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1
Appleby, Mark William. „Oncogene expression and the modulation of keratinocyte self renewal“. Thesis, University of Cambridge, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.306476.
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2
Cristofari, Camilla. „Non Canonical structures within MYC and BCL2 oncogenes: novel targets for gene expression modulation“. Doctoral thesis, Università degli studi di Padova, 2019. http://hdl.handle.net/11577/3422715.
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Cancer diseases are increasing worldwide and more than 20 million new cancer cases per year are expected by 2025. At these days the treatment of neoplastic forms took advantage of classic approaches, based on chemotherapeutics and radiotherapeutics agents. However they are characterized by numerous limitations as remarkable side effects, toxicity and selection of resistant phenotypes to such therapies. This prompted the development of so-called targeted therapies, where selective chemical entities (small molecules, monoclonal antibodies, miRNAs, siRNAs etc.) hit a single molecular target of the tumor phenotype. Despite, these therapies have proven to be efficient alternatives they also present several limitations that make them quite ineffective. In order to overcome these remarkable drawbacks, he modulation of the gene expression, that exploits the ability of nucleic acids to assume different conformations, defined as non-canonical, became extremely interesting. Among these non-canonical conformations, extremely fascinating are the tetrahelical conformations known as G-quadruplex (G4) and i-Motif (iM), that seem to be involved in the blockage of the cancer development.
G4 structures occur at DNA and RNA sequences presenting a high abundance of consecutive guanines that interact each other through Hoogstein hydrogen bonds to generate a planar structure called G-tetrads. Stacking interaction between two or more G tetrads create the overall structure. Bioinformatics studies revealed that prevalently these regions are contained along the telomeres and within the untranslated region (UTR) or within the promoter sites of several oncogenes (approximately 40%) directly implicated in the development of tumor phenotypes. The UTR domains, as the promoter regions, are double-stranded DNA sequences. Therefore the complementary strand results enriched in cytosine, that under specific environmental conditions can folds into a tetrahelical conformation, known as i-Motif. Unlike the G4s, the building block of the entire structure is a dimer of cytosine mainly stabilized by the presence of three Hoogstein hydrogen bonds. The in vivo formation of G4 and iM leads to a steric hindrance at the DNA level; this suggests an inhibition/activation effect on the elongation process of the telomere or on the gene expression process
Under the supervision of Dr. Laurence J. Hurley, the structural characterization of the cytosine rich sequence contained within the NHE(III)1 region of MYC promoter was completed. In particular, was assessing the effect of the loop composition on the stability and folding process of the already characterized iM. Since it was proved that this conformation in vivo is involved in the transcriptional activation, the possibility to target it by using a selected compound (IMC-30) was considered. Furthermore, we took into consideration the possibility to use this compound (IMC-30) as an anticancer drug by testing its ability to induce the apoptosis process in a cancer cell line in which the selected gene was overexpressed.
Besides the several evidence reported for the tetrahelical conformations assumed by the GC-rich promoter regions, more recently the efforts moved forward to the G-rich tract contained in the untranslated (UTR) domains, both the 5â- and the 3â-UTR, of the primary transcript. Since, they can act as modulators of the translation process. Based on this evidence, in this project, the guanine rich sequences contained in the 5'-UTR region, both at the DNA and RNA levels, of the BCL2 gene were considered. In particular, the structural characterization study was initially carried out on the minimal sequences (dBcl2_G and rBcl2_G), then the effect exerts by the presence of additional nucleotides on the folding process towards the G-quadruplex was taken into consideration (dBcl2_G + 3 WC, rBcl2_G + 3 WC and rBcl2_48). Additionally, the cytosine rich tract contained on the DNA complementary strand was considered and characterized. Our data have shown that the dBcl2_G and rBcl2_G are able to assume multiple G4 conformations. While, the presence of additional nucleotides strongly modulates their ability to assume the non-canonical conformation. Indeed, we proved that the presence of 3 WC pairing partially prevents the formation of G4 both in the DNA and in the RNA, while the addition of a greater number of bases (rBcl2_48) leads to the formation of a different conformation that competes with the G4 structure. Regarding the cytosine rich string, its conformational equilibria have been taken into consideration both in a mildly acidic environment and in an environment that mimics the physiological condition. Finally, we implemented our work, by screening a library of compounds on each tested sequences in order to find a ligand that selectively recognizes and stabilizes one conformation. From the acquired data it emerged the feasibility to stabilize/induce the iM using the Bisanthrene compound and its derivative Bis 1-8. For the guanine rich sequences, Sanguinarine and Chelerythrine provide the best results on each tested tracts, therefore they cannot be considered selective compounds. Similarly, also the Bisanthrene derivatives recognize and interact with each tested guanine tracts, although with different selectivity.Oggigiorno una delle “piaghe” che affligge maggiormente la popolazione mondiale è il cancro. Il trattamento di queste forme neoplastiche sfrutta agenti chemioterapici e radioterapici, caratterizzati da numerose limitazioni legate ai notevoli effetti collaterali, alla tossicità e alla selezione di fenotipi resistenti a tali terapie. Ciò ha portato allo sviluppo delle targeted therapy, che sfruttano entità chimiche (small molecules, anticorpi monoclonali, miRNA, siRNA ecc.) selettive per un bersaglio molecolare caratteristico del fenotipo tumorale. Nonostante più mirati anche questi approcci presentano degli effetti collaterali Pertanto la modulazione dell’espressione genica che sfrutta la capacità degli acidi nucleici di assumere differenti conformazioni, definite non canoniche, ha destato sempre più interesse. Tra le possibili strutture non canoniche di notevole interesse sono le conformazioni tetraelicoidali note come G-quadruplex (G4) e i-Motif (iM). La struttura G4 è propria di sequenze di DNA e RNA contenenti un’elevata abbondanza di guanine consecutive che, mediante legami a idrogeno di tipo Hoogstein, generano delle strutture planari chiamate tetradi. Dall’’impilamento di due o più tetradi si genera la struttura a tetraelica. Poiché il DNA è una doppia elica, il filamento complementare a queste regioni G ricche presenta un’elevata abbondanza di citosine. Anche questi domini in particolari condizioni ambientali, possono generare una conformazione tetraelicoidale, nota come i-Motif. A differenza del G4, il building block dell’intera struttura è un dimero di citosine stabilizzato dalla presenza di tre legami a idrogeno. In vivo l’esistenza di queste conformazioni, genera una sorta d’ingombro sterico a livello del DNA e ciò presuppone un effetto d’inibizione/attivazione del processo di elongazione del telomero o del processo trascrizionale. Sotto la supervisione del Dott. Laurence J. Hurley, è stata implementata la caratterizzazione strutturale della stringa di citosine contenute nel promotore del gene MYC. In seguito un selezionato ligando è stato testato con l’idea di poter modulare il processo di folding/unfolding alla base dell’attivazione trascrizionale. Infine, l’effetto mediato da questo composto sul processo apoptotico è stato preso in considerazione lavorando su una selezionata linea cellulare. Di notevole interesse sono le regioni GC-ricche contenute nella porzione non tradotta del trascritto primario (mRNA). Sulla base di ciò, in questo progetto, sono state prese in considerazioni, le stringhe di guanina e citosina contenute nella regione del 5’-UTR, sia a livello del DNA sia del RNA, del gene BCL2. Inizialmente è stato condotto uno studio di caratterizzazione sulle sequenze minimali dBcl2_G, dBcl2_C e rBcl2_G. In seguito è stato preso in considerazione l’effetto della presenza di nucleotidi adiacenti sul processo di folding verso il G-quadruplex (dBcl2_G + 3WC, rBcl2_G + 3WC e rBcl2_48). I dati ottenuti dimostrano che le sequenze dBcl2_G e rBcl2_G sono in grado di assumere molteplici conformazioni G4. La presenza di nucleotidi addizionali modula la loro capacità di assumere queste conformazioni. In particolare, la presenza di tre appaiamenti WC impedisce parzialmente la formazione del G4 sia nel DNA, che nel RNA mentre, l’aggiunta di un maggior numero di basi (rBcl2_48) sposta l’equilibrio conformazionale verso una conformazione in forte competizione con il G4. Per la sequenza ricca di citosine, l’equilibrio conformazionale è stato valutato sia in ambiente blandamente acido, che in un ambiente che mima la condizione fisiologica. Infine, poiché negli ultimi anni è stata dimostrata la capacità di alcuni ligandi sintetici/naturali, di spostare gli equilibri conformazionali del DNA, dalla classica forma a doppio filamento, verso queste conformazioni tetraelicoidali, una selezionata libreria di composti è stata, scrinata allo scopo di individuare un ligando in grado di riconoscere e stabilizzare selettivamente una conformazione al pari di un'altra.
