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1
Evans, Joanne R. "The investigation of internal ribosome entry in the c-myc and c-myb genes." Thesis, University of Leicester, 2003. http://hdl.handle.net/2381/29681.
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The c-myc gene contains an internal ribosome entry site (IRES) within its 5' untranslated region. The IRES was shown to have different activities between cell lines suggesting a requirement for protein trans-acting factors that are present in these cell lines in varying amounts. In addition a number of proteins have been shown to interact with the IRES by north-western and UV cross-linking analysis. Investigation of the protein factors involved in c-myc IRES translation identified PCBP1 (Poly (rC) binding protein 1), PCBP2, HnRNPK (heterogeneous nuclear ribonucleoprotein K), UNR (upstream of N-ras) and UNRIP (unr interacting protein) as having a role in c-myc IRES translation, PCBP1, PCBP2, HnRNPK and UNR were found to directly interact with the IRES RNA by UV cross-linking and electrophoretic mobility shift assays (EMSAs). Investigation of the proteins effect on c-myc IRES activity showed stimulation of IRES activity in HeLa cells by PCBP1 and PCBP2. The factor HnRNPK was found to have a slight stimulatory effect in vivo. In addition PCBP1 and PCBP2 were found to stimulate IRES activity in vitro in combination with UNR and UNRIP. Using the yeast three-hybrid system a number of additional proteins were found to interact with the c-myc IRES RNA. A novel Fibrillarin-like protein was identified and shown to strongly interact with the IRES by EMSA. Studies to determine a direct role of this factor in c-myc IRES translation were inconclusive. The study of translation of the c-myc gene identified an IRES within its 5'UTR. Investigation of the role of trans-acting factors in its translation showed a possible role of the factors PCBP2, HnRNPk and ITAF45 (IRES trans-acting factor 45).
2
Beaudoin, Nicolas. "L’inhibition de c-MYC : l’approche MAX*." Mémoire, Université de Sherbrooke, 2015. http://hdl.handle.net/11143/6739.
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c-MYC est un facteur de transcription oncogénique dont l’expression est dérégulée dans 78% des gliomes. On observe d’ailleurs une corrélation positive entre sa surexpression et le grade des gliomes. De plus, cette surexpression serait essentielle à la survie des cellules souches tumorales, cellules qui seraient davantage résistantes à la chimiothérapie et à la radiothérapie en plus d’avoir un caractère plus invasif. Il a aussi été démontré que l’inhibition de c-MYC par ARN interférents peut sensibiliser les cellules cancéreuses à l’apoptose et réduire leur prolifération. Sa surexpression relative dans les glioblastomes (GBM) est signe de la malignité et l’espérance de vie des patients atteints par ces tumeurs est réduite chez les patients plus âgés. c-MYC doit s’hétérodimériser avec MAX, son partenaire obligatoire afin de se lier aux promoteurs de ses gènes cibles contenant des EBox (CANNTG) et ainsi activer leur transcription. Cependant, il a été proposé que MAX pourrait homodimériser et agir comme antagoniste en compétitionnant pour les mêmes sites de reconnaissance que l’hétérodimère c-MYC/MAX sur l’ADN. Notre étude vise donc à évaluer l’effet dose-dépendant d’un traitement exogène de MAX*WT, correspondant à une version tronquée du facteur de transcription MAX, sur différentes lignées cellulaires de GBM.
Nous avons d’abord étudié les capacités de la protéine à transloquer dans les cellules par microscopie. Ceci a permis de déterminer que le peptide s’internalise rapidement (15 minutes) pour ensuite s’accumuler au niveau nucléaire (24 h, 48 h). Par la suite, des analyses de FACScan ont démonté qu’un traitement de 72 heures provoque une inhibition de la prolifération cellulaire. À l’aide de chambres de Boyden et d’essais de croissance en sphéroïdes dans une matrice de Matrigel(indice supérieur TM]), nous avons observé une diminution importante du caractère invasif des lignées de gliomes malins suite au traitement avec MAX*WT. Ces résultats démontrent que la protéine MAX*WT semble avoir un effet antinéoplasique sur plusieurs lignées de gliomes malins et que la voie de signalisation de c-MYC pourrait constituer une cible thérapeutique intéressante.
3
Hotti, Anneli. "Caspases in c-Myc-induced apoptosis." Helsinki : University of Helsinki, 2000. http://ethesis.helsinki.fi/julkaisut/laa/haart/vk/hotti/.
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Vervoorts, Jörg. "Molekulare Mechanismen der c-Myc-Transaktivierung Identifikation von hASH2, Nucleolin und CBP als neue c-Myc-Koaktivatoren /." [S.l. : s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=97123163X.
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Le, Quesne John P. C. "The c-myc IRES : structure and mechanism." Thesis, University of Leicester, 2000. http://hdl.handle.net/2381/29652.
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The proto-oncogene c-myc is central to the process whereby the cell commits itself to quiescence, differentiation, proliferation of apoptosis, and the expression of Myc protein is controlled at several levels, including translation. The 5' UTR of c-myc has been shown to contain an internal ribosome entry segment (IRES), allowing translation to proceed via an internally initiated mechanism. To determine the secondary structure of the IRES, structural data were obtained by chemical probing of 5' UTR RNA in vitro. These data were used as constraints upon the "mFold" RNA secondary structure prediction algorithm, and the model was refined by phylogenetic analysis. The resulting model contains a number of interesting features. There is no detectable structural homology with viral IRESs. Mutations were introduced to determine the importance of various IRES moieties. Surprisingly, the IRES seemed resistant to relatively gross structural changes, and a number of mutations were seen to significantly activate IRES function, suggesting that the IRES is in a state of constitutive repression. The point at which the ribosome enters and begins scanning was investigated, revealing that entry occurs in an unstructured region of the IRES, upstream of an inhibitory pseudoknot element that must be disrupted before ribosome entry can occur. It has previously been noted that the c-myc IRES fails to function in RRL in vitro translation assays. In order to obtain an in vitro assay to aid isolation of specific trans-acting factors, several cellular extracts were tested for their ability to stimulate IRES activity in vitro. Nevertheless, the IRES was not activated in vitro. From these data, a picture of the c-myc IRES that is distinctly different from the viral paradigms has emerged, and a model of the IRES mechanism is presented and discussed.
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Cannell, Ian G. "Regulation of c-Myc by miR-34c." Thesis, University of Nottingham, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.523121.
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Straaten, J. P. van. "Studies on the human c-myc gene product." Thesis, University of Cambridge, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.377708.
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Fleser, Angelica. "Resténose et expression des proto-oncogènes, c-myc, c-fos et c-jun." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp03/NQ35590.pdf.
