Dissertations / Theses on the topic 'Voie des MAP kinases'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'Voie des MAP kinases.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
Chetoui, Nizar. "Caractérisation du rôle de la protéine kinase MEK1 dans les voies de transduction des MAP kinases." Thesis, Université Laval, 2005. http://www.theses.ulaval.ca/2005/22589/22589.pdf.
Full textAoidi, Rifdat. "Étude du rôle de la voie ERK/MAPK dans le développement embryonnaire chez la souris." Doctoral thesis, Université Laval, 2017. http://hdl.handle.net/20.500.11794/27476.
Full textLes mammifères possèdent deux MAP kinases kinases (MEK1 et MEK2), impliquées dans l’activation de la voie ERK/MAPK essentielle pour la différenciation, la prolifération et la survie cellulaire. Le premier objectif de cette thèse était de déterminer si les fonctions des kinases MEK1 et MEK2 sont redondantes durant le développement embryonnaire. Les souris Mek1-/- meurent à mi-gestation d’une malformation du placenta. Les souris Mek2-/- ne présentent aucun phénotype majeur, suggérant que ces deux protéines ont des rôles différents. Cependant, la plupart des mutants Mek1+/-Mek2+/- meurent pendant la gestation d’un sous-développement du placenta, indiquant que Mek1 et Mek2 ont chacun un rôle dans le développement des tissus extraembryonnaires. À ce jour aucune évidence claire ne permet de statuer sur la redondance fonctionnelle de MEK1 et MEK2. Afin de vérifier la spécificité fonctionnelle de Mek1 et Mek2, nous avons généré au laboratoire un allèle « knockin », exprimant l’ADNc de Mek2 sous contrôle du locus Mek1 (Mek12). L’analyse de ces souris a révélé la redondance fonctionnelle entre MEK1 et MEK2. L’analyse de combinaisons alléliques de Mek a démontré qu’une expression minimale de protéines MEK est cruciale pour le développement embryonnaire et la survie. Le second objectif de cette thèse était de caractériser les mutants Mp1. Les protéines d’échafaudage permettent de moduler l’activité de la voie ERK/MAPK et facilitent la transmission rapide du signal. Parmi les protéines d’échafaudage connues, seule MP1 (Mek Partner 1) a été identifiée comme étant un partenaire spécifique de MEK1 et ERK1. Cette spécificité suggère que MP1 pourrait contribuer à la différence d’activation de MEK1 et MEK2 en spécifiant le signal qui passe par Mek1. Afin d’étudier le rôle de Mp1 au cours du développement chez la souris, nous avons généré des souris Mp1-/-. L’analyse de ces mutants indique que le gène Mp1 est essentiel pour la survie et que sa fonction est nécessaire suite à la post-implantation. La dérégulation de la voie ERK/MAPK dans le développement chez l’homme a aussi des conséquences phénotypiques. Au cours des dernières années, une classe de syndromes a été caractérisée : Les « Rasophaties ». Ces syndromes partagent des caractéristiques communes qui sont, une mutation dans des gènes de la voie ERK/MAPK, une dysmorphologie cranio-faciale, des malformations cardiaques et cutanées ainsi qu’un retard mental. Parmi les mutations de la voie ERK/MAPK qui ont été identifiées, une mutation ponctuelle dans le gène Mek1 (Mek1Y130C) cause le syndrome Cardio-Facio-Cutané (CFC). Le dernier objectif de cette thèse était de générer un modèle animal pour le CFC portant la mutation Mek1Y130C. Les souris portant l’allèle Mek1Y130C présentent les phénotypes associés au CFC (i.e sténose pulmonaire, dysmorphologie cranio-faciale et défauts neurologiques).
Mammals possess two MAP kinase kinase (MEK1 and MEK2), involved in ERK/MAPK pathway. This pathway is essential for proliferation, differentiation and cell survival. The first objective of my thesis was to determinate if MEK1 and MEK2 kinases are redundant during embryonic development. Mek1-/- mice die at embryonic day E10.5 due to placental defects, whereas Mek2-/- mice survive with a normal lifespan suggesting that MEK1 possesses functions not shared by MEK2. However, most Mek1+/-Mek2+/- embryos also die from placental defects, indicating that both Mek genes contribute to placental development. To date, no clear evidence on MEK1 and MEK2 redundancy has been provided. To assess the functional specificity of the Mek1 and Mek2 genes, we produced a Mek1-knockin allele in which the Mek2 coding sequences were placed under the control of Mek1 regulatory sequences. Analyzing these mice allowed us to demonstrate that MEK1 and MEK2 can substitute for each other and that a minimal amount of MEK is critical for placenta development and embryo survival. The second objective of my thesis was to characterize Mp1 mutants. Scaffold proteins modulate MAPK pathway by providing spatial and temporal specificity. Among known ERK/MAPK scaffold proteins, only MP1 (Mek Partner 1) is specific to MEK1 and ERK1, raising the question of the specificity of MP1 in the regulation of ERK/MAPK pathway via MEK1. In order to investigate Mp1 function in vivo, we generated Mp1 knock-out mice. Analyzing these mice enable us to suggest that Mp1 is required for embryonic development and is essential during post-implantation. Deregulation of Ras/MAPK pathway also causes developmental phenotypes in human. During the last decade, a new class of syndromes, which share common phenotypes such as mutations in Ras/MAPK pathway, cranio-facial dysmorphology, cardiac and cutaneous malformations and neurological delay has been described and named Rasophaties. Among the DNA mutations found in rasopathies, the Mek1 mutation, Mek1Y130C, causes cardio-facio-cutaneous syndrome (CFC). The last objective of my thesis was to generate a mouse model of CFC, with the Mek1Y130C mutation. I found that mice carrying the Mek1Y130C mutation partially recapitulate CFC syndrome (i.e pulmonary stenosis, crani-facial dysmophia and neurological defects).
Bouaouina, Mohamed. "Etude de la voie de signalisation activatrice des intégrines beta2 et beta3 dans les neutrophiles et les plaquettes." Paris 6, 2004. http://www.theses.fr/2004PA066013.
Full textPellegrino, Christophe. "Neurotoxicité et neuroprotection médiées par les récepteurs NMDA : organisation spacio-temporelle de la voie des MAP kinases." Aix-Marseille 2, 2009. http://theses.univ-amu.fr.lama.univ-amu.fr/2009AIX22032.pdf.
Full textMy thesis project, is centered on the dichotomous role of the NMDAR and on the activation of the MAPKs signaling pathways. Many deseases and physiologic processes of the central nervous system are under control of the same type of molecules. This molecule is the NMDAR. This ionotropic glutamate receptor can trigger different responses based upon different stimuli. This discrepancy in neuronal cells could lead i) to physiologic responses such as LTP, LTD, neurite outgrowth and synapse formation, ii) to physiopathologic respones and as a final consequence could trigger cell death. The mechanisms underlying these phenomenom are not well known. It becomes crucial to determine how the NMDAR can discriminate between these different situmuli. Previous publications (Ivanov et al. , 2006;Krapivinsky et al. , 2003;Krapivinsky et al. , 2004) have all in common to highlight a specific coupling between NMDAR and the signaling cascades (Ras, Rap). Our work suggests that NMDAR could modulate ERK and p38 MAPK pathways. My hypothesis is that the selectivity occurs at different level, i) depending on the localization of the receptor, ii) depending on the composition of the receptor, iii) and finally depending on the signaling pathway linked to the receptor. During these three years, i tried to understand how these stimuli could modulate the NMDAR. This work leads me i) to develop some technical tools (Ackman et al. , 2009;Buerli et al. , 2007), ii) to make some important discoveries on the NMDAR functionning. That exists a differential ERK regulation depending on the location of the NMDAR (Ivanov et al. , 2006). That specific isoforms of p38 have differential functions in neuronal cells (Pellegrino et al. , in preparation)
Devemy, Emmanuelle. "Transduction du signal de l'erythropoietine : voie des map kinases et systeme glycosylphosphatidylinositol/inositolphosphate-glycanne ; etude dans des cellules normales et cancereuses." Reims, 1995. http://www.theses.fr/1995REIMP203.
