Dissertations / Theses on the topic 'Signalisation du BCR'
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Kheirallah, Samar. "Implication de la signalisation du BCR dans le ciblage thérapeutique des lymphomes folliculaires." Toulouse 3, 2010. http://thesesups.ups-tlse.fr/1259/.
Full textBeside its central role in the recognition of antigen, the BCR (B Cell Receptor) controls a multitude of intracellular mechanisms that regulate B lymphocyte biology. Altered BCR signaling has been demonstrated in various types of B-cell lymphoma and some autoimmune diseases. Thus, therapeutic targeting of BCR signaling has been the focus of my PhD studies. We demonstrate that the monoclonal anti-CD20 antibody, Rituximab, inhibits BCR signaling at least by down-regulating BCR expression. Furthermore, enzastaurin (kinases inhibitor) exerts an anti-tumoral effect on follicular lymphoma cells by inhibiting downstream BCR signaling. Then, we characterized new mechanisms of action of Rituximab and enzastaurin and we focused on the importance of BCR signaling in lymphoma's therapy
Malissein, Emilie. "Physiologie mitochondriale et apoptose couplée à la signalisation du récepteur à l'antigène des lymphocytes B." Limoges, 2005. http://aurore.unilim.fr/theses/nxfile/default/d34a6617-a544-4cab-8d1a-a6725a6a863f/blobholder:0/2005LIMO0009.pdf.
Full textBCR signaling presents differential functional responses, dependent of B cell stage of differentiation. The pro-apoptotic activity of Bad protein and its intracellular traffic are regulated by phosphorylation and dephosphorylation. Modulation of Bad phosphorylation during BCR-induced apoptosis and correlation with cell death mitochondrial pathway are not fully characterized. We show by flow cytometry, immunoprecipitation, Western Blotting and confocal microscopy that : (i) Bad activation (dephosphorylation) is implicated in BCR-induced apoptosis of immature B lymphocytes (ii) regulation of Bad phosphorylation status may contribute to BCR functional duality (survival/apoptosis) (iii) differential subcellular compartmentalization of Bad (in particular in rafts) may contribute to sensitize immature B cells to apoptosis
Amin, Ali Rada. "BCR de classe IgA : signalisation de la cellule B normale et dans un contexte de lymphoprolifération." Limoges, 2009. http://www.theses.fr/2009LIMO4069.
Full textIn order to map new QTL regulating male fertility parameter, we analysed a set of Interspecific Recombinant Congenic strain. We mapped 8 QTL implicated in testis, development, prostate growth, sperm vitality and morphology. We performed fine mapping analysis of a QTL of reduced testis weight associated with teratozoospermia, localised on MMU11. We proposed a candidate locus encompassing four testis expressed gene. Moreover, in order to understand gene expression regulation in interspecific mosaic genome, we analysed testis transcriptome of three IRC strains compared with parental strains testis transcriptome. In this study, we describe how spretus genes are regulated when introgressed in musculus background. This study gives some insight concerning gene flow tolerance across the specie barrier during emergence of mosaic genome
Harouna, Rachidi Abdou Souleymane. "Etudes structurale et fonctionnelle de la protéine Syk dans les cellules B de Leucémie Lymphoïde Chronique." Electronic Thesis or Diss., Paris 13, 2024. http://www.theses.fr/2024PA131024.
Full textChronic Lymphocytic Leukemia (CLL) has a variable clinical course, with some patients remaining stable while others experience progression. By stimulating the B Cell Receptor (BCR) in CLL B cells ex-vivo, it is possible to distinguish between non-responder (NR) and responder (R) cases based on cell survival. This survival rate correlates with overall patient survival. Differential phosphorylation levels of Syk, a key kinase in BCR signaling, suggest that post-translationally modified Syk contributes to CLL progression. Our studies reveal differences in global and specific phosphorylation kinetics and spot patterns of Syk between CLL B cells in basal and BCR-stimulated conditions, arguing for the dedicated role of Syk-specific sites. Functional analysis of Syk phosphorylation mutants targeting its activation process or its ability to bind partners shows their distinct involvement in metabolic activity, cytokine secretion, and signaling pathways upon BCR activation. Collectively, our findings provide new insights into the potential role of Syk conformation in CLL pathogenesis and offer insights into potential therapeutic targets for the disease
Rochelle, Tristan. "Signalisation des GTPases de la famille Rho dans les phénotypes migratoires induits par les différentes formes de Bcr-Abl." Thesis, Poitiers, 2012. http://www.theses.fr/2012POIT1401/document.