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GIOVANNINI, VALENTINA, and VALENTINA GIOVANNINI. "NUOVE STRATEGIE ANTITUMORALI: PEPTIDI RETROINVERSI CHE MIMANO DOMINI FUNZIONALI SPECIFICI DI REGIONI DI C-MYC, COME INIBITORI COMPETITIVI DELLA PROTEINA C-MYC NATIVA." Doctoral thesis, La Sapienza, 2005. http://hdl.handle.net/11573/916799.
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Marhin, Wilson. "Characterization of c-myc as a transcriptional repressor." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/nq41469.pdf.
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Heath, Victoria J. "Inhibition of adipogenesis by the c-myc oncoprotein." Thesis, University of Glasgow, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360306.
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Robinson, Helen. "Interaction between the proteins c-MYC and MLH1." Thesis, University of Glasgow, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.402010.
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Beer, Abigail J. "Development of an Inducible c-MYC Murine Model." The Ohio State University, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=osu1602754882137456.
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Dalgleish, Gillian Denise. "Localisation signals within the c-myc and c-fos 3'untranslated regions." Thesis, University of Aberdeen, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.481826.
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Marfil, Vives Vanessa. "Characterization of novel Hhex partners: SOX13 and c-Myc. New mechanism for the regulation of Wnt/TCF and c-Myc pathways." Doctoral thesis, Universitat Pompeu Fabra, 2010. http://hdl.handle.net/10803/22701.
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Hhex transcription factor is expressed in multiple endoderm-derived tissues, like the liver, where it is essential for proper development. The pleiotropic effect of Hhex in the embryo and its dual role as a transcriptional repressor/activator suggest the presence of different interaction partners capable of modulating its activity and function. In the current study we identified two new Hhex protein interactors: SOX13 and c-Myc.
We show that Hhex interacts directly with SOX13. By doing so, Hhex sequesters SOX13 from the SOX13•TCF1 complex, overturning SOX13-dependent repression of the Wnt pathway. On the other hand, Hhex induces proliferation of non-tumorigenic human fibroblast through a Myc-dependent mechanism. Hhex and c-Myc interact directly upregulating Cyclin D1, a c-Myc target gene involved in cell cycle progression and proliferation. Elevation of Cyclin D1 might be the final effector of Hhex capacity to regulate cell proliferation.
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Gonzalez, Veronica. "Defining the Role of Nucleolin on the Transcriptional Regulation of c-MYC through Modulation of the c-MYC NHE III1 Element." Diss., The University of Arizona, 2010. http://hdl.handle.net/10150/195898.
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The activated product of the c-MYC proto-oncogene is one of the strongest known activators of carcinogenesis. It has been estimated that as many as one-seventh of all cancer deaths are associated with alterations in the c-MYC gene or its expression [1]. Therefore, understanding the regulation of c-MYC expression is a key factor in understanding carcinogenesis in many histologic classes of malignancy. The nuclease hypersensitive element (NHE) III₁ region of the c-MYC promoter has been shown to be particularly important in regulating c-MYC expression. Specifically, the formation of a G-quadruplex structure appears to promote repression of c-MYC transcription. In this dissertation, we investigate the role that nucleolin, a critical player in ribosome biogenesis and cell stress sensing, plays on the transcriptional regulation of the c-MYC promoter through its interaction with the c-MYC G-quadruplex structure. Our studies initiated with the design of a c-MYC G-quadruplex affinity column intended to trap potential c-MYC G-quadruplex-binding proteins that were then identified by LC-MS/MS. After careful examination of the literature of the list of potential c-MYC G-quadruplexbinding proteins, we realized that several of the proteins identified had been previously reported to interact directly with nucleolin. Consequently, we chose to focus our studies on nucleolin, as it could be a central regulator of the (NHE) III region. By performing chromatin immunoprecipitation in HeLa cells, we found that nucleolin indeed interacts with the c-MYC promoter region containing the NHE III₁ element. This binding activity was confirmed by both electromobility shift assay and polymerase stop assay. We provide evidence that nucleolin can induce the formation of the c-MYC G-quadruplex structure from single-stranded DNA, both in linear and circular DNA forms. We show that upon binding, nucleolin increases the stability of the c-MYC G-quadruplex structure leading to repression of c-MYC promoter activity. We also show that nucleolin binds with much higher affinity to G-quadruplex structures with topology similar to that of the parallel c-MYC G-quadruplex, such as those found in the VEGF and PDGF-A promoters; in comparison to G-quadruplexes found in telomeres or the c-MYB promoter, whose have significantly different topology. Interestingly, we also demonstrate that nucleolin binds with higher affinity to the c-MYC G-quadruplex than to its consensus RNA substrate, the nucleolin recognition element (NRE). Furthermore, we show that the C-terminal domain of nucleolin is critical for its interaction and stabilization of the c-MYC G-quadruplex structure. Lastly, we show that the binding of nucleolin to the (NHE) III region causes repression of c-MYC transcription. On the basis of these results, we propose that nucleolin may play an important role in the transcriptional regulation of c-MYC in vivo by inducing the formation of the c-MYC G-quadruplex structure.
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Liu, Qingyuan. "Epigenetic Regulation of hTERT in Human Acute Promyelocytic Leukemia Cell Line NB4 and Role of c-Myc." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T103.
