Dissertations / Theses on the topic 'Oncogenic transformations'
To see the other types of publications on this topic, follow the link: Oncogenic transformations.
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 dissertations / theses for your research on the topic 'Oncogenic transformations.'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse dissertations / theses on a wide variety of disciplines and organise your bibliography correctly.
1
Svingen, Terje, and n/a. "Hox Transcription Factors: Their Involvement in Human Cancer Cells and In Vitro Functional Specificity." Griffith University. School of Biomolecular and Biomedical Science, 2005. http://www4.gu.edu.au:8080/adt-root/public/adt-QGU20050830.135356.
Full textAbstract:
Hox genes are regulatory genes encoding small proteins containing a highly conserved 61-amino acid motif, the homeodomain, that enables Hox proteins to bind to DNA at specifically recognised binding sites and transcriptionally activate their target genes. In mammalian species there are 39 Hox genes and they are structural and functional homologs of the Drosophila homeotic complex (Horn-C). During embryogenesis and early development the Hox genes are expressed in a spatiotemporal fashion, where they operate as master transcriptional regulators. Hox genes are further expressed in fully differentiated adult cells, potentially in a tissue-specific manner involving maintenance of the normal phenotype. In selected oncogenic transformations, dysregulated Hox gene expression has been observed, indicating an involvement of these transcriptional regulators in carcinogenesis and metastasis. Utilising quantitative real-time PCR assays, these studies investigated the expression patterns of 20 Hox genes and two wellcharacterised Hox cofactors (Pbx and Meis) in malignant and non-malignant human breast and skin cancer cells. Dysregulated Hox expression was observed for all malignancies tested, of which some misexpressed Hox genes seemed random, whereas other Hox transcripts showed altered levels potentially corresponding with the invasive capacity of the cells. Also, the Hox cofactors Pbx and Meis showed no marked changes in expression levels from the non-malignant to the malignant phenotypes, indicating that it is dysregulated Hox gene expression rather than dysregulated gene expression of Hox cofactors that potentially commit the cell to redifferentiate and undergo oncogenic transformation. Although the Hox proteins are known to be key transcriptional regulators of development, the mechanisms by which they gain their in vivo functional specificity is still largely unknown. They all show strikingly similar transcriptional specificity in vitro, yet show unique specificity in their in vivo environment. This paradox has been the subject of intense scrutiny, however very few direct Hox target genes have been identified, making it a difficult task to decipher the exact manner in which Hox proteins exert their functional potential. Therefore, the studies presented herein were aimed at identifying further Hox target genes in the human system. Utilising differential display approaches, several potential downstream target genes were isolated. Substantiated with real-time PCR assays, one of these potential targets was selected as a likely direct Hox gene target, and as such subjected to further studies. By the combination of bioinformatic analyses, transfection protocols and luciferase assays, a gene encoding the SR-related protein SRrpl3O was shown to be trans-activated in vitro by HOXD4 via a putative Hox binding element within its promoter region. This is the first reported link between Hox transcription factors and the SR and SR-related family of pre-mRNA splicing proteins, offering a new and exciting insight into the complex nature of Hox functional specificity. Finally, this thesis also puts forward new ideas regarding how the Hox proteins gain their transcriptional and functional specificity. Utilising bioinformatic tools in conjunction with performing an extensive review of the disparate catalogue of Hox-related research reports, work herein offers the first comprehensive analysis of the mammalian Hox gene targets in relation to their promoter structures, as well as with respect to the expanded Hox DNA-binding elements. This work reports that identified Hox targets generally contain TATA-less core promoters, many of which have several GC-box elements. The Hox binding elements show no apparent preference regarding their location relative to the transcription start site (TSS), as they are found both upstream and downstream of the TSS, as well as being located close to proximal core promoter elements for some genes and at more distant positions in other gene promoters. Finally, the core Hox binding element TAAT/ATTA contains only part of the necessary recognition sequence involved in Hox-DNA binding, and the notion that flanking base pairs dictate trans-regulatory potential is further explored with the hypothesis that the immediate 3' base pair dictates an activator/repressor-switch of the Hox trans-regulatory effect.