Full textBcr-Abl chimeric oncogenes (p190bcr-abl and p210bcr-abl) result from the t(9,22) chromosomal translocation that fuse the bcr and the c-abl genes. p210bcr-abl and p190bcr-abl are associated with Chronic Myelogenous Leukemia (CML) and a subset of Acute Lymphoblastic Leukemia (ALL) respectively. The only difference between these two chimeras is the presence of a specific RhoA-GEF domain in the p210bcr-abl oncogene. Bcr-Abl expression in Ba/F3 lymphoblasts induces spontaneous migration of these cells without apparent directionality. Motility triggering of Bcr-Abl-expressing Ba/F3 depends on the RhoGTPase Rac1.RhoA activity is associated with a typical amoeboid movement of Ba/F3p210 cells embedded in Matrigel™ 3D matrix, whereas the Ba/F3p190 cells, devoid of RhoA activity, display a rolling-type motility. In this work we showed that activation of the RhoA effector ROCK1 triggers two parallel pathways which are both necessary for amoeboid movement: 1) the Myosin Light chain (MLC) pathway 2) ADF family proteins (Actin Depolymerizing Factor) pathway, specifically the ADF/destrin isoform. Besides, we showed that Ba/F3p190 cells could assemble invadopodia-like structures. The formation of these structures is driven by the reduction of RhoA activity associated with the absence of the DH/PH domain in p190bcr-abl and correlates with an increase in Cdc42 activity. We finally demonstrated that the RhoA/ROCK pathway is constitutively activated in CD34+ cells isolated from CML patients while not in their normal counterparts. We also demonstrated that this activation is independent of the tyrosine Kinase activity of Bcr-Abl
Aouar, Besma. "Altération de la production d'interféron de type I par les cellules plasmacytoïdes dendritiques : ciblage de la voie de signalisation BCR-like." Thesis, Aix-Marseille, 2015. http://www.theses.fr/2015AIXM5021.
Full textPlasmacytoid dendritic cells are major producers of type I IFN in human organism. During chronic viral infections, such as Hepatitis C Virus infection, pDCs are functionally impaired. More than 50% efficiency of IFN-α treatment, until recently used, suggested that modulation of pDC function could be an important target for HCV treatment. pDCs recognize HCV RNA by Toll-like receptors, and dispose of a set of so-called regulatory receptors that regulate IFN-I production. Crosslinking of these RR such as BDCA-2 and ILT7 has been shown to inhibit IFN-I production by pDCs stimulated with TLR7/9 agonists. In this work we show that HCV envelope glycoprotein E2 is a novel ligand of pDC RR, BDCA-2 and DCIR, and that this binding is responsible for IFN-I inhibition via the activation of the BCR-like pathway. Then we assayed to restore IFN-I in pDCs with crosslinked RR by targeting well-known kinases of BCR-like pathway, Syk and Mek. When inhibiting Syk, IFN-I was only partially restored by subliminal concentrations of Syk inhibitor; high concentrations of Syk inhibitor effectively blocked IFN-I production, suggesting involvement of Syk in the TLR7/9 pathway as it was already demonstrated in TLR activation in macrophages. When inhibiting MEK, the restoration of type I IFN was effective. The underlying mechanisms leading to the restoration are further explored. Pharmacological targeting of BCR-like signaling may constitute an attractive new approach to study mechanisms of modulation of pDC activation in pathophysiological conditions
Louat, Thierry. "Signalisation et (in)stabilité génétique : nouvelles voies de régulation de la réparation de l'ADN." Toulouse 3, 2004. http://www.theses.fr/2004TOU30102.