3
Froux, Aurane. „G-quadruplex binding by transition metal complexes : the whole pathway from design to synthesis, to in cellulo anticancer investigations“. Electronic Thesis or Diss., Université de Lorraine, 2024. https://docnum.univ-lorraine.fr/ulprive/DDOC_T_2024_0206_FROUX.pdf.
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Les cancers du sein triple négatifs et du pancréas sont associés à de faible taux de survie, dû à leur forte résistance aux traitements conventionnels, constituant un réel problème de santé publique et rendant le développement de nouvelles thérapies ciblées crucial. Au niveau des séquences télomériques et des promoteurs d'oncogènes comme cMYC, cKIT et BCL2, les séquences riches en guanines peuvent former des structures secondaires non conventionnelles, appelées G-quadruplexes. Ces structures jouent un rôle important dans la régulation de l'expression génique, constituant ainsi de prometteuses cibles thérapeutiques pour la lutte contre le cancer.Ici, nous avons choisi une approche pluridisciplinaire, alliant synthèse chimique, chimie théorique, et biologie cellulaire et moléculaire, afin d'identifier de nouveaux composés stabilisant ces structures, dans le but de contrôler la prolifération des cellules cancéreuses. Notre laboratoire a précédemment montré l'intérêt des complexes métalliques symétriques et planaires dans la stabilisation spécifique des G-quadruplexes. Ainsi, nous avons synthétisé 12 nouveaux complexes à base des métaux de transition Zn2+, Ni2+, Cu2+, Pd2+ et Pt2+. Leur capacité à sélectivement stabiliser les G-quadruplexes, en comparaison avec l'ADN double brin, a été démontré et des simulations de dynamique moléculaire révèlent un mode d'interaction peu conventionnel, impliquant la boucle du G-quadruplex.Nos composés induisent la formation de G-quadruplexes au sein des lignées cellulaires cancéreuses, entrainant une régulation à la baisse de nombreux oncogènes comme kRAS, RET et cMYC. Cette répression entraine une réduction de la prolifération et la viabilité des cellules cancéreuses, mais n'affecte que peu les cellules saines.Alors que certains composés induisent la mort des cellules cancéreuses par apoptose sans affecter les cellules saines, et inhibent drastiquement l'expression des oncogènes hRAS et cMYC, d'autres complexes causent des dommages à l'ADN dans les cellules néoplasiques pancréatiques T3M4. Aussi, les composés de Zn2+ favorisent l'expression de VEGF-A, en stimulant sa transcription. L'étude de l'impact d'une stabilisation des G-quadruplexes sur la polarisation des macrophages a montré que les composés de nickel promeuvent la polarisation des macrophages naïfs vers un phénotype anticancéreux M1, tout en inhibant l'acquisition de marqueurs pro-tumoraux de type M2.L'ensemble de nos résultats démontre le fort potentiel de nos complexes métalliques en tant que stabilisateurs de G-quadruplexes, présentant de prometteuses propriétés anticancéreuses, notamment en modulant le microenvironnement tumoral. Ces résultats ouvrent la possibilité à de nombreuses perspectives d'investigation, suggérant de nouvelles pistes thérapeutiques en cancérologieTriple-negative breast cancer and pancreatic adenocarcinoma are associated to very low survival-rates due to their high resistance to conventional treatments, posing significant public healthiness issue. The development of new targeted therapeutic options is then crucial. G-rich sequences in nucleic acids can form non-conventional secondary structures, known as G-quadruplexes, identified in telomeric sequences and in the promoters of potent oncogenes, such as cMYC, cKIT, and BCL2. These structures play a critical role in regulating gene expression, making them as promising therapeutic targets in cancer treatment.In this study, we employed a transdisciplinary approach, integrating chemical synthesis, molecular dynamic simulations, and cellular and molecular biology, to identify novel G-quadruplex binders and stabilizers aimed at controlling cancer progression. Previous work in our laboratory demonstrated that symmetric planar metal complexes could specifically bind these structures. In that sense, we synthesized 12 new transition metal complexes of Zn2+, Ni2+, Cu2+, Pd2+ and Pt2+, from the Salphen scaffold. Their ability to selectively bind and stabilize G-quadruplexes over double-stranded DNA were confirmed. Molecular dynamic simulations revealed an unconventional binding mode involving interaction with the G-quadruplex loop.Immunofluorescence assays confirmed that the compounds enhance G-quadruplex formation, in cancer cell lines, leading to the early downregulation of several G-quadruplex-driven oncogenes, such as kRAS, RET, and cMYC. This downregulation reduced cancer cell proliferation and viability, with less effect on non-cancerous cells.Some complexes induced apoptosis in cancer cells without affecting the non-neoplastic cells, after decreased hRAS and cMYC transcript levels, while other compounds caused DNA damage in pancreatic cancer cells T3M4. Notably, Zn2+ compounds increased VEGF-A expression, enhancing its transcription. We also investigated the effects of G-quadruplex stabilization on macrophages polarization, showing that nickel compounds promoted the polarization of M0 macrophages towards the anticancer M1 phenotype, while inhibiting the acquisition of pro-tumoral M2 markers.Overall, our novel metal complexes demonstrate significant potential in stabilizing G-quadruplex and exhibit promising anticancer properties, including modulation of the tumor microenvironment. These preliminary results suggest avenues for further research, with potential implications for advancing strategies in cancer therapy
4
Rost, Nathalie. „Expression et régulation du gène de la proenképhaline dans un modèle expérimental de tumeur cérébrale chez le rat“. Grenoble 1, 1991. http://www.theses.fr/1991GRE10048.
