Dissertations / Theses on the topic 'Voies oncogènes'
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Bachet, Jean-Baptiste. "Récepteurs tyrosine-kinase, voies de signalisation et tumeurs digestives." Versailles-St Quentin en Yvelines, 2013. http://www.theses.fr/2013VERS0019.
Receptor tyrosine kinases (RTKs) are pro-oncogenes involved in the pathogenesis of many gastrointestinal tumors. We conducted several studies of translational and basic research on the RTK KIT and the gastrointestinal stromal tumors (GISTs). GISTs with delWK557-558 and those with a deletion carrying the two tyrosine residues in KIT exon 11 had the same prognosis. Homozygous GISTs appear more often malignant than heterozygous GISTs. We then reported that homozygous GISTs may be secondary to loss of heterozygosity without loss of genetic material. From cell lines, we demonstrated that the biology of KIT in heterozygous cells was closer to that hemizygous unmutated KIT cells that hemizygous mutated KIT. The hemizygous/heterozygous status on the one hand and the loss or non-tyrosine residues of the KIT exon 11 on the other hand were associated with specific expression profiles of mRNA and miRNAs. Finally, we have described three families with a germline mutation in exon 13 of KIT, and we proposed recommendations for their management
Cassinat, Bruno. "Etude de l'interconnexion des voies de signalisation du G-CSF avec la voie des récepteurs nucléaires retinoïques : identification de voies synergiques et application à la différenciation de cellules leucémiques." Paris 7, 2012. http://www.theses.fr/2012PA077045.
The identification of RARa gene rearrangement as the molecular origin of Acute Promyelocytic Leukemia (APL) led to the first targeted therapy aiming at reinducing normal differentiation of tumour cells using retinoic Acid (RA). Because we previously identified a level of heterogeneity in in vitro response of patients' cells to the RA induced differentiation which was correlated to the heterogeneity in clinical response, we developed several studies: -we collaborated to a study which allowed to identify certain mutations of the PML-RARα gene in APL patients with an adverse prognostic. We have also shown in another study that the minimal residual disease analysis using quantitative RT-PCR allowed to better identify patients that will relapse. We also demonstrated that a high frequency of Auer rods in APL cells at diagnosis is correlated to a poorer clinical outcome. -We have analysed whether extracellular signalling of 2 different origins (membrane signalling induced by the G-CSF and nuclear signalling induced by RA) may be interconnected and become synergistic to induce the differentiation of APL cells. In a model of APL cells resistant to the differentiation effect of RA we demonstrated that ERK1/2 pathway can restore transcriptional activation by RA via RARα, CBP/P300 and acetylated histone H3 recruitment on RA target gene promoters
Mahé, Mélanie. "Caractérisation des voies de signalisation des oncogènes FGFR3 muté et FGFR3-TACC3 dans les carcinomes de vessie." Thesis, Paris 11, 2015. http://www.theses.fr/2015PA11T020/document.
Bladder cancer progression can be divided in two main pathways. The pathway of In Situ Carcinoma (CIS) which progress through an invasion of the basement membrane and then the muscle and the pathway of Ta papillary tumors which change little but recur frequently after tumor resection. Approximately 65% of Ta papillary tumors harboring a FGFR3 mutation and recently FGFR3-TACC3 fusion proteins have been observed in bladder tumors (about 10% of bladder tumors). The oncogenic role of the mutated FGFR3 receptor and of the FGFR3-TACC3 fusion protein has been demonstrated in vivo and in vitro. However signaling pathways activated by the mutated FGFR3 receptor or by the FGFR3-TACC3 fusion protein are currently poorly characterized.In this context, two approaches have been developed to characterize these signaling pathways. The first is based on the study of p38, AKT and ERK1/2 phosphorylation by the mutated receptor (S249C) or the wild type receptor in the NIH3T3 fibroblastic cell line. This study allowed identifying p38 and AKT as activated by the mutated FGFR3 receptor. Moreover, activation of p38 and AKT by the mutated receptor is critical for cell transformation. Study of the activation of these two signaling has been realized in human bladder cancer cell lines endogenously expressing the mutated FGFR3 receptor or the FGFR3-TACC3 fusion protein. Moreover, we showed that p38 and AKT are involved in the maintenance of a FGFR3/MYC feedback positive loop: FGFR3 activation induce MYC over expression which in turns promotes FGFR3 expression. The second approach is based on a study whose aim was to identify FGFR3 proteins partners by mass spectrometry after a FGFR3 immunoprecipitation, which has been previously realized in the lab. Data analyze led to the obtaining of a list of 60 proteins identified has FGFR3 protein partners with a high confidence. Construction of a FGFR3 network with this list was not possible (too little interactions existing between these proteins), so we developed an algorithm (PEPPER) in collaboration with a student in bioinformatics in the lab, Remy Nicolle, to propose a FGFR3 signaling network.The two approaches developed during this thesis allowed us to better characterize the FGFR3 signaling pathways. Identification of a FGFR3/MYC feedback loop allowed us to better understand why the altered FGFR3 has oncogenic properties and to propose p38 and AKT as news promising therapeutic targets, to treat human bladder tumors harboring the altered FGFR3 receptor. Construction of the FGFR3 signaling network with the algorithme PEPPER give an overview of the FGFR3 signaling pathways and open new tracks to explore
Lemaire, Frédéric. "Caractérisation de l'expression génique des tumeurs des voies aérodigestives supérieures : perspectives diagnostiques et thérapeutiques." Paris, Institut national d'agronomie de Paris Grignon, 2004. https://pastel.archives-ouvertes.fr/pastel-00000629.
Dormoy, Valérian. "Du développement au cancer : implication des voies néphrogéniques dans la croissance du carcinome à cellules rénales humain." Strasbourg, 2010. https://publication-theses.unistra.fr/public/theses_doctorat/2010/DORMOY_Valerian_2010.pdf.