2
Svingen, Terje. "Hox Transcription Factors: Their Involvement in Human Cancer Cells and In Vitro Functional Specificity." Thesis, Griffith University, 2005. http://hdl.handle.net/10072/365774.
Full textAbstract:
Hox genes are regulatory genes encoding small proteins containing a highly conserved 61-amino acid motif, the homeodomain, that enables Hox proteins to bind to DNA at specifically recognised binding sites and transcriptionally activate their target genes. In mammalian species there are 39 Hox genes and they are structural and functional homologs of the Drosophila homeotic complex (Horn-C). During embryogenesis and early development the Hox genes are expressed in a spatiotemporal fashion, where they operate as master transcriptional regulators. Hox genes are further expressed in fully differentiated adult cells, potentially in a tissue-specific manner involving maintenance of the normal phenotype. In selected oncogenic transformations, dysregulated Hox gene expression has been observed, indicating an involvement of these transcriptional regulators in carcinogenesis and metastasis. Utilising quantitative real-time PCR assays, these studies investigated the expression patterns of 20 Hox genes and two wellcharacterised Hox cofactors (Pbx and Meis) in malignant and non-malignant human breast and skin cancer cells. Dysregulated Hox expression was observed for all malignancies tested, of which some misexpressed Hox genes seemed random, whereas other Hox transcripts showed altered levels potentially corresponding with the invasive capacity of the cells. Also, the Hox cofactors Pbx and Meis showed no marked changes in expression levels from the non-malignant to the malignant phenotypes, indicating that it is dysregulated Hox gene expression rather than dysregulated gene expression of Hox cofactors that potentially commit the cell to redifferentiate and undergo oncogenic transformation. Although the Hox proteins are known to be key transcriptional regulators of development, the mechanisms by which they gain their in vivo functional specificity is still largely unknown. They all show strikingly similar transcriptional specificity in vitro, yet show unique specificity in their in vivo environment. This paradox has been the subject of intense scrutiny, however very few direct Hox target genes have been identified, making it a difficult task to decipher the exact manner in which Hox proteins exert their functional potential. Therefore, the studies presented herein were aimed at identifying further Hox target genes in the human system. Utilising differential display approaches, several potential downstream target genes were isolated. Substantiated with real-time PCR assays, one of these potential targets was selected as a likely direct Hox gene target, and as such subjected to further studies. By the combination of bioinformatic analyses, transfection protocols and luciferase assays, a gene encoding the SR-related protein SRrpl3O was shown to be trans-activated in vitro by HOXD4 via a putative Hox binding element within its promoter region. This is the first reported link between Hox transcription factors and the SR and SR-related family of pre-mRNA splicing proteins, offering a new and exciting insight into the complex nature of Hox functional specificity. Finally, this thesis also puts forward new ideas regarding how the Hox proteins gain their transcriptional and functional specificity. Utilising bioinformatic tools in conjunction with performing an extensive review of the disparate catalogue of Hox-related research reports, work herein offers the first comprehensive analysis of the mammalian Hox gene targets in relation to their promoter structures, as well as with respect to the expanded Hox DNA-binding elements. This work reports that identified Hox targets generally contain TATA-less core promoters, many of which have several GC-box elements. The Hox binding elements show no apparent preference regarding their location relative to the transcription start site (TSS), as they are found both upstream and downstream of the TSS, as well as being located close to proximal core promoter elements for some genes and at more distant positions in other gene promoters. Finally, the core Hox binding element TAAT/ATTA contains only part of the necessary recognition sequence involved in Hox-DNA binding, and the notion that flanking base pairs dictate trans-regulatory potential is further explored with the hypothesis that the immediate 3' base pair dictates an activator/repressor-switch of the Hox trans-regulatory effect.Thesis (PhD Doctorate)
Doctor of Philosophy (PhD)
School of Biomolecular and Physical Sciences
Full Text
3
CALVO, FERNANDA B. "Construcao e caracterizacao in vitro de um vetor retroviral bicistronico codificando endostatina e interleucina-2 para utilizacao em terapia genica." reponame:Repositório Institucional do IPEN, 2009. http://repositorio.ipen.br:8080/xmlui/handle/123456789/9487.
