-alkyl (propyl and butyl) bearing pyrazoloanthrone scaffolds provide promising therapeutic inhibitors for JNK in regulating inflammation associated disorders.
Figure 3. Inhibition of JNK in macrophages by the SPP1 and SPB1 compared to the known SP600125.
Inspired by the results reported in the previous chapter, Chapter 4 is devoted to the generation of a library of compounds based on SPP1 and SPB1 with a purpose to design inhibitors of JNK which perform at the lowest possible concentrations and the consequent evaluation of their potential on endotoxin induced septic shock. Severe sepsis or septic shock is one of the rising causes for mortality worldwide representing nearly 10% of intensive care unit admissions. Susceptibility to sepsis is identified to be mediated by innate pattern recognition receptors and responsive signaling pathways of the host. The c-Jun N-terminal Kinase (JNK)-mediated signaling events play critical role in bacterial infection triggered multi-organ failure, cardiac dysfunction and mortality.
Figure 4. Two selected molecules for specific inhibition studies of JNK at lower concentrations.
It is demonstrated that alkyl and halogen substitution on the periphery of anthrapyrazolone increases the binding potency of the inhibitors specifically towards JNK. Based on the results from both in vitro with macrophages and in vivo with the mouse model of septicemia, the potential role of two selected molecules D1 and D2 (Figure 4) in regulating endotoxin induced inflammation is firmly established. Further, it is demonstrated that hydrophobic and hydrophilic interactions generated by these small molecules effectively block endotoxin-induced inflammatory genes expression in in vitro and septic shock in vivo, in a mouse model, with remarkable efficacies. Altogether, the in vitro as well as the in vivo data clearly potentiates the selective inhibitory capacity of small molecule inhibitors like D1 and D2 which can facilitate the treatment of current inflammatory disorders when used in combination with the available drugs having varied efficacies. The results rationalize the significance of the diversity oriented synthesis of small molecules for selective inhibition of JNK and their potential in the treatment of severe sepsis.
41
Λαγκαδινού, Ελένη. "Διερεύνηση μηχανισμών χημειοαντίστασης στην οξεία μυελογενή λευχαιμία με έμφαση στο ρόλο ενδοκυττάριων μονοπατιών μεταγωγής σήματος." Thesis, 2008. http://nemertes.lis.upatras.gr/jspui/handle/10889/2208.
Full textAbstract:
Η θεραπεία της Οξείας Μυελογενούς Λευχαιμίας (ΟΜΛ) είναι συχνά ανεπιτυχής λόγω ανάπτυξης κυτταρικής αντίστασης στα αντιλευχαιμικά φάρμακα. Εκτός από την έκφραση Ρ-γλυκοπρωτείνης στα λευχαιμικά κύτταρα, άλλοι κυτταρικοί παράγοντες μπορούν επίσης να συμβάλλουν στην χημειοαντίσταση. Η c- Jun N-terminal Kinase (JNK) είναι μία πρωτεινική κινάση που ενεργοποιείται όταν τα κύτταρα εκτεθούν σε χημειοθεραπευτικά φάρμακα (ΧΜΘ). Πρόσφατες μελέτες σε συμπαγείς όγκους συσχετίζουν την χημειοαντίσταση με αδυναμία των καρκινικών κυττάρων να ενεργοποιήσουν τη JNK κατόπιν επίδρασης ΧΜΘ. Σκοπός της εργασίας είναι να διερευνήσει αν η χημειοαντίσταση στην ΟΜΛ οφείλεται σε ενδογενή αδυναμία των λευχαιμικών βλαστών να ενεργοποιήσουν τη JNK. Μεθοδολογία: Συγκρίναμε ευαίσθητες (U937) και ανθεκτικές (U937R) στις ανθρακυκλίνες κυτταρικές σειρές ΟΜΛ ως προς την δυνατότητα in vitro ενεργοποίησης της JNK κατόπιν επίδρασης ΧΜΘ (Western Blot). Επιπλέον, στις λευχαιμικές