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L'expression du gène précurseur de la met-enképhaline (PPE) a été analysée dans un modèle expérimental de tumeur cérébrale chez le rat, provoquée par l'injection stéréotaxique de cellules gliales malignes C6 dans le striatum. Une étude par hybridation in situ a montré une expression élevée de ce gène dans la tumeur, en l'absence in vitro, pour la lignée C6, par Yoshikawa et al. (1986). L'expression élevée du gène PPE, dans les cellules C6, ne résulterait pas d'une amplification de l'ADN, ni de l'absence d'un rétrocontrôle enképhalinergique. Le fait de trouver une expression de gènes codant pour des neuromodulateurs dans les cellules gliales normales, et malignes dans le cas présent, remet en question le concept de leur rôle exclusif de neurotransmetteur et suggère l'implication éventuelle de ce type de gènes dans la carcinogenèse. Nous avons aussi montré que, suite à une déafférentation dopaminergique, l'expression du gène PPE diminue dans la tumeur. La destruction des afférences dopaminergiques entraîne une série de changements, au niveau de plusieurs peptides striataux, variable suivant l'étendue de la lésion. La nature du/des composés responsables de la modulation de l'expression du gène PPE reste à définir. D’autre part, l'analyse de certains oncogènes, dans le modèle tumoral, a révélé l'expression des oncogènes nucléaires FOS et JUN au sein de la tumeur. Une éventuelle corrélation, entre l'expression de ces gènes codant pour des facteurs régulateurs de la transcription et l'expression du gène PPE pourrait permettre une approche originale du processus tumoral.
5
Ellis, D. K. „Cellular oncogene expression during retinal transdifferentiation“. Thesis, University of Nottingham, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.371121.
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6
Chan, Yuk Fai. „Manipulation of EWS oncogene expression using RNAi /“. View abstract or full-text, 2005. http://library.ust.hk/cgi/db/thesis.pl?BIOL%202005%20CHAN.
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7
Radhakrishnan, Vijayababu, Charles Putnam, Wenqing Qi und Jesse Martinez. „P53 suppresses expression of the 14-3-3gamma oncogene“. BioMed Central, 2011. http://hdl.handle.net/10150/610345.
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BACKGROUND:14-3-3 proteins are a family of highly conserved proteins that are involved in a wide range of cellular processes. Recent evidence indicates that some of these proteins have oncogenic activity and that they may promote tumorigenesis. We previously showed that one of the 14-3-3 family members, 14-3-3gamma, is over expressed in human lung cancers and that it can induce transformation of rodent cells in vitro.METHODS:qRTPCR and Western blot analysis were performed to examine 14-3-3gamma expression in non-small cell lung cancers (NSCLC). Gene copy number was analyzed by qPCR. P53 mutations were detected by direct sequencing and also by western blot. CHIP and yeast one hybrid assays were used to detect p53 binding to 14-3-3gamma promoter.RESULTS:Quantitative rtPCR results showed that the expression level of 14-3-3gamma was elevated in the majority of NSCLC that we examined which was also consistent with protein expression. Further analysis of the expression pattern of 14-3-3gamma in lung tumors showed a correlation with p53 mutations suggesting that p53 might suppress 14-3-3 gamma expression. Analysis of the gamma promoter sequence revealed the presence of a p53 consensus binding motif and in vitro assays demonstrated that wild-type p53 bound to this motif when activated by ionizing radiation. Deletion of the p53 binding motif eliminated p53's ability to suppress 14-3-3gamma expression.CONCLUSION:Increased expression of 14-3-3gamma in lung cancer coincides with loss of functional p53. Hence, we propose that 14-3-3gamma's oncogenic activities cooperate with loss of p53 to promote lung tumorigenesis.
8
Watson, Dorothy M. A. „Cyclic nucleotide binding and oncogene expression in breast cancer“. Thesis, University of Edinburgh, 1989. http://hdl.handle.net/1842/19398.
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9
Amouyel, Philippe. „Expression des proto-oncogenes ets dans les astrocytes et dans les tumeurs astrocytaires“. Lille 2, 1988. http://www.theses.fr/1988LIL2M054.
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10
Ritchie, Andrew John. „Endocrinology, oncogene expression and outcome in carcinoma of the lung“. Thesis, Queen's University Belfast, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.357457.
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11
Richards, Sally. „Inhibition of oncogene expression by the formation of Triplex DNA“. Thesis, Institute of Cancer Research (University Of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.368703.
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12
Faulkner, Lee. „Expression of the c-fgr proto-oncogene in monoblastoid cells“. Thesis, University College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.309109.
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13
Marcos-Gutierrez, Camelia Victoria. „Expression, function and conservation of the c-Ret proto-oncogene“. Thesis, Open University, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.361457.
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14
Williams, Alistair Robert William. „Expression of oncogenes in human colorectal neoplasms“. Thesis, University of Edinburgh, 1988. http://hdl.handle.net/1842/19415.
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15
Chung, Maureen. „Expression of the c-fos proto-oncogene, mutant p53 anti-oncogene and statin in colorectal carcinoma and adjacent mucosa“. Thesis, McGill University, 1992. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=56961.
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The purpose of this study was to provide evidence for a field defect around colorectal carcinomas using c-fos, mutant p53 and statin markers. Tissue from ten colorectal carcinomas and mucosa at 1, 5 and 10 cm from the primary lesion was obtained from surgical specimens and frozen in liquid nitrogen. Detergent-extracted protein was separated by electrophoresis through polyacrylamide gells and western blots performed using monoclonal antibodies against c-fos, mutant p53 and statin. Expression of c-fos within the carcinoma was increased relative to its expression at 1 cm, which was increased relative to 5 or 10 cm. The reverse results were obtained for statin with the lowest expression detected in the carcinoma, intermediate expression at 1 cm, and highest values at 5 and 10 cm. Increased mutant p53 expression was detected only within the carcinoma. These results indicate that c-fos gain and statin loss may occur before p53 mutation and be initial steps in oncogenesis.
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Menzel, Garry Edward. „Regulation of proto-oncogene expression during mitogenic activation of T-cells“. Thesis, University of Cambridge, 1989. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.315120.
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17
Demoly, Pascal. „Expression du proto-oncogene c-fos dans l'epithelium bronchique de l'asthmatique“. Montpellier 1, 1992. http://www.theses.fr/1992MON11169.
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18
Shipillis, Nicholas. „Investigation of system properties related to MYCN oncogene expression in neuroblastoma“. Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/investigation-of-system-properties-related-to-mycn-oncogene-expression-in-neuroblastoma(2e3ba06b-faec-449e-85be-730213e697b9).html.