Full textJager, Jennifer. "Implication de la voie de signalisation des MAP kinases ERK dans l'inflammation du tissu adipeux et l'insulinorésistance lors de l'obésité." Nice, 2009. http://www.theses.fr/2009NICE4082.
Full textObesity and type 2 diabetes are characterized by a resistance of the peripheral tissue to insulin action. In obesity, proinflammatory cytokines (TNFα, IL-1β) produced by adipose tissue are involved in the development of insulin resistance. Identification of the mechanisms linking inflammation and insulin resistance would be helpful to design new therapeutic targets to prevent type 2 diabetes. We have shown in vitro that pharmacological inhibition of the MAP kinase ERK pathway prevents IL-1β-induced insulin resistance in adipocytes. To investigate the role of ERK pathway in obesity-induced insulin resistance in vivo, we have invalidated ERK1 in obese and insulin resistant mice. The ob/ob-Erk1-/- mice obtained are obese but show an improvement of the insulin sensitivity, a decrease in adipose tissue inflammation and these mice are partially protected from hepatic steatosis. In a second part we have shown that the kinase Tpl2 specifically mediates inflammatory cytokines effects on ERK activation, lipolysis activation and IRS-1 serine phosphorylation in adipocytes. Moreover, we have shown that IL-1β and TNFα up-regulate Tpl2 expression in an IKKβ/NF-κB-dependant maner, which could explain the deregulated expression of Tpl2 in adipose tissue of obese mice and patients. These results show the implication of ERK pathway in obesity-induced insulin resistance, and that the Tpl2 kinase could be a new pharmacological target to fight type 2 diabetes
Nicolini, Victoria. "Caractérisation de nouvelles voies cellulaires permettant la régulation des Processing-bodies dans le cancer." Electronic Thesis or Diss., Université Côte d'Azur, 2024. http://www.theses.fr/2024COAZ6007.
Full textProcessing-bodies (P-bodies) are cytoplasmic membraneless biocondensates that play an important role in various cellular processes by controlling RNA translation and decay. P-bodies are formed by the coalescence of untranslated mRNA and multiple RNA-binding proteins through liquid-liquid phase separation. Despite recent discoveries about their own key components, the cellular pathways that control the regulation of P-bodies are poorly understood. In this context, we have conducted a high content screening of FDA approved drugs to identify targets able to modulate P-body metabolism.For the first part of my PhD project, we decided to work on drugs that affect P-body dissolution with consequences on oncogene translation. In many human cancers, the MAPK (Mitogen Activated Protein Kinase) pathway is overactivated. Therefore, therapies targeting this pathway have been developed, such as MEK inhibitors, but these lead to resistance in cancer. One possible pathway of resistance has been linked to compensatory RAS oncogenes overexpression but the mechanisms underlying this response remained unclear. We found that upon treatment with MEK inhibitor treatment, P-bodies are dissolved leading to an increase of translation of KRAS and NRAS, two oncogenes upstream of the MAPK pathway. Overall, we have described a new feedback loop mechanism involving P-bodies in the translational regulation of RAS oncogenes and MAPK signaling.For the second part of my project, we worked on modulators that enhance P-body formation. We uncovered that glucocorticoids (GC) were able to reshape P-body number and size after 48 hours of treatment. By combining microscopy and biochemistry experiments, we found that this P-body regulation was associated with the dose-dependent activation of the glucocorticoid receptor (GR) in response to its ligand (such as dexamethasone, a GC). To better understand the link between GR activation and P-body formation, we studied the GR isoforms, of which the alpha and beta isoforms are the most abundant. The GR alpha isoform is known to bind to GC whereas the beta isoform has lost this ability. Therefore, we wanted to decipher what influence the different GR isoforms have on P-body regulation. To do this, we used CRISPR Cas9 cells in which GR was deleted and we compensated this deletion with either the alpha or beta isoform and different mutants. Our results show that the alpha isoform is responsible for GR signaling pathway activation. This activation leads to an increase in P-body number and a decrease in their size, implying that this isoform is important for P-body regulation. Overall, our results reveal a link between the activation of GR alpha and the P-body regulation. We now plan to perform transcriptomic and proteomic analysis on our cells to determine whether GC-induced GR leads to an alteration of mRNA/protein correlation and to find targets that directly regulate P-body formation through GR activation.To conclude, my PhD project focused on deciphering new cellular pathways that control the metabolism of the P-bodies. We demonstrated that drugs can have different effects on the formation of P-bodies, thereby modifying their content and consequently affecting mRNA translation. This phenomenon could be involved in the development of resistance and/or side effects to drugs
Placet, Morgane. "CDK8 : une cible de la voie KRAS/MAP Kinase dans la carcinogénèse colorectale." Mémoire, Université de Sherbrooke, 2014. http://savoirs.usherbrooke.ca/handle/11143/572.
Full textCagnol, Sébastien. "Contrôle de la mort cellulaire par la voie des MAPK 1/3 (ERK 2/1)." Nice, 2005. http://www.theses.fr/2005NICE4033.
Full textProgrammed cell death or"apoptosis"is an evolutionary conserved feature of multicellular organisms necessary for normal development and tissue homeostasis. In living cells, the activity of the proteases that execute the apoptotic cell death program, the caspases, is controlled by survival signals emanating from the cellular environment. The regulatory components of the caspase cascade, caspase 9 and caspase 8, are activated respectively by the apoptosome and by death receptors. Survival signals elicited by extracellular matrix or growth factors activate signaling pathways that control the cell death machinery. The MAPK1/3 signaling pathway is a kinase cascade comprising Raf, MEK1/2 and MAPK1/3 (ERK1/2 or p42/p44 MapKinases) regulated by the proto-oncogene Ras. The MAPK1/3 pathway is implicated in cell proliferation and differentiation and plays an essential role in cell survival. This thesis objective was to characterize the molecular mechanisms involved in the control of cell death by MAPK1/3 pathway. This study relies on the use of an inducible form of Raf-1 kinase (DRaf-1:ER) those strong and persistent activation leads to a pathological induction of MAPK1/3 activity. We have been able to show that, depending on the cell type, DRaf-1:ER activation favors cell survival or induces cell death. In the lung fibroblastic cell line CCL39, DRaf-1:ER activation prevents cell death induced by serum withdrawal from the tissue culture medium. Under this experimental setting, we could show that DRaf-1:ER stimulation inhibits caspase 9 activation but did not prevent cytochrome c release, APAF1 oligomerization and caspase 9 recruitment in the apoptosome. This novel mechanism of cell death inhibition at a post-mitochondrial level requires ongoing protein synthesis and continuous MEK kinase activity. In HEK293, an embryonic kidney cell line that bares properties of neuronal lineage cells, sustained activation of the MAPK1/3 pathway in response to DRaf-1:ER induces massive cell death. Cell death is characterized by caspases activation and DNA fragmentation. It is a slow process, detectable more than 24 hours after DRaf-1:ER stimulation and maximal at 48 hours. Cell death induction needs protein synthesis only during the early stage of activation but requires a continuous activity of the MEK/MAPK module. Cell death results from caspase 8 activation and does not require the mitochondrial pathway of apoptosis. It is characterized by the formation of vacuoles in the cytoplasm that evoke paraptosis, a particular form of apoptosis. Functional inactivation of the death receptor Fas or its adaptator FADD indicates that the activation process of caspase 8 is independent of the death receptor pathway. Altogether, these results extend our understanding on the role of the Raf/MAPk pathway in the control of cell death. We have shown that in different cellular context, this signaling pathway can either promote cell survival or induce cell death. In both cases, cell death control requires protein synthesis and post-traductionnal modifications. Molecular mechanisms that respond to prolonged MAPK1/3 activation could be involved in tumor resistance to proapoptotic treatments as well as in the development of neurodegenerative diseases
Ant, Cemile. "Rôle de la voie de signalisation MAP kinase Mps1 dans la pathogénie fongique et dans le contrôle de l'intégrité de la paroi." Phd thesis, Université de Grenoble, 2011. http://tel.archives-ouvertes.fr/tel-00603704.