κυτταρικές σειρές ελέγξαμε απευθείας τη σημασία της JNK στην χημειοαντίσταση με πειράματα α) αποσιώπησης της JNK με JNK1–στοχεύον siRNA και β) ενεργοποίησης της JNK (διαμόλυνση με τον ΜΚΚ4/SEK1 άνωθεν ενεργοποιητή της JNK) Περαιτέρω, ελέγξαμε την in vitro δυνατότητα ενεργοποίησης της JNK σε 29 πρωτογενή μυελικά δείγματα ΟΜΛ κατόπιν βραχείας διάρκειας (30-60min) έκθεση στην daunorubicin (1μΜ) και συσχετίσαμε τα εργαστηριακά δεδομένα με κλινικά χαρακτηριστικά των ασθενών με ΟΜΛ. Αποτελέσματα: In vitro θεραπεία των U937 κυττάρων με ανθρακυκλίνες προκάλεσε ισχυρή και ταχεία ενεργοποίηση της JNK και απόπτωση. Αντίθετα, στα πολυανθεκτικά U937R κύτταρα δεν παρατηρήθηκε ενεργοποίηση της JNK, ακόμη και σε συνθήκες υψηλής ενδοκυττάριας συγκέντρωσης ανθρακυκλινών. Αποσιώπηση της JNK στα ευαίσθητα U937 κύτταρα τα έκανε ανθεκτικά στις ανθρακυκλίνες (JNK1-siRNA διαμολυσμένα U937 κύτταρα εμφάνισαν 50.4% και 61.3% ελαττωμένη daunorubicin- (DNR, 1μΜ 24hr) και doxorubicin- (DOX, 1.5μΜ 24hr) προκαλούμενη απόπτωση αντίστοιχα, συγκριτικά με U937 κύτταρα-μάρτυρες, P<0.001). Αντίστροφα, εκλεκτική ενεργοποίηση της ανενεργού JNK στα ανθεκτικά U937R κύτταρα τα έκανε 3.3 φορές πιο ευαίσθητα στη DNR και 3.1 φορά πιο ευαίσθητα στη DΟΧ, συγκριτικά με U937R κύτταρα-μάρτυρες. Επιπρόσθετα, παρατηρήσαμε ισχυρή συσχέτιση μεταξύ των in vitro φαρμακοδυναμικών αλλαγών των επιπέδων ενεργοποίησης της JNK στους λευχαιμικούς βλάστες και της ανταπόκρισης των ασθενών με ΟΜΛ στη χημειοθεραπευτική αγωγή (P=0.012). Η απουσία ενεργοποίησης της JNK στα βλαστικά κύτταρα συσχετίστηκε επίσης με αρνητικούς προγνωστικούς παράγοντες για την ΟΜΛ, όπως γηραιότερη ηλικία των ασθενών (P=0.046) και ΟΜΛ αναπτυσσόμενη επί εδάφους μυελοδυσπλασίας (P=0.017).
Συνοψίζοντας, τα in vitro και in vivo αποτελέσματα μας προτείνουν την ενδογενή αποτυχία ενεργοποίησης της πρωτεινικής κινάσης JNK στους λευχαιμικούς βλάστες σαν έναν εναλλακτικό μηχανισμό χημειοαντίστασης στην ΟΜΛ. Η διελεύκανση των μηχανισμών εκείνων που επιφέρουν καταστολή της JNK στην χημειοανθεκτική ΟΜΛ μπορεί να ωφελήσει θεραπευτικά.Chemotherapy resistance is a major challenge in acute myeloid leukemia (AML). Besides the P-glycoprotein efflux, additional cellular factors may contribute to drug-resistance in AML. c- Jun N-terminal Kinase (JNK) is activated after exposure of cells to chemotherapeutics. We asked whether chemoresistance in AML is attributed to intrinsic failure of the AML blasts to activate JNK. In vitro treatment of U937 AML cell line with anthracyclines induced a rapid and robust JNK phosphorylation and apoptosis. In contrast, the anthracyline-resistant derivative cell lines U937R and URD40 showed no JNK activation after exposure to anthracyclines, also at doses that resulted in high accumulation of the drug within the cells. RNA interference-based depletion of JNK1 in drug-sensitive U937 cells made them chemoresistant, whereas selective restoration of the inactive JNK pathway in the resistant U937R cells sensitized them to anthracyclines. Short-term in vitro exposure of primary AML cells (n=29) to daunorubicin showed a strong correlation between the in vitro pharmacodymanic changes of phospho-JNK levels and the response of patients to standard induction chemotherapy (P=0.012). We conclude that JNK activation failure confers another mechanism of anthracycline resistance in AML. Elucidating the ultimate mechanisms leading to JNK suppression in chemoresistant AML may be of major therapeutic value.