Kidney cancer remains resistant to therapies. Several genes play essential roles in human development, particularly during nephrogenesis. The concept suggesting that these actors could be expressed by cancer cells has recently emerged. In our studies, we investigated if cancerogenesis and tumor growth in renal cell carcinoma are linked to the developmental pathways. For this purpose, we focussed particularly on the developmental sonic hedgehog pathway, and then on the nephrogenic transcription factor Lim1. The expression of the SHH pathway and of Lim1 in RCC were analysed on RCC cell lines and tumors from human RCC. The proliferative and apoptosis effects of the SHH pathway and of Lim1 on kidney cancer cells were evaluated in vitro. Their involvement in kidney cancer cells migration and invasion were also studied, as well as their interaction with oncogenic pathways by Western blot. Focussed on the description of therapeutical innovation, we used xenografted mice to analyze the effects of the inhibition of these developmental pathways/markers in vivo. Our results demonstrate that the SHH pathway and Lim1 are reexpressed in RCC cell lines and in human tumors. The inhibition of these actors led to a radical decrease of cancer cells proliferation and migration. In vivo, targeting these pathways/markers, that we showed to participate to the regulation of oncogenic pathways, induced a decrease of tumor growth and even marked tumor regression. The developmental pathways implicated in RCC growth could constitute an important therapeutical innovation in the treatment of this cancer, and allow us to put an additional piece in the molecular puzzle of molecular cancer mechanisms
Denoyelle, Christophe. "La protéine RhoA et ses voies de signalisation : Perspectives d'une nouvelle stratégie thérapeutique dans le traitement des cancers du sein agressifs." Rouen, 2003. http://www.theses.fr/2003ROUES005.
We have shown that HMG-CoA reductase inhibitors (statins) currently used in the treatment of hypercholesterolemia prevent the formation of geranylgeranylpyrophosphate (GGPP) and reduce the membrane localisation (=activation) of RhoA leading to the inhibition of cell proliferation and invasion of aggressive breast cancer cells in vitro and in vivo. Other mechanisms involved in the anticancer activity of statins (action on CDKi, proteases, Wnt-5a) were identified at molecular level using microarray. Finally, we have shown that bisphosphonates, which have a biodisponibility higher than statin, prevent also the membrane localisation of RhoA leading to the reduction of both cell invasion and chemotactic effect of cancer cells. To conclude, the inhibition of RhoA cell signalling pathways seems to be a good strategy to fight aggressive cancers
Lemaire, Frédéric Jean Laurent. "Caractérisation de l'expression génique des tumeurs des voies aérodigestives supérieures: perspectives diagnostiques et thérapeutiques." Phd thesis, INAPG (AgroParisTech), 2004. http://pastel.archives-ouvertes.fr/pastel-00000629.
Goormachtigh, Gautier. "Etude de LMP1, oncogène majeur du virus d'Epstein-Barr : autorégulation de son expression par les effets antagonistes des voies de signalisation cellulaire JNK et NFkB." Lille 2, 2006. http://www.theses.fr/2006LIL2S011.
Lefevre, Gaëlle. "Identification des voies de signalisation participant à la tumorigénèse du mélanome choroïdien humain : implications thérapeutiques." Paris 7, 2004. http://www.theses.fr/2004PA077232.
Uveal melanoma is the most frequent intraocular primary tumour in adults. Although this cancer has a low incidence, its aggressive character as well as the absence of current satisfactory therapeutics to treat it lead us to study its physiopathology. We compared the expression levels of 120 proteins in both normal and tumoral melanocytes. We found that the ERK pathway was deregulated. We further confirmed that this deregulation was a major trait in uveal melanoma cells and that it was important for both the proliferation and transformation of these cells. We also identified two alterations responsible for the overactivation of the ERK pathway: 1) the presence of mutant B-Rafv599E and 2) the existence of an autocrine loop of activation by SCF/c-Kit. Inhibition of this latter with STI571 demonstrated promising in vitro results for future therapeutic application
Medyouf, Hind. "Identification et étude de voies moléculaires oncogéniques dans les lymphomes et leucémies lymphoïdes." Paris 7, 2007. http://www.theses.fr/2007PA077042.
In this study we were interested in evaluating the importance of calcineurin activation, a serine threonine phosphatase, in leukemia développement. We demonstrate that sustained calcineurin activation is observed in ail mouse models of T-cell malignancies tested among which, activated Notchl(ICN1)- or TEL-JAK2-induced T-cell acute lymphoblastic leukemia (T-ALL). Thèse models are highly relevant to human malignancies. Indeed, deregulation of the JAK/STAT pathway has been reported in a number of ALL, and more recently, it has been shown that activating-mutations of Notchl are found in over 50% of T-ALL patients. We further show that in vivo inhibition of calcineurin activity in these two mouse models by CsA or Tacrolimus, two well known inhibitors of calcineurin currently used in human medicine as immunosuppressant, induced apoptosis of leukemic cells, rapid tumor clearance and signifïcantly prolonged mouse survival. Conversely, ectopic expression of a constitutively activated mutant of calcineurin favored leukemia progression, suggesting that calcineurin plays an intrinsic role in leukemic cells. We extended our study to human samples and human derived cell lines and show that similarly to what is observed in mouse models, ail samples obtained from aggressive B- and T-cell lymphoma patients, as well human leukemia (B and T) derived cell lines exhibit a sustained activation of calcineurin. In vitro treatment of these cell lines with CsA or Tacrolimus impaired their proliferation and induced apoptosis. From these results, we conclude that, calcineurin activation is critical for the maintenance of the leukemic phenotype in vivo, identifying this pathway as a potential novel therapeutic target in lymphoid malignancies
Marsolier, Justine. "La transformation lymphocytaire bovine induite par Theileria annulata : un modèle unique et innovant pour identifier de nouvelles oncoprotéines et voies oncogéniques." Paris 7, 2013. http://www.theses.fr/2013PA077083.