Full textMontagner, Alexandra. "Etude de la phosphotyrosine phosphatase SHP2 : régulation de la voie mitogène Ras/MAPK et implication physiopathologique." Toulouse 3, 2006. http://www.theses.fr/2006TOU30114.
Full textThis work aims to understand the molecular mechanisms leading to the Ras/MAPK pathway induced by Epidermal Growth Factor. The activation of this signalling pathway requires tyrosine phosphorylation event, a process regulated by the tyrosine kinases (PTK) and phosphatases (PTP). If most of the PTP are implicated in the downregulation of signalling pathways, some of them are real activators as the PTPase SHP2 which plays a positive role in the Ras activation. We have shown that an important role of SHP2 in this activation is to regulate the recruitment of RasGAP, a Ras inhibitor, from signalling complexes so as to sustain its activation. In the second part of this work we have studied the biochemical and functional features of LEOPARD mutations of SHP2. This study has demonstrated that LEOPARD mutants display a reduced PTP activity both in vitro and in vivo and we have observed heterogeneity between the different mutants
Turgeon, Catherine. "Régulation de la voie MAPK et de l'expression du facteur de transcription induit en hypoxie HIF-1a par l'arginine méthyltransférase PRMT1 via la méthylation de DOCK6." Master's thesis, Université Laval, 2019. http://hdl.handle.net/20.500.11794/35838.
Full textConditions of low oxygen, or hypoxia, are involved in various pathophysiological situations including cancer and cardiovascular diseases. Hypoxic responses are mediated through a highly regulated transcriptional response in which hypoxia-inducible factor-1 (HIF-1) plays an important role. HIF-1transcriptional activity relies on hypoxia-dependent stabilization of HIF-1α, an essential HIF-1 subunit. In previous work, we identified protein-arginine methyltransferase 1 (PRMT1) as a novel repressor of HIF-1αexpression. By inhibiting the activity of specificity proteins 1 and 3 (Sp1, Sp3; Sp1/3) transcription factors, PRMT1 regulates HIF-1α subunit availability and HIF-1 activity. PRMT1 blocks Sp1/3 activity by preventing phosphorylation through the inhibition of the mitogen-activated protein kinases (MAPK) pathway. MAPK pathway iscomposed of ERK1/2 (extracellular signal-regulated kinases) and MEK (MAPK/ERK kinase), which can itself be activated by PAK1 (p21-activated kinases). In addition, we identified the guanine nucleotide exchange factor (GEF) DOCK6 as a novel PRMT1 binding partner and as an intermediate for the regulation of MAPK pathway. Therefore, the aim of this study is to better characterize the role of DOCK6 in HIF-1α expression and MAPK regulation. Our results show that DOCK6 is directly methylated by PRMT1. PRMT1 methylation of DOCK6 alters its GEF activity and results in the inactivation of downstream PAK1/MEK/ERK1/2signaling. Interestingly, our results indicate that DOCK6 levels are increased by hypoxia in a HIF-1 dependent manner. Finally, we show that HIF-1αis required for MAPK pathway activation in hypoxic conditions. These studies demonstrate the intricate feedback mechanism that can regulate HIF-1, highlight the complexity of HIF-1 regulation under hypoxic conditions and identify novel targets for potential intervention.
Röttinger, Éric. "Rôles de la voie de signalisation du FGF et des MAP Kinases ERK et NLK au cours du développement de l'embryon d'oursin Paracentrotus lividus." Nice, 2006. http://www.theses.fr/2006NICE4102.
Full textDuring my PhD, I have focused on molecular mechanisms involved in specification and differentiation of the endo- and mesoderm. In the sea urchin embryo, endomesoderm is specified early during development by maternal mechanisms at the vegetal pole. I was mainly interested in formation of the primary mesenchyme cells, which will form the skeleton of the larvae, and of the secondary mesenchyme cells which give rise to varity of cell types such as muscle cells and cells of the immune system. First, I have characterized a Mek/Erk signaling pathway and shown that this pathway is activated in the primry mesenchyme cell precursors. In these cells activity of Mek/Erk is required to activate the transcription factor Ets, a key factor in primary mesenchyme specification, migration and differentiation. In another study, we analyzed the role of a Tak/Nlk signaling pathway in segregation of the endo-mesoderm. We have shown that the nemo like kinase in the mesenchyme precursors is able to block endoderm formation by inhibition of the Wnt/b-catenin pathway and to act in synergy with Delta/Notch to promote secondary mesenchyme call fate. Finally, I have identified a ectoderm to mesoderm signaling network and shown that morphogenetic mouvements of gastrulation and differentiation of the sea urchin skelton is under triple control of Wnt8, TGFb and FGF signaling pathways
Lanzarotti, Nina. "Régulation de la réponse immunitaire T par l’apoptose et hyperactivation de la voie RAS." Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05T038/document.
Full textLymphocytes apoptosis is essential in maintaining homeostasis and avoiding abnormal proliferation. When defective, autoimmune diseases as the Autoimmune LymphoProliferative Syndrome (ALPS), due to mutations of the death receptor FAS, can occur. Several pathways are important actors influencing the apoptosis cascade, including the RAS proto-oncogene signaling. The RAS Associated Lymphoproliferative Disease (RALD) is a newly described entity, similar to ALPS but with RAS mutations instead of FAS mutations, enlightening the primary role of RAS in apoptosis regulation. Interestingly, the same RAS mutations as observed in RALD are also the cause of a malignant proliferation, the Juvenile Myelo Monocytic Leukemia (JMML). In the case of JMML, RAS mutations can lead either to a mild (LS-JMML) or a severe (S-JMML) phenotype. Thus, three different phenotypes can be caused by the same oncogenic RAS mutations. In order to better understand and characterize the influence of oncogenic RAS mutations in lymphocytes’ apoptosis we studied it in patients presenting with RALD, LS-JMML and JMML. We showed that isolated RAS hyperactivity is not sufficient to induce an immune deregulation. Additional factors are required to do so. These factors influence both mitochondrial and extrinsic apoptosis pathways at a post-transcriptional level. They are due to probable genetic events, and their identification can lead to new therapeutic strategies. Furthermore, activated lymphocytes’ in vitro apoptosis assessment can help differentiating the three phenotypes and thus facilitate prognosis prediction
Pin, Anne-Laure. "Rôle des microarns dans la régulation de la voie pro-migratoire p38 activée par le VEGF." Thesis, Université Laval, 2012. http://www.theses.ulaval.ca/2012/29073/29073.pdf.
Full textEndothelial cell migration in response to VEGF is a crucial step of angiogenesis. VEGF binding to its receptor VEGFR2 results in the autophosphorylation of the receptor at tyrosine 1214, which induces the downstream activation of the p38 MAP-kinase pathway leading to actin cytoskeleton remodeling and cell migration. MicroRNAs are short, non-coding RNAs that regulate post-transcriptionally gene expression. We identified two microRNAs, miR-20a and miR-196a, whose levels of expression were increased and decreased respectively in response to VEGF in endothelial cells. Both microRNAs modulate VEGF dependent-endothelial cell cytoskeleton remodeling, migration and angiogenesis. Also, we described that they are involved in regulating the p38 pathway. First, miR-20a acts upstream of p38, and negatively regulates MKK3 by specifically binding on MKK3 3’UTR. As MKK3 is a direct activator of p38 in response to VEGF, overexpression of miR-20a impairs p38 activation, the downstream activation of MAPKAPK2 and the phosphorylation of HSP27. Consequently, miR-20a reduces stress fibers formation, and subsequent endothelial cell migration and angiogenesis. We conclude that miR-20a may act in a feedback loop to regulate the p38 pathway-mediated VEGF-induced endothelial cell migration. Then, miR-196a is decreased in response to VEGF and we demonstrate its specific binding on ANXA1 3’UTR. In accordance with our previous work demonstrating that ANXA1 is important for VEGF-induced endothelial migration downstream of p38 pathway, overexpression of miR-196a impairs lamellipodia and endothelial cell migratory capacities upon VEGF treatment, leading to angiogenic defects. We conclude that miR-196a acts in a synergetic mechanism with VEGF to facilitate endothelial cell migration, by maintaining high level of the pro-migratory protein ANXA1. Finally, our results implicate miR-20a and miR-196a in the angiogenic process and give new insights in p38 pathway-dependent endothelial cell migration regulation in response to VEGF. The present work opens new avenues for strategies and future development of therapeutics in line with the treatment of angiogenic pathologies.
