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Buehler, Christoph. "Gerechtigkeit am Kreuze Die Informationspolitik des IKRK aus ethischer Perspektive /." St. Gallen, 2006. http://www.biblio.unisg.ch/org/biblio/edoc.nsf/wwwDisplayIdentifier/02603496001/$FILE/02603496001.pdf.
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Schorr, Michael. "Der Wandel der humanitären Aktion internationaler Organisationen : die institutionellen sowie materiell-rechtlichen Konsequenzen dargestellt am Beispiel des IKRK, UNHCR und UNHCHR /." Hamburg : Kovač, 2004. http://www.gbv.de/dms/spk/sbb/recht/toc/373362889.pdf.
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Ea, Chee-Kwee. "Ubiquitination-dependent activation of IKK." Access to abstract only; dissertation is embargoed until after 12/20/2006, 2005. http://www4.utsouthwestern.edu/library/ETD/etdDetails.cfm?etdID=125.
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Drew, Devin Lee. "Biophysical Characterization of NEMO and IKK₂." Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2006. http://wwwlib.umi.com/cr/ucsd/fullcit?p3239883.
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Thesis (Ph. D.)--University of California, San Diego, 2007.Title from first page of PDF file (viewed January 12, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 110-121).
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Criollo-Cespedes, Alfredo. "Regulation of autophagy by IP3R and IKK complex." Paris 11, 2009. http://www.theses.fr/2009PA11T099.
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Harris, Jennifer. "Regulation of nuclear factor kappa B subunit c-Rel through phosphorylation by two IKK-related kinases, IKK epsilon and TBK-1." Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=82250.
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The nuclear factor kappaB (NF-kappaB) transcription factors are key regulators of immunomodulatory genes regulation. NF-kappaB activity is regulated through the phosphorylation of inhibitory proteins (IkappaBs) by the IkappaB kinase (IKK) complex (IKK alpha/beta/gamma), leading to IkappaB degradation and NF-kappaB translocation to the nucleus where they promote transcription of immunoregulatory genes. Moreover, cRel and p65 activities are also regulated by direct phosphorylation of their transactivation domain. Recently, two IKK non-canonical homologues, IKKepsilon and TBK-1 (TANK binding kinase-1) have been identified with functions distinct from the classical IKKalpha/IKKbeta. TBK-1/IKKepsilon trigger antiviral immunity through direct phosphorylation of the IRF3/IRF7 transcription factors, which are key regulators of the interferon response. Since IKKepsilon modulates the activity of IRF3/IRF7, it is of interest to assess whether IKKepsilon/TBK-1 also regulates the transactivation activity of NF-kappaB. Our hypothesis was that IKKepsilon/TBK-1 modulates the activity of cRel by direct phosphorylation of its transactivation domain (TD). In this study, we demonstrate that IKKepsilon and TBK-1 directly phosphorylate cRel in vitro and in vivo. Two of the three consensus sequences recognized by IKKepsilon/TBK-1 in the cRel TD are directly phosphorylated by IKKepsilon. cRel was translocated to the nucleus in cells expressing wild type versus kinase dead variant. The expression of IKKepsilon increases c-Rel transactivation in reporter gene assays. Serine to alanine mutation was further used to characterize the function of this phosphorylation at the level of nuclear translocation and transactivation potential using immunofluorescence and reporter gene assay. Furthermore, co-expression studies revealed that IKKepsilon and not the kinase dead variant is responsible for cRel degradation in a dose-dependent manner and this effect is partially revert
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Moreira, Bernardo Pereira. "Identificação dos microRNAs expressos em macrófagos estimulados com alta ou baixa dose de DNA plasmideal e avaliação dos seus papéis na cascata de sinalização." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/17/17147/tde-05062012-142837/.
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Nosso grupo demonstrou que a captura de baixas doses de DNA plasmideal pode inibir a apresentação de antígeno e induzir um padrão de resposta anti-inflamatória, e que após a captação do DNA plasmideal por macrófagos, estas moléculas podiam prevenir a acidificação de vesículas endossomais, um passo essencial para a apresentação de antígenos para células T CD4+. Além disso, em modelos in vivo, a baixa dose de DNA foi suficiente para amenizar o quadro inflamatório e diminuir a produção de citocinas inflamatórias. Estes resultados estão em contraste com os modelos de vacinas gênicas comumente utilizadas. A baixa dose de DNA plasmideal, no contexto da indução da resposta imune, pode levar à modificação na apresentação do antígeno e ativação celular levando ao controle da resposta imune exacerbada desencadeada por outro antígeno, tornando o tratamento por DNA um importante foco de estudo para o combate de doenças autoimunes e inflamações. O objetivo deste trabalho foi identificar os microRNAs expressos em macrófagos tratados com alta ou baixa dose de DNA plasmideal e avaliar o papel destas moléculas na modulação da cascata de sinalização intracelular visando esclarecer o mecanismo imunomodulador observado. Macrófagos da linhagem J774 foram estimulados por 2 horas com o vetor plasmideal pcDNA3, nas concentrações de 10 g ou 100 g de pcDNA3/mL de RPMI. O RNA total foi extraído e o ensaio de microarray para microRNAs foi realizado. Os miRNAs diferencialmente expressos foram confirmados pela RT-qPCR, e o programa de bioinformática miRDB foi utilizado para predição de genes alvos. Os miRNAs e genes selecionados também foram dosados em macrófagos estimulados com LPS e tratados com pcDNA3. Foram detectados 6 miRNAs (miR-494-3p, miR-21-3p, miR-1897-5p, miR-1894-3p, miR-294-3p e miR-483-5p) diferencialmente expressos em macrófagos estimulados somente com pcDNA3. A expressão do miR-494-3p foi aumentado somente em células tratadas com DNA em baixa concentração tanto na ausência quanto presença de LPS. O gene IBk (IKK-) foi identificado como alvo do miR-494-3p, dosado e teve sua função detectada por western blot, mostrando que seu papel biológico foi alterado na presença deste miRNA. Além disso, os dados do tratamento com pcDNA3 em camundongos knockout para o receptor TLR9, sugerem que a expressão do miR-494-3p é independente deste tipo de receptor, porém é inibida na presença do mesmo quando no tratamento com alta dose de DNA. Os dados sugerem que quando macrófagos são tratados com baixa dose de DNA plasmideal (10 g/mL), o miR-494-3p age como regulador negativo do fator de transcrição NF-B, por meio da inibição da expressão e função da proteína IKK-.Our group demonstrated that the capture of low doses of plasmid DNA can inhibit antigen presentation and induce an anti-inflammatory response pattern together with the decrease of pro-inflammatory cytokines expression, as observed in in vivo experimental models. Moreover, we observed that after the uptake of plasmid DNA by macrophages, these molecules could prevent endosomal vesicles acidification, an essential step for antigen presentation to CD4+ T cell. These results are in contrast with the usual DNA vaccines models commonly used. The low dose of plasmid DNA, in the context of immune response induction, can take to a modification in antigen presentation leading to the control of the response already established, what can be a potential treatment in auto-immune diseases and inflammation. The objective of this work is to identify expressed microRNAs on J774 macrophages triggered by different concentrations of plasmid DNA stimuli in order to evaluate the observed immunomodulatory mechanism. J774 macrophages were treated with low (10 µg/mL) and high (100 µg/mL) doses of pcDNA3 for 2 hours. Total RNA was extracted and microarray (Agilent plataform) was performed for detection of differentially expressed microRNAs. All obtained data was normalized in Genespring GX11.5 software. The microRNAs expression was confirmed by RT-qPCR and their mRNA targets were predicted by miRDB software. The miRNAs and their respective targets were also evaluated on DNA and LPS-treated macrophages. We detected 6 differentially expressed microRNAs (miR-494-3p, miR-21-3p, miR-1897-5p, miR-1894-3p, miR-294-3p e miR-483-5p) between the two conditions (fold change 2, p-value 0,05). The miR-494-3p expression increased only in cells treated with low dose of pcDNA3, on either previously LPS-stimulated cells or not. IBk (IKK-) was one of the predicted targets for miR-494-3p. RT-qPCR was performed to calculate its expression and its biological function was assessed by western blot. Besides, results from pcDNA3-treated cells from TLR9 knockout mice suggest that miR-494-3p expression is TLR9 independent although the receptor presence impaired miR-494-3p expression on high dose of pcDNA3-treated cells. Together, the data indicate that when macrophages are treated with low dose of plasmid DNA, miR-494-3p expression is increased, acting as negative regulator of the transcription factor NF-B, through IKK- inhibition.
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Anderson, Jeff. "Genetic Analysis Of Specialized Tumor Associated Macrophages And Tumor Associated Fibroblast." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1228083946.
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Aljeffery, Abdullah. "The role of IKK alpha in prostate cancer bone metastasis." Thesis, University of Sheffield, 2019. http://etheses.whiterose.ac.uk/23005/.