Full textAbstract:
Made available in DSpace on 2014-10-09T12:27:15Z (GMT). No. of bitstreams: 0Made available in DSpace on 2014-10-09T13:57:04Z (GMT). No. of bitstreams: 0
Dissertacao (Mestrado)
IPEN/D
Instituto de Pesquisas Energeticas e Nucleares - IPEN-CNEN/SP
4
Lehmann, Kerstin Elisabeth. "Regulation of epithelial cell transformation and survival by Raf activation." Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.248242.
Full text
5
Pierro, Cristina. "Remodelling of Ca2+ signalling mechanisms during K-RAS-driven oncogenic transformation." Thesis, University of Cambridge, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.610740.
Full text
6
Ye, Fang. "PPARγ and Smad2 Mediate Ski Induced Energy Metabolism Shift and Oncogenic Transformation." Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1280930750.
Full text
7
Kabbout, Mohamed Nazih. "ETS1 AND ETS2 ROLE IN RAS ONCOGENIC TRANSFORMATION IN MOUSE EMBRYONIC FIBROBLASTS." The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1275408102.
Full text
8
Shima, Yasuko. "In vitro transformation of mesenchymal stem cells by oncogenic H-ras[Val12]." Kyoto University, 2007. http://hdl.handle.net/2433/135685.
Full text
9
Sumner, Evan T. "Characterizing the Oncogenic Properties of C-terminal Binding Protein." VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4153.
Full textAbstract:
The paralogous C-terminal binding proteins (CtBP) 1 and 2 are evolutionarily conserved transcriptional coregulators that target and disrupt the expression of several genes essential for multiple cellular processes critical to regulating tumor formation. CtBP’s ability to govern the transcription of genes necessary for apoptosis, tumor suppression, invasion/migration and EMT gives rise to its oncogenic activities. Both isoforms of CtBP are found to be overexpressed in cancers including colorectal, pancreatic, ovarian, and breast, with higher levels correlating to lower overall median survival. Although multiple lines of evidence suggest CtBP plays a role in tumorigenesis, it has never been formally characterized as an oncogene. For this reason, the goal of this dissertation was to design a set of experiments to determine the transforming ability of CtBP2 in vitro using both murine and human fibroblast and in vivo using the Apcmin/+ mouse model of cancer. Specifically, we demonstrate that overexpression of CtBP2 alone can drive transformation of NIH3T3 cells leading to loss of contact inhibition, increased x invasion/migration, and anchorage independent growth. In addition, CtBP2 was found to cooperate with the large T-antigen (LT) component of the simian virus 40 (SV40) to lead to transformation of murine embryonic fibroblasts (MEFs) and with both LT and small T-antigen (ST) to induce migration/invasion and anchorage-independent growth in BJ human foreskin fibroblasts. To confirm the role of Ctbp2 in a mouse tumor model with Ctbp overexpression, we bred Apcmin/+ mice to Ctbp2 heterozygous (Ctbp2+/-) mice, which otherwise live normal lifespans. CtBP is a known target of the APC tumor suppressor and is thus stabilized in APC mutated human colon cancers and is found in high levels in Apcmin/+ polyps. Remarkably, removing an allele of Ctbp2 doubled the median survival of Apcmin/+ mice (P <0.001) and reduced polyp formation to near undetectable levels. These data suggest the importance of CtBP2 in driving cellular transformation and identify it as a potential target for prevention or therapy in APC mutant backgrounds.
10
Webster, Marc A. "Mechanisms of polyomavirus transformation of the mouse mammary gland /." *McMaster only, 1996.