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Hidding, Ute Maria Antonia. "Die Rolle von c-Jun N-terminalen Kinasen (JNK) in mikrogliären Zellkulturen." 2005. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=014906349&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Staak, Nils Holger [Verfasser]. "Einfluss von c-Jun und den c-Jun N-terminalen Kinasen, JNK1, JNK2 und JNK3, auf die Regeneration des Nervus facialis / vorgelegt von Nils Holger Staak." 2009. http://nbn-resolving.de/urn:nbn:de:gbv:8-diss-53957.
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Gopalan, Archana. "Targeting breast cancer with natural forms of vitamin E and simvastatin." Thesis, 2012. http://hdl.handle.net/2152/ETD-UT-2012-05-5520.
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Breast cancer is the second leading cause of death due to cancer in women. A number of effective therapeutic strategies have been implemented in clinics to cope with the disease yet recurrent disease and toxicity reduce their effectiveness. Hence, there is a need to identify and develop more effective therapies with reduced toxic side effects to improve overall survival rates. This dissertation investigates the mechanisms of action of two natural forms of vitamin E and a cholesterol lowering drug, simvastatin, as a therapeutic strategy in human breast cancer cells. Vitamin E in nature consists of eight distinct forms which are fat soluble small lipids. Until recently, vitamin E was known as a potent antioxidant but emerging work suggests they may be resourceful agents in managing a number of chronic diseases including cancer. Anticancer properties of vitamin E have been identified to be limited to the γ- and δ- forms of both tocopherols and tocotrienols. Gamma-tocopherol ([gamma]T) and gamma-tocotrienol ([gamma]T3) have both already been identified to induce death receptor 5 (DR5) mediated apoptosis in breast cancer cells. Studies here show that similar to [gamma]T3, [gamma]T induced DR5 activation is mediated by c-Jun N-terminal kinase/C/EBP homologous protein (JNK/CHOP) proapoptotic axis which in part contributed to [gamma]T mediated dowregulation of c-FLIP, Bcl-2 and Survivin. Also, both agents activate de novo ceramide synthesis pathway which induces JNK/CHOP/DR5 proapoptotic axis and downregulates antiapoptotic factors FLICE inhibitory protein (c-FLIP), B-cell lymphoma 2 (Bcl-2) and Survivin leading to apoptosis. Simvastatin (SVA) has been identified to display pleiotropic effects including anticancer effects but mechanisms responsible for these actions have yet to be fully understood. In this dissertation, it was observed that simvastatin induced apoptosis in human breast cancer cells via activation of JNK/CHOP/DR5 proapoptotic axis and down regulation of antiapoptotic factors c-FLIP and Survivin which are in part dependent on JNK/CHOP/DR5 axis. The anticancer effects mediated by simvastatin can be reversed by exogenously added mevalonate and geranylgeranyl pyrophosphate (GGPP), implicating the blockage of mevalonate as a key event. Furthermore, work has been done to understand the factors responsible for drug resistance and identify therapeutic strategies to counteract the same. It was observed that development of drug resistance was associated with an increase in the percentage of tumor initiating cells (TICs) in both tamoxifen and Adriamycin resistant cells compared to their parental counterparts which was accompanied by an increase in phosphorylated form of Signal transducer and activator of transcription 3 (Stat3) proteins as well as its downstream mediators c-Myc, cyclin D1, Bcl-xL and Survivin. Inhibition of Stat3 demonstrated that Stat3 and its downstream mediators play an important role in regulation of TICs in drug resistant breast cancer. Moreover, SVA, [gamma]T3 and combination of SVA+[gamma]T3 has been observed to target TICs in drug resistant human breast cancer cells and downregulate Stat3 as well as its downstream mediators making it an attractive agent to overcome drug resistance. From the data presented here, the mechanisms responsible for the anticancer actions of [gamma]T, [gamma]T3 and SVA have been better understood, providing the necessary rationale to test these agents by themselves or in combination in pre-clinical models.text
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Körner, Julia [Verfasser]. "Die Rolle der c-Jun N-terminalen Kinasen (JNK) in der DSS-Colitis / vorgelegt von Julia Körner." 2008. http://d-nb.info/993003273/34.