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IκB kinase subunit alpha (IKKalpha), a key component of the NFκB pathway, is implicated in prostate cancer progression and bone remodelling, but its role in the regulation of prostate cancer associated bone disease remains unknown. Here, we tested the effects of IKKalpha manipulation on prostate cancer cell behaviour in vitro and on osteolysis in a xenograft model of human prostate cancer bone metastasis. The pharmacological inhibition of IKKalpha using the novel and highly selective IKKalpha inhibitor SU1349 and stable knockdown of IKKalpha in PC3 cells significantly reduced cell viability, migration and invasion, whereas IKKalpha overexpression was stimulatory. In prostate cancer cell - osteoclast co-cultures, IKKalpha overexpression in PC3 enhanced RANKL-induced osteoclastogenesis, whereas SU1349 treatment and IKKalpha knockdown reduced these effects. Exposure of osteoblasts to SU1349 enhanced alkaline phosphatase activity and bone nodule formation. Protein microarray analysis of tumour-derived factors in PC3 conditioned medium showed that these effects were associated with significant inhibition of various NFκB-mediated pro-inflammatory factors and reduction in PC3 conditioned medium induced NFκB activation in osteoclast and osteoblast precursors. In osteoclast and osteoblast precursors SU1349 lead to inhibition of both canonical and non-canonical NFκB signalling. Interestingly, NFκB inhibition in osteoblasts was accompanied by an increase in GSK3β phosphorylation indicative of activation of the Wnt/β-catenin pathway, whereas the opposite occurred in osteoclast precursors. In vivo, administration of SU1349 (20mg/kg/3times-weekly) in immuno-deficient BALB/c mice after intra-cardiac injection with human PC3 cells enhanced trabecular bone volume and this was associated with reduced osteoclast and increased osteoblast numbers. Paradoxically, SU1349 treatment reduced cortical bone volume, and this was associated with increased osteoclast and reduced osteoblast numbers. Thus, the novel IKKalpha inhibitor SU1349 is of potential therapeutic value in protecting against prostate cancer-induced osteolysis. However, exacerbation of bone loss in the cortical compartment may limit its usefulness as a bone sparing agent.
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Perez, Jessica Marie. "Phosphorylation and mechanistic regulation of a novel IKK substrate, ITCH." Case Western Reserve University School of Graduate Studies / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=case1512569748748798.
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Zhang, Jiazhen. "An investigation of the activation of protein kinase complexes in the MyD88 signalling network." Thesis, University of Dundee, 2017. https://discovery.dundee.ac.uk/en/studentTheses/de0ade75-5c10-4134-a7f7-27c2f315b58f.
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The TAK1 and canonical IKK complexes are the two master protein kinases of the innate immune system that control the production of inflammatory mediators, but the mechanisms by which they are activated in this system are still unclear. In this thesis, I present the research I have carried out to solve these problems. The IKKb component of the canonical IKK complex is required to activate the transcription factors NF-kB and IRF5 and the protein kinase Tpl2, but how IKKβ itself is activated in vivo is still unclear. It was found to require phosphorylation by one or more ‘upstream’ protein kinases in some reports, but by autophosphorylation in others. In the first part of this thesis, I describe my work that has resolved this controversy by demonstrating that the activation of IKKb induced by IL-1 (interleukin-1) or TNF (tumour necrosis factor) in embryonic fibroblasts, or by ligands that activate Toll-like receptors in macrophages, requires two distinct phosphorylation events: first, the TAK1 catalysed phosphorylation of Ser177 and, secondly, the IKKb-catalysed autophosphorylation of Ser181. The phosphorylation of Ser177 by TAK1 is a priming event required for the subsequent autophosphorylation of Ser181, which enables IKKk to phosphorylate exogenous substrates. I also present genetic evidence which indicates that the IL-1-stimulated, LUBAC (linear ubiquitin chain assembly complex)-catalysed formation of Met1-linked/linear ubiquitin (Met1-Ub) chains and their interaction with the NEMO (NF-kB essential modulator) component of the canonical IKK complex permits the TAK1-catalysed priming phosphorylation of IKKb at Ser177 and IKKa at Ser176. These findings may be of general significance for the activation of other protein kinases. The activation of the TAK1 complex by inflammatory stimuli is thought to be triggered by the binding of Lys63-linked ubiquitin chains to the TAB2 or TAB3 components of the TAB1-TAK1-TAB2 and TAB1-TAK1-TAB3 complexes. In the second part of the thesis I tested whether this broadly accepted model was correct by knocking out the genes encoding TAK1 and its regulatory subunits TAB1, TAB2 and TAB3 by CRISPR/Cas9 gene-editing technology, alone and in combination, in an IL-1 receptor expressing human cell line. These genetic studies led me to discover that the IL-1-dependent activation of TAK1 occurs by two different mechanisms. The first, involves the previously described interaction of Lys63-linked ubiquitin chains with TAB2 and TAB3, while the second can take place in the complete absence of TAB2 and TAB3. The second mechanism, which involves activation of the TAB1-TAK1 heterodimer is more transient than the first, but is sufficient for the IL-1-dependent transcription of immediate early genes (A20, IkBa). I show that the activation of the TAB1-TAK1 complex requires the expression of the E3 ubiquitin ligase TRAF6 and the TRAF6-generated formation of Lys63-linked ubiquitin chains, which leads to the phosphorylation of TAK1 at Thr187 and activation. However, neither TAB1 nor TAK1 bind directly to Lys63-linked ubiquitin chains. I identify one novel IL-1-dependent phosphorylation site on TAB1 and two on TAK1 and propose that Lys63-linked ubiquitin chains activate an as yet unidentified protein kinase, which phosphorylates one or more of the novel phosphorylation sites on the TAB1-TAK1 heterodimer inducing a conformational change that permits TAK1 to autophosphorylate Thr187.
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Simkovsky, Nadja Melitta. "Synthesis of some potential IKK inhibitors based around a pyrimidine scaffold." Thesis, University of Liverpool, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.367619.
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Adli, Mezher Baldwin Albert Sidney. "Investigating the role of IKK epsilon in cancer-associated NF-kappaB activity." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,1274.
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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.Title from electronic title page (viewed Mar. 27, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Biology Graduate Studies in Molecular, Cell, and Developmental Biology." Discipline: Biology; Department/School: Biology. On t.p., Greek letters appear as symbols.
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Asare, Yaw [Verfasser]. "Role of the COP9 signalosome and IKK complexes in Atherosclerosis / Yaw Asare." Aachen : Hochschulbibliothek der Rheinisch-Westfälischen Technischen Hochschule Aachen, 2013. http://d-nb.info/1044570229/34.
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Wilson, Alastair. "Disrupting the inhibitory Kappa B kinase (IKK)-Aurora A axis in cancer." Thesis, University of Strathclyde, 2013. http://oleg.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=22402.
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The IKK complex is an essential regulator of the NF-κB- signalling pathway. It is comprised of three sub-units; catalytic subunits IKKα and IKKβ and the catalytically inactive scaffolding protein IKKγ/NF-κB Essential Modulator (NEMO). The complex can be assembled in multiple conformations as either hetero- or homo-dimers of IKKα/β with or without the scaffolding protein IKKγ. This regulates NF-κB signalling and related cellular inflammatory responses that are often constitutively active in many cancer cells. Beyond regulation of NF-κB signalling a number of other potential IKK substrates have been proposed including the mitotic kinase Aurora A, one of three serine/threonine kinases of the Aurora kinase family that mediate mitotic progression in cells. Aurora A kinase specifically has several roles in the cell cycle, regulating spindle formation/attachment, centrosome maturation and cytokinesis, and has been observed to be overexpressed in several cancers. Several studies have linked IKK complex to Aurora A signalling, as either a substrate of IKKα (Prajapati et al, 2006) or as a target for IKKβ-mediated βTRCP-regulated degradation (Irelan et al, 2007) both linked to cell cycle progression independent of NF-κB signalling. Aurora A kinase has however also been linked to NF-κB signalling through the phosphorylation and degradation of IκBα in primary breast tumours in a subgroup of patients exhibiting Aurora A gene amplification (Briassouli et al, 2007). Prostate cancer is a significant worldwide health issue and is the 2nd most prevalent cancer in males and 5th most prevalent cancer overall with over 900,000 new cases diagnosed in 2008 (Ferlay et al, 2010). The current therapies treating prostate cancer are far from ideal and have significant side effects. Both Aurora A and NF-κB-related kinases have been shown to be over-expressed or constitutively active in prostate cancer and therefore the suggested novel interaction may serve as a potential mechanism for intervention in cancer. This study aimed to validate IKK-Aurora A interactions and potentially identify novel targets for the development of therapeutics in prostate cancer. Using recombinant protein methodologies the direct interaction of IKKα and IKKβ with Aurora A were confirmed. Utilising peptide array technology, it has been possible to further elucidate the nature of the interaction between Aurora A and IKKα/β. The interaction of Aurora A and IKKα/β was mapped to two key regions of the IKKs, the kinase domain and the NEMO binding domain. The NEMO-Binding Domain is a conserved hexapeptide sequence, L-D-W-S-W-L, across both IKKα and IKKβ mediating the interaction with the scaffolding protein IKKγ/NEMO. This highlighted a novel role of the NBD as a multi-protein docking site. Binding of these proteins was further confirmed endogenously in a cellular setting, by means of co-immunoprecipitation and also the kinetic profiles of these interactions were characterised using recombinant proteins and Surface Plasmon Resonance. Thereafter Cell Permeable Peptides (CPPs) based on the IKK NBD were utilised as pharmacological tools, to examine potential competitive perturbation of Aurora A-IKK interactions mediated by the NBD in prostate cancer cells. This identified in a cellular setting treatment with NBD CPPs resulted in the inhibition of Aurora A phosphorylation and induced Aurora A degradation, which correlated with cell cycle arrest. It was also suggested through molecular modeling that the IKK NBD peptides could bind to the Aurora A protein, potentially at sites engaged by TPX2, an activation accessory protein for Aurora A. This purported mechanism may account for the observed IKK NBD peptide-mediated de-phosphorylation and subsequent degradation of Aurora A. Therefore, this study has identified the NEMO binding d omain as a potential multi-protein binding site and has identified novel functionality of the IKK NBD cell permeable peptides. This may represent a novel target for the intervention of IKK-mediated regulation of the cell cycle and serve as the basis for the development of novel peptidomimetics and related small molecules for the treatment of Prostate cancer.
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Forbes, Jonathan. "BIOCHEMICAL CHARACTERIZATION OF SUPPRESSOR OF IKK-ε AND NAK-ASSOCIATED PROTEIN 1." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/86.