Full textCells and DNA are exposed to various endogenous or exogenous genotoxic insults. Cells dispose of six DNA repair mechanisms. Among these, the nucleotide excision repair, NER, corrects a large variety of damage. We focused on the impact of kinase expression, p210BCR-ABL and PKCzeta, in DNA repair activity modulation. P210bcr-abl oncogene transfection in myeloid cells increases NER activity in a kinase activity-dependant pathway. Inversely, p210BCR-ABL expression in a lymphoid cell line represses NER activity and sensitises cells to UVC in a kinase activity-dependant pathway. P210BCR-ABL seems to target the initial steps of the NER process, before XPB recruitment occurs. We also show that ectopic expression of PKCzeta confers cell resistance to UVC, cisplatin and melphalan. PKCzeta overexpression stimulates NER activity by increasing global genome repair and transcription-coupled repair detection complex levels. CSA and CSB proteins are overexpressed by Sp1-mediated transcriptional stimulation. Reasons for XPC/hHR23B overexpression were unable to be elucidated thought transcriptional and direct phosphorylation, however are excluded. PKCzeta interacts with, and phosphorylates, the mismatch detection complex, hMutSalpha. Its phosphorylation prohibits proteasome degradation and increases mismatch repair activity. .
Bourgeais, Jérôme. "Fonctions oncogéniques de STAT5 : rôle dans la régulation du métabolisme oxydatif." Thesis, Tours, 2015. http://www.theses.fr/2015TOUR4051.
Full textThe Signal Transducer and Activator of Transcription factors 5A and B are two closely related STAT family members that play a major role in normal and leukemic hematopoiesis. STAT5 proteins are frequently activated in hematopoietic neoplasms and are targets of various tyrosine kinase oncogenes such as BCR-ABL and JAK2V617F. Both oncogenes were shown to stimulate the production of intracellular ROS (Reactive Oxygen Species) in leukemic cells and evidences for a cross talk between STAT5 and ROS metabolism have recently emerged. Herein, we demonstrate that sustained activation of STAT5 induced by BCR-ABL promotes ROS production in Chronic Myeloid Leukemia (CML) cells by repressing expression of two antioxidants, catalase and glutaredoxin1 and by possible functional interactions with NADPH oxidase complexes. We also provide compelling evidences that tyrosine phosphorylation regulate the pro-oxidant activity of STAT5 and that non phosphorylated STAT5 displays antioxidant properties and protection against oxidative stress via non-genomic effects. This dual function of STAT5 is also illustrated in an in vitro microenvironment model that we develop in our laboratory to analyze interactions between bone marrow stromal cells and CML cells. Using these coculture experiments, we show that STAT5 phosphorylation was reduced and its antioxidant activity enhanced in leukemic cells in contact with stromal cells. We also demonstrate in this model that leukemic cells stopped dividing, entered a quiescent G0 state and became resistant to Imatinib, a BCR-ABL kinase inhibitor. Collectively, these findings suggest an important link between antioxidant activity of STAT5, quiescence and resistance to chemotherapeutic agents in leukemic cells
Fournier, Emilie. "Régulation positive et négative de l'activation des lymphocytes B humains normaux et pathologiques." Paris 6, 2008. http://www.theses.fr/2008PA066150.
Full textNicolle, Delphine. "Implication des voies de signalisation Toll (TLR) dans la réponse immunitaire aux mycobactéries." Orléans, 2004. http://www.theses.fr/2004ORLE2043.
Full textBonnefond, Marie-Laure. "Rôle de la signalisation calcique dans la sensibilisation des cancers ovariens chimiorésistants aux stratégies anti-Bcl-xL." Thesis, Normandie, 2017. http://www.theses.fr/2017NORMC424.