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Neuroblastoma (NB) is one the most common cancers in infancy and childhood, andpossession of amplified MYCN gene sequence (gene locus 2p24) is related toaggressive disease and poor prognosis, with a clear distinction established regardingthe survival of patients based on the gene copy-number of MYCN. However, theexpression of MYCN has been reported to vary between patients of even the sameNB subgroups and more importantly its significance in relation to NB prognosis isstill not clearly established with various reports presenting contradicting results.In this study, a bottom-up Systems Biology approach is suggested for studying boththe significance of MYCN expression, but also the distribution of control in therelated pathways that regulate this expression. An initial model was constructeddescribing the basic steps in MYCN expression and it was parameterised with valuesobtained from the literature. The results from the model simulations and analysisgenerated the hypothesis that the expression of MYCN cannot be used exclusively asa predictive factor without taking into account the relative levels of its dimerisationpartner, the protein MAX. Additionally, it was predicted that the amplification ofMYCN had a more pronounced relative effect at lower rather than at higher MYCNgene copy numbers.In order to create separate models for 4 NB cell-lines, it was necessary to performabsolute measurements for MYCN at the DNA, mRNA and protein level, as well asfor the MAX protein. The MYCN gene copy numbers were measured using theqPCR method, while a new data analysis method was suggested for performingabsolute quantification with the use of house-keeping genes, appropriate statisticalmethods and no reference samples. The relative amounts of MYCN mRNA werealso measured using qPCR and the results obtained were in agreement with thesuggested levels from the literature.The absolute measurement of the N-Myc and MAX proteins was attempted usingtwo complementary methods, western blots and ELISA. A series of optimisationexperiments and data analysis steps were taken that resulted in the refinement of theexperimental conditions to the point where they can be used for successfulquantification of the absolute levels of the N-Myc protein. Alternatively, theprocedure used for the MAX protein proved problematic and was not as successful.Overall, this study was successful in becoming the first step for an expanded bottomupsystems biology study regarding the significance of MYCN expression in NB.The combination of both the modelling and experimental parts of this workillustrated some of the potential benefits of Systems Biology approaches in studyingdisease. In this case the resulting model, once fully parameterised with experimentaldata, can be expanded in a number of suggested ways that address questions like therole and control of MYCN expression in relation to the cell-cycle deregulation ormulti-drug resistance in NB, giving in the process a better understanding regardingsuitable treatment targets for individual NB cases.
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Tuthill, Matthew Charles. „N-myc oncogene expression in neuroblastoma is dependent on Sp1 and Sp3“. Thesis, University of Hawaii at Manoa, 2003. http://hdl.handle.net/10125/987.
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Regulation of N-myc oncogene expression is an important determinant of the
biological behavior of neuroblastoma. The N-myc promoter contains several potential
binding sites for transcription factors of the Sp1 family. Mutation of a CT-box motif
contained within a 26 base pair region required for N-myc downregulation by retinoic
acid decreased basal transcriptional activity and altered DNA-protein interactions of the
promoter, while mutations flanking this motif did neither. On gel shift this region
generated 3 specific DNA-protein complexes that were reliant on wild type sequence of
the core CT element within it. Both Spl and Sp3 bound to the wild type probe as distinct
complexes in specifically retarded bands, while neither protein was present on mutated
sequences. Lysates from Drosophila S2 cells expressing exogenous Sp1 and Sp3
proteins were able to reproduce the gel shift complexes seen with neuroblastoma nuclear
extract. Transient transfections of S2 cells showed that individually or together, Sp1 and
Sp3 were able to trans-activate a N-myc CT-box-containing luciferase reporter construct
in a dose-dependent manner. Conversely, transfection of CT-box oligonucleotide was
able to decrease endogenous N-myc expression in neuroblastoma cells. Together these
results suggest that the CT-box element serves a critical functional role, and in the basal
state allows for N-myc transactivation by Spl and Sp3.
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Rao, Mira A. „Regulated expression of the v-rel oncogene in vitro and in vivo“. Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape8/PQDD_0026/MQ50863.pdf.
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21
Liang, Huiling. „Genomic structure and expression of the MDM2 proto-oncogene in human cancer“. Thesis, University of Newcastle Upon Tyne, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297574.
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Akbay, Burkitkan. „Regulation of the Akt/mTORC1 Pathway by HIV Transcriptional Activator Tat in B Cells Modulation of mTORC1 Signaling Pathway by HIV-1 Production of Stable Cell Lines on the Basis of the Cultured RPMI 8866 B-Cells with Constant and Inducible Expression of the Human Immunodeficiency Virus Tat Protein HIV-1 Tat Activates Akt/mTORC1 Pathway and AICDA Expression by Downregulating Its Transcriptional Inhibitors in B Cells“. Thesis, université Paris-Saclay, 2021. http://www.theses.fr/2021UPASL026.
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Les lymphomes agressifs à cellules B sont la principale cause de décès chez les personnes infectées par le VIH-1, bien que les cellules B ne soient pas ciblées par le virus. Les mécanismes exacts du développement de ces lymphomes ne sont pas connus. Des études antérieures de notre équipe ont révélé que le HIV-1 Tat peut pénétrer les cellules B, où il peut induire la production de ROS, endommager l'ADN et augmenter les chances de translocations oncogènes spécifiques au lymphome de Burkitt. En outre, dans de nombreuses cellules immunitaires, le VIH-1 et ses protéines (par exemple Tat) peuvent réguler la voie Akt/mTORC1, un intégrateur central de nombreux signaux intra et extracellulaires, y compris l'infection virale et les dommages à l'ADN. Cependant, aucune étude n'a examiné la régulation de la voie Akt/mTORC1 par Tat dans les cellules B. J'ai testé dans cette thèse l'hypothèse selon laquelle Tat pourrait produire des effets oncogènes dans les cellules B en modulant la voie de signalisation Akt/mTORC1 et en régulant l'expression des gènes impliqués dans la lymphomagenèse. J'ai découvert que HIV-1 Tat activait la voie de signalisation Akt/mTORC1, ce qui entraîne une activation aberrante de l'AICDA (cytidine désaminase induite par l'activation) en raison de l'inhibition des répresseurs transcriptionnels c-Myb et E2F8 de l'AICDA. Ces perturbations peuvent finalement conduire à une instabilité génomique accrue et à une prolifération qui pourrait provoquer des malignités des cellules BAggressive B cell lymphomas are the main cause of death in HIV-1 infected individuals, although B cells are not targeted by the virus. The exact mechanisms of the development of these lymphomas are not known. Previous studies of our team revealed that HIV-1 Tat can penetrate B cells, where it can induce ROS production, DNA damage and increase the chances of the oncogenic translocations specific for Burkitt lymphoma. In addition in many immune cells HIV-1 and its proteins (e.g. Tat) can regulate Akt/mTORC1 pathway, a central integrator of many intra and extracellular signals including viral infection and DNA damage. However, no studies have examined the regulation of Akt/mTORC1 pathway by Tat in B cells. In this thesis I have tested the hypothesis that HIV-1 Tat might produce oncogenic effects in B cells by modulating Akt/mTORC1 signaling pathway and regulating expression of genes involved in lymphomagenesis. I found that HIV-1 Tat activated Akt/mTORC1 signaling pathway, which leads to aberrant activation of AICDA (activation induced cytidine deaminase) due to inhibition of AICDA transcriptional repressors c-Myb and E2F8. These perturbations may ultimately lead to an increased genomic instability and proliferation that might cause B cell malignancies
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El, Khyari Saïd. „Implication des oncogenes nucleaires et de surface dans les mecanismes cellulaires de chimioresistance“. Aix-Marseille 2, 1993. http://www.theses.fr/1993AIX22951.