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Innate immunity provides the first line of defense against invading pathogen by recognizing and mounting a response to the pathogenic challenge. Among the cellular mechanisms of the innate immune response, Toll-like receptor 3 (TLR3) recognizes viral dsRNA and signals subsequent production of type-I interferon. The TLR3:interferon signaling cascades contains a kinase complex composed of two kinases and a scaffold protein, NAK-associated protein 1 (NAP1). The role of NAP1 in modulating kinase activation or regulation is unknown. A key inhibitory protein identified in the TLR3:interferon pathway, silencer of inhibitor of κBα kinase ε (SIKE), blocks the activity of this kinase complex through an unknown mechanism. The long term goal of this project is to define how protein:protein interactions modulate signal transduction in this pathway as mediated by host in the context of an immune response, pathogen as it attempts to subvert the host immune system and in disease states such as cancer and obesity. Objectives for this thesis were to produce recombinant SIKE and NAP1 material that could be used to elucidate the self-association pattern and hetero-interactions mediated by these components within the pathway. SIKE full-length, SIKE 72 (residues 72-207), NAP 270 (residues 1-270) and NAP 255 (residues 1-255) expression constructs were completed and recombinant protein produced using either a bacterial or baculovirus/insect cell expression system. Self-association was characterized by size exclusion chromatography and analytical ultracentrifugation. Hetero-interactions were explored via co-precipitation assays of recombinant proteins. SIKE 72 formed a primarily dimeric structure whereas NAP 255 forms a single species that appears to be monomeric at this stage of analysis. Hetero-interactions form between the kinase TBK-1 and NAP 255 and also TBK-1 and SIKE 72. TBK-1 shows a higher preference for binding NAP 255 in the prescence of both NAP 255 and SIKE 72. This work provides methodology to produce recombinant material for two components of the TLR3:interferon pathway and their initial biochemical characterization for both self-association and hetero-interactions.
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Bikman, Benjamin Thomas Dohm G. Lynis. "Modulation of IKK[beta] with AMPK improves insulin sensitivity in skeletal muscle." [Greenville, N.C.] : East Carolina University, 2008. http://hdl.handle.net/10342/1081.
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Thesis (Ph.D.)--East Carolina University, 2008.Presented to the faculty of the Department of Exercise and Sport Science. Advisor: G. Lynis Dohm. Title from PDF t.p. (viewed Apr. 23, 2010). Includes bibliographical references.
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Sriskantharajah, Srividya. "The role of IKK-induced NF-κB1 p105 proteolysis in T lymphocytes." Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/1446121/.
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Proteolysis of NF-kB1 p105 is vital for its function as a precursor to p50 and as an IkB. This occurs in two ways, both mediated by the proteasome. A constitutive proteolytic removal of the p105 C-terminus, termed processing, generates the mature transcription factor p50. In contrast, a signal-induced p105 proteolysis is triggered by phosphorylation of serines 927 and 932 in the p105 PEST region by the IKK complex. This promotes p105 poly-ubiquitination and subsequent complete degradation. IKK-induced p105 proteolysis has been demonstrated to regulate the kinase activity of the MAP3K TPL-2, since all detectable TPL-2 is found in a complex with p105. Furthermore, NF-kB1 p105 retains Rel subunits in the cytoplasm via interaction with the p105 C-terminal ankyrin repeat region. However, it is unclear whether IKK-induced p105 proteolysis contributes to NF-kB activation, though this process would be expected to release Rel subunits to translocate into the nucleus. A large body of evidence exists to suggest a major role for NF-kB in T cell development and function. To investigate the significance of IKK-induced p105 degradation in T cells, a knock-in mouse strain, Nfkb1S927A'S93ZA, in which serines 927 and 932 of NF-kB1 p105 were mutated to alanine residues was analysed. Previous work has shown that constitutive processing of pio5S927A S932A to p50 occurs normally, but this mutated p105 is refractory to IKK-induced proteolysis. Work presented here demonstrates that whilst p105 mutation did not affect thymic differentiation of CD4+ and CD8+ T cells, numbers of CD4+CD25+ regulatory T cells, memory-phenotype CD4+ T cells and thymic NKT cells were significantly reduced. Analysis of BM chimeras revealed cell autonomous and non-haematopoietic defects required for generation of these sub-populations. In vitro experiments indicated that TCR-induced proliferation was significantly impaired in /Vflcb7S927A S932A CD4+ T cells, due partly to reduced interleukin-2 production. In contrast, p105 mutation had no effect on CD4+ T cell survival. These defects were not due to a lack of TPL-2 activity, based on analysis of TPL-2-deficient mice. This study presents evidence to suggest a critical role for IKK-induced p105 proteolysis in regulating NF-kB activation in T lymphocytes.
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Rusilowicz, Emma Victoria. "Chemical biology approaches for the identification of novel p53 regulatory signalling pathways." Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/11774.
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p53 is a critical tumour suppressor which acts to repair or remove abnormal cells and thus prevent cancer. Aberrant function of p53 is therefore a critical step in tumourigenesis and p53 is mutated in half of all cancers. Mutation of p53 leads to both a loss of normal wildtype function as well as the gain of oncogenic function. p53 is considered to be a promising therapeutic target and therapeutic strategies for targeting of the p53 pathway include: 1. Activation of wild-type p53 (wtp53) protein function, 2. Refolding of mutant p53 (mtp53) into the wtp53 conformation, 3. Reduction of mtp53 protein levels. In this work a number of small molecule screening assays were used to identify potentially novel regulators of both wtp53 and mtp53. Screening of a protein kinase inhibitor library for small molecules which can stimulate wtp53 activity identified the GSK3 pathway and a CDK pathway as dominant suppressors of wtp53 function. Screening of the library for inhibitors which reduce mtp53 protein levels led to the identification of two IKKβ inhibitors. The work then focused on investigating the effects of one of these compounds, IMD0354, on the mutant p53 pathway; with a specific focus on MDM2 as the most rapidly responding biomarker. IMD0354 is a well characterised inhibitor which has been shown to specifically inhibit IKKβ leading to the repression of the Nf-κB pathway. This study shows that IKKβ inhibition leads to the loss of a number of oncogenic proteins including mtp53, MDM2 and cyclin D. Mass-spectrometry based (ITRAQ) proteomic analysis was then employed to identify potential mediators and/or co-regulated factors in response to IKKβ-inhibition via IMD0354 treatment. This led to the identification of RPS3 as a potential negative regulator of MDM2 protein expression; the reduction in MDM2 protein in response to IMD0354 treatment is shown to be partially dependent on RPS3. Together this data has identified, using small molecule kinase inhibitor libraries: (i) dominant kinase signalling pathways that suppress wt-p53 and (ii) a dominant kinase signalling pathway that sustains expression of mutant p53 and MDM2 in cancer cell lines. This latter data supports further investigation to aid understanding of how the IKK signalling pathway cross-talks to the p53-MDM2 axis.
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Barken, Derren. "Temporal encoding and homeostatic control in the IKK-IkappaB-NF-kappaB signaling system." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2007. http://wwwlib.umi.com/cr/ucsd/fullcit?p3250073.
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Thesis (Ph. D.)--University of California, San Diego, 2007.Title from first page of PDF file (viewed April 4, 2007). Available via ProQuest Digital Dissertations. Vita. Non-Latin script record Includes bibliographical references (p. 146-153).
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He, Jiajia [Verfasser]. "Effects of IKK/NF-κB signaling in MYC-driven liver tumorigenesis / Jiajia He." Ulm : Universität Ulm, 2018. http://d-nb.info/1162953837/34.
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Stellzig, Julia [Verfasser]. "The role of the non-canonical IKK complex in glioblastoma multiforme / Julia Stellzig." Gießen : Universitätsbibliothek, 2014. http://d-nb.info/106833052X/34.
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Baiget, Jessica. "Synthesis of inhibitors of the IKK-complex for the treatment of prostate cancer." Thesis, University of Strathclyde, 2012. http://digitool.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=25981.
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Prostate cancer is the second most prevalent cancer in men. Activation of the NF-ҡB pathway is involved in the development of prostate cancer resistance to current therapies and contributes to the high mortality rate associated with this cancer. NF-ҡB has been shown to be inactive in the cytosol when bound with IҡB proteins. Activation of the IҡB kinase (IKK) complex degrades IҡB via phosphorylation and subsequent targeting by the proteasome, which enables transcription of NF-ҡB into the nucleus to control gene expression. The IKK-complex is formed by the two catalytic subunits IKKα and IKKβ and a regulatory subunit, NEMO, which is essential for its activation. The key interaction between these three units occurs in a localised region characterised by a hexapeptide sequence (LDWSWL). Disruption of the IKK-complex suppresses the transcription of NF-ҡB and can suppress tumour development. This project focuses on the suppression of this pathway using two different approaches. Firstly, the disruption of the interaction of NEMO with the two catalytic subunits was attempted using short modified-hexapeptide sequences based upon LDWSWL. We sequentially varied the six residues to identify the most efficacious sequence that disrupts the IKK-complex with the view to producing drug-like peptidomimetics with increased stability, potency and an improved pharmacokinetic profile. The synthesis of these novel peptides was accomplished by solid phase peptide synthesis and using SP-HPLC for their purification. A novel and simple method based fluorescence techniques was investigated to evaluate the interaction of NEMO with these hexapeptide sequences. The second approach to disrupt NF-ҡB activation was investigated by designing and developing selective heterocyclic ATP competitive inhibitors against IKKα and IKKβ. β-carbolines are known to be selective inhibitors of IKKβ, but other carboline-derived scaffolds (α-, γ- or δ-carbolines) have not yet been explored. Our efforts have been focussed on the synthesis of these scaffolds and to produce potent and selective drug-like molecules for the inhibition of IKKα and IKKβ. Our results have shown that a derivative of β-carboline inhibits IKKβ with high potency and selectivity and that the α-carboline offers an extremely promising scaffold for the synthesis of very potent IKKα-inhibitors.