Cancer is a progressive disease that involves a chain of cellular and molecular events, which threaten individual survival It is fundamental to understand signaling pathways involved in cancer formation and propagation, to improve treatment of this disease. My projects focused on a bovine disease induced by an eukaryote parasite: Theileria annulata. Parasite infected cells acquire a cancer phenotype. This tumor phenotype is curable with a theilericide, which specifically kills the parasite. I developed two projects aimed at understanding how T. Annulata manipulates the host cell to induce its transformation. 1- Host genes: We found that miR155 was regulated by the parasite. We also identified a new miR155 target: transcripts encoding the DET1 protein, which is involved in targeting c-Jun for degradation by ubiquitination. Thus, miR155 expression leads to DET1 down-regulation, accumulation of the c-Jun protein and activation of the miR155 promoter. This feedback loop is essential for the host cell transformation. 2. Parasite genes: Based on T. Annulata genome analysis, we identified a Peptidyl-Prolyl c/s- trans Isomérase (PPIase): TaPIN, which is secreted in bovine infected cells and plays a role in parasite induced host cell transformation. We then demonstrated that TaPIN interacts with FBW7, a ubiquitin ligase which induces c-Jun degradation via ubiquitination. In parallel, we found that, by stabilizing PKM2, TaPIN up-regulates glycolytic enzymes expression and host cell metabolism leading to a « Warburg like effect ». In conclusion, by targeting two different pathways (overexpression of miR155 and secretion of TaPIN), Theileria induces host cell transformation
Daubon, Thomas. "Mobilité cellulaire induite par les chimères Bcr-Abl : un nouveau modèle pour l'exploration des voies effectrices des petites protéines G de la famille Rho." Poitiers, 2008. http://theses.edel.univ-poitiers.fr/theses/2008/Daubon-Thomas/2008-Daubon-Thomas-These.pdf.
Bcr-Abl chimeras are produced by a reciprocal t(9;22) chromosomal translocation that fuses varying amounts of the bcr with the abl genes. The only structural difference between p190bcr-abl, associated with acute lymphoid leukaemia, and p210bcr-abl, responsible for chronic myelogenous leukaemia, resides in a DH/PH domain only present in p210bcr-abl. We previously showed that Rac1 was activated in both p190bcr-abl- and p210bcr-abl-expressing cells whereas RhoA was activated in p210bcr-abl-expressing cells only (Harnois et al. , Oncogene, 2003). Ba/F3 cells were not spontaneously motile in 3D matrigel while Ba/F3p210 and Ba/F3p190 cells moved spontaneously. P210bcr-abl-expressing cells presented typical amoeboid movements in contrast to 190bcr-abl-expressing cells, which showed a rolling-type mobility. The results obtained using mutated GEF domain of Vav or p210bcr-abl allowed to propose a model in which Vav, in complex with Bcr-Abl, is responsible through Rac1 activation for triggering the motility of Bcr-Abl expressing cells. The GEF of p210bcr-abl specific of RhoA does not trigger motility by itself, but RhoA activation is crucial for committing leukaemic cells to amoeboid movements (Daubon et al. , Oncogene, 2008). Bcr-Abl-expressing cells represent then a powerful model to explore the still un-understood amoeboid motility. Then, we characterized a Rac1/PAK1/LIMK1/Cofilin pathway in which each element is critical for triggering the rolling-type motility. We also showed that the classical RhoA/ROCK/MLC pathway was only partially involved in the amoeboid motility of the Ba/F3p210 cells. Surprisingly, we found that RhoA and ROCK1 induced the activation of the ADF/destrin isoform of the Actin Depolymerizing Factor family, through the specific down-regulation of LIMK2 both at the transcriptional level and by proteasome-dependent degradation. This original pathway drives to characteristic amoeboid movements. Taken together, these results on the Ba/F3 cells motility improve the understanding of the molecular mechanisms leading to these 3 dimensional motility modes
Redon, Richard. "Contribution au modèle génétique de progression tumorale des cancers des voies aéro-digestives supérieures : Application de la technologie des puces à ADN au criblage génomique des tumeurs." Université Louis Pasteur (Strasbourg) (1971-2008), 2002. http://www.theses.fr/2002STR13105.
Synnott, Geneviève. "Mode d'action antiprolifératif des Nutlins dans les cellules tumorales et son application dans l'évaluation des mécanismes de contrôle du cycle cellulaire et des voies de signalisation de p53." Thesis, Université Laval, 2007. http://www.theses.ulaval.ca/2007/24146/24146.pdf.
Hussenet, Thomas. "Toward the identification of oncogenes by high resolution mapping of gene amplifications of the 3q25-qter region in malignant fibrous histiocytoma and squamous cell carcinoma." Strasbourg 1, 2005. https://publication-theses.unistra.fr/public/theses_doctorat/2005/HUSSENET_Thomas_2005.pdf.
This thesis work specifically applied the positional cloning strategy to the high resolution mapping of chromosome 3 aberrations in different tumour types to identify new candidate oncogenes located at 3q, amplified and consequently over-expressed. A first part was dedicated to Malignant Fibrous Histiocytomas (MFH). We first characterized overlapping amplicons at 3q28 in a MFH cell line and two other MFH primary tumours. From this region, we identified a microRNA encoding gene, hsa-miR-28 as an oncogene candidate and further identified three targets of miR-28 which all play roles in cell cycle regulation. A second part was dedicated to Squamous Cell Carcinoma (SCC). We analyzed chromosome 3 aberrations in a series of 25 lung SCC using array CGH and delineated a common region of high-level amplifications at 3q26. 3 for 20% of the tumours. Further high-resolution mapping pinpoint a 2 Mb consensus region. Analyses of the transcriptional consequences of these high-level amplifications were carried out for 9 genes. Most of them are recurrently over-expressed but two, SOX2 and SOX2OT, likely represent the 3q26. 3 amplification driver genes. Our strategy also enabled us to isolate cyclin L1 (CCNL1) gene at 3q25. 3 as a candidate oncogene in head and neck SCC (HNSCC). Investigations of CCNL1 gene alterations in a large series of HNSCC revealed consistent copy number gains and over-expression. Using array CGH we finally delineated several high-level amplifications at 3q in a series of 25 analyzed HNSCC, defining a common region overlapping with the consensus region defined for lung SCC thus suggesting that similar genes at 3q26. 3 may be involved in SCC pathogenesis independently of the localization. In conclusion we were able to isolate several candidate oncogenes located at 3q in different tumour types, illustrating the power of the positional cloning strategy applied to tumour genomes. Further investigations are needed to assess their oncogenic status
Ambroise, Gorbatchev. "Caractérisation de nouvelles voies régulant l’expression et l’activité des protéines Mcl-1 et PUMA." Thesis, Université Paris-Saclay (ComUE), 2015. http://www.theses.fr/2015SACLS079/document.