Full textOvarian cancer is the leading cause of death from gynecological cancer. There is an urgent need to find new therapeutic strategies due to failure of treatments associated to development of chemoresistance. In this context, the laboratory has shown the cooperation of two anti-apoptotic proteins overexpressed in ovarian cancer, Mcl-1 and Bcl-xL, for preventing apoptotic cell death. ABT-737, a Bcl-xL inhibitor BH3-mimetic, was developed by Abbvie and has a clinically derivative named ABT-263. In contrast, no Mcl-1 inhibitor is currently available in clinic. The inhibition of this anti-apoptotic protein is therefore one of the objectives of the laboratory. Since inhibition of PI3K / Akt / mTOR signaling pathway leads to inhibition of Mcl-1 expression and calcium is able to modulate this pathway, we wondered if the modulation of calcium fluxes allowed the inhibition of Mcl-1 in ovarian cancer cells. First we were able to show that calcium chelation by BAPTA-AM allowed to inhibit Mcl-1 expression via mTORC1 pathway and to sensitize the cells to ABT-737. In a second step, we investigated the effect of an inhibitor of calcium fluxes that is evaluated in clinical studies, carboxyamidotriazole. We show that the inhibition of capacitive calcium channels could lead to Mcl-1 down-expression via inhibition of mTORC1 and promote apoptosis in combination with ABT-737. Finally, we observed that CAI induces a morphological change resulting in cell death. This type of death seems to be related to disruption of metabolism in IGROV1-R10 cancer cells and would be close to a cell death recently described in the literature: autosis
Cottin, Vincent. "Signalisation intracellulaire par le récepteur CD120a pour le TNFα : rôle de la phosphorylation du domaine intracellulaire de CD120a dans la régulation des effets biologiques cellulaires du TNFα." Lyon 1, 2001. http://www.theses.fr/2001LYO1T026.
Full textOzenne, Peggy. "Contrôle de la signalisation oncogénique du mutant L858R de l'EGFR par la protéine suppresseur de tumeur p14ARF dans les adénocarcinomes pulmonaires." Phd thesis, Université de Grenoble, 2011. http://tel.archives-ouvertes.fr/tel-00767340.
Full textLasfer, Malika. "Etude des voies de signalisation de l'apoptose induite par les molécules anticancéreuses conventionnelles et hybrides dans les lignées d'hépatomes humains." Paris 7, 2006. http://www.theses.fr/2006PA077118.
Full textHepatocellular carcinoma is the most frequent among the primitive hepatic tumours of the liver and constitutes one of the most widespread cancers in the world having very bad prognostic. Conventional chemotherapy appears often not very effective and cause sévère toxicity for adjacent healthy tissues with the tumour. It consists of the administration of anti-cancer molecules which induce the apoptosis of tumoral cells. This work of thesis concern the study. In hepatoma cell lines, of the induction of apoptosis signaling pathway by these molecules witch can be dependent and independent of p53. For that, we studied at the same time the effect of the conventional anti-cancer molecules and that of new hybrid molecules able to target the tumoral cells selectively. In the first part of this work. We were interested in the suppressor of tumour p53 signaling pathway induced by the anti-cancer molecules. The protein p53 is extremely regulated in response to a cellular stress. Indeed, the post-translational modifications of p53 constitute a major mechanism of the regulation of its activity. We observed the induction by the DOX and the octreotide. Of a shorter protein of 40 kPa, resulting from a post-translational cleavage of the p53 C-terminal region (p40 ΔC). This cleavage of p53 is induced in the tumoral and non tumoral cells and depends neither on the statute of p53 nor of the nature of the lesions which damage the cell. We showed that p40 is localised in the nucleus and is not resulting from an alternative splicing of p53. Moreover. Our study showed that this proteolytic cleavage of p53 is independent of the action of the caspases. Of the calpaïnes and the proteasome. In the second part we studied the apoptotic effect of a hybrid molecule, the AN-238. Associating a cytotoxic molecule, the AN-201, with the somatostatin analogue of the SST. The RC-121, in the hepatoma cell lines expressing or not p53. The concept of these new molecules including a target peptide, is based on the fact that the tumoral cells strongly express the receptors of the SST. Whereas the non tumoral cells do not have any or very little. The results which we obtained show the presence of the sst2 and sst5 in the human hepatoma cell lines. In addition, we showed that the AN-238 is able to eftectively induce the apoptosis independent of p53. After only 15 minutes of incubation of these molecules with the cells. In the rat isolated hepatocytes. The exposure to the AN-238 does not cause the apoptosis contrary to the rat hepatoma cell lines. These results show that in the cancer of the human liver, the cytotoxic analogue of the SST is a powerful agent able to induce apoptosis bv the intermediary of the sst;, independently of p53. In the third part, we studied the apoptotic signaling pathways independent of p53. P73 and Pas, induced by conventional anti-cancer molecules in the hepatoma cell line. Hep3B. Using a technology antisens and specific inhibitors. Gleevec and rottlerin. We showed that this apoptosis was dependent on c-Abl and PKC5. These genotoxic molecules induce the translocation of c-Abl and PKC6 to mitochondria and their interaction with the Bel-XL protein. A consecutive induction of ROS witch is sensitive to the inhibitors of these two kinases was also highlighted
Fremond-Laizeau, Cécile. "Etude des récepteurs de reconnaissance et des voies de signalisation mis en oeuvre lors de la réponse aux mycobactéries dans les modèles murins de tuberculose à Mycobacterium bovis BCG et Mycobacterium tuberculosis." Orléans, 2006. http://www.theses.fr/2006ORLE2048.