Find full text
11
MacAuley, Iain Alasdair Somerled. "An analysis of the effects of oncogenes and growth factors on rat adrenal cortex cells." Thesis, University of British Columbia, 1987. http://hdl.handle.net/2429/27438.
Full textAbstract:
The process of oncogenic transformation in vitro has been examined in an attempt to define the molecular mechanisms of carcinogenesis. Transformation in Ki-MSV-infected rat adrenal cortex cells appears to be a multistep process (Auersperg et al., 1981), as does the process of transformation in other nonestablished cells (Land et at., 1983b). The Ki-MSV-infected adrenal cortex cells initially express a partially transformed phenotype and after further passaging progress to a highly transformed phenotype (Calderwood and Auersperg, 1984). Examination of Ki-MSV-infected adrenal cortex cells indicated that progression to a highly transformed phenotype could occur in the absence of significant changes in the level of the expression of the viral ras oncogene. These results indicated that an oncogenically activated ras gene could be expressed in these nonestablished cells in the absence of transformation.
Since ras and myc cooperate to transform primary fibroblasts the effect of the co-introduction of myc on Ki-MSV-induced transformation of adrenal cortex cells was examined. It could be demonstrated that myc and ras cooperate to transform the adrenal cortex cells more efficiently than either oncogene alone, but that the infected cultures initially only express some of the phenotypes associated with transformation. The appearance of a fully transformed phenotype, as monitored by growth in soft agar, was not expressed until several passages after infection. An analysis of the Ki-MSV/MMCV-infected cultures indicated that some of the phenotypes associated with activated oncogenes in immortalized cell lines appeared to be suppressed in the coinfected adrenal cortex cells. Transformation by ras and myc appears to require a further cellular change resulting in a loss of the suppression of oncogene action. The emergence of transformed cultures from the Ki-MSV-infected rat adrenal cortex cells was correlated with the reduced expression of a novel ras-related protein of 27000 Mr.
Transformation induced by src and myc was also examined. These two oncogenes appeared to cooperate in a two step pathway of transformation that was not susceptible to cellular suppression. The transformed phenotype did not appear to be entirely free of external influence as the growth rate of the transformed cells could be modified by culture conditions. The ability of myc to cooperate with src and ras in the transformation of the early passage adrenal cortex cells provides further support for mutistep carcinogenesis.
The effect of oncogenes on steroidogenesis was examined in the Y-1 adrenocortical tumour cell line. The effect of the virally borne oncogenes on growth and morphology of the Y-1 cells was relatively subtle. The oncogenes appear to stimulate the production of fluorogenic steroids, each in a distinct fashion. A model of transformation can be derived in which the roles of the oncogenes and their interaction with the cell can be evaluated. The differences in the pathways of transformation for the two combinations of oncogenes illustrates the potential complexity of the transformation process and provides an in vitro model system for further study.Science, Faculty of
Microbiology and Immunology, Department of
Graduate
12
Knarr, Matthew J. "The Monkey in the Wrench: MiR-181a's Role in Promoting Adipogenesis and Ovarian Cancer Transformation." Case Western Reserve University School of Graduate Studies / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=case1554481048956007.
Full text
13
Dhanraj, Karen Nalini. "The oncogenic transformation of T51B rat liver epithelial cells alters their sensitivity to apoptotic stimuli." Thesis, University of Ottawa (Canada), 1998. http://hdl.handle.net/10393/4372.