Cancer is a major public health issue, killing millions of people worldwide each year. The inhibition of apoptosis, a programmed cell death, in its onset and development has been well documented, making it one of the hallmarks of cancer. The regulation of the intrinsic (mitochondrial) pathway of apoptosis is regulated by the Bcl-2 (B cell lymphoma-2) family. Up until now, PUMA, a pro-apoptotic protein, was thought to be mainly expressed at the mitochondria, based on experiments where it had been overexpressed. We showed that endogenous PUMA is mainly expressed in the cytosol of activated or resting B cells. However, upon apoptotic stress, PUMA was able to translocate from the cytosol to the mitochondria, in a caspase-independent but p38-dependent manner, allowing PUMA to bind and inhibit the anti-apoptotic proteins Bcl-2 and Mcl-1, and thereby leading to cell death. The anti-apoptotic proteins, especially Mcl-1, are often overexpressed in tumors. Mcl-1 is a protein with a short half-life, degraded rapidly by the proteasome. This degradation is ubiquitin-dependent, requiring E3 ligases (E3). A handful of E3s and one deubiquitinase (DUB), that hydrolyses the ubiquitin chains, have been reported to regulate Mcl-1 expression. However, they were either very poorly expressed or their inhibition had no impact on Mcl-1 expression in our model. We thus undertook to characterize new E3s and DUBs mediating Mcl-1 ubiquitination. After an immunoprecipitation of Mcl-1 in our cells, followed by a mass spectrometry analysis, we identified the DUB USP14. When knockdown, Mcl-1 expression was selectively increased and its stability enhanced. Our results could help build “double-edge” therapies, removing the breaks on apoptosis on one hand via Mcl-1 downregulation while activating it on the other via PUMA translocation
Yassine, May. "Analyse de l'intérêt pronostique du profil moléculaire dépendant de la sortiline nucléaire dans le cancer de poumon." Electronic Thesis or Diss., Limoges, 2023. http://www.theses.fr/2023LIMO0099.
Sortilin, a glycoprotein of the Vps10 family, is widely recognized for its key role in protein sorting. However, its dual role in oncology, as either tumor promoter or tumor suppressor, has given rise to much debate. In non-small cell lung cancer (NSCLC), and more specifically in adenocarcinoma (LUAD), an inverse correlation was observed between sortilin expression and tumor growth, as well as tumor grade. Identified as a novel membrane inhibitor, sortilin promises to remodel EGFR trafficking. It provides a promising pathway for limiting proliferative signaling and counteracting resistance to EGFR inhibitors, especially in LUAD with EGFR mutations. This perspective suggests its major involvement in moderating tumor aggressiveness. In the absence of data concerning the nuclear localization and role of sortilin at this level, our team has highlighted its colocalization with EGFR in the nucleus. Furthermore, sortilin interacted with chromatin and competed with EGFR at the transcription initiation sites (TSS) of EGFR-targeted genes. This points to a potential influence of sortilin on gene transcription, notably through its involvement in the recruitment of RNA polymerase II. In the present study, we show that sortilin plays a much more prominent nuclear role than previously recognized, adding to its known role as a tumor suppressor like. Our transcriptomic analyses, carried out in LUAD lines, revealed that sortilin down-regulates a large set of genes involved in oncogenic pathways, in addition to EGFR target genes. This role appears to be intrinsically linked to the regulation of DNA repair, transcription and chromatin organization orchestrated by sortilin. Sortilin would also associate with key proteins involved in these mechanisms at the nuclear level. These results challenge the traditional view of sortilin, which extends beyond the simple framework of protein sorting. Its highlight its varied functions in various tumors. Moreover, sortilin is emerging as a therapeutic target of interest for developing innovative strategies against LUAD
Vasseur, Romain. "Etude de la régulation de la mucine MUC4 par l’oncogene K-ras dans le cancer du pancréas." Thesis, Lille 2, 2015. http://www.theses.fr/2015LIL2S051/document.
K-ras oncogene is a small GTPase of the RAS superfamily, highly implicated in cancer, mainly in pancreatic cancer, one of the most deadly cancers in occidental countries. K-ras mutations are considered as an initiating event of pancreatic carcinogenesis and K-ras oncogenic activities are necessary components of cancer progression. However, K-ras clinical targeting remains ineffective until now. Focus on early downstream K-ras signalling may thus appear as an interesting strategy target in this cancer. The membrane-bound mucin MUC4 is a high molecular weight glycoprotein frequently deregulated in cancer. In pancreatic cancer, MUC4 is neo-expressed in the preneoplastic stages and thereafter is involved in cancer cell properties leading to cancer progression and chemoresistance. MUC4 regulation by K-ras in pancreatic carcinogenesis remains unknown. Using the Pdx1-Cre; LStopL-K-rasG12D mouse model of pancreatic carcinogenesis, we show that the in vivo early neo-expression of the mucin Muc4 in pancreatic intraepithelial neoplastic lesions (PanINs) induced by mutated K-ras is correlated with the activation of ERK, JNK and NF-ΚB signalling pathways. In vitro, transfection of constitutively activated K-rasG12V in human pancreatic cancer cells led to the transcriptional upregulation of MUC4. This activation was shown to be mediated at the transcriptional level by AP-1 and NF-ΚB transcription factors via MAPK, JNK and NF-ΚB pathways and at the post-transcriptional level by a mechanism involving the RalB GTPase. Altogether, these results identifies MUC4 as a transcriptional and post-transcriptional target of K-ras in pancreatic cancer. This opens avenues in developing new approaches to target the early steps of this deadly cancer
Genest, Mallory. "Rôle de la surexpression des flotillines dans l'activation de voie de signalisation oncogéniques induisant la transition épithélio-mésenchymateuse." Thesis, Montpellier, 2019. http://www.theses.fr/2019MONTT001.