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24
Candelière, G. Antonio (Giuseppe Antonio). „Expression of the c-fos proto-oncogene during normal and pathological bone development“. Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=28429.
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The expression of the c-fos proto-oncogene during normal and pathological bone development was studied. The regulation of c-fos expression in bone cells by calcitriol and its contribution to the etiology of fibrous dysplasia was addressed. We have shown that treatment of osteoblasts with calcitriol, the active form of vitamin D, transiently stimulated the expression of c-fos, fos-B, c-jun and jun-B in a specific and dose-dependent manner. The expression of the Fos protein correlated with the expression of the c-fos gene. Finally, calcitriol appeared to modulate c-fos transcription in osteoblasts, whereas it stimulated c-jun and jun-B expression by a post-transcriptional mechanism distinct from mRNA stabilization. The transcriptional stimulation of c-fos was explored further and we identified a novel vitamin D response element (VDRE) in the c-fos promoter. We report that a 36 bp sequence centered around position-161 upstream of the c-fos transcription start site is responsive to 1,25-(OH)$ rm sb2D sb3$ in osteoblastic cells. This sequence binds the VDR, and mutations that abrogate binding to this element also abolish transcriptional activation by 1,25-(OH)$ sb2D sb3,$ demonstrating that we have identified a functional VDRE. Structure-function analysis revealed that the c-fos VDRE has an unusual structure that does not correspond to the classical direct repeat (DR)-type elements. Supporting this observation, our results show that the VDR requires a novel dimerizing partner to bind the c-fos VDRE. Finally, we report increased expression of c-fos in bone lesions from patients with fibrous dysplasia. The elevated c-fos mRNA levels were detected only in fibrous dysplasia lesions and not in samples from patients with other bone diseases where high bone turnover and fibrous marrow tissue are present. Our results support the implication of c-fos in the etiology of fibrous dysplasia.
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Grover, Rajiv. „Oncogene expression in malignant melanoma : markers of prognosis and targets for gene therapy“. Thesis, Queen Mary, University of London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266579.
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Feller, J. Kyle. „Correlation of amplification and expression of the c-myc oncogene in Kaposi's sarcoma“. Thesis, Boston University, 2012. https://hdl.handle.net/2144/12373.
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Thesis (M.A.)--Boston University
PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you.The c-myc proto-oncogene is involved in various cellular processes including cell growth, proliferation, and apoptosis. Overexpression and deregulated expression of the gene have been previously linked to several lineage-unrelated, aggressive, poorly differentiated tumors. Oncogenic expression of c-myc has also been implicated in several vascular neoplasms as having a crucial role in angiogenesis. This gives c-myc a dual oncogenic function in that tumor growth requires both cell proliferation and angiogenesis to ensure survival and confer an effective malignancy. In vitro studies have shown that the c-Myc protein is an important regulatory molecule of spindle cell proliferation and migration in Kaposi's sarcoma (KS), an angioproliferative tumor that is commonly associated with HIV. In light of the above and recent findings demonstrating amplification of c-myc in select angiosarcomas secondary to irradiation or chronic lymphedema, our primary aim was to ascertain the same in KS. We also attempted to determine what correlation existed, if any, between the immunohistochemical (IHC) expression of the c-Myc protein and c-myc gene copy amplification using fluorescent in situ hybridization (FISH). Samples analyzed during this study included archival tissue samples of KS (N=24 ). For FISH analyses, a dual-labeled technique was employed and probes against the c-myc gene and chromosome 8 (CEP-8) were used. For IHC, the monoclonal anti-c-myc antibody, 9E10, was used and tissue from hemangiomas (N=11) and non-radiation induced angiosarcomas (N=6) served as the controls. PCR for detection of KS-associated herpesvirus (KSHV) DNA was performed on all KS cases. While FISH analyses revealed no amplification of c-myc in any of the cases of KS, IHC analyses revealed positive staining for c-Myc in 13/24 cases (54%) with stain localization throughout the cell. As such, no correlation could be found between gene amplification and protein expression. KSHV-PCR analyses revealed that 19/24 cases (79%) were positive for KSHV-DNA. Ten of 24 cases (42%) were positive for c-Myc IHC and KSHV-PCR, while one case (4%) was negative for both indicating a lack of correlation (using McNemar's test for statistical analysis) between c-Myc IHC protein levels and presence of KSHVDNA. Our findings indicate that c-myc gene amplification is not normally found in KS and cannot be correlated with the expression of the c-Myc protein. Thus, unlike other tumors we have discussed where gene amplification was a common occurrence; it seems to have little clinical significance in KS. The absence of c-myc amplification raises the question of why 54% of the samples in this study still exhibited protein expression as determined by IHC. To grasp a further understanding of what is truly going on in these cases, it would be necessary to use techniques such as RT-PCR or in situ hybridization to study c-myc at the RNA level.
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Lanaud, Philippe. „Etude de l'expression neuronale des oncogenes a expression immediate et precoce dans differents modeles d'epilepsie chez le rat“. Besançon, 1992. http://www.theses.fr/1992BESA3711.
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28
Bauters, Christophe. „Expression des oncogenes nucleaires c-myc et c-fos dans les surcharges hemodynamiques du coeur de rat adulte“. Lille 2, 1990. http://www.theses.fr/1990LIL2M006.
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29
Protopopova, Marina. „Modulation of activity of the tumour suppressor p53 by small molecules and damaged DNA /“. Stockholm, 2004. http://diss.kib.ki.se/2004/91-7349-926-9/.
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30
MARECHAL, GAEL. „Oestrogenes et expression de l'oncogene c-fos dans les cellules d'endometres de cobaye en culture primaire“. Besançon, 1991. http://www.theses.fr/1991BESA3086.
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31
Sharma, R. „Modulation of carbohydrate expression in intestinal mucosa“. Thesis, University of Southampton, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285783.
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Urcia, Roby Joseph. „The modulation of tumour suppressor MST2 and proto-oncogene Raf-1 kinases by the scaffold protein CNK1“. Thesis, University of Glasgow, 2011. http://theses.gla.ac.uk/4183/.