Full textAbstract:
Rat liver non-parenchymal epithelial cells were stably transfected with the following plasmids: (i) pRSVNeo containing a neomycin resistance gene (Neo) under control of the Rous sarcoma virus (RSV) long terminal repeat element and (ii) pMT3 containing the Neo gene and the coding sequence of the polyoma middle T antigen (mT) under control of the SV40 enhancer region. Soft agar assays revealed no neoplastic transformation of cells expressing pRSVNeo plasmids, however overexpression of pMT3 plasmids generated a highly tumorigenic cell line. Two approaches were used to induce apoptosis in these cell lines, i.e. serum withdrawal and treatment with a chemotherapeutic drug, teniposide (VM26). The Neo cells were resistant to serum deprivation and sensitive to the VM26 treatment. In contrast, the highly transformed mT cells were very sensitive to the lack of growth factors but became extremely resistant to the VM26 treatment. These cells could arrest their growth and survive for 2 days in the presence of 10 $\mu$M VM26. Under the same experimental conditions, the viability of Neo cells dropped and they could only survive for a few hours. Analysis of several growth arrest and DNA-repair related proteins was performed and correlated with the cells' responsiveness to apoptosis. For example, in the VM26-resistant mT cells, the level of DNA repair-associated proteins was upregulated in response to the drug treatment. The results of this study clearly demonstrated that the mT protein brought about cellular phenotypic and metabolic changes, manifested not only as tumorigenic transformation, but also as a resistance to treatment with the chemotherapeutic drug, VM26.
14
Agochiya, Mahima. "Aspects of the regulation and role of focal adhesion kinase and Src in oncogenic transformation." Thesis, University of Glasgow, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312784.
Full text
15
Young, Nathan Price. "Tissue-specific interactions between oncogenic K-ras and the p19A̳r̳f̳_p53 pathway determine susceptibility to transformation." Thesis, Massachusetts Institute of Technology, 2010. http://hdl.handle.net/1721.1/58199.
Full textAbstract:
Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2010.In title on title page, doubled underscored "Arf" appears as superscript. Vita. Cataloged from PDF version of thesis.
Includes bibliographical references.
Tumor development is a multi-step process driven by the collective action of gain-of-function mutations in oncogenes and loss-of-function alterations in tumor suppressor genes. The particular spectrum of mutations in a given cancer is rarely the result of random chance but instead derives from the intimate connections between proliferative networks and those suppressing growth and transformation. Specifically, hyper-active oncogenes directly engage tumor suppressor programs, such that cells harboring oncogenic lesions frequently must acquire secondary mutations that disable these anti-proliferative responses before progressing to overt transformation. This tight coupling represents a critical checkpoint protecting against tumor formation. Whether different cell types exhibit variability in the extent and/or timing of this oncogene-induced tumor suppression is largely unknown. The ability of oncogenic Ras to induce the tumor suppressive p1 9 Arf-p5.3 pathway and cause irreversible cell cycle arrest typifies this phenomenon. Using this-well established interaction as model, we investigated the cell-type specificity of oncogene-induced tumor suppression. By combining K-rasL mice with a reporter for p19Arf expression (Ar FP), we identify a tissue-specific, onocogenic K-ras-dependent expression pattern of 19Arfin lung tumors and sarcomas that correlates with each tissue's genetic requirements for tumorigenesis. Lung tumors, which can arise in the presence of p19Arf and show modest increases in tumor progression in its absence, exhibit very minimal p19 Arf induction. Conversely, sarcomas, which depend on p19 f-p53 mutation for tumor formation, display robust p 1 9 Af up-regulation. While previous studies proposed oncogene levels as the main determinant of p19A induction, we find equivalent signaling levels and instead highlight tissue-specific differences in the epigenetic regulation of Ink4a/Arf Using in vivo RNAi, we implicate Polycomb group (PcG) proteinmediated repression in lung tumors and SWI/SNF-dependent activation in sarcomas as being critically important for each tissue's unique expression pattern of p1 9 Arf During normal tumor progression, mutations in oncogenes and tumor suppressors occur in a sequential fashion, although whether unique orders of mutations dictate distinct phenotypes is unknown. The requirement for complete p53 pathway abrogation during oncogenic K-rasdependent sarcomagenesis suggested that tumor development in the muscle critically depends on early p53 mutation. To test this we generated a Flp-inducible allele of K-rasG12D (K-rasFSF-G12D) that when combined with established reagents for Cre-dependent p53 deletion permits the separate regulation of K-ras activation and p53 loss. Strikingly, although simultaneous mutation results in robust tumor formation, delaying p53 deletion relative to oncogenic K-ras expression
(cont.) significantly diminishes tumor penetrance. This indicates that the tumorigenic capacity of KrasG12D mutant muscle cells is rapidly and severely compromised by a strong p53-dependent response, which is entirely different from the mode of action of p53 during lung tumorigenesis. Further genetic analysis implicates the p53 target gene p21 in this suppression, implying that p53 irreversibly constrains sarcoma development through cell cycle arrest mechanisms. Together, these results highlight tissue-specific variability in the relationship of oncogenic K-ras and the p53 pathway. Robust pathway up-regulation, as seen in muscle cells, affords potent inhibition of tumor initiation, while modest induction, such as in lung cells, permits tumor development and only hinders more advanced stages of progression. These differences might help explain the spectrum of tumors associated with K-Ras mutations as well as the overall frequency of difference cancer types.