Tumor cell invasion and consecutive metastasis formation are the main cause of death in cancer patients. One crucial process of tumor cell invasion is the epithelial to mesenchymal transition (EMT), a reversible process during which polarized epithelial cells convert into motile mesenchymal cells. This process is characterized by gene expression changes involved, in particular, in the perturbation of cell adhesion, polarity and cytoskeletal structures.Flotillin 1 and 2 are two ubiquitous and highly conserved membrane proteins that assemble in large oligomers, known to participate in membrane protein clustering and endocytosis. Flotillins are upregulated in many invasive cancers and are considered as markers of poor prognosis. At physiological expression level, flotillins are mainly located at the plasma membrane. The cellular distribution of upregulated flotillins is dramatically modified with a strong enrichment in vesicular compartments that we characterized as non-degradative-endolysosomes.During my PhD project, we identified that flotillins are key EMT inducer. We upregulated flotillins in normal mammary cells and demonstrated that it is sufficient to promote EMT. Using several global comparative analyses (transcriptomic, phosphokinase arrays), we showed that flotillin upregulation activates key oncogenic signaling pathways and plasma membrane receptors. We identified that flotillin overexpression induces a trafficking pathway that we named UFIT-pathway (Upregulated flotillin Induced Trafficking pathway), which promotes the endocytosis of several cargos, amongst them membrane receptors involved in the activation of oncogenic pathways.Our results suggest that the UFIT pathway generates flotillin-positive endolysosomes acting as as “signalosome compartments” involved in the activation of signaling pathways stimulating EMT and cellular invasion
Bonetta, Anaëlle. "Exploration de nouvelles voies thérapeutiques contre le cancer du col de l'utérus : approche combinée par adénovirus et ARN interférence." Phd thesis, Université de Strasbourg, 2013. http://tel.archives-ouvertes.fr/tel-00870000.
Morel, 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.
Schistosomiasis 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
Voltz, Emilie. "Apoptose tumeur-spécifique : Mécanisme et potentiel thérapeutique de la voie de signalisation de TRAIL." Université Louis Pasteur (Strasbourg) (1971-2008), 2006. https://publication-theses.unistra.fr/public/theses_doctorat/2006/VOLTZ_Emilie_2006.pdf.
Sartelet, Hervé. "L'activation de la voie AKT dans le neuroblastome et son implication thérapeutique." Paris 11, 2009. http://www.theses.fr/2009PA11T009.
Mendoza-Gaviria, José-Andrés. "Impact de l'expression de la protéine E6 des papillomavirus humains oncogènes de type 5 et 8 sur la voie de signalisation cellulaire du TGF-BETA." Paris 7, 2007. http://www.theses.fr/2007PA077008.
Some human papillomavirus (HPV) genotypes are responsible of ano-genital cancers (HPV16 and 18) and cutaneous carcinomas (HPV5 and 8) (in patients suffering epidermodysplasia verruciformis [EV]). The oncogenic potentiel of HPVs is mainly related to the activity of E6 and E7 early proteins. In the case of genital high risk HPVs (HPV16 et 18), thèse oncoproteins induce degradation of p53 (E6) and pRb (E7), two key inhibitor proteins of thé cell cycle. In contrast, the biological properties of thèse two oncoproteins from HPVS and 8 are poorly understood. Our aim was to study the role of the oncoprotein E6 from HPVS and 8. We identified cellular partners of E6 by yeast two-hybrid screening. The interactions found were validated by diverse molecular and cellular biology methods. Our work allowed us to show the interaction between E6 and SMAD3, a cellular protein that plays a central role in TGF-beta signaling pathway. This association is specific of HPVS and 8 and induces degradation of SMAD3/4 complexes. The functional impact of this interaction was studied by regulation of a luciferase reporter gene. We equally identified fixation of E6 on SnoN, a cellular inhibitor of SMAD proteins. This association seems to synergize for dégradation of SMADs. The TGF-beta transduction pathway is crucial for the synthesis of proteins that block cell cycle passage from phase G1 to S. Thus, the inhibition of TGF-beta signaling by E6 may constitute a crucial step towards viral replication. Moreover, the interaction specificity of E6 proteins from EV HPVs suggests that TGF-beta signaling may be a privileged target in the way of immortalizing keratinocytes upon viral infection
Ben, Khalifa Youcef. "Etude de la modulation du transcriptome par les oncogènes des papillomavirus humains dans le cancer du col de l'utérus : Identification et caractérisation d'une nouvelle voie E6/p63." Paris 11, 2008. http://www.theses.fr/2008PA11T074.
Rolloy, Caroline. "Altération de la voie du TGF-β par la protéine E6 de papillomavirus humain cutané de type 5." Paris 7, 2011. http://www.theses.fr/2011PA077045.
Human papillomaviruses (HPVs) are non-enveloped DNA viruses of icosahedral symmetry. More than 150 HPVs genotypes have been described so far. Most of them cause benign skin or mucosal hyperproliferative lesions. Infections with certain genotypes of HPVs are associated with malignant transformation such as ano-genital cancer (HPV 16, 18) in the general population or cutaneous carcinoma (HPV 5, 8) in the context of the inherited disorder epidermodysplasia verruciformis (EV). These HPVs are considered as "high-risk" genotypes because of their tight association with cancer. Their oncogenic potential mainly relies on the activity of the two early viral oncoproteins, E6 and E7. The transforming activity of E6 protein of mucosal high-risk HPVs clearly implicates the tumor suppressor p53 degradation. In contrast, little is known on the functional properties of E6 oncoproteins from oncogenic cutaneous HPVs. Previous studies in the laboratory had shown the interaction between oncogenic HPV5 E6 (5E6) and the SMAD3 protein of the TGF-beta signalling pathway. This pathway is involved in many cellular events as control of cellular prolifération, differentiation, apoptosis and is known to be misregulated in numerous cancers. Our goal in this thesis was to dissect TGF-beta pathway rewired by E6 protein from oncogenic HPV 5. Combining deletion mutagenesis and linker scanning approaches we mapped on E6 N-terminal half the SMAD3 interacting area. Then, interactomic studies showed a redundant targeting of the TGF-beta by 5E6 that not only interact with SMAD3 but also with SnoN and Arkadia, two key regulators. To better understand the consequences of these interactions, we developed a ternary complex detection assay that leads us to show that besides proteosomal degradation of SMAD3/4 complexes, 5E6 also recycles SnoN-mediated repression to rewire the TGF-beta signaling pathway for viral benefit. Our results support the hypothesis that inhibition of this pathway, by eliciting cell proliferation in differenciating layers of epidermis, facilitates the viral cycle and accordingly, contributes to the oncogenic potential of E6 proteins from cutaneous HPVs
Gaiffe, Emilie. "Les cellules apoptotiques vecteurs d'oncogènes viraux : Une voie alternative de la carcinogenèse associée aux HPV." Thesis, Besançon, 2011. http://www.theses.fr/2011BESA3006/document.