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McKinley, Sean W. "Using structural analysis to investigate the function of Suppressor of IKK-epsilon (SIKE)." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3670.
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The innate immune system provides the body’s first line of defense against pathogenic challenge through pathogen recognition and initiation of the immune response. Among the various cellular mechanisms of pathogen recognition in mammals, Toll-like receptor 3 (TLR3) recognizes viral dsRNA. Stimulation of TLR3 signaling pathway leads to transcription of pro-inflammatory cytokines and type-1 Interferons. Suppressor of IKKε (SIKE) interacts with two kinases in the signaling pathway, IKKε and TANK binding kinase 1 (TBK1), inhibiting the transcription of type I interferons. Recently, the Bell Laboratory discovered that SIKE blocks TBK1-mediated activation of type I interferons by acting as a high affinity, alternative substrate of TBK1.
To further characterize SIKE’s function within the antiviral response, this study focused on defining the overall SIKE structure. Using recombinant protein expressed from E. coli and purified via immobilized metal affinity chromatography, SIKE crystals were obtained from a sample concentrated to 15 mg/ml under several crystallization conditions. Yet, reproducing these results has been difficult. In this study, we have modified the purification scheme to remove an E. coli contaminant, SlyD. Purification under denaturing conditions, removal of soluble proteins, incorporation of ion exchange and different IMAC (immobilized metal ion affinity chromatography) resins has been tested. For each scheme, size exclusion chromatography and SDS-PAGE/Coomassie/silver stain were used to assess purity. Crystallization trials for samples from each purification scheme were completed. In addition to crystallization trials, hydrogen-deuterium exchange (HDX) was investigated, accompanied with pepsin digests, in order to further characterize the dynamic structure of SIKE.
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Sabbaugh, Adam. "Characterizing the Effects of Mutant Huntingtin and IKK Beta on IL-34 Expression." Thesis, California State University, Los Angeles, 2017. http://pqdtopen.proquest.com/#viewpdf?dispub=10270139.
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A major determinant of Huntington’s disease (HD) pathology is the expansion of a polyglutamine (polyQ) repeat in the exon-1 of Huntingtin protein (HTT). Proteolytic processing of mutant HTT liberates exon-1 (mHDx1) monomers, which oligomerize and disrupt cellular homeostasis. mHDx1 oligomers interact with various signaling proteins including the IkappaB kinase (IKK)/nuclear factor-kappaB (NF-κB) complex, a prominent regulator of inflammation. Neuroinflammation is implicated in the onset and progression of HD. A hallmark of neuroinflammation is the expansion of activated microglia in the central nervous system (CNS). Microglia communicate with neurons by several receptor-ligand systems. One is interleukin-34 (IL-34), a cytokine which plays a prominent role in microglial development and function. In the CNS, neurons produce and secrete IL-34, which binds to colony stimulating factor 1-receptor (CSF1-R) expressed by microglia. Factors that regulate neuroinflammation in Huntington’s disease remain unknown. For my thesis project, I participated in various experiments to determine whether mHDx1 influences IL-34 production in neurons. The accumulated data suggest that mHDx1 induces IL-34 expression in dopaminergic neurons derived from human embryonic stem cells. IL-34 production is also induced by stressful stimuli known to activate IKKβ. IKKβ-dependent aggregation of mHDx1 is critical for the production of IL-34. Secreted IL-34 has no visible effect on the aggregation of mHDx1 in neurons suggesting that it may influence other CNS cells such as microglia. Overall, my efforts helped to identify IL-34 production as a downstream effect of mHDx1 aggregation in neurons and will facilitate further studies on neuron-microglia communications in Huntington’s disease.
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Hou, Yanjun. "Analysis Of The Ikkβ/Nf-Κb Signaling Pathway During Embryonic Angiogenesis And Tumorigenesis Of Breast Cancer." The Ohio State University, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=osu1222108300.
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Lau, Rosanna. "cIAP2 Negatively Regulates Proliferation and Tumourigenesis by Repressing IKK Activity and Maintaining p53 Function." Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/22845.
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The cellular inhibitor of apoptosis protein (cIAP)-2 plays an important role in the protection against apoptosis by inhibiting the endogenous IAP inhibitor Smac, thus allowing other members of the IAP family, such as XIAP to block caspases. Additionally, cIAP2 functions as a ubiquitin ligase and mediates survival/proliferative signaling through NF-κB. cIAP2 is overexpressed in many human cancers and is believed to play an oncogenic role. This led to the development of small molecule IAP antagonists aimed at eliciting apoptosis in cancer cells. However, the loss of cIAP2 is also associated with multiple myeloma, in which constitutively active NF-κB signaling contributes to pathogenesis of the disease and suggests that cIAP2 may also perform a tumour suppressive function.
We demonstrate a novel role for cIAP2 in maintaining p53 levels in mammary epithelial cells that express wildtype p53. Downregulation of cIAP2 resulted in activation of IKKs, which led to increased Mdm2-mediated degradation of p53. cIAP2 depletion also led to increased phosphorylation of ERK1/2. Reduction of p53 levels, in combination with survival signaling provided by NF-κB and MEK-ERK pathways were associated with increased colony formation in vitro and increased DMBA-induced adenocarcinomas in cIAP2-null mice.
Treatment of cells with IAP antagonists resulted in significant cytotoxicity only in p53-mutant MDA-MB-231 cells, which was associated with autocrine production of TNF-α. We propose that the transcription of TNF-α is potentiated by gain-of-function mutation in p53 since downregulation of mutant p53 in MDA-MB-231 cells decreased TNF-α mRNA. Downregulation of cIAPs in p53-mutant cells resulted in a decrease in nuclear IKK-α, which may result in decreased IKK-α-mediated survival signaling. In contrast, cIAP downregulation in p53-wildtype cells resulted in no change in nuclear IKK-α, degradation of the corepressor SMRT and cell survival. We show that the effects of cIAP2 downregulation are context-dependent. Downregulation of cIAP2 in p53-wildtype cells results in a decrease in p53 and an increase in survival and proliferative signaling. These results suggest a tumour suppressor function for cIAPs that may account for cIAP mutation-associated cancers such as multiple myeloma. Moreover, our data also defines gain-of-function p53 mutation as a possible contributor to IAP antagonist sensitivity.
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Paquette, Tyna. "Functional characterization of the E-4031 sensitive repolarization current, Ikr in rabbit ventricular myocytes." Thesis, McGill University, 1999. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=30722.
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The delayed rectifier potassium current IKr (hERG) participates in repolarization of the cardiac action potential and is implicated in one form of inherited Long QT Syndrome. The goal of this study was to characterize the biophysical properties of IKr in isolated rabbit ventricular myocytes and hERG expressed in a mammalian cell line using mathematical, electrophysiological and molecular biological techniques. Incorporation of results into a mathematical gating model of IKr revealed that the current did not follow the typical Hodgkin-Huxley type gating formulation and therefore comprised a gating model paradox. Furthermore, it was found that different groups of divalent cations selectively affected specific kinetic properties of I Kr, with the relief of rectification of the current by the Cd 2+-like class of divalent cations (Cd2+, Ni 2+, Co2+ and Mn2+; mM range) and the block of the current by Zn2+ (0.1--1 mM) being the most prominent effects. The biophysical properties of hERG were found to be more sensitive to Cd2+ compared to rabbit IKr (muM as opposed to mM concentrations). The relief of rectification of native rabbit IKr and expressed human hERG by the Cd2+-like group of divalent cations and block of rabbit IKr by Zn2+ may be attributed to specific interactions with distinct sites associated with different regions of the channel.
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Salem, Heba [Verfasser]. "Modulation of IKK/NF-kappaB signaling iin pancreatic β-cells induces diabetes / Heba Salem." Ulm : Universität Ulm. Fakultät für Naturwissenschaften, 2013. http://d-nb.info/1044350245/34.
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Mittestainer, Francine Cappa 1986. "Ação anti-inflamatória da insulina = efeitos agudos sobre a via IKK/I'capa'B/NF-'capa'B." [s.n.], 2011. http://repositorio.unicamp.br/jspui/handle/REPOSIP/311242.