by Nathan Price Young.
Ph.D.
16
Armitage, Mark. "Cytogenetic damage, oncogenic transformation and p53 induction in human epithelial cells in response to irradiation." Thesis, University of St Andrews, 1994. http://hdl.handle.net/10023/13910.
Full textAbstract:
Ionizing radiation can have several different effects on cells, some are almost instantaneous such as the generation of DNA damage, other cellular responses take a matter of minutes or hours - DNA repair protein induction/activation, and others may take months or even years to be manifested - carcinogenesis. Human epithelial cell lines derived from both normal, non-neoplastic tissues and from a malignant source were cultured in order to examine several effects of ionizing radiation on such cell types. Cells not from a malignant source were previously immortalized by viral infection or by transfection with viral sequences. Simian virus 40 immortalised uroepithelial cells (SV-HUC) were found to be approximately a factor of two fold more radioresistant than cells of malignant origin (T24) in terms of unrepaired clastogenic damage i.e. assessment of micronuclei levels following irradiation. SV-HUC lines unlike T24 cells are non-tumourigenic when inoculated into nude athymic mice. SV-HUC lines proved very resistant to full oncogenic transformation using radiation and chemical carcinogens. However, morphological alterations and decreased anchorage dependant growth was observed in post carcinogen treated cells after appropriate cell culture conditions were utilized. The progression from this phenotype to a fully tumourigenic one was not recorded in this study. The ability of ionizing radiation to induce increased levels of the nuclear phosphoprotein p53 was also assessed using several different cell lines. SV- HUC and T24 cell lines failed to exhibit any increased p53 stabilization following irradiation. One cell line, a human papilloma virus transformed line (HPV) did show an approximate two fold increase of the wild type p53 protein after treatment with radiation. Only the cell line HPV showed any cell cycle delay, resulting in accumulation of cells in the G2/M compartment in post irradiation cell cycle analysis. The status of p53 was also assessed i.e. wild type or mutant conformation in all the above cells lines and two other control lines HOS (a human osteosarcoma cell line) and H Tori-3 (SV40 immortalised thyroid epithelial cells).
17
Wise-Draper, Trisha Michel. "The DEK proto-oncogene: roles in cellular death and transformation." Cincinnati, Ohio : University of Cincinnati, 2007. http://www.ohiolink.edu/etd/view.cgi?acc_num=ucin1201403348.
Full textAbstract:
Thesis (Ph.D. of Cell and Molecular Biology)--University of Cincinnati, 2007.Advisor: Dr. Susanne Wells. Title from electronic thesis title page (viewed May 12, 2008). Includes abstract. Includes bibliographical references.
18
WISE-DRAPER, TRISHA MICHEL. "The DEK proto-oncogene: roles in cellular death and transformation." University of Cincinnati / OhioLINK, 2008. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1201403348.
Full text
19
Fernandes, Tânia Patrícia Dias. "Role of SOX2 on RasV12-mediated transformation." Master's thesis, Universidade de Aveiro, 2017. http://hdl.handle.net/10773/22010.
