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Cell interaction --- Cellular signal transduction

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Immunology --- Natural immunity --- Immune System --- Immune System Phenomena --- Signal Transduction --- physiology --- immunology --- Receptor Mediated Signal Transduction --- Signal Transduction Pathways --- Signal Transduction Systems --- Receptor-Mediated Signal Transduction --- Signal Pathways --- Pathway, Signal --- Pathway, Signal Transduction --- Pathways, Signal --- Pathways, Signal Transduction --- Receptor-Mediated Signal Transductions --- Signal Pathway --- Signal Transduction Pathway --- Signal Transduction System --- Signal Transduction, Receptor-Mediated --- Signal Transductions --- Signal Transductions, Receptor-Mediated --- System, Signal Transduction --- Systems, Signal Transduction --- Transduction, Signal --- Transductions, Signal --- Immune System Concepts --- Immune System Phenomenon --- Immune System Process --- Immune System Processes --- Concept, Immune System --- Concepts, Immune System --- Immune System Concept --- Phenomena, Immune System --- Phenomenon, Immune System --- Process, Immune System --- Processes, Immune System --- Immune Systems --- System, Immune --- Systems, Immune --- Disease resistance --- Host resistance --- Innate immunity --- Innate resistance --- Native immunity --- Natural resistance --- Nonspecific immunity --- Resistance to disease --- Cell Communication --- Receptor-CD3 Complex, Antigen, T-Cell --- Receptor Cross-Talk --- Feedback, Physiological --- Gasotransmitters --- Seroconversion --- Immunity --- Immunology. --- Natural immunity. --- Immune System Phenomena. --- physiology. --- immunology. --- Immunobiology --- Life sciences --- Serology --- Agriculture Sciences --- Soil Chemistry, Microbiology, Fertility & Fertilizers