Apoptotic cells in mammals may be completely degraded by specialized phagocytic cells or serve as a DNA vector. The oncogene transfer via apoptotic cells leads to the transformation of récipient cells but only when they are p53 deficient. As the E6 oncogene of high-risk human papillomavirus (HPV) leads to p53 dégradation, its transfer from apoptotic cells may be the cause of an alternative mechanism of HPV-associated carcinogenesis. To confirm this hypothesis, we induced apoptosis of cervical cancer cells that may harbor HPV sequences. In collaboration with Patrick Sandoz's team at the FEMTO-ST optical laboratory, we used their position-referenced microsystem for the automated observation of apoptotic cell internalization. We also found that apoptotic cells are phagocytized by fibroblasts regardless of their virological status. Only apoptotic cells from cells harboring HPV DNA transform recipient cells. Viral DNA expression, including E6, in transformed fibroblasts and the loss of p53 and p21 protein expression suggest that HPV oncogènes may cause transformation. These results highlight a new mechanism of HPV-associated carcinogenesis via apoptotic cell phagocytosis. This mechanism may be involved in thé transformation of primary cells and the progression of HPV-associated tumors
Zhao, Yajie. "Étude du rôle des voies de signalisation des Activines dans l'initiation et la progression du cancer du pancréas." Thesis, Lyon, 2019. http://www.theses.fr/2019LYSE1159.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease worldwide and remains the ranking of 7th leading cause of cancer related death in the past 5 years. Because of the lack of highly sensitive and specific detective tools in an early stage of this disease and low curative treatments, most of the patients are diagnosed in an incurable stage and end up with a high mortality. Understanding the molecular pathology especially the early stage of this lethal disease is of great importance to improve the outcome of these patients. The first and major part of my work was based on gene profiling analysis in which they emphasized the role of TGFβ/Activin signalling and ALK4-receptor during the development of PDAC in addition to the four common oncogenic genes (KRAS, CDKN2A, TP53 and SMAD4). On the other hand, INHBA(encoding for ActivinA) as a key member of TGFβ-superfamily ligands is a target of Kras oncogenic activation in pancreatic duct cell and has been pointed a potential SASP candidate component through a secretome analysis of cells undergoing Kras induced senescence. Therefore, the aim of my work is to investigate the impact of ActivinA-signalling during PDAC initiation. In the first part of my project, I demonstrated that ActivinA as a tumour-protecting SASP factor, produced by ADM/PanINs senescent cells, that limit their proliferation and expansion into highly proliferative lesions through its ALK4 receptor in the initiation of PDAC. Furthermore, our work revealed that senescent Dclk1+ cells limit the expansion of preneoplastic lesions and partly impact the stromal component which is sustained by ActivinA-signalling. Besides, I also explored the autocrine and paracrine functions of ActivinA-signalling in the late stage of PDAC. We found that lack of ActivinA-ALK4 signalling in mice leads to an increased proliferative capacity in tumor cells and a reduced accumulation of stromal cells, which might help to explain their diverse metastasis and a relative longer survival time. To conclude, my work gives another insight of ActivinA-signalling and Dclk1 in the onset of pancreatic cancer and their existence in senescent cells within low grade pancreatic precursor lesions should be considered a crucial step for developing novel diagnostic and therapeutic strategies for PDAC patients
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.
Gilbert, Marie. "Etude des mécanismes moléculaires impliqués dans la régulation de TTF-1 et recherche de nouvelles cibles thérapeutiques dans le carcinome papillaire de la thyroïde : rôle de l'oncogène RET/PTC1 et de la voie Wnt/Bêta-caténine." Paris 11, 2010. http://www.theses.fr/2010PA114827.
The papillary thyroid carcinoma (PTC) represents 80% of thyroid tumors and is characterized by a RET/PTC1 fusion oncogene (60-70% of cases) and the expression of the TTF-1 transcription factor. This factor leads to the expression of specific proteins of the thyroid as thyroglobulin and is found in many papillary cancers. The Wnt /β-catenin pathway is particularly studied because of its multiple roles in particular during development. It has also been extensively studied in many cancers and plays a fundamental role. These pathways were the subject of the work and the aim of the thesis was to show their roles and justify a targeted therapeutic approach. Our studies show that TTF-1 gene is regulated by the Wnt /β-catenin pathway in the PTC. In addition, we designed a specific and effective siRNA against the RET/PTC1 junction. The siRNA was vectorized with nanoparticles of squalene for a therapeutic use. We also showed that the siRNA induce TTF-1 expression and could be considered in the case of its therapeutic use in aggressive or resistant PTC
Teissier, Sébastien. "Importance de la voie E2F dans la régulation transcriptionnelle du papillomavirus de type 18 et dans la modification du transcriptome des cancers associés." Paris 7, 2006. http://www.theses.fr/2006PA077168.
In the normal epithelium, keratinocytes stop to divide to differenciate. The E2F family members are transcription factors negatively regulated by pRb that play a crucial role in the cellular cell cycle. Differentiation of the keratinocytes implies a cell cycle arrest due to the replacement of the E2F activators by the E2F5/p130 repressor complex. These viruses infect the basal cell layers of the epithelium and their replication requires a cell proliferation that needs to bypass the programmed cell-cycle arrest. The high risk HPV are the causal agents of the cervical cancer and express two oncogenes E6 and E7 that degrade p53 and inactivate pRb respectively. I have shown a hijack of thé E2F5/p130 repressor complex into an activator of HPV-18 transcription through E7. The roles of E7 played on E2F5/p130 and on the activation of the E2F pathway by the modulation of pRb could explain the take over of the cell-cycle control by HPV-18 in cancer and in the viral cycle. In micro-arrays analyses of the cervical carcinoma HeLa cells transcriptome expressing E6 and E7 or not allowed us to find out a number of cellular genes controlled by E6 and E7 through the p53 and pRb pathways Among these genes, we identified many mitotic genes that are controlled by E2F and that are modulated in cervical cancer biopsies indicating that these genes could be used for diagnosis and prognosis of cervical cancer
Amarir, Samira. "L' activation constitutive de la voie Notch supprime la transformation induite par v-Src : implication de la signalisation TGF-β." Paris 7, 2009. http://www.theses.fr/2009PA077010.