Full textAbstract:
Mestrado em Biologia Molecular e CelularThe SRY (sex-determining region Y) - box 2 (SOX2) is a master factor in the maintenance of pluripotency and stemness. The transcription factor SOX2 allows the cells to maintain the unique characteristics of the embryonic stem cells (ESCs), such as clonogenicity, pluripotency, self-renewal ability, and conservation of the anti-apoptotic properties of cancer stem cells (CSCs). This factor has an important role in carcinogenesis of several tumors, including gastric, breast, pancreatic, and lung cancers. SOX2 overexpression can contribute to resistance of cancer cell to drug therapy and has been associated with tumor aggressiveness and worse prognosis. Ras GTPase is a proto-oncogene activated in several types of cancer with low success rate, including carcinomas of the pancreas, colon, lung, thyroid, and myeloid malignancies. This oncogene activates several signalling pathways, which includes the MAPK, PI3K, and RAL. It’s signalling is involved in many cellular functions, such as cell proliferation, apoptosis, migration, fate specification, and differentiation. This project aims to investigate the role of SOX2 on RasV12-mediated transformation and the genetic requirements for SOX2 induction mediated by Ras using immortalized mouse fibroblasts and primary mouse embryonic fibroblasts. We also study the effect of SOX2 overexpression on drug therapy using human lung carcinoma and human breast adenocarcinoma cell lines. We have demonstrated that RasV12 overexpression induced the expression of SOX2 and this induction is at level of transcription. We also determined that p53, Rb, and p19ARF factors are not essential for SOX2 induction and that MAPK pathway is required, but not sufficient for SOX2 induction by RasV12. Through a transformation assay we demonstrate that SOX2 overexpression increases the effect of RasV12 in cell transformation and SOX2 silencing mediated by siRNA decreases the transformation capacities of RasV12, so this factor is important in transformation mediated by RasV12. Several studies show that SOX2 not only influences tumor growth, but it also influences the response of tumor cells to therapeutic drugs. We observed that SOX2 overexpression increased the resistance of human breast adenocarcinoma cells to docetaxel. In conclusion, SOX2 is a key factor in cell transformation mediated by RasV12, as well as has an important role in chemoresistance of cancer cells. Looking at these results, this factor can be a novel target for anti-cancer therapy.
O fator de transcrição SOX2 (Sex-determining region Y (SRY)-Box2) é um fator importante na manutenção da pluripotência e “stemness”. Este fator permite que as células preservem as características únicas das células embrionárias estaminais (ESCs), como a clonogenicidade, pluripotência, capacidade de autorrenovação e a conservação das propriedades anti-apoptóticas de células estaminais cancerígenas (CSCs). O SOX2 tem um papel importante na carcinogénese de vários tumores, como no cancro gástrico, da mama, pancreático e do pulmão. A sobre-expressão de SOX2 pode contribuir para a resistência das células cancerígenas à terapia farmacológica e tem sido associada à agressividade tumoral e mau prognóstico. O proto-oncogene Ras GTPase está ativo em vários cancros com baixa taxa de sucesso, como os carcinomas do pâncreas, colón, pulmão, tiroide e mielomas malignos. Este oncogene ativa múltiplas vias de sinalização, incluindo a MAPK, PI3K e RAL e estas vias estão envolvidas em funções celulares como proliferação celular, apoptose, migração e diferenciação. Este projeto tem como objetivo investigar o papel de SOX2 na transformação mediada por RasV12 e os fatores genéticos importantes na indução de SOX2 usando fibroblastos imortalizados de rato e fibroblastos embrionários primários de rato e o efeito da sobre-expressão de SOX2 na terapia farmacológica usando células do carcinoma do pulmão humano e células do adenocarcinoma da mama humano. Foi possível demostrar que a sobre-expressão de RasV12 induz a expressão de SOX2 ao nível da transcrição. Os fatores p53, Rb e p19ARF não são essenciais na indução de SOX2 por RasV12, no entanto a via de sinalização MAPK é necessária neste processo. Através de ensaios de transformação foi possível demonstrar que a sobre-expressão de SOX2 incrementa o efeito de RasV12 na transformação celular e que o silenciamento de SOX2 usando siRNA diminui a capacidade transformante de RasV12, desta forma este fator é importante para a transformação celular mediada por RasV12. Vários estudos demonstram que o fator de transcrição SOX2 não só influencia o desenvolvimento tumoral, mas também a resposta das células tumorais à terapia farmacológica. Foi possível verificar que a sobre-expressão de SOX2 aumenta a resistência de células do adenocarcinoma da mama humano ao agente farmacológico docetaxel. Em conclusão, SOX2 é um fator essencial na transformação celular mediada por RasV12, assim como tem um papel importante na resistência das células cancerígenas à terapia. Olhando para estes resultados, este fator pode ser o novo alvo terapêutico na luta contra o cancro.