Armelle, Calipel Armelle. "Etude de L'implication de la voie RAF/MEK/ERK dans la tumorigenese du mélanome choroïdien humain." Paris 7, 2006. http://www.theses.fr/2006PA077085.
Full textThe choroidal melanorna is the most frequent of the malignant intraocular tumors in adult humans. New methods of radiotherapy (protontherapie) are very effective and allow the conservation of the eye. However, very early hepatic disseminations occur in approximately 50% of the subjects and sometimes several years after the initial diagnostic. Althouqh the study of the molecular mechanisms involved in the control of cell proliferation may be important for the development of therapeutic strategies, little is known about the molecular pathoqenesis of the choroidal melanoma. We have shown firstly that ERK1/2 is a kev signalinq pathway for the acquisition of oncogenic behaviour in choroidal melanoma cells. Secondly, the implication of B-Raf (mutated or not) is highlighted in the suractivation of MEK/ERK. Raf-1 is not committed in this suractivation. Thirdly, B-Raf is activated by cAMP via constitutive activation of the PKA. Finally an autocrine loop, SCF/c-Kit activates module MEK/ERK in certain cells lines of choroidal melanoma. Based on these observations, we can propose potentials therapeutic target for choroidal melanoma. Preliminary in vitro studies showed that a pharmacological inhibitor of c-Kit, the STI571 reduces proliferation and transformation of the choroidal melanoma cells expressed the receptor c-Kit. Similar effects were observed with BAY 43-9006, a Raf inhibitor. Therefore these two molecules could be used in therapeutics strategies and future treatments, although they must be validated in vivo
Gailhouste, Luc. "Spécificité fonctionnelle de la voie des MAP Kinases MEK/ERK dans la croissance tumorale des cellules hépatiques transformées : microscopie multiphoton appliquée à l’étude de la fibrose du foie." Rennes 1, 2009. http://www.theses.fr/2009REN1S060.
Full textChronic liver diseases lead to fibrosis, cirrhosis and the development of hepatocarcinoma. The MAP Kinases MEK/ERK pathway plays a critical role by regulating several processes in normal and tumoral cells. This study point out the central role of MEK1/2 and ERK1/2 kinases in cancer. The crucial function of MEK1 and ERK2 proteins in tumor growth of human hepatocellular carcinoma is demonstrated in vitro and in vivo, as well as a specific phosphorylation of ERK1/2 by MEK1 in response to growth factors. Targeting MEK1 and MEK2 could improve significantly therapeutic protocols by chemotherapy. Efficient and reproducible tools improving diagnosis of liver fibrosis before the development of hepatocarcinoma is a real necessity. The second part of this work allowed the development of a new method making an accurate histopathological assessment of liver fibrosis (SHG Fibrosis Index) possible by multiphoton microscopy, employing scoring of second harmonic signals generated by fibrillar collagen deposits
Delépine, Etienne. "Implication de la voie MAPK ERK5 et de la famille TORC dans l'expression de Cycline D1 et le cancer du sein." Montpellier 2, 2007. http://www.theses.fr/2007MON20219.
Full textChaveroux, Cédric. "Identification d'une nouvelle voie de signalisation impliquée dans la régulation des gènes par les acides aminés, chez les mammifères." Phd thesis, Université d'Auvergne - Clermont-Ferrand I, 2009. http://tel.archives-ouvertes.fr/tel-00726314.
Full textChâtel, Amélie. "Voies de signalisation des MAP kinases et apoptose chez l'éponge Suberites domuncula et la moule Mytilus galloprovincialis." Phd thesis, Université de Bretagne occidentale - Brest, 2009. http://tel.archives-ouvertes.fr/tel-01068372.
Full textArachiche, Amal. "Recherche des signaux effecteurs dans l'exposition membranaire de la phosphatidylsérine procoagulante : exploration des voies MAPK/ERK et pro-apoptotique mitochondriale." Paris 7, 2009. http://www.theses.fr/2009PA077090.
Full textPhosphatidylserine (PS) exposure at the surface of activated platelets or cells is important in coagulation. Indeed, exposed PS can promote assembly and activation of the coagulation factors. Impaired PS exposure can be responsible for bleeding events, as in Scott syndrome, while excessive PS exposure leads to thrombotic events. PS exposure also occurs at the membrane of apoptotic cells, and is essential for their clearance by phagocytes. The aim of this work was to identify in hematopoietic cells (platelets and lymphocytic cell lines) the molecular mechanisms controlling the rapid Ca²⁺-dependent PS exposure. Understanding this mechanism is essential to modulate PS exposure in thrombotic disorders. In this work, the involvement in PS exposure of the MAPK/ERK pathway, and the hypohesis that the process is a rapid apoptotic phenomenon controlled by loss of mitochondrial transmembrane potential (ΔΨm) were examined. The results show that although they may occur concurrently, neither the MAPK/ERK pathway activation, nor the loss of A\|/m control the rapid procoagulant PS exposure. The data also highlight the key role of an increase in intracellular Ca²⁺ brought about by a massive influx in the process. Therefore, the importance of other factors associated to (and dependent on) Ca²⁺ influx must be analyzed, such as activation of membrane ion channels (K⁺, Na⁺. . . ), which has been shown to influence phospholipid membrane remodelling in different cells models
Kicka, Sébastien. "Contribution à l'étude de l'altération Crippled Growth chez le champignon filamenteux Podospora anserina : implication de voies de signalisation MAP kinases." Paris 7, 2005. http://www.theses.fr/2005PA077033.
Full textBernatchez, Chantale. "Signalisation du récepteur des lymphocytes T (TCR) dans le thymus : interactions entre différentes voies MAPK (mitogen activated protein kinase) et régulation par l'adénosine." Thesis, Université Laval, 2004. http://www.theses.ulaval.ca/2004/21803/21803.pdf.
Full textNava, Caroline Cavé Hélène. "Le syndrome Cardio-Facio-Cutané et les syndromes apparentés l'implication des gènes de la voie RAS-MAPK /." Créteil : Université de Paris-Val-de-Marne, 2009. http://doxa.scd.univ-paris12.fr:80/theses/th0510280.pdf.
Full textMassip, Violaine. "Rôles biologiques de la voie de signalisation intracellulaire ERK 1/2 induite par un alphaherpèsvirus, le virus de la pseudorage, au cours du cycle lytique." Versailles-St Quentin en Yvelines, 2010. http://www.theses.fr/2010VERS0010.
Full textPseudorabies virus (PrV), an alphaherpesvirus, represents a good model to study herpesvirus-induced signaling pathways and their effects on viral replication and innate immune response. Many viruses activate, during infections, the ERK 1/2 pathway wich generally stimulates viral replication. However, the cellular mechanisms involved remain poorly understood. We demonstrate here that PrV induces at high MOI in porcine PK15 cells, early and transient ERK 1/2 activation. To investigate more deeply the effects of this activation on the viral cylce and infected cells, we blocked it with the specific inhibitor U0126 : we observed a blockade of extracellular and intracellular infectious virions production thus demonstrating requirement of ERK 1/2 activation for viral cycle achievement. Moreover, we noticied no significant effect on incoming virion DNA nuclear entry in early viral cycle, but a strong inhibition of viral DNA replication in infected cells and decrease of viral protein synthesis. Interestingly, it was possible to reactivate the viral cycle in presence of U0126 : addition of feta calf serum 18h p. I. Resulted in increased extracellular virus titers reaching normal levels in the next 12h. This indicated that infected cells kept their ability to produce virions despite ERK 1/2 blockade and that serum stimulation overrides this blockade. The effects of ERK 1/2 blockade observed in our model provide a good opportunity to study the cellular functions modulated during viral infection by this pathsway. To identify them, we are developing global microarray approache comparing at different time p. I. The transcriptome of PrV-infected cells in the presence or absence of U0126
Gaggioli, Cédric. "Etude de l'expression de la fibronectine dans les cellules de mélanome : rôle de la voie de signalisation des MAP kinases ERK et du facteur de transcription Egr-1." Paris 7, 2005. http://www.theses.fr/2005PA077021.