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Frick, Elisabeth [Verfasser]. "Die Rolle der c-Jun N-terminalen Kinasen (JNK1 und JNK2) im niedrig dosierten DSS-Colitis-Modell / vorgelegt von Elisabeth Frick." 2009. http://d-nb.info/999997157/34.
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Li, Li-Fu, and 李立夫. "Apoptosis Signal-Regulated Kinase 1 and c-Jun N-terminal Kinase Regulated Ventilation-Induced Inflammatory Cytokine and Lung Apoptosis." Thesis, 2005. http://ndltd.ncl.edu.tw/handle/98554179740295415443.
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博士長庚大學
臨床醫學研究所
93
Positive pressure ventilation with large tidal volumes has been shown to cause release of cytokines, including macrophage inflammatory protein-2 (MIP-2), a functional equivalent of human Interleukin (IL)-8. The mechanisms regulating ventilation-induced cytokine production are unclear. We designed three experiments to explore the mechanisms underlying ventilator-induced lung injury. We hypothesized that high tidal volume ventilation-induced IL-8 or MIP-2 production and lung apoptosis are dependent on the activation of apoptosis signal-regulated kinase 1 (ASK1) and c-Jun N-terminal kinase (JNK). We exposed A549 cells, a type II-like alveolar epithelial cell line, to cyclic stretch at 20 cycles/minute for 5 minutes to two hours and C57BL/6 mice to high tidal volume (30 ml/kg) or low tidal volume (6 ml/kg) mechanical ventilation for 5 hours. Cyclic stretch induced IL-8 protein production, IL-8 mRNA expression and JNK activation, but only transient activation of p38 and ERK1/2. High tidal volume ventilation induced neutrophil migration into the lung, airway epithelial apoptosis, MIP-2 protein production, MIP-2 mRNA expression, and activation of ASK1, JNK, and activator protein-1 (AP-1) DNA binding. Inhibition of stretch-induced JNK activation by adenovirus- mediated gene transfer of SEK-1 (KR), a dominant inhibitory mutant of SEK-1, the immediate upstream activator of the JNKs, and pharmacological JNK inhibitor II SP600125, blocked IL-8 mRNA expression and attenuated IL-8 production. Inhibition of p38 and ERK1/2 did not affect stretch-induced IL-8 production. Stretch-induced activation nuclear factor (NF)-kB and AP-1 was blocked by NF-kB inhibitor and JNK inhibitor, respectively. NF-IL-6 site was not essential for cyclic stretch-induced IL-8 promoter activity. Stretch also induced NF-kB-inducing kinase (NIK) activation, and inhibition of NF-kB attenuated IL-8 mRNA expression and IL-8 production. Large tidal volume ventilation of JNK knockout mice, and pharmacological JNK inhibition with SP600125 and ASK1 inhibition with thioredoxin attenuated neutrophil sequestration, and blocked MIP-2 mRNA expression, MIP-2 production, airway epithelial cell apoptosis, activation of JNK and AP-1 DNA binding. We conclude that lung cell stretch in vitro and in vivo, results in increased neutrophil sequestration, apoptotic cell death, and increased IL-8 or MIP-2 production, which were, at least in part, dependent, on the ASK1/JNK pathway.
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Betigeri, Seema S. "Jun N-terminal kinase 1 (JNK1) as a molecular target to limit cellular mortality under hypoxia." 2009. http://hdl.rutgers.edu/1782.2/rucore10001600001.ETD.000050494.
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Hsiao, Ya-Hsin, and 蕭雅心. "Anti-inflammatory effects of Physalin A via regulation nuclear factor κB and c-Jun N-terminal kinase activation." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/79fya5.