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Orientador: Mário José Abdalla SaadDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
Made available in DSpace on 2018-08-19T22:12:54Z (GMT). No. of bitstreams: 1 Mittestainer_FrancineCappa_M.pdf: 2379142 bytes, checksum: cb6178fdb335fdabb4a29e4767a5c1b5 (MD5) Previous issue date: 2011
Resumo: A infusão da insulina durante a inflamação aguda melhora os resultados clínicos, mas o exato mecanismo desse efeito benéfico da insulina ainda não foi bem compreendido. Estudos recentes mostraram que a insulina tem um efeito antiinflamatório de modo que o hormônio também exibe um efeito inibidor sobre a mediação da transcrição de NF-kB em células mononucleares. Assim, o objetivo do presente estudo foi investigar os efeitos agudos da administração de insulina regular sobre a modulação de proteínas da via IKK/IkB/NF-kB e das proteínas chave da via de sinalização da insulina em tecido hepático, muscular e adiposo, a expressão de NF-kB nesses tecidos através de ELISA, o efeito do tratamento com insulina em macrófagos extraídos do peritônio de ratos e a influência dos inibidores da PI3K e MAPK na via inflamatória. Ademais, fizemos um ensaio da proteína fosfatase PP2A usando a imunoprecipitação com anticorpos anti-IKKbeta. Para o experimento, ratos machos adultos Wistar compuseram aleatoriamente 4 grupos diferentes. Três deles foram submetidos à infusão de insulina na veia porta e, então foram estimulados em 1, 3 e 5 minutos, enquanto o outro grupo (0) não foi estimulado com insulina. Em nossos resultados, observamos um aumento da fosforilação de IR, IRS1 e Akt induzida pela insulina nos três tecidos estudados. Em paralelo, houve uma redução na fosforilação de IKK e IkB após o estimulo da insulina. A ativação de NF-kB p65 no núcleo das células mostrou a redução na fosforilação do IKK e IkB no fígado, músculo e tecido adiposo. Na cultura de macrófagos tratada com insulina, após a adição dos inibidores específicos para PI3K e MAPK, observamos um aumento na fosforilação de IKK e IkB. Nossos resultados também mostraram que após estímulo da insulina houve um aumento na atividade da proteina fosfatase PP2A associada ao IKK nos três tecidos estudados. Desta forma, podemos sugerir que insulina pode induzir uma interação entre PP2A e IKK, o que resultará em mais desfosforilação de IKK e, assim, uma inibição da atividade da proteína quinase, revelando um potencial mecanismo de ação efeito anti-inflamatório da insulina
Abstract: Insulin infusion during acute inflammation improves clinical the outcomes but the exact mechanism of this beneficial effect is unclear. Recent studies have suggested that insulin has an anti-inflammatory effect in such a way that this hormone exhibits an inhibitory effect on the mediation of transcription of NF- kB in mononuclear cells. Thus, the aim of this study was to investigate the acute effects of regular insulin administration in modulation of IKK/IkB/NF-kB pathway and insulin signaling pathway (IR, IRS1 and Akt) and the DNA binding of NF-kB p65 in liver, muscle and adipose tissue of rats and also analyze the effect of treatment with insulin on macrophages of rats and the influence of PI3K and MAPK inhibitors on pathway. And finally, we analyze a phosphatase assay by using an immunoprecipitation with anti-IKKbeta antibody and PP2A phosphatase assay. For the experiment, male adult Wistar rats were divided in 4 groups. Three of them were submitted to insulin injection in the portal vein and were stimulated for 1, 3 and 5 minutes and the other group (0) was not stimulated (saline). In our results, we observed an increase in insulin-induced phosphorylation of IR, IRS1 and Akt during insulin injection in the three tissues studied. In parallel, there was a reduction in the phosphorylation of IKK and IkB after insulin stimulation. The DNA binding of NF-kB p65 in the cell nucleus showed a reduction of the IKK and IkB phosphorylation after insulin injection in liver, muscle and adipose tissue. In macrophages culture of treated with insulin and when added the specific inhibitor for PI3K and MAPK we observed an increased on phosphorylation of IKK and IkB. Our results also showed that after insulin stimulus there was an increase in PP2A phosphatase activity associated with IKK in the three tissues studied. Thus, we can suggest that insulin might induce an interaction between PP2A and IKK, which will result in more IKK dephosphorylation and thus an inhibition of this protein kinase activity, showed a possible anti-inflammatory effect of insulin
Mestrado
Mestre em Ciências
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Niculaita, Roxana. "The role of AKT1 and IKK[beta] in ovarian cancer tumorigenesis and chemotherapeutic resistance." [Kent, Ohio] : Kent State University, 2008. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=kent1227665461.
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Rastrick, Joseph. "The role of the IKK-2/NF-kB signaling in cigarette smoke-induced airway inflammation." Thesis, Imperial College London, 2012. http://hdl.handle.net/10044/1/39413.
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Chronic Obstructive Pulmonary Disease (COPD) is an inflammatory lung disease largely associated with cigarette smoke (CS) exposure. The mechanism by which CS leads to the pathogenesis of COPD remains unclear, however many inflammatory mediators present in the COPD lung are thought to be regulated by the transcription factor Nuclear Factor-kappaB (NF-kB) and its upstream signalling kinase, Inhibitor of kB kinase-2 (IKK-2). The IKK- 2/NF-kB signalling pathway may therefore be crucial in the pathogenesis of the inflammation associated with COPD. To investigate this hypothesis, mice were exposed to acute or sub-chronic CS and inflammatory end-points, including NF-kB pathway activation were measured. Acute CS generated a predominantly neutrophilic response in the lung, whereas the inflammatory phenotype following sub-chronic exposure was more persistent and included monocytes/macrophages and lymphocytes. In contrast to lipopolysaccharide (LPS)-induced lung inflammation however, neither acute nor sub-chronic CS generated an increase in NF-kB:DNA association in whole lung nuclear extracts. To determine if distinct cell types were responsible for a CS-induced change in NF-kB:DNA association, that could not be detected in whole lung nuclear extracts, mice lacking IKK-2 exclusively in the airway epithelium or in myeloid-derived cells were exposed to acute and sub-chronic CS. These mice were shown to have reduced IKK-2 gene expression in the targeted cell types and both strains showed a functional decrease in LPS-induced NF-kB:DNA association. CS-induced lung inflammation however, was not reduced by ablation of IKK-2 in either cell type. This was confirmed using 2 small molecule, structurally distinct 3 IKK-2 specific inhibitors, with proven efficacy against LPS-induced NF-kB:DNA association and neutrophilia. In support of these findings, lung tissue taken from human COPD patients also showed no change in NF-kB:DNA association compared to 'healthy smokers' and non-smokers, leading to the conclusion that contrary to previous reports, NF-kB may not play a prominent role in CS-induced lung inflammation.
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Lattke, Michael [Verfasser]. "Functional analysis of astroglial IKK/NF-KappaB signaling in brain development and homeostasis / Michael Lattke." Ulm : Universität Ulm. Fakultät für Naturwissenschaften, 2013. http://d-nb.info/1029507171/34.
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Fong, Carol Ho Yan. "The anti-inflammatory role for IkappaB kinase (IKK) beta through inhibition of 'classical' macrophage activation." Thesis, Queen Mary, University of London, 2010. http://qmro.qmul.ac.uk/xmlui/handle/123456789/466.
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Recent research has revealed a role of NF-B in the resolution of inflammation. Using Cre-lox mediated gene targeting, IKK was selectively deleted in macrophages (IKKβ∆Mye). From in vitro studies, LPS stimulated IKKMye macrophages increased STAT1 phosphorylation, iNOS, MHC II and IL-12 production, suggesting negative cross talk between NF-B and STAT1 signalling pathways. Since IKK is required for TNF gene expression and TNF signalling, I investigated the hypothesis that TNF inhibits ‘classical’ macrophage activation through IKK activation. Macrophages from p55-/- and mice treated with anti-TNF antibody show increased STAT1 activation and IL-12 expression after LPS and IFN stimulation. BMDM infected with adenovirus expressing IKKβ dominant negative rescued the inhibitory effect of TNFα on IL-12p40 production, indicating TNFα inhibits IL-12p40 via IKKβ activation. Macrophages are antigen presenting cells while IL-12 and MHC II are critical factors for TH1 cell development. I thus investigate the inhibitory effects of IKKβ∆Mye macrophages in TH1 responses. FACS analysis showed higher MHC II, costimulatory molecules expression on IKKβ∆Mye macrophages after LPS stimulation. In a DTH model, recall assay has shown increased antigen-specific IFN production from IKKMye splenocytes compared to IKKβF/F splenocytes. Furthermore, IFN production was greatly enhanced by CD4+ OTII T cells co-cultured with IKKMye macrophages. Further analysis of CD4+ OTII T cells with qRT-PCR showed increased TH1 genes including IRF1, IFN, IL-12R1 and IL-12R2 and reduced TH2 marker IL-4. In addition to the enhanced antigen-specific T cell responses, IKKMye macrophages also increased anti-tumour immunity. Injection of H-Y positive MB49 tumour cells into IKKF/F and IKKMye female mice has shown tumour rejection, but no tumours were rejected after CD8+ T cells depletion, suggesting tumour rejection is associated with enhanced CTL activity. Taken together, these studies demonstrated the negative regulatory roles of IKK in macrophage activation and their impact to the innate and adaptive immunity.
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Neil, Jason Robert. "TGF-ß promotes cancer progression through the xIAP:TAB₁:TAK₁:IKK axis in mammary epithelial cells /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2008.
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Thesis (Ph.D. in Pharmacology) -- University of Colorado Denver, 2008.Typescript. Includes bibliographical references (leaves 117-147). Free to UCD Anschutz Medical Campus. Online version available via ProQuest Digital Dissertations;
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Supekar, Vinit Mark. "Stress stimuli and pro-inflammatory kinases : structural studies of p38-α, -β2, -δ and IKK-α." Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.619692.
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Baratchian, M. "Mechanism of IKK activation by the Kaposi's sarcoma-associated herpesvirus protein vFLIP and its cellular homologues." Thesis, University College London (University of London), 2015. http://discovery.ucl.ac.uk/1461227/.
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Activation of the NF-κB pathway is linked to cancer development and progression. Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV8) encodes vFLIP which binds to the NEMO/IKKγ subunit of IKK and constitutively activates NF-κB, leading to tumourigenesis. Cellular FLIPs, which share sequence homology with KSHV vFLIP and induce NF-κB activation, are upregulated in a variety of malignancies and are therefore promising targets for anti-cancer therapies. The cFLIP family consists of three splice variant isoforms (cFLIPL, cFLIPS and cFLIPR) and two proteolytic fragments (p43-FLIP and p22-FLIP). Much is known about how cFLIPs regulate apoptosis but the mechanisms by which they activate NF-κB are not well understood. Potential similarities to vFLIP-induced activation have been suggested but not investigated. Here we show that, unlike KSHV vFLIP, cFLIP variants are not found in stable complexes with NEMO and all require upstream events to mediate signalling to IKK. By mutational analysis on NEMO and protein expression knockdowns, we demonstrate that all cFLIP isoforms require the ubiquitin binding domain (UBD) of NEMO while it is redundant for vFLIP’s function. Similarly, our data reveals that TAK1 is essential for induction of IKK by cFLIP isoforms but not vFLIP. We further show that different cFLIP isoforms have different requirements for IKK activation. While cFLIPL needs LUBAC to activate NF-κB, cFLIPS and p22-FLIP require FADD and RIP1. Contrary to existing reports, our results suggest that processing of cFLIPL to p22-FLIP or p43-FLIP fragments by caspase-8 is not necessary for its IKK activation. Finally, we propose that vFLIP-mediated activation of IKK is most likely to occur through induction of multimerisation and re-orientation of the IKK complexes within higher order IKK assemblies that lead to autophosphorylation of the enzymatic subunits, IKKα and β. In conclusion, the work in this thesis provides evidence that vFLIP, cFLIPL, cFLIPS and p22-FLIP have specific and different mechanisms of inducing IKK activation. This has implications for the design of therapeutics to block pathological NF-κB activation in viral and non-viral tumours.