Full textLeghmari, Kaoutar. "La protéine Tat du virus d'immunodéficience humaine (VIH) induit la production de l'IL-10 et du TNF-alpha dans le monocyte/macrophage humain : étude des mécanismes d'activation de la voie NF-kappaB." Toulouse 3, 2008. http://thesesups.ups-tlse.fr/446/.
Full textIn human immunodeficiency virus infection, a progressive disturbance of cytokines network is observed. Thus, increasing levels in of the immunosuppressive cytokine, IL-10 and the pro-inflammatory cytokine, TNF-allpha are secreted in the HIV-1+ patients sera, before T lymphocytes decrease and seem to be linked in to AIDS progression and HIV associated dementia. The mainly viral factor implicated in this immunodeficiency is the transcription activating protein (Tat). Our previous results have shown that the N-terminal region of Tat protein was able to induce both IL-10 and TNF-alpha production by human monocytes by acting at the cell membrane. In this thesis, we focused on the characterization of the signaling pathways involved on IL-10 and TNF-alpha production, by monocytes/macrophages, and the role of TLR4 as a potential Tat receptor. Our results have shown that: i) Like in monocytes, Tat protein is also able to induce IL-10 production by human macrophages, in a PKC dependent pathway. Ii) The calcium pathway is not required for IL-10 production, although it is essential in Tat-induced TNF-alpha production. Our data suggest a new mechanism, implicating Tat protein, by which HIV-1 may maintain a constant production of the immunosuppressive IL-10 cytokine, even in the absence of TNF-alpha production. In consequence, HIV-1 may escape immune surveillance and thus promote the establishment of an immunosuppressive state. Iii) Tat is able to induce both classical and alternative NF-kappaB pathways. .
Muselet-Charlier, Céline. "Rôle des voies de signalisation intracellulaire dans la régulation de l'inflammation pulmonaire dans la mucoviscidose." Paris 6, 2008. http://www.theses.fr/2008PA066490.
Full textBen, Mkaddem Sanae. "Activation différentielle des voies de signalisation des MAP KINASES dépendantes des récepteurs Toll-Like au cours de l'ischémie-reperfusion rénale." Paris 7, 2009. http://www.theses.fr/2009PA077263.
Full textIschemia/reperfusion (I/R) injury induces potent inflammatory response and tissue damage that may lead to renal insufficiency. Among Toll-like receptors TLR2 and TLR4 play key roles in the pathogenesis of ischemic inflammatory responses. However, the regulatory mechanisms of TLR2- and TLR4-mediated signaling pathways involved in the control cell survival, inflammatory responses and cell apoptosis still remain elusive. Here we analyze the role of TLR2- and TLR4-mediated signaling pathways using wild-type (WT) and TLR2- or TLR4-deficient mite subjected to transient I/RI and post-hypoxic primary cultures of renal tubule epithelial tells (RTECs). I/R injury induced the phosphorylation of ERK1/2 in wild type and 171-4-/- RTECs but not in T1r2-/- RTECs, indicating that TLR2 selectively mediates the activation of ERK1/2 during hypoxia. Silencing of the chaperone heat shock protein gp96 restored the phosphorylation of ERK1/2 in T1r21- RTECs via the inhibition of phosphatase protein 5 (PP5). Renal I/R also stimulated a non-phagocytic NAD(P)H oxidase 4 (NOX4) isoform of 28 kDa which acts as a sensor of the TLR4-mediated cell apoptosis. Inactivation of NOX4 prevented TLR4-dependent activation of the apoptosis signaling-regulating kinase 1 (ASK1), JNK proapoptotic pathway. Overall, these findings indicate that I/R induces selective activation of distinct TLR-mediated pathways via the interaction of the TLR/gp96 complex with distinct protein clients involved in the induction of renal tubule cell apoptosis
Lemieux, Étienne. "Rôle de la voie KRAS/ERK MAP kinase dans la différenciation, la transformation et la tumorigénèse des cellules de l’épithélium intestinal." Thèse, Université de Sherbrooke, 2014. http://hdl.handle.net/11143/5391.
Full textMalka, mahieu Hélène. "Implication du complexe d'initiation de la traduction eIF4F dans la résistance aux inhibiteurs de la voie des MAPK." Thesis, Université Paris-Saclay (ComUE), 2015. http://www.theses.fr/2015SACLS236.
Full textIn BRAF(V600) or NRAS(Q61)-mutant tumours, most mechanisms of resistance to drugs that target the BRAF and/or MEK kinases rely on reactivation of the RAS–RAF–MEK–ERK mitogen-activated protein kinase (MAPK) signal transduction pathway or on activation of the alternative PI(3)K–AKT–mTOR pathway (which is ERK independent). These two pathways converge to regulate the formation of the eIF4F eukaryotic translation initiation complex. By using an in situ method to detect the eIF4E-eIF4G and eIF4E-4EBP1 interactions, we recently showed that the persistent formation of the eIF4F complex, comprising the eIF4E cap-binding protein, the eIF4G scaffolding protein and the eIF4A RNA helicase, is associated with resistance to anti-BRAF and/or anti-MEK in BRAF(V600)-mutant cancer cell lines. We next focused on NRAS-mutant cancer cell lines and found that this complex is also involved in the resistance to anti-MEK compounds. Strikingly, inhibiting the eIF4F complex in BRAF or NRAS-mutated cell lines is able to overcome resistance and to synergize with drugs targeting BRAF or MEK kinases. As a result, eIF4F appears to be a promising therapeutic target in a BRAF or NRAS-mutation context
Dance, Marie Raynal Patrick. "Nouveaux mécanismes d'activation des voies Ras/MAPK et P13K par GAB1 en aval des récepteurs à activité tyrosine kinase exemple des récepteurs de l'EGF et du VEGF /." Toulouse (Université Paul Sabatier, Toulouse 3), 2008. http://thesesups.ups-tlse.fr/228.
Full textEl, Mabrouk Mohammed. "Rôle de l'activation des MAP kinases dans les voies impliquées dans la croissance des cellules du muscle lisse vasculaire dans l'hypertension artérielle." [Montréal] : Université de Montréal, 2002. http://wwwlib.umi.com/cr/umontreal/fullcit?pNQ80440.
Full text"NQ-80440." "Thèse présentée à la faculté des études supérieures en vue de l'obtention du grade de philosophiae doctor (Ph. D.) en sciences biomédicales." Version électronique également disponible sur Internet.
Russo, Christophe. "Dynamique et modularité de la voie Mitogen Activated Protein Kinase dans les ovocytes de Xénope : modélisation et approches expérimentales." Thesis, Lille 1, 2009. http://www.theses.fr/2009LIL10109/document.