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碩士中國醫藥大學
基礎醫學研究所碩士班
102
Physalis angulata L. has been traditionally used in the supportive treatment of diabetes, hepatitis, and asthma. Physalin A is a major component of chalcones from Physalis angulata. The anti-inflammatory effects of Physalin A were studied by using lipopolysaccharide (LPS)-stimulated mouse macrophage RAW 264.7 cells and λ-carrageenan (Carr)-induced hind mouse paw edema model. Physalin A was tested for its ability to reduce nitric oxide (NO) and prostaglandin E2 (PGE2) production, and the inducible nitric oxide synthase (iNOS) and cyclooxygenase 2 (COX-2) expressions. Physalin A was tested in the inhibitor of mitogen-activated protein kinase (MAPK) [extracellular signal-regulated protein kinase (ERK), c-Jun NH2-terminal kinase (JNK), p38], and nuclear factor kappa-light-chain-enhancer of activated B-cells (NF-κB), nuclear factor of kappa light polypeptide gene enhancer in B-cells inhibitor (Iκ-B) and IκB kinase (IKK) protein expressions in LPS-stimulated RAW 264.7 cells. In vitro tests, Physalin A significantly inhibited PGE2, NO, interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor (TNF-α) production in a dose-dependent manner in LPS-induced RAW 264.7 cells. Physalin A significantly blocked the protein expression of iNOS, COX-2, NF-κB and suppressed IκB and JNK phosphorylation in LPS-stimulated RAW 264.7 cells in a dose-dependent manner. In vivo tests, Physalin A decreased the paw edema and suppressed the NO, malondialdehyde (MDA) and TNF-α level as did indomethacin (Indo) on serum after carrageenan injection in mice. That decreased activities of anti-oxidative enzymes such as superoxide dismutase, catalase, and glutathione peroxidase caused by LPS were reversed by Physalin A. These results indicate that the effect of anti-inflammation of Physalin A is through inhibition of MAPK, NF-κB and AP-1 activation and upregulation of anti-oxidative enzymes. This study also suggests that the potential utilization of Physalin A, as a lead for the development of anti-inflammatory drugs.
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Lin, Bor-tyng, and 林伯庭. "The Role of c-Jun N-terminal Kinase in Angiotensin II-induced Cellular Senescence of Vascular Smooth Muscle Cells." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/10684685523838938535.
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碩士國立成功大學
細胞生物及解剖學研究所
96
Abdominal aortic aneurysm (AAA) is present in 8% of the population over 60 years of age and exhibits a high mortality rate when rupture. AAA is characterized by extracellular matrix destruction and depletion of vascular smooth muscle cells (VSMC) in the tunica media. Angiotensin II (Ang II) was shown to induce AAA formation in animal models and c-Jun N-terminal kinase (JNK) was shown to play a critical role. A previous study suggested that Ang II induces premature senescence of VSMCs via a p53/p21-dependent pathway. We hypothesized that JNK activation mediates VSMC senescence and loss during AAA formation. Ang II treatment for 24 or 48 h induced cellular senescence of VSMC assessed by senescence-associated β-galactosidase (SA β-gal) activity. SA β-gal-postive cells were detected in atherosclerotic lesions of the aortic root in 20 weeks-old ApoE-/- mice but not in the aortic root of 21 weeks-old B6 mice. JNK phosphorylation and expression levels were examined in specimens of AAA and punctured ascending aorta from coronary artery bypass graft (CABG) surgery as control. JNK2 phosphorylation levels in AAA specimens were markedly higher than those in CABG specimens. In contrast, JNK1 expression was not detectable in those specimens with low phosphorylation levels. Interestingly, in cultured human aortic SMCs (HASMCs), Ang II stimulated JNK1, but not JNK2, phosphorylation that peaked at 5 min and returned to basal levels at 60 min. Long-term Ang II treatment up to 48 h tended to increase JNK1 phosphorylation and expression but did not reach significant difference. Neither phosphorylation nor changes in expression of JNK2 was detected in HASMCs following long-term Ang II-treatment. Moreover, JNK inhibition by treating SP600125, a selective JNK inhibitor, inhibited Ang II-induced cellular senescence of HASMCs. The expression of p21Cip1 did not increase significantly after Ang II stimulation. Upon Ang II stimulation, hydrogen peroxide (H2O2) production in HASMCs increased at 2 min and 5 min decreased to near basal levels, and then increased again at 60 min. These results suggested that JNK activation, possibly JNK1, may play a role in Ang II-induced cellular senescence of VSMC.