Full textHarati, Rania. "Blood-Brain Barrier during cerebral maturation : impact of neuro-inflammation on the regulation of drug-efflux/influx transporters." Phd thesis, Université Paris Sud - Paris XI, 2012. http://tel.archives-ouvertes.fr/tel-00829110.
Full textEthier, Sheila. "Contribution des protéines issues du liquide synovial dans la protection et la survie des PMN humains : chimioprotection : étude comparative des mécanismes d’action impliqués par rapport au GM-CSF." Thèse, 2011. http://hdl.handle.net/1866/6855.
Full textCirculating polymorphonuclear neutrophils (PMN) possess a short half-life and are constantly renewed by the bone marrow to ensure the first-line of defense. Therefore, homeostasis must be maintained through a well-regulated process of apoptosis. Survival of PMN can be regulated by several cytokines as well as conditioned media (CM). Although PMN are crucial for protection against microorganisms, activated neutrophils can lead to severe tissue damage in diseases characterized by chronic inflammation. Indeed, in rheumatoid arthritis (RA), activated PMN contribute to tissue damage by releasing a number of destructive agents. On the other hand, chronic activation of PMN could prevent opportunistic infections present in immunosuppressed patients. This project addresses the isolation and mechanism of action of synovial liquid components on the survival of neutrophils based on previous work (Lagraoui, 1999). Following tangential flow filtration (MW cut off: 30 and 50 kDa), concentrated CM enhanced the viability (75%) of 24-hour cultured human neutrophils isolated from peripheral blood of healthy volunteers (39% ± 9.5 vs 68% ± 2.5, p<0.01) as seen in Lagraoui (1999) previous work. N-terminal protein sequence analysis of the concentrated CM and fractionated conditioned media from previous work revealed 2 known proteins contained in both analysis: albumin, and fetuin. In view of the importance of neutrophiles in immune defense, we compared the benefits of albumin and fetuin to those of granulocytes macrophages-colony stimulating factor (GM-CSF), a growth factor used as an adjunct to cancer chemotherapy. Albumin and fetuin were tested by the AnnexinV-FITC/7-AAD method and displayed an inhibition of neutrophil apoptosis of two to three folds relative to control value. Moreover, albumin (A : 200μM) and fetuin (F : 200μM) rescue human PMN from mutamycin-induced apoptosis, comparable to GM-CSF (GM : 10ng/ml); (Ctrl : 43% ± 10; A : 74% ± 3; F : (82% ± 6 et GM : 74% ± 7; p<0.01). Albumin also induces cellular signaling pathways activation via PI3-K and ERK, whereas fetuin acts through PI3-K pathway only. They induce the differentiation of HSCs into erythrocytes progenitors BFU-E. In immunosuppressed mice, albumin protects white blood cells depletion induced by cytotoxic agent from spleen and blood. Considering all the benefits of albumin and fetuin, their targeting as an adjunct to cancer chemotherapy could be disappointing in view of their lack of specificity. On the other hand, their multiple benefits could have a major impact on neurodegenerative disorders and ischemic events.