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Koppe, Christiane [Verfasser], Marc [Akademischer Betreuer] Spehr, and Tom [Akademischer Betreuer] Lüdde. "Funktionen der IKK-Komplex-Untereinheiten in der Leberentzündung und Hepatokarzinogenese / Christiane Koppe ; Marc Spehr, Tom Lüdde." Aachen : Universitätsbibliothek der RWTH Aachen, 2016. http://d-nb.info/1126040940/34.
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Ip, Wing Hang [Verfasser], and Thomas [Akademischer Betreuer] Dobner. "Modulation of cellular IKK complexes by human Adenovirus Type 5 / Wing Hang Ip ; Betreuer: Thomas Dobner." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2017. http://d-nb.info/1134866089/34.
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Koppe, Christiane Verfasser], Marc [Akademischer Betreuer] [Spehr, and Tom [Akademischer Betreuer] Lüdde. "Funktionen der IKK-Komplex-Untereinheiten in der Leberentzündung und Hepatokarzinogenese / Christiane Koppe ; Marc Spehr, Tom Lüdde." Aachen : Universitätsbibliothek der RWTH Aachen, 2016. http://d-nb.info/1126040940/34.
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CARTA, STEFANIA. "Role of the IKK/NF-κB pathway in the regulation of apoptosis during influenza virus infection." Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2009. http://hdl.handle.net/2108/202341.
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The influenza virus represents one of the most important viral pathogens causing respiratory illness in humans and in animals. New influenza virus strains are constantly produced by protein mutation (antigenic drift) or genome reassortment (antigenic shift) and this high variability determines a resistance to antiviral drugs. In the recent years, the emergence of new avian and swine influenza A virus strains able to infect humans represents a serious threat to global human health. Given the high mutation rate of the viral proteins, a more innovative approach to anti-influenza therapy is the search for selected cellular targets essential for viral replication. In particular, the study of virus-regulated signal transduction pathways leading to metabolic changes in the host cell may lead to the discovery of novel drug targets. On this basis, one of the objectives of this work was to investigate the effects of influenza virus infection on the modulation of pathways involved in the control of cell survival and in particular on the IKKNF-κB pathway. Altogether, the results obtained indicate the existence of a complex network of pro- and anti -apoptotic signals induced by influenza virus, including activation of JNK and Akt kinases, and suggest that the balancing of various factors can determine the fate of infected cells. In particular, the activation of the IKK/NF-κB pathway, which is dependent on the viral strain and the cell type, appears to play an important role in host cell survival regulation, leading to expression of several anti-apoptotic proteins. In addition, in view of the emergence of highly pathogenic avian influenza strains able to infect humans, in the second part of this work we have utilized the H5N9-A/Ck/It/9097/97 strain to set up an in vitro model of avian influenza virus for the study of novel antiviral molecules. We have shown that A/Ck virus replicates efficiently in MDCK cells, causing a rapid shut-off of cell protein synthesis, massive disassembly of the host microtubular network, and sustained production of viral progeny particles in the supernatant of infected cells. Using this model, we have shown that cyclopentenone prostanoids (CyPG) potently inhibits A/Ck virus replication, causing dysregulation of viral protein synthesis, associated with cytoprotective HSP70 expression, and inhibition of virus-induced NF-κB activity. These results indicate that CyPG possess antiviral activity against avian influenza virus acting at a level different from the currently available anti-influenza drugs, suggesting a possible therapeutic use of cyclopentenone prostanoids or prostanoids-derived molecules during clinical complications of avian influenza-virus infection.
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Mikuda, Nadine. "The IkB kinase complex is a regulator of mRNA stability." Doctoral thesis, Humboldt-Universität zu Berlin, 2018. http://dx.doi.org/10.18452/19128.
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Bisher wurde davon ausgegangen, dass der IKK-komplex durch Regulation des Transkriptionsfaktors NF-kappaB die stressinduzierte Expression von Zielgenen steuert. Im Rahmen der hier vorgelegten Dissertation konnte jedoch gezeigt werden, dass der IKK-Komplex unabhängig von seiner Rolle in der NF-kappaB-Aktivierung die Stabilität einer Vielzahl von mRNAs kontrolliert. Mittels der Kombination von Ko-Immunopräzipitationsstudien und SILAC-MS konnte die induzierte Interaktion der regulatorischen Untereinheit des IKK-Komplexes IKKgamma mit dem Gerüstprotein EDC4 (Enhancer of Decapping 4) nachgewiesen werden. EDC4 ist eine essentielle Komponente sogenannter zytoplasmatischer „Processing Bodies“ (P-Bodies). Diese fungieren als Depots für die Speicherung von mRNAs, aber auch als Orte der mRNA-Degradation und der miRNA-vermittelten Repression spezifischer Zielgene. Die Interaktion von IKKgamma mit EDC4 konnte durch verschiedene Stimuli induziert werden. Dazu zählen DNA-Schäden durch Doppelstrangbrüche, aber auch die Aktivierung von Oberflächenrezeptoren durch TNFalpha und IL-1beta. EDC4 dient darüber hinaus als Substrat der Kinase IKKbeta. Mittels Massenspektrometrie und Kinaseassays konnten vier IKK-abhängige Phosphorylierungsstellen identifiziert werden. Die IKK-vermittelte Phosphorylierung von EDC4 ist essentiell für die Regulation von mRNAs und die damit verbundene Bildung der zytoplasmatischen P-Bodies. Diese Befunde konnten sowohl in stabilen induzierbaren Zelllinien, mittels transienter Transfektion und durch den Gebrauch von Kinaseinhibitoren in primären als auch in Krebszelllinien bestätigt werden. mRNA-Stabilitätsassays und eine RNA-Seq Analyse bestätigten die stressinduzierten Änderungen in den Halbwertszeiten spezifischer Transkripte und offenbarten einen gemeinsamen Regulationsmechanismus des IKK-Komplexes mit EDC4.The IKK complex is deemed to regulate gene expression through the activation of the transcription factor NF-kappaB. Here I describe an NF-kappaB-independent function of the IKK complex in regulating mRNA stability across different cell types and stimuli. A SILAC-MS screen for interaction partners of the regulatory subunit IKKgamma revealed an inducible interaction with Enhancer of mRNA Decapping 4 (EDC4). EDC4 is an essential component of cytoplasmic processing bodies (P-bodies). P-bodies function as sites of mRNA storage, degradation and miRNA-mediated silencing. Interaction between IKKgamma and EDC4 can be induced by various stimuli, including DNA damage, TNFalpha and IL-1beta. EDC4 was identified as a novel IKK substrate and four IKKbeta phosphorylation sites were determined by mass spectrometry and in kinase assays. Stable inducible cell lines, transient transfection and kinase inhibitors were used in different human cancer and in primary cell lines and demonstrated that phosphorylation of EDC4 by IKK is essential for formation of P-Bodies in response to numerous stimuli. mRNA stability assays confirmed stress-induced changes in the half-life of target mRNAs and revealed common regulation of mRNA stability by IKK and EDC4. The transcriptome-wide reach of this joint regulation was assessed via RNA-Seq analysis.
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Rodrigues, Felipe Silva. "Explorando a quinase IKK como um alvo terapêutico para células iniciadoras de tumor pulmonares induzidas pelo oncogene KRAS." Universidade de São Paulo, 2018. http://www.teses.usp.br/teses/disponiveis/46/46131/tde-26112018-080111/.