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La régulation de la télomérase s’effectue à de nombreux niveaux dont la transcription de la sous-Unité catalytique (hTERT). Les travaux du laboratoire effectués sur les cellules NB4, modèle de Leucémie Aiguë Promyélocytaire (LAP), ont montré que l'acide rétinoïque tout-Trans (ATRA) réprime la transcription de hTERT. Cette répression peut être associée à la différenciation (cas des cellules NB4) ou en être dissociée conduisant à la mort des cellules (cas des cellules NB4-LR1 résistantes à la maturation induite par l’ATRA). A partir de la lignée NB4-LR1 a été sélectionnée la lignée NB4-LR1SFD résistante à cette mort cellulaire du fait de la ré-Expression de hTERT même en présence d’ATRA. Cependant cette résistance à la répression de hTERT peut être levée par le co-Traitement ATRA et trioxide d’Arsenic (As2O3) qui conduit à la mort des cellules. Il s'agit donc d'une propriété nouvelle de cette lignée dont le mécanisme reste à élucider.Les résultats obtenus par le laboratoire suggèrent l'importance du statut de méthylation de l’ADN du promoteur de hTERT jusque là peu explorée qui pourrait rendre compte de la résistance à la répression de hTERT. Mon projet a pour objectif de valider cette hypothèse en tirant profit de la diversité des réponses biologiques (différenciation, prolifération, mort cellulaire et expression de hTERT) des variants cellulaires du modèle NB4. Une coopération entre le statut épigénétique (méthylation de l’ADN et modification des histones) du promoteur de hTERT et la fixation de facteurs activateurs et/ou répresseurs sera étudiée. Le statut de méthylation du promoteur de hTERT sur une région allant de -2500pb à +1000pb par rapport au site d’initiation de la transcription a été étudié par la technique de séquençage (Illumina) après traitement des cellules NB4-LR1SFD par l’ATRA seul ou en combinaison avec As2O3. Le résultat obtenu à ce jour montre une hypométhylation d’une région limitée du domaine distal (de -1300pb à -800pb) du promoteur de hTERT associée à la répression de hTERT dans les cellules traitées par la combinaison ATRA+ As2O3 par rapport aux traitements seuls par ATRA ou As2O3. Ceci renforce l’importance du statut de méthylation de cette région du promoteur dans la régulation de l’expression de hTERT. Ce co-Traitement induit également une diminution de l’expression protéique de cMyc et WT1, et aussi de l’ADN methyltransférase 1 (DNMT1) suggérant un rôle de cette enzyme dans le maintien de la méthylation de cette région du promoteur de hTERT. Dans le but d’évaluer le rôle de c-Myc dans la régulation de hTERT, nous avons montré qu’un analogue de l’AMPc, le 8-CPT-CAMP, induisait une dégradation (en partie protéasome dépendant) de la protéine c-Myc dès 6h de traitement dans la lignée résistante NB4-LR1SFD et non la lignée parentale NB4. La lignée NB4-LR1SFD est caractérisée par un déficit en sous unité régulatrice PKA RII. Spécifique knock-Down de PKA RII et l’utilisation d’agonistes et d’antagonistes spécifiques de PKAI a montré : 1) PKAI et PKAII ont des rôles différents sur la stabilité de la protéine c-Myc; 2) le rapport PKAI/PKAII déterminait la stabilité de c-Myc suite à l’activation de la signalisation PKA. Ces résultats suggèrent un rôle possible de PKA comme régulatrice de expression de hTERT via son implication dans le maintien de la stabilité de la protéine c-MycThe regulation of telomerase occurs at various levels, including the transcriptional regulation of hTERT. Previous results in our laboratory from acute promyolocytic leukemia cell model NB4, have shown that all-Trans retinoid acid (ATRA) repress the transcription of hTERT. This repression can be associated with differentiation (in the case of NB4 cells), or be dissociated with differentiation and triggers cellular death (the case of maturation resistant NB4-LR1 cells). Another variant NB4-LR1SFD cells were isolated from NB4-LR1 cells with continuous presence of ATRA and were resistant to the cellular death induced by ATRA. In fact, this resistance is related to the re-Expression of hTERT in presence of ATRA. However, this resistance can be overcome by combination of ATRA and AS2O3 and triggers cellular death.The results obtained in our laboratory suggested the importance of the DNA methylation status in the promoter region of hTERT and could be the one mechanism of the resistance to the repression of hTERT induced by ATRA. My project is by taking the diversity of biological response of the NB4 cells variants to validate the hypothesis. And the cooperation between epigenetic modifications and the binding of transcriptional factors will be equally studied.The DNA methylation status in the promoter region of hTERT from -2500bp to +1000bp has been analyzed with the sequencing technique (illumina) in NB4-LR1SFD treated by ATRA alone or in combination with AS2O3. The results showed a distal hypomethylated region from -1300bp to -800bp associated with the repression of hTERT by the co-Treatment of ATRA and AS2O3 compared with the treatment by ATRA or AS2O3 alone. This result strengthens the importance of methylation status in this region in the regulation of hTERT. The co-Treatment induces also a diminution in protein expression of cMyc, WT1 and DNA methyltransferase 1 (DNMT 1), suggesting this enzyme may play a role in the maintenance of methylation level in this region.In order to evaluate the role of cMyc in the regulation of hTERT, we have shown that an analog de cAMP, 8-CPT-CAMP, induces degradation (partly proteasome-Dependent) of c-Myc protein since 6h in NB4-LR1SFD cells but not in NB4 cells. NB4-LR1SFD cells are characterized by a defect of the PKA regulatory subunit II. Specific knockdown of PKA RII and utilizations of agonists and antagonists of PKA I have shown that: 1) PKA I and PKA II have distinct functional roles on the steady-State of c-Myc protein. 2) The ratio of PKA I/PKA II determines the stability of c-Myc protein with the activation of PKA signalization. These results suggest a possible role of PKA in the regulation of hTERT expression through its modulation on the stability of c-Myc
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Ferrari, Ana Luiza. "Expressão dos protooncogenes c-fos, c-myc e c-jun em miométrio e mioma humanos." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2006. http://hdl.handle.net/10183/6629.
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Beaulieu, Marie-Ève. "Biologie structurale de c-Myc et Max évidences pour un nouveau mécanisme de transrépression par Myc." Thèse, Université de Sherbrooke, 2011. http://hdl.handle.net/11143/5809.
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The transcription factor c-Myc plays a central role in cell growth and proliferation owing to the large number of genes it transactivates or transrepresses and to the fact that these genes are in turn implicated in these cellular processes. Also, c-Myc's deregulation and/or overexpression contribute to most aspects of tumoral cellular biology. As a heterodimer with Max, c-Myc activates the transcription of genes leading to cell proliferation and represses the transcription of cytostatic genes such as p15[superscript ink4b] and p21[superscript CiP1]. In contrast to the transactivation mechanism, our current understanding of the transrépression by c-Myc is still incomplete, aside from the fact that an interaction with Miz-1 is essential. Coupling preliminary results from a collaboration with Martin Eilers' group to data obtained following a bioinformatics' approach to predict Miz-1 DNA binding, we were able to elaborate a now transrepression mechanism for c-Myc/Miz-1. In this mechanism, the c-Myc/Max heterodimer directly binds the noncanonical E-box sequences present in the promoters and provoke the supercoiling of DNA assisted by the interaction between c-Myc and Miz-1. This supercoiling impairs accessibility to the initiation site to the transcriptional machinery. This thesis aims at the study on a structural and biophysics viewpoint of the determinants for the specific heterodimerization and DNA binding by c-Myc and Max and the interaction between c-Myc and Miz-1 in order to validate our mechanistic model for the transrépression by c-Myc. In chapter 1, we present an overview of the actual knowledge on Myc and the repression model along with some of the results that led to its elaboration. Chapters 2 and 3 report the study of the structural determinants for the heterodimerization and E-box binding by the b-HLH-LZ domains of c-Myc and Max. Our model allows to predict that b-HLH-LZ peptides able to bind the E-box present in the repressed promoters without interaction with Miz-1 could reverse the inaccessibility and reactivate p15[superscript ink4b] and p21[superscript Cip1] expression in cancer cells where c-Myc is overexpressed.The results presented in this thesis will find application in the development of new inhibitors of c-Myc eventually leading to novel therapies to fight cancer.
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Pulverer, Bernd J. "Regulation of nuclear protooncogens c-Jun and c-Myc by protein serine-kinases." Thesis, Open University, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.315301.
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Lux, Christoph. "Untersuchungen zur transkriptionellen Regulation des Proto-Onkogens c-myc." Diss., lmu, 2005. http://nbn-resolving.de/urn:nbn:de:bvb:19-44401.