Full textThe scientific context of this thesis is based on the study of the signaling pathway Mos-MEK-MAPK in Xenopus laevis ovocytes during the G2/M transition of the cell cycle. An interdisciplinary approach from the biological and physical sciences led us to an experimental and theoretical analysis of the pathway. A bibliographical study identified the key articles related to this field. The articles of Huang, Ferrell (1998) and Angeli et al. (2004) gave us a theoretical basis to describe the interactions within the pathway. A critical analysis of the latter paper has been performed by means of an analytical solution of the differential equations defining the model proposed by Angeli and colleagues. Thus, the importance of the kinetic formulation type and the choice of the mathematical terms of the equations has been underlined ; especially in regard to the time variation of the Mos protein. Moreover, we have proposed an interpretation of the Mos-MEK-MAPK cascade behavior via an analytical approach within the context of the experimental parameter values given by Angeli. In addition, new results regarding to the long time evolution of Mos protein have been recovered when the ovocytes are stimulated with progesterone in presence of MEK inhibitor U0126. Furthermore, ovocytes of Xenopus laevis were stimulated by MPF in presence or absence of U0126. Western blot analysis gave information about the time evolution of Mos accumulation and the states of MEK, MAPK and cyclin B2 phosphorylation. Data showed the importance of MPF in Mos accumulation. In absence of MAPK, MPF is produced and plays an important role in the initiation of the signaling pathway. In contrast to other models, our model has been proposed to take into account three forms of the Mos protein : an unstable inactive state, an unstable active state and a stable active state. The model considers the influence of either MPF and MAPK on the accumulation of the active stable of Mos. The influence of MPF has never been used in previous model of the Mos-MEK-MAPK signaling pathway. Our model is based on a biological and physical point of view. The parametrization of the model is based on : (1) experimental values found in literature, (2) arbitrary values constraints by the known system behavior, (3) theoretical estimations from interval of experimental values. Bifurcation analysis of the system indicated the influence of the parameters values on the system behavior and equilibrium states. This approach produces a prediction for the behavior of the cascade in function of the MPF concentration value. It produces also a discussion for the strength of the interactions between MAPK and the active non-stable form of Mos protein. Simulation results from our model were compared with the experimental observations from our experiments. A good qualitative agreement was found
Sznajer, Yves. "Etude des manifestations cardiovasculaires chez les patients présentant un syndrome de Noonan porteurs de mutation au sein du gène PTPN11: rôles des gènes de la voie de signalisation des MAP kinases pour les syndromes apparentés." Doctoral thesis, Universite Libre de Bruxelles, 2009. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210210.
Full textAfin d’appréhender les implications possibles du gène PTPN11 dans la survenue des cardiopathies chez les patients porteurs de ces deux syndromes, nous avons conduit une étude chez 272 patients au syndrome de Noonan et une étude chez 19 patients porteurs du syndrome LEOPARD. Parmi la cohorte de patients atteints du syndrome de Noonan, 104 ont été diagnostiqués porteurs d’une mutation du gène (38%). Une prévalence de survenue de cardiopathies affectant les structures droites du cœur se dégage chez les patients identifiés porteurs d’une mutation avec une différence significative pour la SVP, une tendance est relevée pour le canal atrio-ventriculaire et la communication inter-auriculaire de type Ostium Secundum. L’absence de mutation est corrélée avec la survenue de cardiomyopathie hypertrophique et de cardiopathies du cœur gauche. Parmi les patients atteints du syndrome LEOPARD, il n’existe pas de différence statistiquement significative pour les patients porteurs d’une mutation ou non et/ou pour une cardiopathie particulière.
Toutes les mutations identifiées du gène PTPN11 sont des mutations ‘faux-sens’. Ce gène appartient à la famille des gènes codant pour une protéine tyrosyl phosphatase, SHP-2, ne possédant pas de récepteur trans-membranaire. Cette phosphatase est impliquée dans la voie de signalisation cellulaire des MAP (‘Mitogen-activated protein’) kinases dont l’expression est ubiquitaire et inclut le coeur. Depuis nos travaux, le concept de syndrome « neuro-cardio-facio-cutané » est établi puisque, à ce jour, 9 gènes (SOS1, RAF1, BRAF, KRAS, NRAS, HRAS, NF1, SPRED1 et SHOC2), tous impliqués dans la voie de signalisation RAS (voie des MAP kinases) sont identifiés. Un spectre phénotypique existe avec des signes communs mais aussi distinctifs chez les patients présentant le syndrome de Noonan, le syndrome LEOPARD, le syndrome de Costello, le syndrome Cardio-Facio-Cutané (CFC), le syndrome « Noonan-NF1 », le syndrome de Legius et le syndrome « Noonan/Multiple Giant Cell Lesion ». Nous rapportons enfin l’observation d’une patiente atteinte du syndrome CFC et porteuse d’une mutation (p.R257Q) au sein du gène BRAF ayant développé une cardiomyopathie hypertrophique.
Ces travaux de cohortes de patients au phénotype du syndrome de Noonan, du syndrome LEOPARD et cette dernière description d’une patiente au syndrome CFC ont permis de participer à la découverte de l’implication d’une voie de signalisation cellulaire dont l’origine génétique est maintenant démontrée. Les résultats de nos travaux réalisés depuis 2002 auront permis, avec les équipes travaillant sur le même sujet, d’orienter les investigations et les nouveaux projets de recherche qui étudient spécifiquement le rôle du gène PTPN11 dans l’embryologie du cœur. Les études des orthologues (zebrafish, murin et Drosophila) porteurs à l’état hétérozygote d’une mutation du gène PTPN11 permettent d’intégrer les anomalies phénotypiques et cardiaques observées. Ces études permettent de postuler les effets cellulaires produits par les mutations chez les patients atteints du syndrome de Noonan et chez les patients atteints du syndrome LEOPARD engendrant in vitro une activation de la phosphatase (effet « gain de fonction ») pour les premiers ou une réduction de l’activité phosphatase (« dominant négatif ») mais engendrant un effet gain de fonction in vivo. Nous discutons les connaissances acquises, les compréhensions obtenues et intégrées et traçons enfin les perspectives offertes par ces travaux.
Doctorat en Sciences médicales
info:eu-repo/semantics/nonPublished
Haupaix, Nicolas. "Régulation de la voie MEK/ERK par la signalisation éphrine lors du développement neural chez l'ascidie Ciona intestinalis." Electronic Thesis or Diss., Nice, 2014. http://theses.unice.fr/2014NICE4003.
Full textDuring my thesis study, I was involved in functional studies to demonstrate that p120-RasGAP, a GTPase-activating-protein (GAP), is a cytoplasmic mediator of the ephrin-mediated ERK attenuation. To confirm this notion, I conducted a co-immunoprecipitation experiment and demonstrated that p120-RasGAP associates with an ephrin receptor, Eph3, when the latter is activated by an ephrin ligand in ascidian embryos. These results strongly indicate that FGF and ephrin signals converge at the level of Ras and control its activity antagonistically. Following this finding, I looked for other cell fate specification events controlled by the antagonism between ephrin and FGF signals. In ascidian embryos, FGF signals are known to induce neural fates in ectodermal cells which otherwise adopt epidermal fates. Ascidian neural induction takes place at the 32-cell stage, resulting in specification of specific four cells as ERK1/2-active neural precursors among 16 ectodermal cells. I was able to demonstrate that ephrin/Eph/RasGAP signals counterbalance FGF neural inducing signals to generate the ON-OFF response of ERK activation among the ectodermal cells. Finally, in collaboration with a PhD student in Dr. Mike Levine’s lab (UC Berkeley), the antagonism between ephrin and FGF signals plays a role in regionalisation of the neural plate along the anterior-posterior axis
Haupaix, Nicolas. "Régulation de la voie MEK/ERK par la signalisation éphrine lors du développement neural chez l'ascidie Ciona intestinalis." Phd thesis, Université Nice Sophia Antipolis, 2014. http://tel.archives-ouvertes.fr/tel-01059798.
Full textFouchs, Audrey. "Stress osmotique et activation des MAP Kinases ERK1/2 chez les hépatocytes de turbot, Scophthalmus maximus : implication des voies de signalisation intracellulaire du processus de RVD." Brest, 2011. http://www.theses.fr/2011BRES2045.