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An emerging concept in the regulation of signal transduction specificity is the mediation of scaffold proteins embedded in the circuitry of signalling pathways. The multidomainbased architecture of scaffold proteins facilitates the assembly and modulation of protein complexes to regulate cellular signals to bring about an exacting biological output. The work presented in this thesis aimed to investigate the mechanisms of the protein scaffold CNK1 (connector enhancer of Ras 1) in the pro-apoptotic MST2 pathway and the prooncogenic Raf-1 signalling pathways. Here, by using several molecular, biochemical and cell biology techniques, I demonstrated that CNK1 regulates the interaction of the protooncogene Raf-1 and the tumour suppressor MST2 kinase. Perturbations of CNK1 levels exhibit a biphasic signalling response typical of a scaffold protein. Transient expression of CNK1 upon growth factor withdrawal results in a concentration-dependent increase of the Raf-1/MST2 complex, thus preventing apoptosis, but this complex dissociates at higher expression levels, hence promoting an apoptotic response. Moreover, CNK1 is involved in the regulation of Fas-induced apoptosis via the MST2/RASSF1A pathway by influencing the time-scale kinetics of MST2 docking and release from the Raf- 1/CNK1 complex and its eventual activation. SiRNA-silencing of CNK1 destabilizes the Raf-1 and MST2 interaction, and enhanced MST2/LATS1 interaction that promotes apoptosis. Thus, CNK1 is required for Raf-1 inhibitory function, but is also necessary for MST2-mediated apoptosis. Remarkably, CNK1 selects and switches complex formation of opposing anchored proteins depending on the stimulus. In response to Fas ligand stimulation, MST2 is released, whereas Raf-1 is retained in complex with CNK1. Conversely, CNK1 retains MST2 and whilst releasing Raf-1 from the complex following growth factor treatment. Mapping the multidomain binding sites of CNK1 using peptide array demonstrates specific interaction sites of client protein complexes. Specific CNK1 point mutants were generated, and found to alter wild-type regulation of client protein complexes. Thus, the work described in this thesis may reveal a regulatory crosstalk between the MST2 apoptotic pathway and the Raf-1 proliferative pathway through CNK1 by coordinating assembly of appropriate pathway components to possibly drive discrete stimulus-specific responses.
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Ritchie, Andrew John. „Endocrinology, oncogene and tumour suppressor gene expression in Barrett's oesophagus, oesophageal and gastric cardia carcinoma“. Thesis, Queen's University Belfast, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.238950.
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Bradbury, Andrew W. „Cyclic AMP binding proteins and ras p21 oncogene expression in human colorectal cancer and mucosa“. Thesis, University of Edinburgh, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.531024.
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Rotondetto, Salvatore. „Modulation of antioxidant enzyme expression in mononuclear phagocytes“. Thesis, Keele University, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.287976.
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36
Galdemard, Catherine. „Regulation transcriptionnelle de l'expression du proto-oncogene fgf-3 dans les cellules d'adenocarcinome du colon humain : bases fondamentales de l'oncogenese)“. Paris 11, 1997. http://www.theses.fr/1997PA11T006.
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林秀華 und Sau-wah Selma Lin. „Modulation of cyclin expression by over-expression of the forkhead boxtranscription factor FoxM1“. Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2001. http://hub.hku.hk/bib/B31224817.
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Adenis, Antoine. „Recepteurs d'hormones et de facteur de croissance, proteinases, produits d'oncogene et d'anti-oncogene, dans les cancers colorectaux humains ; expression et valeur pronostique“. Lille 2, 1997. http://www.theses.fr/1997LIL2T010.
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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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Zhang, Yi [Verfasser], Rosalia [Gutachter] Deeken und Wolfgang [Gutachter] Dröge-Laser. „Regulation of Agrobacterial Oncogene Expression in Host Plants / Yi Zhang. Gutachter: Rosalia Deeken ; Wolfgang Dröge-Laser“. Würzburg : Universität Würzburg, 2014. http://d-nb.info/1102827614/34.
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Pleasant, Chaucola K. „TARGETING EXPRESSION OF AN ONCOGENE BY SPLICING INTERFERENCE (SPLICEi) IN HUMAN MAMMARY CARCINOMA CELL CULTURE MODEL“. Cleveland State University / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=csu1328206596.
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Ahn, Misol. „Modulation of the neuronal voltage-gated sodium channel Nav1.2 by the non-receptor tyrosine kinase fyn /“. Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/6260.
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Zhang, Fan. „Modulation of genomic expression in the central nervous system“. Doctoral thesis, Universite Libre de Bruxelles, 1997. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/212219.
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Vani, Susheel Narendra. „Pharmacologic modulation of endometrial intracrinology and steroid receptor expression“. Thesis, University of Edinburgh, 2013. http://hdl.handle.net/1842/25269.
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Steroid hormones, acting via their cognate receptors, are key players in fundamental reproductive events: implantation and endometrial bleeding. To understand local mechanisms regulating function and the effect of pharmacologic modulation it is essential to have an understanding of factors regulating ligand availability and steroid receptor expression in the physiological state and after pharmacologic manipulations. This thesis encompasses studies analysing expression of steroid metabolising enzymes (intracrinology) and steroid receptor expression in human endometrium after three different pharmacologic manipulations. 1. Endometrium exposed to a GnRH antagonist during controlled ovarian hyperstimulation Mid-luteal phase endometrial biopsies were obtained from oocyte donors undergoing ovarian stimulation and from control women with regular periods. Immunohistochemistry and real-time quantitative polymerase chain reaction (QRT-PCR) were used to compare protein and mRNA expression of sex steroid receptors and steroid metabolising enzymes. Significant alterations in the expression of sex-steroid receptors and their metabolizing enzymes were demonstrated. These changes may lead to alterations in the activity and intracellular availability of estrogens, progestogens and androgens in endometrium of women treated with a GnRH antagonist during controlled ovarian hyperstimulation. Their impact on embryo implantation merits further evaluation. 2. Endometrium exposed to hormone replacement therapy (HRT) Endometrial biopsies from postmenopausal women not using HRT and from HRT users were collected during and outside unscheduled bleeding episodes. Immunohistochemical analysis of endometrial sex steroid receptors was performed and the relationship between expression and bleeding patterns studied. Despite the predominantly progestational effect of continuous combined HRT used in the study, the steroid receptor expression in the postmenopausal endometrium differed from that seen in the premenopausal secretory phase of menstrual cycle and after long-term progestogen-only administration, suggesting that different local mechanisms are involved in HRT-related unscheduled bleeding. 3. Endometrium exposed to intrauterine delivery of a progesterone receptor antagonist Women were randomised to intrauterine administration of either the antigestogen, ZK230211 (ZK-IUS) or Levonorgestrel (LNG-IUS) prior to hysterectomy. Endometrium was obtained from hysterectomy specimens. Bleeding patterns, endometrial morphology and content of ZK230211 were evaluated. Expression of sex steroid receptors, proliferation markers; phosphorylated Histone 3 (PH3) and Ki-67, and Insulin-like Growth Factor- Binding Protein-1 (IGFBP-1) were evaluated by immunohistochemistry (IHC). Administration of the antigestogen demonstrated novel effects such as an absence of IGFBP-1 and increase in progesterone receptor expression. These results suggest that intrauterine administration of an antigestogen is feasible and trials need to be undertaken to test clinical efficacy. These studies, in pre and postmenopausal women, demonstrate that endometrial sex steroid receptor expression and enzymes determining intracellular steroid (ligand) availability are modulated by exogenous steroid manipulation.