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Zhang, Yandong. "Pim kinases phosphorylate p21 CiP1/WAF1 and c-Myc." Online access for everyone, 2007. http://www.dissertations.wsu.edu/Dissertations/Summer2007/y_zhang_062907.pdf.
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Royla, Nadine [Verfasser]. "Analysis of metabolic feedbacks regulating c-MYC / Nadine Royla." Berlin : Freie Universität Berlin, 2018. http://d-nb.info/1170814441/34.
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Riley, Timothy E. W. "Post-transcriptional regulation of the c-myc proto-oncogene." Thesis, University of Cambridge, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.257194.
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Ferre, François. "Pouvoir transformant et régulation de l'oncogène humain c-myc." Lille 1, 1986. http://www.theses.fr/1986LIL10081.
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Lucas, John Mark. "Regulation of the C-MYC and FGF-4 Oncogenes /." The Ohio State University, 1994. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487859879939229.
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Ferre, François. "Pouvoir transformant et régulation de l'oncogène humain c-myc." Grenoble 2 : ANRT, 1986. http://catalogue.bnf.fr/ark:/12148/cb375975871.
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Arabi, Azadeh. "Regulation of the ribosomal RNA transcription by c-MYC oncoprotein /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-947-5/.
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TEYSSIER, MAGALI. "Expression des oncogenes c-fos et c-myc et immunomodulation de la lignee monocytaire." Paris 11, 1992. http://www.theses.fr/1992PA112239.
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The p388d1 murine macrophage cell line has been chosen to study events resulting from the transduction of immunomodulatory signals. Owing to the frequent implication of the c-myc gene in the tumorigenicity of hematopoietic cells, the normal c-myc status in this cell line is demonstrated by southern analysis. The early modulation of the c-fos and c-myc proto-oncogene expression has been studied by northern analysis and the dna synthesis by #3h-thymidine incorporation after treatment of p388d1 cells by tpa, calcium ionophore a23187, mdp and csf-1. No correlation could be evidenced in this cell line between the mitogenic effect and the c-fos and c-myc modulation induced by these immunomodifiers. The impact of lps, tpa and dibutyryl-cyclic amp on mhc class ii antigen (ia) has been revealed by radio-immuno-assay. These compounds inhibited constitutive or induced by interferon-gamma ia expression. This inhibition seemed to be in relation with c-fos expression. The ia expression was therefore analysed either after c-fos translation blockage by a dna antisense either after overexpression of c-fos by transfection of p388d1 cells with a plasmid containing the c-fos gene. The first results seemed to confirm an inverse correlation between the c-fos induction and the inhibition of ia expression
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Eriksson, Jonathan. "WT1 påverkar proliferationen för cancercellinjer troligen via reglering av c-Myc." Thesis, Umeå universitet, Biomedicinsk laboratorievetenskap, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-58625.
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Sunohara, Maxwell. "Targeting the Process of c-MYC Stabilization in Chronic Myelogenous Leukemia." Thesis, Université d'Ottawa / University of Ottawa, 2017. http://hdl.handle.net/10393/35884.
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Currently there is no curative therapy for Chronic Myelogenous Leukemia (CML), and patients must remain on the current prescribed treatment, tyrosine kinase inhibitors (TKI), indefinitely. Although many patients can survive in the chronic phase of the disease under TKI treatment, some patients do progress to the terminal blast crisis phase of the disease. Patients in this terminal phase do not respond to TKI treatment. We evaluated the therapeutic benefit of targeting the oncogene c-MYC in CML, using the CML cell line K562. This was achieved by inhibiting the enzyme O-linked β-N-acetylglucosamine Transferase (OGT), using two indirect inhibitors 2-deoxyglucose and Azaserine, and the direct inhibitor ST078925. Treatment with these inhibitors resulted in decreased half-life of c-MYC protein in K562, reduced c-MYC protein in K562 cells, and reduced K562 cell growth. Together these results suggest that targeting c-MYC through OGT may be a potential therapeutic option for patients with CML.
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Lima, Caroline Rocha de Oliveira. "Classificação morfológico, critérios de malignidade, expressão gênica de C-MYC e imunoistoquímica de C-MYC, p53, p21 e p27 no tumor venéreo transmissível canino." Universidade Federal de Goiás, 2013. http://repositorio.bc.ufg.br/tede/handle/tede/3258.
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The present concept about carcinogenesis is that normal cells are transformed into tumor by mutations that activate oncogenes, inhibit tumor suppressor genes or trigger genetic instability. However, studies suggest that some neoplastic types can behave like infectious agents and be transmitted from one host to another, similar to what occurs with the canine transmissible venereal tumor (TVT). The TVT histogenesis is not fully known, because the studies are controversial and do not bring about the results elucidating cell line that characterized the neoplasm. However, research continues in order to elucidate this question and identify the ancestral genetic TVT. Recently, a cytomorphological classification was proposed for the TVT, including plasmacytoid types, linfocitoide and mixed. Nevertheless, many features of the development and behavior of this dogs transmissible neoplasm are still poorly understood. Accordingly, we evaluated the different morphological patterns of the tumor, the macroscopic aspects, the criteria of malignancy, the molecular identification of the tumor, by inserting the element LINE-1 in the C-MYC gene, the immunohistochemical expression of the C-MYC, p53, p21 and p27, and the relationship between the proteins C-MYC, p53, p21 and p27, the block of the cell cycle and apoptosis of tumor cells. The results indicate that the cytological examination allows better characterization of patterns and cytomorphologic criteria of malignancy of TVT compared to histological examination, which can identify the types plasmacytoid, linfocitoide and mixed. It was further observed that the TVT presents morphological peculiarities that may interfere with tumor behavior and response to chemotherapy, especially those related to more aggressive and have been observed in plasmacytoid TVT, cytomorphological most common type of this tumor. The identification of molecular rearrangement LINE-1/C-MYC features specific molecular changes for TVT that may be introduced as supplementary diagnostic method of cancer, especially in highly undifferentiated tumors. Immunohistochemical analysis and the relationship between C-MYC, p53, p21 and p27 revealed functional abnormalities in these proteins, interfering with biological events in cell cycle control and apoptosis, and may thus contribute to the genesis and neoplastic progression.