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As alterações genéticas mais frequentes em câncer de pulmão são mutações pontuais que ativam o oncogene KRAS. Embora estas mutações estejam causalmente relacionadas à oncogênese, até hoje diferentes abordagens para inibir as proteínas RAS diretamente não obtiveram sucesso. Portanto, para que melhores alvos terapêuticos para o câncer de pulmão se tornem disponíveis é necessário identificar os mecanismos moleculares ativados por KRAS que estão diretamente envolvidos com a aquisição de propriedades malignas importantes, como o desenvolvimento e a manutenção de um fenótipo tronco-tumoral pelas células iniciadoras de tumor (CITs). CITs, também conhecidas como células tronco-tumorais, são definidas como uma subpopulação de células tumorais capazes de se autorrenovar, iniciar a formação de tumores e sustentar o crescimento tumoral. O desenvolvimento de estratégias terapêuticas dirigidas a estas células é imprescindível para melhorar a eficácia da terapia antitumoral. Uma vez que KRAS está associada a manutenção de um fenótipo tronco-tumoral e ativa o fator de transcrição NF-kB através da quinase IKKβ para promover a tumorigênese pulmonar, nós hipotetizamos que a quinase IKKβ contribui para o fenótipo tronco-tumoral induzido por KRAS em câncer de pulmão. Nós utilizamos ensaios de formação de tumoresferas para enriquecer e avaliar a função de CITs das linhagens pulmonares positivas para KRAS A549 e H358. As células A549 e H358 formaram tumoresferas em cultura de baixa aderência e, quando comparadas às células derivadas da cultura aderente, as células oriundas da cultura de tumoresferas apresentaram maior crescimento clonogênico, maior expressão de genes associados ao fenótipo tronco por qPCR e maior atividade da quinase IKKβ. A inibição da atividade de IKKβ através de um inibidor farmacológico altamente específico (Composto A) diminuiu levemente a proliferação de células A549 e H358, sem resultar em morte celular significativa. Entretanto, a inibição da atividade ou da expressão de IKKβ por interferência de RNA reduziu a expressão de genes associados ao fenótipo tronco e diminuiu a formação de tumoresferas. A inibição da expressão de IKKβ em células A549 reduziu também a capacidade de autorrenovação de CITs. Estes resultados sugerem que IKKβ desempenha um papel importante na manutenção do fenótipo tronco-tumoral de CITs pulmonares induzidas por KRAS. Em seguida, nós demonstramos que a inibição da atividade de IKKβ afetou preferencialmente a proliferação celular e o crescimento clonogênico de células oriundas da cultura de tumoresfera, sugerindo que IKKβ desempenha um papel mais importante em CITs do que em células derivadas da cultura aderente. A análise por citometria de fluxo identificou que células derivadas da cultura de tumoresfera apresentam um enriquecimento para células CD24+ na linhagem A549 e células CD44+ na linhagem H358, sugerindo que estes possam ser marcadores promissores para purificação de CITs nestas linhagens. Adicionalmente, demonstramos, por ensaios de wound-healing de células A549 e H358, que a inibição da atividade de IKKβ reduziu a migração celular, uma outra uma propriedade aumentada em CITs. Além disso, mostramos que a atividade da quinase IKKβ em células A549 e H358 não depende das vias da MAPK ou PI3K/Akt. Interessantemente, a inibição combinada de IKK (um efetor downstream de KRAS) e de EGFR/ERRB2 (reguladores upstream de KRAS que ativam as vias MAPK e PI3K/Akt) reduziu de forma aditiva a formação de tumoresferas, proliferação e migração celular. Quando avaliados em conjunto, nossos resultados sugerem que a quinase IKKβ desempenha um papel importante na biologia de CITs pulmonares portadoras de KRAS oncogênica e que a inibição desta quinase sozinha ou em combinação com a inibição de outras vias pode representar uma estratégia terapêutica promissora a ser explorada para reduzir a recidiva e metástase no câncer de pulmão induzido por KRAS.The most frequent genetic alterations in lung cancer are point mutations that activate the KRAS oncogene. Although these mutations are causally related to oncogenesis, different approaches to inhibit RAS proteins directly have not been successful to date. Therefore, for better therapeutic targets for lung cancer to become available, it is necessary to identify the molecular mechanisms activated by KRAS that are directly involved with important malignant features, such as the development and maintenance of a cancer stem-like phenotype by the tumour-initiating cells (TICs). TICs, also known as cancer stem cells, are defined as a subpopulation of tumour cells able to self-renew, promote tumour initiation, and sustain tumour growth. The development of therapeutic strategies to target these cells is imperative to improve the efficacy of antitumor therapy. Since KRAS is associated with the maintenance of a cancer stem-like phenotype and activates the transcription factor NF-kB through the IKKβ kinase to promote lung tumourigenesis, we hypothesised that IKKβ kinase contributes to the cancer stem-like phenotype induced by KRAS in lung cancer. We used tumoursphere formation assays to enrich and evaluate the function of TICs of KRAS-mutant cell lines A549 and H358. A549 and H358 cells formed tumourspheres in low adhesion culture and, when compared to cells grown in adherent culture, sphere-derived cells displayed increased clonogenic growth, higher expression of stemness genes by qPCR, and increased IKKβ kinase activity . Inhibition of IKKβ activity through a highly specific pharmacological inhibitor (Compound A) slightly decreased proliferation of A549 and H358 cells without inducing significant cell death. On the other hand, inhibition of IKKβ activity or expression by RNA interference reduced the expression of stemness genes and decreased tumoursphere formation. Inhibition of IKKβ expression in A549 cells also reduced TICs self-renewal . These results suggest that IKKβ plays an important role in maintaining the cancer stem-like phenotype of KRAS-driven lung TICs. Next, we demonstrated that IKKβ inhibition preferentially reduced cell proliferation and clonogenic growth of sphere-derived cells, suggesting that IKKβ plays a more important role in TICs than in adherent culture-derived cells. Flow cytometry analysis identified that sphere-derived cells display an enrichment for the surface marker CD24 in A549 cells and CD44 in H358 cells, indicating that these could be promising markers for the purification of TICs in these cell lines. Furthermore, we have shown by wound-healing assays of A549 and H358 cells that IKKβ inhibition reduced cell migration , another feature increased in TICs. In addition, we have shown that IKKβ activity in A549 and H358 cells does not depend on the MAPK or PI3K/Akt pathways. Interestingly, combined inhibition of IKKβ (a downstream effector of KRAS) and EGFR/ERBB2 (upstream regulators of KRAS that activate the MAPK and PI3K/Akt pathways) additively reduced tumoursphere formation, cell proliferation and migration. Taken together, our results suggest that IKKβ kinase plays an important role in the biology of KRAS-driven lung TICs, and that inhibition of this kinase alone or in combination with inhibition of other signalling pathways may represent a promising therapeutic strategy to be explored in order to reduce tumour recurrence and metastasis in KRAS-driven lung cancer.
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Menagh, Gillian. "The regulation of Toll-like receptor (TLR)-stimulated inducible inhibitory kappa B kinase (IKK-i) expression in murine macrophages." Thesis, University of Strathclyde, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.432751.
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Neto, Glauco Baiocchi. "Perfil da expressão imunoistoquímica de HER-2, NF-kB e IKK em câncer de colo uterino tratado com radioterapia." Universidade de São Paulo, 2011. http://www.teses.usp.br/teses/disponiveis/5/5155/tde-24112011-154630/.
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INTRODUÇÃO: O tratamento padrão do câncer do colo uterino é a histerectomia radical para doença inicial e quimio-radioterapia para doença avançada. A radioterapia após a histerectomia radical tem impacto em ganho de sobrevida caso hajam fatores de risco histopatológicos para recidiva. Portanto, a busca de marcadores preditores de radiossensibilidade torna-se importante para a individualização do planejamento terapêutico. O HER-2/ErbB-2 faz parte da família de proteínas ErbB que formam um grupo de receptores de membrana e tem um papel crítico no controle de diversas funções celulares básicas como diferenciação, proliferação, migração e sobrevida celular. A ação do NF-B na carcinogênese pode ocorrer através da regulação da apoptose e controle do ciclo celular. Para ativação do NF-B é necessário a enzima quinase IKK e a atividade do NF-B foi relacionada com resistência tumoral a quimioterapia e radioterapia. A via PI3K/Akt mediada pela hiperexpressão de HER-2 pode estar envolvida na ativação do NF-B. Os objetivos foram: a) avaliar os padrões de expressão imunoistoquímica de HER-2, NF-B-p65, NF-B-p50 e IKK em pacientes portadores de câncer do colo uterino submetidos à radioterapia; b) avaliar o status do gene HER2 através de FISH; c) avaliar o papel da expressão imunoistoquímica de NF-B-p65, NF-B-p50, IKK e HER-2 como fator prognóstico para sobrevida livre de doença e sobrevida global. MATERIAIS E MÉTODOS: Trata-se de estudo retrospectivo que avaliou uma série de 32 pacientes portadores de câncer do colo do útero submetidos a tratamento com radioterapia seguido de histerectomia no período de janeiro de 1992 a junho de 2001. RESULTADOS: A idade mediana foi 45 anos (22-67). Um paciente apresentava-se no estádio IB2 (FIGO) e 31 (96,9%) estádio IIB. Todos os pacientes foram submetidos à teleterapia e braquiterapia com alta taxa de dose com caráter neoadjuvante à histerectomia radical (HR). Dezesseis (50%) pacientes apresentaram doença residual após radioterapia. O tempo de seguimento mediano foi de 73,5 meses. A sobrevida global da amostra foi de 66,5% em 5 anos. As expressões imunoistoquímicas de NF-B-p65 e NF-B-p50 em citoplasma nos tumores primários foram encontradas em respectivamente 90,6% e 96,9% dos casos. As expressões de NF-B-p65 e NF-B-p50 em núcleo nos tumores primários 59,4% dos casos em ambos. As expressões de NF-B-p65 e NF-B-p50 em citoplasma nos tumores residuais após tratamento com radioterapia foram encontradas 50% dos casos em ambos. A expressão em núcleo de NF-B-p50 nos tumores residuais após tratamento com radioterapia foi encontrada em 75% dos casos. Não houve expressão em núcleo de NF-B-p65 nos tumores residuais. A expressão imunoistoquímica de HER-2 nos tumores primários foi de encontrada em 21,9% dos casos. Não houve expressão imunoistoquímica de HER-2 nos tumores residuais do colo uterino. A amplificação gênica de HER-2 nos tumores primários foi encontrada em 1 (3,1%) caso. Não houve expressão imunoistoquímica de IKK nos tumores primários ou residuais. As expressões imunoistoquímicas de HER-2, NF-B-p65 e NF-B-p50 não se correlacionaram com a resposta ao tratamento radioterápico pré-operatório. As expressões imunoistoquímicas positivas de NF-B-p65, NF-B-p50, IKK e HER-2 não se associaram a piores taxas de sobrevida livre de doença e sobrevida global. CONCLUSÕES: Nossos dados sugerem que as expressões imunoistoquímicas de NF-B e HER-2 não são capazes de predizer resposta à radioterapia e não estão relacionadas com pior prognóstico. O NF-B parece ser constitutivamente ativado no câncer do colo uterinoINTRODUCTION: The standard treatment of early cervical cancer is radical hysterectomy and concomitant radiation therapy and chemotherapy for advanced stages. After radical hysterectomy, adjuvant radiation therapy is indicated if risk factors are present. HER-2 is part of protein membrane family that has a critical role in cellular differentiation, proliferation and survival. The NF-B regulates apoptosis, cellular cycle, adhesion and cellular migration. NF-B is activated by IKK kinase. NF-B activation is related to resistance to radiotherapy and chemotherapy. The overexpression of HER-2 may activate the NF-B pathway through PI3K/Akt. Our aims were: a) analyze the immunohistochemical expression of HER-2, NF-B-p50, NF-B-p65 and IKK in patients with cervical cancer treated with radiation therapy followed by radical hysterectomy; b) analyze the HER-2 amplification gene with FISH; c) evaluate the immunohistochemical expression of HER-2, NF-B-p50, NF- B-p65 and IKK as a prognostic factor to recurrence and death. MATERIALS AND METHODS: A retrospective analysis was carries out on 32 patients with cervical cancer submitted to radical hysterectomy after neoadjuvant radiotherapy from January 1992 to June 2001. RESULTS: The median age was 45 years (22-67). One patient was stage IB2 (FIGO) and 31 IIB (96,9%). All patients received external beam radiotherapy and high dose vaginal brachytherapy. Sixteen (50%) patients had residual pathological disease after radical hysterectomy. Median follow-up time was 73.5 months and overall 5-year survival was 66.5%. Immunohistochemical cytoplasmic expression of NF-B-p65 e NF-B-p50 before radiotherapy was found in respectively 90.6% and 96.9% of cases. Immunohistochemical nuclear expression of NF-B-p65 and NF-B-p50 before radiotherapy was found in both 59.4% of cases. Immunohistochemical cytoplasmic expression of NF-B-p65 and NF-B-p50 in the residual tumors after radiotherapy was found in both 50% of cases. Immunohistochemical nuclear expression of NF-B-p50 in the residual tumors was found in 75% of cases. There was no nuclear expression of NF-B-p65 in the residual tumors. Immunohistochemical expression of HER-2 was found in 21.9% of cases. However, gene amplification was found in one case (3.1%). There was no expression of IKK in neither primary nor residual tumors. HER-2 and NF-B were not correlated to the risk of residual tumor after radiotherapy. Immunohistochemical expression of HER-2 and NF-B were not correlated to risk of recurrence or death. CONCLUSIONS: Our data suggest that NF-kB is constitutively activated in advanced cervical cancer. NF-kB and HER-2 may not predict response to radiotherapy and do not correlate to poor outcome
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Chen, Liang. "IkappaB Kinase beta in the Regulation of Cell Migration, Senescence and Fibrosis." University of Cincinnati / OhioLINK, 2012. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1329495227.