Understanding how disruption of differentiation contributes to the cancer cell phenotype is required to identify alterations essential for malignant transformation and provide experimental basis for their correction. We have been using quail neuroretina cells transformed by v-Sr6 (QNR/v-src), as an ex vivo model to study this question. We report that stable activation of Notch signalling, which is involved in retina differentiation, suppresses v-Src-induced transformation of QNR cells. This phenotypic reversion coincides with a major switch in cell identity, since these undifferentiated cells acquire glial differentiation traits. Cells restored to a normal and differentiated phénotype hâve undergone changes in the functioning of JNK and Rho/Rac GTPases pathways, which essentially regulate cell morphology and cytoskeleton organization. This phenotypic reversion is partially mediated by an auto/paracrine mechanism, since revertant cells secrete a factor, which inhibits transformation properties of QNR/v-src cells. Transcriptome anlaysis revealed an increase of TGFβ3 RNA in QNR/v-src/Notch cells. This increase is associated with an activation of TGFβ signalling in these cells. Treatment of QNR/v-src cells with a TGFβ3 recombinant protein or chemical inhibition of TGFβ signaling in QNR/v-src/Notch showed that TGFβ signalling is involved in restoration of normal morphology and cytoskeleton organization but also, in part, in commitment to glial differentiation
Yahiaoui-Bentounsi, Ouardia Imene. "Analyse de l'activation de la voie PI3K/AKT dans le lymphome folliculaire." Thesis, Aix-Marseille, 2014. http://www.theses.fr/2014AIXM5060.
The phosphoinositide 3- kinase (PI3K) pathway is involved in the growth of various human cancers, including lymphoid malignancies. However its role in the pathogenesis of follicular lymphoma (FL) has not been yet described.The PhD work focuses on the study of alterations in the PI3K/AKT pathway in follicular lymphoma, in order to provide a new therapeutic target.To clarify this point, biopsy tissue samples from 38 human FL cases were investigated for PIK3CA somatic mutations in exons 9 and 20 using Sanger sequencing. The same samples were analyzed using western blotting and immunohistochemistry to detect expression of AKT, phosphorylated AKT (pAKT), and PTEN proteins. Two cases of benign lymphadenitis were used as controls. AKT expression was present in all FL and lymphadenitis cases. 14/38 (37%) FL and 2/2 lymphadenitis cases expressed pAKT. 9/38 (24%) FL samples showed high level of pAKT, whereas 5/38 (13%) FL cases and 2/2 benign lymphadenitis samples expressed pAKT at low level. PTEN expression was observed in 30/38 (79%) FL and 2/2 benign lymphadenitis cases, whereas 8/38 (21%) of FL cases showed loss of PTEN expression. In addition, 3 cases with positive pAKT did not express PTEN. PIK3CA mutations were not detected in any sample. These data suggest that the PI3K/AKT signaling pathway could be activated in a subset of FL cases, due to either AKT phosphorylation or PTEN downregulation, in the absence of PIK3CA mutations
Gibault, Floriane. "Conception, synthèse et évaluation d’inhibiteurs du complexe protéique YAP-TEAD à visée anticancéreuse." Thesis, Lille 1, 2017. http://www.theses.fr/2017LIL10097.
The Hippo pathway, firstly described in Drosophila and highly conserved in mammals, has been demonstrated to play a crucial role in the organ size control. This kinase cascade regulates the phosphorylation of the downstream effector YAP (or its paralogue TAZ), a transcriptional coactivator with oncogenic activity. Its function is mediated by its nuclear translocation and interaction with the transcriptional factor TEAD, to form YAP-TEAD complex which activates the genes expression in charge of cell proliferation triggering organ growth. Overexpression of YAP/TAZ/TEAD protein in several cancers disrupts the Hippo pathway balance and urges on YAP-TEAD complex formation causing excessive proliferation and cancer development. Inhibiting this protein-protein interaction is thus a promising therapeutic target for the design of new anti-cancer drugs. In this goal, the laboratory has considered two strategies. The first one consists in targeting the YAP protein by synthesizing dipyrrins, representing Verteporfin fragments to define the minimal requirement yielding the expected biological activity. A second approach involves synthesizing TEAD ligands able to fit in specific interface 3. Based on molecular modeling, a triazole scaffold family was optimized to establish structure-activity relationship. Thanks to the biological and binding tests development, synthesized molecules evaluation is still in progress and the present first results have already allowed identifying a promising compound
Narbonnet, Stéphane. "Mécanismes de rétrocontrôle de l'activité de l'oncoprotéine LMP1 du virus d'Epstein-Barr." Toulouse 3, 2006. http://www.theses.fr/2006TOU30088.
The Epstein-Barr virus is associated to different human lymphoid or epithelial tumour pathologies. The BNLF1 gene is considered as the main viral oncogene and encodes the LMP1 which displays numerous activities: induction of various signalling pathways (like the NF-kB pathway) but also blocking of cell division or protein synthesis. In this thesis, we have described a new property of LMP1 and shown that it very efficiently inhibits the activity of several natural complex promoters, of viral or cellular origin. We have also described a new LMP1 isoform, In89LMP1, and shown that it was able to inhibit the activity of the full length LMP1 on the NF-kB pathway. Thus, we have identified two novel retrocontrol mechanisms acting on LMP1, that could be required for long term survival of LMP1 expressing cells
Pène, Sabrina. "L’oncoprotéine Tax du HTLV-1 et la voie NF-κB : une histoire de conjugaison : nouvelle exploration du rôle des machineries de SUMOylation et d’ubiquitinylation dans l’activation de la voie NF-κB par Tax." Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015PA05T020/document.