O conceito atual sobre carcinogênese refere que células normais se transformam em tumorais por mutações que modificam proto-oncogenes transformando-os em oncogenes, inibem genes supressores tumorais ou que disparam instabilidades genéticas. No entanto, estudos sugerem que alguns tipos neoplásicos podem se comportar como agentes infecciosos e ser transmitidos de um hospedeiro a outro, a exemplo do que ocorre com o tumor venéreo transmissível canino (TVT). A histogênese do TVT não é totalmente conhecida, pois os estudos são controversos e não trazem resultados elucidativos quanto à linhagem celular que caracterizou a neoplasia. Entretanto, as pesquisas continuam com o objetivo de elucidar essa questão e identificar o ancestral genético do TVT. Recentemente, uma classificação citomorfológica foi proposta para o TVT, incluindo os tipos plasmocitoide, linfocitoide e misto. Apesar disso, muitas características de desenvolvimento e comportamento dessa neoplasia transmissível dos cães ainda são pouco entendidas. Nesse sentido, foram avaliados os diferentes padrões morfológicos do tumor, os aspectos macroscópicos, os critérios de malignidade, a identificação molecular da neoplasia, por meio da inserção do elemento LINE-1 no gene C-MYC, a expressão imunoistoquímica das proteínas C-MYC, p53, p21 e p27, e a relação entre as proteínas C-MYC, p53, p21 e p27, o bloqueio do ciclo celular e a apoptose das células tumorais. Os resultados indicam que o exame citopatológico permite melhor caracterização dos padrões citomorfológicos e critérios de malignidade do TVT em relação ao exame histopatológico, sendo possível identificar os tipos plasmocitoide, linfocitoide e misto. Constatou-se ainda que o TVT apresenta particularidades morfológicas que podem interferir no comportamento tumoral e na resposta à quimioterapia, especialmente aquelas relacionadas à maior agressividade e que foram observadas no TVT plasmocitoide, tipo citomorfológico mais comum da neoplasia. A identificação do rearranjo molecular LINE1/C-MYC caracteriza alteração molecular específica do TVT e pode ser utilizada como método diagnóstico complementar da neoplasia, principalmente em tumores indiferenciados. A análise imunoistoquímica e a relação entre C-MYC, p53, p21 e p27 indicam anormalidades funcionais nessas proteínas, interferindo nos eventos biológicos de controle do ciclo celular e da apoptose, podendo, dessa forma, contribuir nos processos de crescimento e progressão do TVT.
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Arnaud, Nicolas. "Les lymphomes B diffus à grandes cellules de type activé : rôle de NF-κB et c-Myc." Thesis, Limoges, 2017. http://www.theses.fr/2017LIMO0105/document.
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A l’instar du lymphome de Burkitt (LB) avec la translocation de MYC, les lymphomes diffus à grandes cellules B (DLBCL) par d'autres mécanismes (mutation, amplification, dérégulation du promoteur) sont associés à une dérégulation de c-Myc, facteur de transcription maitre de la prolifération. Les DLBCL sont classés en deux sous-groupes: « centre germinatif » (GCB) et « cellule B activée » (ABC) avec activation constitutive de NF-κB. Cette activation constitutive de NF-κB peut être le résultat d'altérations génétiques (MYD88, A20, TRAF2 et TRAF5) ou de l'activation du BCR ou CD40. Ces caractéristiques soulèvent la question de la synergie d’action entre NF-κB et c-Myc dans les ABC-DLBCL. Nous avons analysé l’effet d'une activation continue de c-Myc dans un contexte de sur-activation de NF-κB par plusieurs inducteurs. Nos résultats montrent que la surexpression de c-Myc dans un contexte d'induction de NF-κB, i) par le programme EBV latence III, apporte un avantage sélectif à ces cellules (expression génique en faveur d'un métabolisme élevé, prolifération intense et protection contre apoptose), ii) par le TLR9 (modèle in vivo et in vitro), augmente la survie et la prolifération des lymphocytes B des souris λc-Myc (augmentation des cellules B activées, splénomégalie, augmentation de la prolifération des lymphocytes B, modification du microenvironnement tumoral), et iii) par CD40, induit une lymphomagenèse B très agressive dans les souris doubles transgéniques CD40/Myc, les tumeurs ont un phénotype proche des ABC-DLBCL. Ces résultats suggèrent que c-Myc est un événement co-transformant dans les lymphomes agressifs avec un phénotype activé par NF-κB, tel que les ABC-DLBCLNot only Burkitt lymphoma (BL) with the translocation of MYC, but also diffuse large B-cell lymphoma (DLBCL) by other mechanisms (mutation, amplification, promoter dysregulation…) are associated with dysregulation of c-Myc, the master transcription factor for proliferation. DLBCL’s are classified in two subgroups: “Germinal center B-cell” (GCB) without and “activated B-cell” (ABC) with constitutive NF-κB activation. This constitutive activation of NF-κB can be the result of genetic alterations (MYD88, A20, TRAF2, and TRAF5) or the activation of B-cell receptor or CD40. These features raise the question of the synergy of action between NF-κB and c-Myc in ABC-DLBCL. We analyzed the effect of a continuous activation of c-Myc in a context of over-activation of NF-κB by several inductors. Our results show that overexpression of c-Myc in the context of induction of NF-κB, i) by EBV latency III program, provides a selective advantage to those cells (gene expression in favor of a high metabolism, intense proliferation and protection against apoptosis), ii) by TLR9 (in vivo and in vitro model) increases the survival and proliferation of B lymphocytes of λc-Myc mice (increase of activated B cells, splenomegaly, increased B cells proliferation, modification of tumor microenvironment), and iii) by CD40, induces a very aggressive B lymphomagenesis in CD40/Myc double transgenic mice, the tumors have a phenotype close to ABC-DLBCL. These results suggest that c-Myc is an NF-κB co-transforming event in aggressive lymphomas with an activated phenotype by NF-κB, such as ABC-DLBCL
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Hoelzel, Michael. "Regulation von Teilungswahrscheinlichkeit und Zellzyklusdauer durch das Onkoprotein c-Myc." Diss., lmu, 2004. http://nbn-resolving.de/urn:nbn:de:bvb:19-23912.
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Helander, Sara. "Structural biology of transcriptional regulation in the c-Myc network." Doctoral thesis, Linköpings universitet, Kemi, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-106185.
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The oncogene c-‐Myc is overexpressed in many types of human cancers and regulation of c-‐Myc expression is crucial in a normal cell. The intrinsically disordered N-‐terminal transactivation domain interacts with a wide range of proteins regulating c-‐Myc activity. The highly conserved Myc box I region includes residues Thr58 and Ser62, which are involved in the phosphorylation events that control c-‐Myc degradation by ubiquitination. Aggressive cell growth, leading to tumor formation, occurs if activated c-‐ Myc is not degraded by ubiquitination. Such events may be triggered by defects in the regulated network of interactions involving Pin1 and phospho-‐dependent kinases. In this thesis, the properties of the intrinsically disordered unphosphorylated c-‐Myc1-‐88 and its interaction with Bin1 are studied by nuclear magnetic resonance (NMR) spectroscopy and surface plasmon resonance (SPR). Furthermore, the interaction of Myc1-‐88 with Pin1 is analyzed in molecular detail, both for unphosphorylated and Ser62 phosphorylated c-‐Myc1-‐88, providing a first molecular description of a disordered but specific c-‐Myc complex. A detailed analysis of the dynamics and structural properties of the transcriptional activator TAF in complex with TBP, both by NMR spectroscopy and crystallography, provides insight into transcriptional regulation and how c-‐Myc could interact with TBP. Finally, the structure of a novel N-‐terminal domain motif in FKBP25, which we name the Basic Tilted Helix Bundle (BTHB) domain, and its binding to YY1, which also binds c-‐Myc, is described. By investigating the structural and dynamic properties of c-‐Myc and c-‐Myc-‐interacting proteins, this thesis thus provides further insight to the molecular basis for c-‐Myc functionality in transcriptional regulation.