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Cancer development results from a multi-step process that involves a set of genetic abnormalities allowing the clonal selection of cells with proliferative advantages. Some of these genetic abnormalities increase the autonomous proliferation of tumor cells by aberrant activation of signal transduction of growth factors that provide survival and proliferative signals in normal cells under physiological conditions.
The in vitro tumorgenesis model studied in this master thesis is based on cytokine-dependent cells that acquired cytokine-independence through two selection steps. First, BaF3 cells expressing a non-functional IL-9 receptor developed IL-9 responsiveness. This adaptation to IL-9 was accompanied by overexpression of the JEAK1 protein kinase, which is associated with IL-9 receptor and implicated in its signal transduction. IL-9-responsive cells could further give rise to totally cytokine-independent, autonomous clones.
In the first part of this work, we showed that these autonomous clones harbour point mutations in JAK1. Certain of these mutations were recently described in patients with acute lymphoblastic leukaemia, further illustrating the relevance of our model. We subsequently characterized the different JAK1 mutants functionally. All of them constitutively activated signalling molecules downstream of JAK1-binding receptors, such as IL-2 and IL-9 receptor, allowing for cytokine-independence of BAF3 cells. Moreover, 13 of the 18 identified mutants conferred hypersensitivity to the anti-proliferative effects of type I interferons.
The second part of this master thesis focuses on the study of the genetic factors promoting the apparition of spontaneous point mutations. JAK1 overexpression is a prerequisite for the selection of JAK1-mutated autonomous clones suggesting a favourable cellular context for further mutations. Therefore, we investigated systematically the different possible mechanism of JAK1 overexpression. Using transcription and translation inhibitors, we demonstrated that kinetics of JAK1 messenger RNA and JAK1 protein degradation were not altered by selection in IL-9 excluding post-transcriptional deregulation mechanisms. Treatment of cells with demethylating or acetylating agents and bisulfite sequencing ruled out the direct epigenetic regulations like modification of promoter methylation pattern or histones acetylation. Complementary experiments are needed in order to identify the mechanism underlying JAK1 overexpression in our model and to assess its impact on apparition of spontaneous activating mutations in JAK1 Le développement d’un cancer est le résultat d’un processus séquentiel qui implique une succession d’anomalies génétiques et de sélections clonales de cellules présentant un avantage de prolifération. Certaines de ces anomalies génétiques accroissent l’autonomie des cellules tumorales moyennant une signalisation aberrante des facteurs de croissance dont elles sont physiologiquement dépendantes.
Le modèle de tumorgenèse in vitro étudié dans ce travail met en scène des cellules au départ dépendantes de cytokines qui acquièrent la capacité de proliférer de façon autonome au terme d’un processus en deux étapes de sélection. Dans un premier temps, des cellules BaF3 exprimant un récepteur pour l’interleukine-9 (IL-9) non-fonctionnel développent une faculté de réponse à l’IL-9. Nous avons observé que cette adaptation s’accompagne systématiquement d’une surexpression de la protéine kinase JAK1 associée au récepteur à l’IL-9 et impliquée dans sa signalisation intracellulaire. Les cellules adaptées à l’IL-9 peuvent, dans un second temps, donner naissance à des clones totalement autonomes.
Dans le premier volet de ce mémoire, nous montrons que les clones autonomes présentent des mutations ponctuelles de JAK1. L’intérêt de ces mutations est illustré par le fait que récemment certaines d’entre elles ont également été identifiées chez des patients atteints de leucémies lymphoblastiques aiguës. Nous avons caractérisé fonctionnellement les différents mutants de JAK1. Ils activent constitutivement les molécules de signalisation en aval des récepteurs de cytokines tels ceux de l’IL-9 ou l’IL-2 assurant l’autonomie des cellules. Par opposition, 13 des 18 mutants identifiés confèrent une hypersensibilité aux effets anti-prolifératifs des interférons de type 1.
Le second volet de ce travail est l’étude des facteurs génétiques favorisant la survenue de telles mutations. La surexpression de JAK1 est un prérecquis à l’émergence de cellules autonomes évoquant un contexte propice à l’apparition de mutations. Nous avons entrepris l’examen systématique des divers mécanismes de surexposition envisageables. En faisant usage d’inhibiteurs de la transcription ou de la traduction, nous avons démontré que les cinétiques de dégradation de l’ARN messager et de la protéine n’étaient pas modifiées par la sélection en IL-9 écartant par conséquent une dérégulation post-transcriptionnelle. Le traitement des cellules par agents déméthylants ou acétylants ainsi que le séquençage d’ADN génomique traité au bisulfite excluent une régulation épigénétique telle qu’une modification dans la méthylation du promoteur ou l’acéthylation des histones. Des expériences complémentaires sont nécessaires afin d’élucider la cause de la surexposition de JAK1 dans notre modèle et de comprendre son éventuel impact sur l’apparition de mutations spontanées

Janus Kinase 1 --- Signal Transduction --- Angiogenic Proteins --- STAT Transcription Factors --- Neoplasm Proteins --- Smarcd3 protein, mouse --- Clone Cells

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Multicellular organisms must be able to adapt to cellular events to accommodate prevailing conditions. Sensory-response circuits operate by making use of a phosphorylation control mechanism known as the ""two-component system."" This volume, the third in a three-volume treatment edited by the same group of editors, includes a wide range of methods, including those dealing with the Sln-1 kinase pathway, triazole sensitivity in C. albicans, and histidine kinases in cyanobacteria circadian clock. * Includes time-tested core methods and new innovations applicable to any res

Cellular signal transduction. --- Chemotaxis. --- Signal Transduction. --- Enzymology. --- Phosphoproteins -- Physiological effect. --- Protein kinases. --- Human Anatomy & Physiology --- Health & Biological Sciences --- Animal Biochemistry --- Chemiotaxis --- Chemotropism --- Cellular information transduction --- Information transduction, Cellular --- Signal transduction, Cellular --- Biochemistry --- Growth --- Taxes (Biology) --- Bioenergetics --- Cellular control mechanisms --- Information theory in biology

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Bacteria --- Cell receptors --- Cellular signal transduction --- Bactéries --- Récepteurs cellulaires --- Transduction du signal cellulaire --- Physiology --- Physiologie --- Bactéries --- Récepteurs cellulaires --- Monograph --- Bacteria - Physiology