Full textAmongst intracellular signalling pathways, the MAPK (Mitogen-Activated Protein Kinases) ERK1/2 (Extracellular-signal-Regulated Kinase 1/2) play a central role: they are activated by a wide range of environmental factors and can be involved in many cellular functions. In turbot hepatocytes, a hypo-osmotic shock, but not a hyper-osmotic shock, induces a rapid increase in ERK1/2 phosphorylation, maintained for at least 50 minutes. Despite being rapidly activated by a decrease in extracellular osmolality, the ERK1/2 do not seem to play a role in the RVD process established to counteract the volume changes induced by the aniso-osmotic conditions. However, there is a strong link between these two mechanisms, the signaling pathways involved in RVD being able to modulate the ERK1/2 signal. Indeed, in turbot hepatocytes, the ERK1/2 activation occurs in two stages: a transient activation (from O to 5 minutes after the hypo-osmotic shock) and a sustained activation (10 minutes after the shock). This sustained activation is dependent on ATP, calcium, cytoskeleton, stretch activated channels and protein kinases such as PKC, PI3K or PTK, all of the aforementioned being major signaling pathways of the RVD process
Trouillas, Marina-Laurie. "Etude sur les cellules souches embryonnaires de souris : modalités de la pluripotence, de l'engagement en différenciation et de l'établissement de la voie neuronale." Bordeaux 2, 2006. http://www.theses.fr/2006BOR21355.
Full textMurine embryonic stem (ES) cells remain pluripotent in vitro when grown in the presence of Leukaemia Inhibitory Factor (LIF). By microarray analysis, we have characterized the overall LIF transcriptome and identified new mediators regulating cell survival and pluripotency. Furthermore, we identified "competence genes", involved in transition between pluripotency and commitment. LIF starvation leads to apoptosis of some of the ES-derived differentiated cells. In these apoptotic cells, MAPK (Mitogen Activated Protein Kinase) p38α is activated. Blocking apoptosis by p38α inhibitor leads to an alteration of differentiation markers. Bcl-2, a direct p38α target, protects differentiated precursors from apoptosis and favours neural default pathway
König, Sandra. "Voie de signalisation MAP kinase/ERK et second messager AMPc dans le système nerveux : contribution de la régulation de la protéine B-Raf par la PKA." Paris 11, 2000. http://www.theses.fr/2000PA11T068.
Full textMorel, Marion. "Les récepteurs venus kinase (VKRs) de schistosoma mansoni : étude des voies de signalisation de SmVKR1 et rôle de la protéine adaptatrice SmShb." Thesis, Lille 2, 2016. http://www.theses.fr/2016LIL2S003/document.
Full textSchistosomiasis is a parasitic disease caused by trematode flatworm species belonging to the genus Schistosoma. Responsible for about 300,000 deaths per year, the disease is mainly due to the high fertility of the worms and to encystment of eggs in host tissues. In order to fight against schistosomiasis, a single drug (Praziquantel) is efficient and massively distributed in endemic areas. To deal with the emergence of resistance to Praziquantel, one alternative is to consider the design of molecules that target parasite reproduction.Venus Kinase Receptors (VKRs) constitute an invertebrate Receptor Tyrosine Kinase (RTK) family initially discovered in the parasite Schistosoma mansoni. VKRs are atypical RTKs formed by an extracellular Venus Fly Trap (VFT) ligand binding domain associated via a transmembrane domain with an intracellular tyrosine kinase (TK) domain. Two VKRs are expressed in S. mansoni: SmVKR1 and SmVKR2. They both activate Erk, Akt and JNK signaling pathways and act on the parasite reproduction.As they are absent from the human genome and as they have potential roles in the modulation of reproductive processes and development of parasites, SmVKRs appear as attractive targets to fight schistosomiasis.The first part of my thesis work sets known data concerning the role of RTKs in schistosome reproduction. Here, we show that the catalytic domains are conserved across various RTKs and we open the perspective to design drugs which could inhibit several RTKs at the same time to control egg laying by schistosomes.The second part of my work describes the importance of using an alternative strategy of inhibiting downstream partners of RTKs. By screening a kinase inhibitor library, we defined the Akt pathway components as potential targets to fight schistosomiasis. Nanomolar doses of Akt inhibitors can inhibit schistosome pairing and egg laying.In the last part, we present the specific interaction of the adaptor protein SmShb with the phosphorylated form of SmVKR1. This binding occurs between the SH2 domain of SmShb and a phosphotyrosine residue (pY979) located in the juxtamembrane region of the receptor. That interaction leads to the phosphorylation of SmShb and promotes the signal of SmVKR1 towards a JNK pathway. In situ hybridization experiments highlighted that SmShb and Smvkr1 transcripts were both located in mature oocytes and testes of adult worms. RNA interference experiments using double-stranded RNA targeting SmShb led to an accumulation of mature sperm in testes of male worms. Finally, a yeast three hybrid screening, using SmShb phosphorylated by SmVKR1 as prey, allowed us to identify various protein partners. Taking advantage of previous results, we focused on two partners and confirmed their interaction with SmShb. 1) RhoU GTPase which has potential functions in JNK signalling and cytoskeleton dynamic. 2) The dynein light chain TcTex-1, with potential role in sperm motility. Altogether, this results argue for a potential role of SmShb in the regulation of the SmVKR1 activity by forming a multiprotein complex including proteins with various roles in cytoskeleton reorganization
Baetz, Delphine. "Transporteurs membranaires dépendants du sodium, NBC et NHE1 : activité et voies de régulation dans les cardiomyocytes." Paris 7, 2003. http://www.theses.fr/2003PA077133.
Full textBarruet, Emilie. "Rôle de la voie de transduction P38MAPK dans la différenciation des cellules souches embryonnaires de souris." Thesis, Aix-Marseille 2, 2010. http://www.theses.fr/2010AIX20697.
Full textEmbryonic stem (ES) cells give rise, in vivo, to all of the three germ layers and, invitro, to differentiate into a broad variety of cell lineages which opens up largeperspectives in regenerative medicine. We previously found that the p38MAPKpathway controls the commitment of ES cells toward either cardiomyogenesis (p38on) or neurogenesis (p38 off ). In this study, we show that p38a knock-out ES cellsdo not differentiate into cardiac, endothelial, smooth muscle, and skeletal musclelineages. Reexpression of p38MAPK in these cells partially rescues theirmesodermal differentiation defects and corrects the high level of spontaneousneurogenesis of knock-out cells. Wild-type ES cells were treated with a p38MAPKspecificinhibitor during the differentiation process. These experiments allowed us toidentify 2 early independent successive p38MAPK functions in the formation ofmesodermal lineages. Further, the first one correlates with the regulation of theexpression of Brachyury, an essential mesodermal-specific transcription factor, byp38MAPK. Moreover, we also showed that p38MAPK is required for the late stageskeletal muscle differentiation. In conclusion, by genetic and biochemicalapproaches, we demonstrate that p38MAPK activity is essential for the commitmentof ES cell into cardiac, endothelial, smooth muscle, and skeletal muscle mesodermallineages
Catozzi, Simona. "Rétroactivité dans la transduction du signal : étude comparative des réponses en aval et en amont dans les cascades de signalisation." Thesis, Université Côte d'Azur (ComUE), 2016. http://www.theses.fr/2016AZUR4122/document.
Full textLiving cells communicate with their external environment, by means of a signal transduction network, which allows them to interpret physico-chemical signals and produce appropriate responses. This complex machinery is orchestrated by signaling cascades, which play the role of intracellular transmitters, by transferring biochemical stimuli between cellular membrane and nucleus. It has been shown that a perturbation can propagate upstream (and not only downstream) a cascade, through a phenomenon called retroactivity. Our investigation aims to compare the biochemical conditions promoting one and/or the other direction of signaling in linear cascades. By means of analytical and numerical approaches, we have answered to this question, by characterizing the arising different signaling regimes, and we have designed a compact graphical representation to relay the gist of such conditions. We have also developed the concept of pathway activation profile which is, for a given stimulus, the sequence of activated proteins at each tier of the cascade, at steady state. Such sequences correspond to pieces of orbits of a two-dimensional discrete dynamical system. From the study of the possible phase portraits, as a function of the biochemical parameters, we focused on the contraction/expansion properties around the fixed points of this discrete map, and their bifurcations. We have deduced a classification of the cascade tiers into three main types, whose biological impact within a signaling network has been examined. This method also provided global insights about the interplay between forward and retroactive signaling, and how signal is amplified along the cascade activation profile
Beaujois, Rémy. "Motifs de régulation et dynamique de la voie Mitogen Activated Protein Kinase lors de la transition G2/M des ovocytes de Xénope." Thesis, Lille 1, 2010. http://www.theses.fr/2010LIL10150/document.