The Human T-cell Leukemia Virus type I is the first human oncoretrovirus discovered. The regulatory Tax protein is the main responsible of the immortalization process of primary CD4+ T lymphocytes, the preferential target cells of HTLV-1 in vivo, which is associated with adult T-cell leukemia/lymphoma (ATLL), a highly aggressive malignant proliferation of CD4+ T lymphocytes. The oncogenic property of Tax is mainly due to its capacity to interact with many different cellular proteins belong to several pathways which control cell proliferation and survival. Constitutive activation of the NF-κB pathway induced by Tax plays a crucial role in this oncogenic mechanism. Our laboratory, and others, demonstrated that Tax ubiquitination, notably with K63-linked ubiquitin (Ub) chains, is required for the activation of the cytoplasmic IκB kinase (IKK) complex by directly interacting with the regulatory subunit NEMO. Moreover, in previous studies, we and others describe that Tax is also conjugated to either SUMO-1 or SUMO-2/3 molecules which facilitates its interaction with the NF-κB dimers in particular structures named Tax nuclear bodies, inducing promoter activation of target genes in the nucleus. However, many questions remain concerning the exact role of each Tax post-translational modification in the NF-κB pathway activation process. In the laboratory, we recently reconsidered the importance of Tax SUMOylation, provoking a controversy in our field. So, we decided to reexamine the role of this modification on NF-κB activation. To do this, we designed a novel strategy based on the inhibition of the endogenous SUMOylation machinery by blocking or silencing Ubc9, the unique E2-conjugating enzyme involves in this process. We found that an ubiquitinated but not SUMOylated Tax protein is still able to activate a transfected, an integrated or an endogenous NF-κB promoters, demonstrating that Tax SUMOylation is not required for Tax induced NF-κB pathway activation contrary to its ubiquitination. Another interrogation concerning the formation of the Tax/NEMO/IKKα/IKKβ complex, in which Tax ubiquitination is critical. We studied the role of TRAF5 in these mechanisms because this enzyme could be a potential Ub E3-ligase of Tax, which remains unknown. Thanks to the blockage of TRAF5, we showed that this protein interacts with Tax and that TRAF5 is necessary for Tax ubiquitination, notably with K63-linked Ub chains. However, TRAF5 is not the direct E3-ligase of Tax since we demonstrated that its ligase activity is not involved in Tax conjugation to ubiquitin. We also discovered that TRAF5 induces the formation of the Tax/ IKKα/IKKβ complex but not the association between Tax and NEMO, showing a new model for the recruitment and the activation of the IKK complex by Tax. In conclusion, our results led us to propose a new light on the impact of Tax SUMOylation and ubiquitination in the NF-κB pathway activation and to figure out the different steps of this process, which is crucial for the oncogenic mechanism induced by the HTLV-1 Tax protein
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.
Lymphocytes 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
Schrepfer, Emilie. "Détermination des fonctions du gène E4F1 dans la voie p53 : caractérisation d’un nouveau niveau de régulation impliquant l’oncoprotéine Mdm2." Thesis, Montpellier 1, 2012. http://www.theses.fr/2012MON13516.
E4F1 is a multifunctional protein that was first identified as a cellular target of the viral oncoprotein E1A during adenoviral infection. We, and others, have shown that E4F1 impinges at different level of the p53 pathway, which is frequently inactivated during tumorigenesis. During my PhD, I have highlighted and characterized a novel level of regulation implicating E4F1 and an other key regulator of the p53 pathway: the Mdm2 oncoprotein.My work have shown for the first time that Mdm2 and E4F1 directly interact in a same multiprotein complex associated with chromatin, and this recruitment occurs independently of p53. The Mdm2-E4F1 complex formation is dependant of some cellular stresses, such as oxidative stresses reponses. Our preliminary data also indicate that E4F1 and Mdm2 ubiquitylate each other without promoting their proteolysis, and influence their stability on chromatin. Our preliminary results indicate that this Mdm2-E4F1 chromatinian complex is involved in the regulation of a transcriptional program dependant of oxidative stresses. These data support the notion that Mdm2 presents unexpected functions on chromatin, independently of its very well described p53 regulation
Cizkova, Magdalena. "Pronostic and Predictive Markers in Breast Cancer - PI3K Signaling Pathway." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA11T021.
Results of the presented research projects bring information about several aspects of the PI3K signaling pathway roles in breast cancer development and treatment response. The particular projects covered the subjects connected with the signaling pathway, ranging from the HER family receptors activating the pathway, and PI3K to the downstream levels of signalisation. The prognostic and predictive effect of PI3K deregulation was the central subject of the described research. The decreased expression of PIK3R1 associated with reduced survival of our patients. A special focus was put on the PIK3CA mutations which are common in breast cancer. Whereas the PIK3CA mutations act as a good prognostic marker in patients non-treated with the HER2 inhibitors, these mutations predict a negative response to trastuzumab treatment. The described results, furthermore, draw attention to the role of several altered molecular signaling pathways in breast cancer development, especially to the Wnt signaling pathway. The lapatinib plasma levels showing the relevant increase in comparison with the already described efficient steady-state levels were also described in one of the projects. Moreover, various modifications to EGFR status assessment were compared and showed that EGFR FISH and IHC count interpretation depended significantly on method and thresholds used. All these subjects are connected by the PI3K pathway, the need to deepen current knowledge and bring new useful information applicable in future clinical practice
Poirson, Juline. "Interactome des oncoprotéines E6 et E7 des HPV : du système ubiquitine-protéasome à la voie de signalisation Hippo." Thesis, Strasbourg, 2016. http://www.theses.fr/2016STRAJ052.
The human papillomavirus (HPVs) are the archetype of DNA oncogenic viruses. High-risk mucosal HPVs (mainly HPV16) are the main causative agents of cervical cancer and are also involved in other cancers. HPV oncogenic properties are mainly due to the expression of E6 and E7 proteins. We built a resource composed of 600 cDNA encoding the human ubiquitin-proteasome system (UPS) effectors and identified novel E6 and E7 potential targets by using a method based on the complementation of the Gaussia princeps luciferase (GPCA). HPV16 E6 binds to specific LxxLL motifs present in E6AP and IRF3. We have solved the crystallographic structure of the E6/E6AP LxxLL/p53 and E6/IRF3 LxxLL complexes. Furthermore, HPV may target a novel tumour suppressor pathway, the Hippo signalling pathway with its two main mediators YAP and TAZ. We have built a cDNA library dedicated to the 265 human PDZ domains and identified news potential partners of YAP and TAZ proteins by using the GPCA. The results provide novel insights on HPV biology and their oncogenic property
Carbonneau, Mélissa. "Activation de la voie oncogénique mTOR par les formes mutées de l'isocitrate déshydrogénase 1/2 retrouvées chez les gliomes." Thèse, 2015. http://hdl.handle.net/1866/13693.