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Benedetti, Giacomo. "Analisi computazionale e confronto con dati sperimentali della corrente rapida di potassio nei modelli di cardiomiocità ventricolare umano." Bachelor's thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amslaurea.unibo.it/7093/.
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Tomás, Hernández Sara. "Characterization of the biological effects of natural compounds against inflammation, metabolic syndrome and cancer." Doctoral thesis, Universitat Rovira i Virgili, 2017. http://hdl.handle.net/10803/456815.
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Els productes naturals han sigut àmpliament utilitzats per al tractament i prevenció de moltes malalties. L’objectiu principal d’aquesta tesi ha estat caracteritzar compostos naturals bioactius que podrien ser utilitzats per a la prevenció o tractament d’algunes malalties rellevants com ara la síndrome metabòlica, les malalties neurodegeneratives i el càncer. Aquestes condicions mèdiques representen un problema de salut important ja constitueixen les principals causes de mort a nivell mundial.
Atès que nombrosos estudis han demostrat que el procés d’inflamació crònica està directament involucrat en l'aparició de la síndrome metabòlica i les malalties neurodegeneratives, hem intentat identificar compostos naturals que puguen mitigar aquest persistent i nociu estat d'inflamació. En aquest sentit, vam investigar si el compost natural o-orsellinaldehid podria modular la resposta inflamatòria actuant com a inhibidor d’IKK-2. Els nostres resultats confirmen que l’o-orsellinaldehid posseeix propietats antiinflamatòries potents suggerint que podria tractar-se d’un possible candidat preventiu o terapèutic per al tractament de patologies relacionades amb processos d’inflamació crònica com són la síndrome metabòlica i les malalties neurodegeneratives.
Posteriorment, estudiàrem els efectes antidiabètics d’un altre compost natural, la 2,4,6-Trimethoxibenzofenona. Concretament, vam analitzar els efectes d’aquest nou modulador selectiu de PPARγ en la inhibició de la fosforilació de la Ser273 de PPARγ duta a terme per l’enzim Cdk5, així com la seua influència en l’adipogènesi. Les nostres dades demostren que la 2,4,6-trimetoxibenzofenona podria millorar la resistència a la insulina ja que és capaç d’inhibir la fosforilació de PPARγ, i minimitza els efectes secundaris habituals dels fàrmacs existents, com l'adipogènesi, degut a la seua baixa activitat agonística.
L'última part d'aquesta tesi va tenir com a objectiu estudiar l'efecte combinat de la quercetina i el resveratrol sobre el procés autofàgic en cèl·lules HepG2, concloent que el resveratrol contraresta potentment l’autofàgia induïda per la quercetina sota una situació de restricció calòrica i sensibilitza les cèl·lules canceroses a l’apoptòsi.Los productos naturales han sido ampliamente utilizados para el tratamiento y prevención de muchas enfermedades. El objetivo principal de esta tesis es caracterizar compuestos naturales bioactivos que podrían utilizarse para la prevención o tratamiento de algunas enfermedades relevantes como son el síndrome metabólico, las enfermedades neurodegenerativas y el cáncer. Estas condiciones médicas representan un problema de salud importante ya que constituyen las principales causas de muerte a nivel mundial. Dado que numerosos estudios han demostrado que la inflamación crónica está directamente involucrada en la aparición del síndrome metabólico y las enfermedades neurodegenerativas, hemos intentado identificar compuestos naturales que puedan atenuar este persistente y nocivo estado de inflamación. Por ello, investigamos si el compuesto natural o-orsellinaldehido podría modular la respuesta inflamatoria actuando como inhibidor de IKK-2. Nuestros resultados confirman que el o-orsellinaldehido posee propiedades antiinflamatorias potentes sugiriendo que podría tratarse de un posible candidato preventivo o terapéutico para el tratamiento de patologías relacionadas con procesos de inflamación crónica como el síndrome metabólico y las enfermedades neurodegenerativas. Posteriormente, estudiamos los efectos antidiabéticos de otro compuesto natural, la 2,4,6-Trimethoxibenzofenona. Analizamos los efectos de este nuevo modulador selectivo de PPARγ en la inhibición de la fosforilación de la Ser273 de PPARγ mediada por la enzima CdK5, así como su influencia en la adipogénesis. Nuestros datos demuestran que la 2,4,6-trimetoxibenzofenona podría mejorar la resistencia a la insulina ya que es capaz de inhibir dicha fosforilación, y minimiza los efectos secundarios habituales de los fármacos existentes, como la adipogénesis, debido a la su baja actividad agonística. La última parte de la tesis tuvo como objetivo estudiar el efecto combinado de la quercetina y el resveratrol sobre el proceso autofágico en células HepG2, concluyendo que el resveratrol contrarresta potentemente la autofagia inducida por la quercetina bajo una situación de restricción calórica y sensibiliza las cáncerosas a la apoptosis.
Natural products (NPs) have been used for the treatment and prevention of many diseases and illnesses since early human history. The main goal of this doctoral thesis is the characterization of bioactive natural compounds that could be used for the prevention or treatment of some major significant diseases, such as metabolic syndrome, neurodegenerative diseases and cancer. These medical conditions constitute an important health problem worldwide since they are included in the world leading causes of death. Since numerous studies have shown that the chronic inflammation process is directly involved in the onset of metabolic syndrome and neurodegenerative diseases we aimed to identify NP that could mitigate this harmful persistent inflammation state. In that sense, we investigated if the natural compound o-oresllinaldehyde might modulate the inflammatory response by acting as IKK-2 inhibitor. Our results confirm that o-orsellinaldehyde possesses strong anti-inflammatory properties suggesting that it may be a potential preventive or therapeutic candidate for the treatment of pathologies that deal with chronic inflammation such as metabolic syndrome and neurodegenerative diseases. Then, we examined the anti-diabetic effects of another natural compound kwon as 2,4,6-Trimethoxybenzophenone. Concretely, we analyzed the effect of this novel selective PPARγ modulator (SPPARγM) on the Cdk5-mediated phosphorylation of PPARγ as well as its influence on adipogenesis. Our data demonstrated that 2,4,6-Trimethoxybenzophenone would retain the benefits of improving insulin resistance since its able to inhibit Cdk5-meditated PPARγ phosphorylation at ser273, but minimizes the common side effects of existent drugs, such as adipogenesis, by alleviating PPARγ agonistic activity. The last part of this thesis aimed to clarify the combined effect of the two natural compounds, Quercetin and Resveratrol, on the autophagic process in HepG2 cancer cells, concluding that resveratrol potently counteracts quercetin starvation-induced autophagy and sensitizes HepG2 cancer cells to apoptosis.
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Vinolo, Emilie. "Etude structurale et fonctionnelle de mutations dans la protéine NEMO, régulateur essentiel de la voie de signalisation NF-kappaB, associées à des pathologies orphelines." Paris 6, 2006. http://www.theses.fr/2006PA066325.
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Maier, Eduard [Verfasser], Ralf C. [Gutachter] Bargou, and Albrecht [Gutachter] Müller. "Molekulare Analyse des IKK-Komplexes als Zielstruktur für potentielle Therapieoptionen im Multiplen Myelom / Eduard Maier. Gutachter: Ralf C. Bargou ; Albrecht Müller." Würzburg : Universität Würzburg, 2016. http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-127198.
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