Full textDuring G2/M transition in Xenopus oocyte, p39Mos-MEK1-MAPK cascacade harbors specific dynamic and physical properties, such as ultrasensitivity, bistability, irreversibility, and all-or-none responses. These properties are generally considered in the context of the positive feedback loop that embeds the p39Mos-MEK1-MAPK pathway architecture. The objective of this work was focused onto p39Mos oncoprotein and regulation motifs recruitment enabling together the generation of such properties. Both experimental and in silico approaches were undertaken in order to yield a realistic modelisation, physically and biologically relevant for this network. We developed a model that takes into account the influence of MPF onto p39Mos accumulation, and adjusts the role of the positive feedback loop. Also, we were able to show that p90Rsk, target of MAPK, was degraded. This signaling pathway was activated in the absence of p39Mos. Our results show that 1,10 Phénanthroline monohydrate (1,10-PA) is able to induce gradual and ultrasensitive MAPK activation. 1,10-PA action is then exerted in the absence of protein synthesis and positive feedback loop. In this context, a feed forward loop model can be considered, and phosphatase inhibitors were used for MAPK activation in the absence of p39Mos. Our results confront the role attributed to the positive feedback loop in MAPK activation, and show that this ultrasensitive response may be generated in vivo through feed forward regulation motifs
Pohorecka, Magdalena. "Rôle de c-Jun dans la réponse aux inhibiteurs de la voie des MAPK dans les mélanomes." Thesis, Toulouse 3, 2018. http://www.theses.fr/2018TOU30373.
Full textIt is clearly recognized that the MAPK pathway is essential for melanomagenesis. The development of new drugs targeting this pathway such as BRAF inhibitors and/or MEK inhibitors has been a major advance in the therapeutic management of melanoma. However, patients still relapse suggesting the emergence of mechanisms of resistance. Many data show that both the expression and activation of the transcription factor c-Jun are induced after treatment of BRAF-mutant cells with MAPK pathway inhibitors (MAPKi). Furthermore, depletion of c-Jun sensitizes cells to these inhibitors triggering apoptosis. We depleted BRAF-mutant melanoma cell lines for c-Jun by siRNA and treated cells with a BRAF inhibitor (PLX4032). Whole genome expression was then analysed by transcriptomic study to determine target genes of c-Jun that could be associated with pharmacological response to MAPKi. This study revealed that SLIT And NTRK Like Family Member 6 (SLITRK6) is a target gene of c-Jun that could be associated with antitumor pharmacological response to MAPKi. Indeed, SLITRK6 mRNA and protein are induced in BRAF-mutant melanoma cell lines after BRAF inhibitor treatment alone or in combination with MEK inhibitor (AZD6244). We also show that the combination of MAPKi with an antibody conjugated with a cytotoxic drug targeting SLITRK6 increases BRAF-mutant melanoma cell death triggering apoptosis in vitro. Finally, our data show that SLITRK6 could be a new pharmacological target for the treatment of BRAF-mutant metastatic melanoma and/or a potential biomarker of resistant cells to MAPKi
Mennour, Sabrina. "Activité de liaison à l’ARN des protéines de la voie de signalisation MAPK (Mitogen-Activated Protein Kinase) dans le mélanome LncRNA-Mediated Protein-Protein Scaffolding in Intracellular Signal Transduction Pathways." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL062.
Full textRecent studies have underscored the importance of RNAs in the regulation of protein-protein interactions. By allowing the assembly of protein complexes, non-coding RNAs act as scaffolds and thus promote protein-protein interactions in order to regulate the chromatin state. RNAs are also able to interact with proteins in order to modulate their activities, interactions or localisation. In the cytoplasm, signalling pathways are regulated through a cascade of protein-protein interactions. In the MAPK (Mitogen-Activated Protein Kinase) signalling pathway, the binding of a ligand to a membrane receptor triggers a cascade of phosphorylation and protein-protein interactions that allow the transduction of the signal. Abnormal activity of this pathway through increased ligand binding or activating mutations lead to cellular dysfunction associated with tumor initiation and progression.The potential role of RNAs in the direct regulation of protein-protein interactions of key cytoplasmic signal transduction pathways remains largely unknown. The aim of the thesis was to investigate and demonstrate the direct RNA binding activity of proteins involved in the MAPK pathway and to evaluate the role of RNA-protein interactions on intracellular signalling.Using a combination of CLIP (crosslinking and immunoprecipitation) and silica matrix-based affinity capture (2C complex capture) approaches that can uncover direct interactions between proteins and RNAs in vivo, we demonstrated a direct interaction between key MAPK signalling proteins and RNA in melanoma cells. Subsequent microscopy studies using proximity ligation assay (PLA) led us to demonstrate an RNA-dependent modulation of protein-protein interactions in the MAPK pathway, suggesting that an RNA component is involved in the stabilization of these protein-protein interactions. We specifically identified a deletion mutant in BRAF, a central oncogenic protein and therapeutic target in melanoma, that lacks RNA binding activity and harbors decreased signalling activity.By highlighting the existence of an RNA-mediated modulation of protein-protein interactions, this study shows the unprecedented importance of the RNA binding activity of key signal transduction proteins that should be considered in the understanding and targeting of tumor cells
Duquesnes, Nicolas. "Signalisation cellulaire et formation de complexes protéiques lors de l'étirement des cardiomyocytes de rats nouveaux-nés." Phd thesis, Université Paris-Est, 2008. http://tel.archives-ouvertes.fr/tel-00842230.
Full textCalatayud, Anna-Line. "Développement et caractérisation de modèles précliniques de carcinomes hépatocellulaires pour l'évaluation de la réponse thérapeutique et l'étude des mécanismes de l'hépatocarcinogenèse." Thesis, Université de Paris (2019-....), 2020. https://theses.md.univ-paris-diderot.fr/CALATAYUD_Anna_Line_va2.pdf.
Full textHepatocellular carcinoma (HCC) is a very aggressive malignancy, which is resistant to current therapeutic options for advanced stages. In addition, most of recent phase 2 or 3 clinical trials failed due to the development of multiple resistance mechanisms. In this context, preclinical models are very useful to understand the molecular biology of HCC and looking for new therapeutic targets or specific biomarkers of treatment response. Thus, in this work, the study of HCC cell lines that represent a subgroup of aggressive tumors but recapitulate the molecular diversity of HCC enabled us to show associations between specific molecular contexts and response to treatments allowing to establish several new therapeutic hypotheses. Thanks to these cell lines we also understand that the overexpression of MET as a criterion for inclusion of patients in tivantinib clinical trials explained its failures and to propose the expression of Ki67 as a better biomarker predictive of its antitumor efficacy. Finally, by studying murine models of oncogenic cooperation, we highlighted for the first time the tumor suppressor role of RSK2 in hepatic carcinogenesis, in cooperation with the inactivation of AXIN1 or the activation of the Wnt/β-catenin pathway. Overall, this study shows that preclinical models are extremely informative, despite their various limitations, they allow to bring new therapeutic hypotheses. In particular we demonstrated the crucial role of the RAS-MAPK pathway activation in HCC development reinforcing the interest of the use of MEK1/2 inhibitors in future clinical trials in candidate subgroups
Costes, Safia. "Voies de signalisation au sein de la cellule β pancréatique : aspects normaux et physiopathologiques." Montpellier 1, 2007. http://www.theses.fr/2007MON1T023.
Full text