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Paulin, Fiona E. M. "A study of c-myc translational regulation in multiple myeloma." Thesis, University of Leicester, 1997. http://hdl.handle.net/2381/29701.
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In cell lines derived from patients with multiple myeloma (MM), a B-cell neoplasia, a 10-20 fold elevation in the level of c-myc protein has been observed. This was not accompanied by a concomitant increase in c-myc mRNA levels and there was no alteration in the half life of the protein suggesting that a translational mechanism could be responsible for the elevated c-myc protein levels.;Sequence analysis of c-myc exon 1, a region previously implicated in translational control, revealed no gross sequence abnormalities of the c-myc gene in the MM cell lines. However, in 4 out of 5 MM cell lines examined, a consistent CT transition at position 2756 was observed. This mutation was not seen in any control cell lines or in peripheral blood samples derived from healthy patients implying that the sequence alteration is not merely a polymorphism of this locus and may be associated with the malignant phenotype. Additionally, the MM cell line which did not possess the mutation displayed atypical antigenic expression.;Examination of proteins binding to the c-myc 5'UTR revealed a large number of proteins with this capacity. In addition, the mutant sequence displayed enhanced binding affinity to proteins, specifically polypeptides of 98 and 38 kD. Differences in RNA binding factors were also detected between the control and MM cell lines.;c-myc exon 1 was found to inhibit the translation of heterologous reporter genes in vitro. However, this region was also found to be capable of promoting the internal initiation of ribosomes in dicistronic reporter constructs. Moreover, the mutant sequence displayed an augmented capacity for internal initiation of translation.;Both the mutation and altered protein factors in the multiple myeloma cell lines thus appear to affect the translational efficiency of c-myc mRNA and their combinatorial effects may be sufficient to account for the elevated levels of c-Myc observed.
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Labrie, Mireille. "Rôle des protéines BH3 dans l'apoptose dépendante de C-MYC." Thesis, Université Laval, 2005. http://www.theses.ulaval.ca/2005/23275/23275.pdf.
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La dérégulation de l'oncogène c-myc sensibilise les cellules à la mort programmée induite par le cisplatine en agissant sur la voie mitochondriale de l'apoptose. Les membres de la famille de protéines Bcl-2 sont essentiels à la régulation de ce sentier apoptotique. Parmi ceux-ci on retrouve une sous-famille de protéines pro-apoptotiques incluant Bid, Bad, Bim, Noxa et PUMA qui ont comme caractéristique de posséder un domaine BH3 unique. Suite à divers stress cellulaires, ces protéines BH3 interagissent avec les autres membres de la famille Bcl-2 via le domaine BH3 et favorisent ainsi la sortie du cytochrome c de la mitochondrie et l'initiation de la cascade des caspases. L’influence de la dérégulation de l’oncogène c-myc sur l’expression, la phosphorylation et/ou localisation intracellulaire des protéines BH3 a donc été analysée. Ainsi, il semble que Bid et Noxa ne soient pas impliquées car ni leur expression ni leur localisation intracellulaire sont influencées par c-Myc. Par contre, c-Myc augmente légèrement l'expression de Bim et module sa localisation intracellulaire. Les résultats démontrent également que la phosphorylation de Bad est négativement régulée par c-Myc, mais que son expression et sa localisation en sont indépendantes. Finalement, l'expression de PUMA, tant au niveau de l'ARNm que de la protéine, est augmentée par c-Myc, mais cette protéine ne semble pas jouer de rôle fonctionnel dans cette apoptose. Ainsi, au moins trois protéines BH3 sont modulées par c-Myc mais aucune n’a pu être identifiée clairement comme étant impliquée dans l’apoptose dépendante de c-Myc suite à un traitement au cisplatine.
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Ryan, Kevin M. "Regulation of myeloid differentiation by c-myc and its antagonists." Thesis, University of Glasgow, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.318117.
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Kenneth, Niall S. "Mechanisms of RNA polymerase III transcriptional activation by c-Myc." Thesis, University of Glasgow, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.439250.
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Littlewood, Trevor David. "An investigation of the functions of the c-Myc oncoprotein." Thesis, Anglia Ruskin University, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.357338.
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Lapham, Abigail. "Mechanisms of transcriptional repression by the proto-oncogene c-Myc." Thesis, University of Southampton, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.420247.
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Seth, Alpna. "Functional Analysis of the c-MYC Transactivation Domain: A Dissertation." eScholarship@UMMS, 1992. https://escholarship.umassmed.edu/gsbs_diss/315.
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Many polypeptide growth factors act by binding to cell surface receptors that have intrinsic tyrosine kinase activity. Binding of these growth factors to their cognate receptors results in the initiation of mitogenic signals which then get transduced to the interior of the cell. A critical target for extracellular signals is the nucleus. A plethora of recent evidence indicates that extracellular signals can affect nuclear gene expression by modulating transcription factor activity. In this study, I have determined that the transactivation domain of c-Myc (protein product of the c-myc proto-oncogene) is a direct target of mitogen-activated signaling pathways involving protein kinases. Further, my study demonstrates that transactivation of gene expression by c-Myc is regulated as a function of the cell cycle.
c-Myc is a sequence-specific DNA binding protein that forms leucine zipper complexes and can act as a transcription factor. Although, significant progress has been made in understanding the cellular properties of c-Myc, the precise molecular mechanism of c-Myc function in oncogenesis and in normal cell growth is not known. I have focused my attention on the property of c-Myc to function as a sequence-specific transcription factor. In my studies, I have employed a fusion protein strategy, where the transactivation domain of the transcription factor c-Myc is fused to the DNA binding domain and nuclear localization signal of the yeast transcription factor GAL4. This fusion protein was expressed together with a plasmid consisting of specific GAL4 binding sites cloned upstream of a minimal E1b promoter and a reporter gene. The activity of the c-Myc transactivation domain was measured as reporter gene activity in cell extracts. This experimental approach enabled me to directly monitor the activity of the c-Myc transactivation domain.