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Hutschenreuther, Antje, Marina Bigl, Nasr Y. A. Hemdan, Tewodros Debebe, Frank Gaunitz und Gerd Birkenmeier. „Modulation of GLO1 expression affects malignant properties of cells“. Universitätsbibliothek Leipzig, 2017. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-217965.
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The energy metabolism of most tumor cells relies on aerobic glycolysis (Warburg effect) characterized by an increased glycolytic flux that is accompanied by the increased formation of the cytotoxic metabolite methylglyoxal (MGO). Consequently, the rate of detoxification of this reactive glycolytic byproduct needs to be increased in order to prevent deleterious effects to the cells. This is brought about by an increased expression of glyoxalase 1 (GLO1) that is the rate-limiting enzyme of the MGO-detoxifying glyoxalase system. Here, we overexpressed GLO1 in HEK 293 cells and silenced it in MCF-7 cells using shRNA. Tumor-related properties of wild type and transformed cells were compared and key glycolytic enzyme activities assessed. Furthermore, the cells were subjected to hypoxic conditions to analyze the impact on cell proliferation and enzyme activities. Our results demonstrate that knockdown of GLO1 in the cancer cells significantly reduced tumor-associated properties such as migration and proliferation, whereas no functional alterations where found by overexpression of GLO1 in HEK 293 cells. In contrast, hypoxia caused inhibition of cell growth of all cells except of those overexpressing GLO1. Altogether, we conclude that GLO1 on one hand is crucial to maintaining tumor characteristics of malignant cells, and, on the other hand, supports malignant transformation of cells in a hypoxic environment when overexpressed.
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Hutschenreuther, Antje, Marina Bigl, Nasr Y. A. Hemdan, Tewodros Debebe, Frank Gaunitz und Gerd Birkenmeier. „Modulation of GLO1 expression affects malignant properties of cells“. MDPI, 2016. https://ul.qucosa.de/id/qucosa%3A15256.
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The energy metabolism of most tumor cells relies on aerobic glycolysis (Warburg effect) characterized by an increased glycolytic flux that is accompanied by the increased formation of the cytotoxic metabolite methylglyoxal (MGO). Consequently, the rate of detoxification of this reactive glycolytic byproduct needs to be increased in order to prevent deleterious effects to the cells. This is brought about by an increased expression of glyoxalase 1 (GLO1) that is the rate-limiting enzyme of the MGO-detoxifying glyoxalase system. Here, we overexpressed GLO1 in HEK 293 cells and silenced it in MCF-7 cells using shRNA. Tumor-related properties of wild type and transformed cells were compared and key glycolytic enzyme activities assessed. Furthermore, the cells were subjected to hypoxic conditions to analyze the impact on cell proliferation and enzyme activities. Our results demonstrate that knockdown of GLO1 in the cancer cells significantly reduced tumor-associated properties such as migration and proliferation, whereas no functional alterations where found by overexpression of GLO1 in HEK 293 cells. In contrast, hypoxia caused inhibition of cell growth of all cells except of those overexpressing GLO1. Altogether, we conclude that GLO1 on one hand is crucial to maintaining tumor characteristics of malignant cells, and, on the other hand, supports malignant transformation of cells in a hypoxic environment when overexpressed.
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Xue, Liting. „Oncogene Function in Pre-Leukemia Stage of INV(16) Acute Myeloid Leukemia: A Dissertation“. eScholarship@UMMS, 2014. https://escholarship.umassmed.edu/gsbs_diss/740.
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The CBFbeta-SMMHC fusion protein is expressed in acute myeloid leukemia (AML) samples with the chromosome inversion inv(16)(p13;q22). This fusion protein binds the transcription factor RUNX with higher affinity than its physiological partner CBFbeta and disrupts the core binding factor (CBF) activity in hematopoietic stem and progenitor cells. Studies in the Castilla laboratory have shown that CBFbeta-SMMHC expression blocks differentiation of hematopoietic progenitors, creating a pre-leukemic progenitor that progresses to AML in cooperation with other mutations. However, the combined function of cumulative cooperating mutations in the pre-leukemic progenitor cells that enhance their expansion to induce leukemia is not known. The standard treatment for inv(16) AML is based on the use of non-selective cytotoxic chemotherapy, resulting in a good initial response, but with limited long-term survival. Therefore, there is a need for developing targeted therapies with improved efficacy in leukemic cells and minimal toxicity for normal cells.
Here, we used conditional Nras+/LSL-G12D; Cbfb+/56M; Mx1Cre knock-in mice to show that allelic expression of oncogenic N-RasG12D expanded the multi-potential progenitor (MPP) compartment by 8 fold. Allelic expression of Cbfbeta-SMMHC increased the MPPs and short-term hematopoietic stem cells (ST-HSCs) by 2 to 4 fold both alone and in combination with N-RasG12D expression. In addition, allelic expression of oncogenic N-RasG12D and Cbfbeta-SMMHC increases survival of pre-leukemic stem and progenitor cells. Differential analysis of bone marrow cells determined that Cbfb+/MYH11 and Nras+/G12D; vii Cbfb+/MYH11 cells included increased number of blasts, myeloblasts and promyelocytes and a reduction in immature granulocytes, suggesting that expression of N-RasG12D cannot bypass Cbfbeta-SMMHC driven differentiation block.
N-RasG12D and Cbfbeta-SMMHC synergized in leukemia, in which Nras+/G12D; Cbfb+/MYH11 mice have a shorter median latency than Cbfb+/MYH11 mice. In addition, the synergy in leukemogenesis was cell autonomous. Notably, leukemic cells expressing N-RasG12D and Cbfbeta-SMMHC showed higher (over 100 fold) leukemia-initiating cell activity in vivo than leukemic cells expressing Cbfbeta-SMMHC (L-IC activity of 1/4,000 and 1/528,334, respectively).
Short term culture and biochemical assays revealed that pre-leukemic and leukemic cells expressing N-RasG12D and Cbfbeta-SMMHC have reduced levels of pro-apoptotic protein Bim compared to control. The Nras+/G12D; CbfbMYH11 pre-leukemic and leukemic cells were sensitive to pharmacologic inhibition of MEK/ERK signaling pathway with increasing apoptosis and Bim protein levels but not sensitive to PI3K inhibitors. In addition, knock-down of Bcl2l11 (Bim) expression in Cbfbeta-SMMHC pre-leukemic progenitors decreased their apoptosis levels.