Results listed in Chapter II demonstrate that the transactivation domain of c-Myc at Ser-62 is a target of regulation by mitogen-stimulated signaling pathways. Furthermore, I have determined that a mitogen activated protein kinase, p41mapk, can phosphorylate the c-Myc transactivation domain at Ser-62. Phosphorylation at this site results in a marked increase in transactivation of gene expression. A point mutation at the MAP kinase phosphorylation site (Ser-62) causes a decrease in transactivation.
c-Myc expression is altered in many types of cancer cells, strongly implicating c-myc as a critical gene in cell growth control. The molecular mechanisms by which c-Myc regulates cellular proliferation are not understood. For instance, it is not clear where in the cell cycle c-Myc functions and what regulates its activity. In exponentially growing cells, the expression levels of c-Myc remain unchanged as the cells progress through the cell cycle. The function of c-Myc may therefore be regulated by a mechanism involving a post-translational modification, such as phosphorylation. Results described in chapter IV demonstrate that the level of c-Myc mediated transactivation oscillates as cells progress through the cell cycle and was greatly increased during the S to G2/M transition. Furthermore, mutation of the phosphorylation site Ser-62 in the c-Myc transactivation domain diminishes this effect, suggesting a functional role for this phosphorylation site in the cell cycle-specific regulation of c-Myc activity.
Taken together, my dissertation study reveals a molecular mechanism for the regulation of nuclear gene expression in response to mitogenic stimuli.
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Penglong, Tipparat. "Molecular Basis of Erythroid Cell Proliferation and Differentiation." Thesis, Paris 11, 2015. http://www.theses.fr/2015PA11T022.
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Pour assurer la production de milliards de globules rouges, l’érythropoièse doit parfaitement contrôler les processus de prolifération et de différenciation. Ces deux processus sont régulés par l’expression de gènes spécifiques dépendant d’une coordination entre l’activité des facteurs de transcription (FT) et les fonctions épigénétiques portées par exemple par les protéines à bromodomaine. Cette étude se concentre sur les conséquences de l’association ou la dissociation du FT clef de l’érythropoièse GATA-1 avec les FT déterminant pour le cycle cellulaire, pRb et E2F. Dans la première partie de ma thèse, j’ai participé à l’étude du rôle de l’association/dissociation de GATA-1 et FOG-2 avec pRb/E2F dans le contrôle la balance prolifération/différenciation cellulaire. Nos résultats montrent que les souris exprimant une mutation de GATA-1 sur la sérine 310 (GATA-1S310A), qui a la capacité accrue à séquestrer E2F-2, présentent une anémie létale lorsqu’un mécanisme de compensation de production de E2F-2 induit par l’IGF-1 est inhibé. Puis, nous avons trouvé que les propriétés décrites pour GATA-1 sont partagées par le FT FOG-2 et montré que l’abrogation de sa fixation avec pRb induit une perturbation de l’adiposité dans des souris FOG-2pRb-. Dans la deuxième partie, l’expression de c-Myc étant régulé différentiellement par GATA-1 et E2F, j’ai testé si la drogue « JQ1 », premier inhibiteur épigenétique chimique de l’expression de c-Myc, pouvait contrôler l’érythropoièse. Pour cela, j’ai utilisé la ligné érythroleucémique UT7 qui prolifère sans se différencier en présence d’érythropoiétine (stade proérythroblaste). Les résultats montrent que le traitement par JQ1 bloque la prolifération des cellules UT7 et permet de réinitier le programme de différentiation érythroide terminale. J’ai alors recherché les mécanismes moléculaires impliqués dans cette régulation et trouvé que l’inhibition transcriptionnelle de c-Myc par JQ1 est associée à l’inhibition de l’activité transcriptionnelle de STAT5 sans modification de son état de phosphorylation. Enfin, j’ai montré que JQ1 pouvait avoir une activité comparable à celle du TGF-b mais sans implication les voies Smad. Des études in vivo montre que JQ1 augmente la viabilité cellulaire et accélère la maturation des cellules érythroides à la fois chez les souris sauvages et thalassémiques. Cette différence d’action de JQ1 sur l’érythropoièse normale et pathologique implique des modifications épigénétiques différentielles entre ces deux types cellulaires et sont à la base de nouvelles stratégies du traitement du cancer. Le rôle clef de la régulation de l’association/dissociation de GATA-1 ou FOG-2 avec pRb/E2F dans l’érythropoièse et l’adipogénèse, nous a conduit, dans une troisième partie, à déterminer in vivo, les conséquences physiologiques de la séquestration de E2F par pRb. Pour cela nous avons crée une souris transgénique exprimant de façon conditionnelle un peptide contenant la partie N terminale de GATA-1 qui se fixe à pRb (GATA-1Nter). In vitro, ce peptide séquestre E2F dans le complexe GATA-1Nter/pRb et inhibe la prolifération cellulaire de façon irréversible. In vivo, aucune souris transgéniques exprimant le peptide GATA-1Nter n’a pu être sélectionnée et une mortalité au stade embryonnaire est observée. Une expression induite de ce peptide au stade adulte ne produit que des souris chimériques avec une fréquence de recombinaison du transgène GATA-1Nter importante. L’établissement de lignées stables de souris exprimant le peptide GATA-1Nter permettra de déterminer les conséquences physiologiques de la séquestration de E2F dans le complexe GATA-1Nter/pRbTo ensure the generation of billions of erythrocytes daily, erythropoiesis must be well controlled by proliferation and differentiation processes. These two processes are regulated by expressions of specific genes, coordinated by transcription factors (TFs) and epigenetic factors, such as bromodomain proteins. This study focused on the effects of the binding and dissociation of a key erythroid TF, GATA-1, to the crucial cell cycle TFs, pRb and E2F. In the first part of this thesis, the role of GATA-1 and FOG-2 binding to pRb/E2F in a control balances between cell proliferation and differentiation was studied. Mice bearing a GATA-1 mutation (GATA-1S310A) displayed higher levels of E2F2 sequestration and suffered from fatal anemia when the compensatory pathway of E2F2 production via IGF-1 signaling was also inhibited. The properties described for GATA-1 were found to be common to FOG-2, and the abolition of FOG-2 binding to pRb led to obesity resistance in FOG-2pRb- mice. In the second part of this work, as c-Myc is regulated by GATA-1 and E2F, the first chemical epigenetic inhibitor repressing c-Myc expression to be described, JQ1, was investigated to see if it could control erythropoiesis. The UT7 erythroleukemia cell line, which proliferates without differentiating was used. This cell line stops differentiation at the proerythroblast stage, in response to erythropoietin. JQ1 treatment inhibited UT7 proliferation and restored terminal erythroid differentiation. The molecular mechanism underlying this regulation by JQ1 was shown that the inhibition of c-Myc expression was associated with the inhibition of STAT5 transcription, with no change in the phosphorylation of this protein. It was found that JQ1 had a putative TGF--like activity, which did not involve the Smad pathway. It was shown in the ex vivo studies that JQ1 increased the viability of erythroid cells and accelerated the maturation of these cells in both WT and thalassemic mice. The observed differences between leukemic and normal erythropoiesis involved differential epigenetic modifications that could be at the basis of new strategies regarding cancer treatment.The key role of the association of GATA-1 or FOG-2 had with pRb/E2F, and the dissociation of these factors, in erythropoiesis and adipogenesis, respectively, led us to investigate, in vivo, the physiological consequences of E2F sequestration by pRb. As a result, transgenic mice displaying conditional expression of a peptide containing the N-terminal part of GATA-1 that binds to pRb (GATA-1Nter) were developed. In vitro, this peptide traps E2F in a GATA-1Nter/pRb complex, resulting in the irreversible inhibition of cell proliferation. The yield of transgenic mice expressing the GATA-1Nter peptide in vivo was unsuccessful, as this expression lead to lethality at the embryonic stage. Using an alternative approach, based on the inducible expression of the peptide in adults, chimeric mice with a high frequency of recombination of the GATA-1Nter transgene were obtained for this study. The establishment of a stable mouse line expressing the GATA-1Nter peptide should make it possible to determine the pathophysiological consequences of E2F sequestration in the GATA-1Nter/pRb complex
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Veyrune, Jean-Luc. "Devenir des ARNm c-fos et c-myc dans le cytoplasme : dégradation, traduction et localisation." Montpellier 2, 1996. http://www.theses.fr/1996MON20218.
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Les messagers des proto-oncogenes c-fos et c-myc font partie des arnm eucaryotes les plus instables. Cette instabilite a ete reliee a differentes sequences localisees soit dans la partie 3' non codante comprenant une region riche en au, soit dans les parties codantes du messager. Il a ete montre que la partie 3' non codante de ces messagers confere une tres mauvaise efficacite de traduction. De plus nous savons que l'utilisation de drogues bloquant la synthese des proteines (puromycine, cycloheximide) entraine le phenomene de super induction du a une stabilisation des messagers. Ces donnees experimentales suggeraient fortement un lien entre degradation et traduction. A l'aide du systeme ire/irp inspire de la regulation traductionnelle de l'arnm de la ferritine, nous avons montre l'existence d'une relation entre degradation et traduction de l'arnm de c-fos. La degradation du messager c-fos, qu'elle soit relayee par les elements d'instabilite de la region traduite ou 3' non traduite, semble etre dependante de sa traduction. En parallele, nous avons aborde l'etude de la localisation sub-cellulaire de l'arnm de c-myc. Deux techniques ont ete utilisees aux cours de ces travaux: l'hybridation in situ et le fractionnement biochimique des polysomes en fonction de leur association a des structures subcellulaires. Cela nous a permis de mettre en evidence une region de 85 nucleotides, incluse dans la region 3' non traduite du messager c-myc, necessaire et suffisante a la localisation perinucleaire du messager et a sa presence dans les polysomes lies au cytosquelette. Des mutations ponctuelles dans cette region ont revele l'importance de l'integrite du pentamere auuua pour une localisation canonique du messager
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Cheung, Ronald Se-Yuen. "Contrasting tumorigenic growth interactions of apoptosis-deficient MYC alleles with Transforming Growth Factor-alpha /." Thesis, Connect to this title online; UW restricted, 2006. http://hdl.handle.net/1773/5000.
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Al-Sallami, Dheyaa Abdul Salam. "INTERROGATION OF CHROMOSOME 8Q24.21 REGION FOR GENES CRUCIAL FOR CARCINOGENESIS USING CRISPR-CAS9 APPROACHES." OpenSIUC, 2016. https://opensiuc.lib.siu.edu/theses/1994.
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8q24.21 is a highly amplified region in cancer and associated with many epithelial cancer such as bladder, breast, colorectal and prostate cancer. The proto-oncogene c-myc is located in this region and surrounded by many lncRNAs genes such as PCAT family, CCAT family, PRNCR1. In this study, we used CRISPR-Cas9 constructs to knock out PCAT1, PRNCR1, CASC8, CASC11 and also the sequences between PCAT1-CASC11 and CASC8-CASC11in the prostate cancer cell PC3. The transfected cells with CRISPR-Cas9 targeting CASC11 gene had less proliferation ability comparing with the transfected cells with CRISPR-Cas9 targeting PCAT1, PRNCR1 or CASC8. The role of CASC11 in cancer progression and development is obscure. In our study, The CASC11 Knockout efficiency was 90% compare to the control cell. Furthermore, the study showed the importance of CASC11 in cell proliferation by significantly decreasing in the forming colonies and the growth rate comparing to the control. Also, MMP2, MMP3 and MMP9 expression levels were detected in the transfected cell by using real time PCR and the result revealed the crucial role for CASC11 in metastasis and migration. The slug and vimentin expression levels were reduced in the transfected and the double transfected clones which indicate the possible role of CASC11 in epithelial mesenchymal transition and cell motility. Taken together, our study revealed that the lncRNA CASC11 plays important roles in prostate cancer progression and metastasis by promoting the cell proliferation and migration.
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Kuschak, Theodore I. "c-Myc dependent genomic instability of the ribonucleotide reductase R2 gene." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape2/PQDD_0020/NQ53061.pdf.
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Chana, Jagdeep. "The prognostic and therapeutic significance of C-MYC expression in melanoma." Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.314348.
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Ross, David Anthony. "Clinical significance of the p53 and c-myc proteins in melanoma." Thesis, University College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338852.
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Lombardi, Olivia. "Investigating the role of mRNA capping enzyme in C-MYC function." Thesis, University of Dundee, 2017. https://discovery.dundee.ac.uk/en/studentTheses/4816aeec-c481-4494-9a07-56e74a83c08e.
Full textAbstract:
C-MYC is a transcription factor and a potent driver of many human cancers. In addition to regulating transcription, C-MYC promotes formation of the mRNA cap which is important for transcript maturation and translation. However, the mechanistic details of C-MYC-dependent mRNA capping are not fully understood. Since anti-cancer strategies to directly target the C-MYC protein have had limited success, enzymatic co-factors or effectors of C-MYC present attractive alternatives for therapeutic intervention of C-MYC-driven cancers. mRNA capping enzyme (CE) initiates mRNA cap formation by catalysing the linkage of inverted guanosine via a triphosphate bridge to the first transcribed nucleotide. The involvement of CE in C-MYC-dependent mRNA capping and C-MYC function has not yet been explored. Therefore, I sought to determine whether C-MYC regulates CE, and whether CE is required for C-MYC function. I found that C-MYC promotes CE recruitment to RNA polymerase II (RNA pol II) transcription complexes and to regions proximal to transcription start sites on chromatin. Consistently, C-MYC increases RNA pol II-associated CE activity. Interestingly, cells driven by C-MYC are highly dependent on CE for C-MYC-induced target gene expression and cell transformation, but only when C-MYC is overexpressed; C-MYC-independent cells or cells retaining normal control of C-MYC expression are insensitive to CE inhibition. C-MYC expression is also dependent on CE. Taken together, I present a bidirectional regulatory relationship between C-MYC and CE which is potentially therapeutically relevant. Studies here strongly suggest that inhibiting CE is an attractive strategy to selectively target cancer cells which have acquired deregulated C-MYC.