In collaboration with Dr. John Bushweller’s and other research laboratories, we recently developed a CBFbeta-SMMHC inhibitor named AI-10-49, which specifically binds to CBFbeta-SMMHC, prevents its binding to RUNX proteins and restores CBF function. Biochemical analysis in human leukemic cells showed that AI-10-49 has significant specificity in reducing the viability of leukemic cells expressing CBFbeta-SMMHC (IC50= 0.83μM), and negligible toxicity in normal cells. Likewise, mouse Nras+/G12D; viii Cbfb+/MYH11 leukemic cells were sensitive to AI-10-49 (IC50= 0.93μM). By using the NrasLSL-G12D; Cbfb56M mouse model, we also show that AI-10-49 significantly prolongs the survival of mice bearing the leukemic cells. Preliminary mechanistic analysis of AI-10-49 activity has shown that AI-10-49 increased BCL2L11 transcript levels in a dose and time dependent manner in murine and human leukemic cells, suggesting that the viability through BIM-mediated apoptosis may be targeted by both oncogenic signals.
My thesis study demonstrates that Cbfbeta-SMMHC and N-RasG12D promote the survival of pre-leukemic myeloid progenitors primed for leukemia by activation of the MEK/ERK/Bim axis, and define NrasLSL-G12D; Cbfb56M mice as a valuable genetic model for the study of inv(16) AML targeted therapies. For instance, the novel CBFbeta-SMMHC inhibitor AI-10-49 shows a significant efficacy in this mouse model. This small molecule will serve as a promising first generation drug for targeted therapy of inv(16) leukemia and also a very useful tool to understand mechanisms of leukemogenesis driving by CBFbeta-SMMHC.
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Xue, Liting. „Oncogene Function in Pre-Leukemia Stage of INV(16) Acute Myeloid Leukemia: A Dissertation“. eScholarship@UMMS, 2010. http://escholarship.umassmed.edu/gsbs_diss/740.
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The CBFbeta-SMMHC fusion protein is expressed in acute myeloid leukemia (AML) samples with the chromosome inversion inv(16)(p13;q22). This fusion protein binds the transcription factor RUNX with higher affinity than its physiological partner CBFbeta and disrupts the core binding factor (CBF) activity in hematopoietic stem and progenitor cells. Studies in the Castilla laboratory have shown that CBFbeta-SMMHC expression blocks differentiation of hematopoietic progenitors, creating a pre-leukemic progenitor that progresses to AML in cooperation with other mutations. However, the combined function of cumulative cooperating mutations in the pre-leukemic progenitor cells that enhance their expansion to induce leukemia is not known. The standard treatment for inv(16) AML is based on the use of non-selective cytotoxic chemotherapy, resulting in a good initial response, but with limited long-term survival. Therefore, there is a need for developing targeted therapies with improved efficacy in leukemic cells and minimal toxicity for normal cells.
Here, we used conditional Nras+/LSL-G12D; Cbfb+/56M; Mx1Cre knock-in mice to show that allelic expression of oncogenic N-RasG12D expanded the multi-potential progenitor (MPP) compartment by 8 fold. Allelic expression of Cbfbeta-SMMHC increased the MPPs and short-term hematopoietic stem cells (ST-HSCs) by 2 to 4 fold both alone and in combination with N-RasG12D expression. In addition, allelic expression of oncogenic N-RasG12D and Cbfbeta-SMMHC increases survival of pre-leukemic stem and progenitor cells. Differential analysis of bone marrow cells determined that Cbfb+/MYH11 and Nras+/G12D; vii Cbfb+/MYH11 cells included increased number of blasts, myeloblasts and promyelocytes and a reduction in immature granulocytes, suggesting that expression of N-RasG12D cannot bypass Cbfbeta-SMMHC driven differentiation block.
N-RasG12D and Cbfbeta-SMMHC synergized in leukemia, in which Nras+/G12D; Cbfb+/MYH11 mice have a shorter median latency than Cbfb+/MYH11 mice. In addition, the synergy in leukemogenesis was cell autonomous. Notably, leukemic cells expressing N-RasG12D and Cbfbeta-SMMHC showed higher (over 100 fold) leukemia-initiating cell activity in vivo than leukemic cells expressing Cbfbeta-SMMHC (L-IC activity of 1/4,000 and 1/528,334, respectively).
Short term culture and biochemical assays revealed that pre-leukemic and leukemic cells expressing N-RasG12D and Cbfbeta-SMMHC have reduced levels of pro-apoptotic protein Bim compared to control. The Nras+/G12D; CbfbMYH11 pre-leukemic and leukemic cells were sensitive to pharmacologic inhibition of MEK/ERK signaling pathway with increasing apoptosis and Bim protein levels but not sensitive to PI3K inhibitors. In addition, knock-down of Bcl2l11 (Bim) expression in Cbfbeta-SMMHC pre-leukemic progenitors decreased their apoptosis levels.
In collaboration with Dr. John Bushweller’s and other research laboratories, we recently developed a CBFbeta-SMMHC inhibitor named AI-10-49, which specifically binds to CBFbeta-SMMHC, prevents its binding to RUNX proteins and restores CBF function. Biochemical analysis in human leukemic cells showed that AI-10-49 has significant specificity in reducing the viability of leukemic cells expressing CBFbeta-SMMHC (IC50= 0.83μM), and negligible toxicity in normal cells. Likewise, mouse Nras+/G12D; viii Cbfb+/MYH11 leukemic cells were sensitive to AI-10-49 (IC50= 0.93μM). By using the NrasLSL-G12D; Cbfb56M mouse model, we also show that AI-10-49 significantly prolongs the survival of mice bearing the leukemic cells. Preliminary mechanistic analysis of AI-10-49 activity has shown that AI-10-49 increased BCL2L11 transcript levels in a dose and time dependent manner in murine and human leukemic cells, suggesting that the viability through BIM-mediated apoptosis may be targeted by both oncogenic signals.
My thesis study demonstrates that Cbfbeta-SMMHC and N-RasG12D promote the survival of pre-leukemic myeloid progenitors primed for leukemia by activation of the MEK/ERK/Bim axis, and define NrasLSL-G12D; Cbfb56M mice as a valuable genetic model for the study of inv(16) AML targeted therapies. For instance, the novel CBFbeta-SMMHC inhibitor AI-10-49 shows a significant efficacy in this mouse model. This small molecule will serve as a promising first generation drug for targeted therapy of inv(16) leukemia and also a very useful tool to understand mechanisms of leukemogenesis driving by CBFbeta-SMMHC.
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Hamon, Martial. „Expression des oncogenes nucleaires dans l'aorte de lapin apres angioplastie : influence de l'heparine sur l'expression de c-myc, c-fos et c-jun“. Lille 2, 1991. http://www.theses.fr/1991LIL2M347.
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Opitz, Armin Walter. „Structural and functional investigations of a molecular imaging nanoparticle for magnetic resonance imaging of oncogene expression in the pancreas“. Access to citation, abstract and download form provided by ProQuest Information and Learning Company; downloadable PDF file, 490 p, 2008. http://proquest.umi.com/pqdweb?did=1459924631&sid=13&Fmt=2&clientId=8331&RQT=309&VName=PQD.
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Thesis (Ph.D.)--University of Delaware, 2008.Principal faculty advisors: Norman J. Wagner, Dept. of Chemical Engineering, University of Delaware; Eric Wickstrom, Dept. of Biochemistry and Molecular Biology, Thomas Jefferson University. Includes bibliographical references.