20
McGrath, Mark. "Studies on the transforming proteins of adenovirus 12 with regard to their functions in oncogenic transformation." Thesis, University of Leeds, 1988. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.328960.
Full text
21
Kabarowski, Janusz Henryk. "The mechanism of transformation by the BCR-ABL tyrosine kinase oncogene." Thesis, Institute of Cancer Research (University Of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266577.
Full text
22
Steinbrück, Lisa. "The role of the herpesviral proteins LMP2A, K1, and K15 during oncogenic transformation of primary B cells." Diss., lmu, 2012. http://nbn-resolving.de/urn:nbn:de:bvb:19-141298.
Full text
23
Drayton, Sarah. "Neoplastic transformation of p16INK-deficient human fibroblasts by co-operating cellular oncogenes." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.404410.
Full text
24
Quattrochi, Brian J. "Subtle Controllers: MicroRNAs Drive Pancreatic Tumorigenesis and Progression: A Dissertation." eScholarship@UMMS, 2015. https://escholarship.umassmed.edu/gsbs_diss/776.
Full textAbstract:
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies in the United States, with an average five-year survival rate of just 6.7%. One unifying aspect of PDAC is mutational activation of the KRAS oncogene, which occurs in over 90% of PDAC. Therefore, inhibiting KRAS function is likely an effective therapeutic strategy for this disease, and current research in our lab and others is focused on identifying downstream effectors of KRAS signaling that may be therapeutic targets. miRNAs are powerful regulators of gene expression that can behave as oncogenes or tumor suppressors. Dysregulation of miRNA expression is commonly observed in human tumors, including PDAC. The mir-17~92 cluster of miRNAs is an established oncogene in a variety of tumor contexts, and members of the mir-17~92 cluster are upregulated in PDAC, but their role has not been explored in vivo. This dissertation encompasses two studies exploring the role of miRNAs in pancreatic tumorigenesis. In Chapter II, I demonstrate that deletion of the mir-17~92 cluster impairs PDAC precursor lesion formation and maintenance, and correlates with reduced ERK signaling in these lesions. mir-17~92 deficient tumors and cell lines are also less invasive, which I attribute to the loss of the miR-19 family of miRNAs. In Chapter III, I find that Dicer heterozygosity inhibits PDAC metastasis, and that this phenotype is attributable to an increased sensitivity to anoikis. Ongoing experiments will determine whether shifts in particular miRNA signatures between cell lines can be attributed to this phenotype. Together these findings illustrate the importance of miRNA biogenesis, and the mir-17~92 cluster in particular, in supporting PDAC development and progression.
25
Quattrochi, Brian J. "Subtle Controllers: MicroRNAs Drive Pancreatic Tumorigenesis and Progression: A Dissertation." eScholarship@UMMS, 2004. http://escholarship.umassmed.edu/gsbs_diss/776.
Full textAbstract:
Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal malignancies in the United States, with an average five-year survival rate of just 6.7%. One unifying aspect of PDAC is mutational activation of the KRAS oncogene, which occurs in over 90% of PDAC. Therefore, inhibiting KRAS function is likely an effective therapeutic strategy for this disease, and current research in our lab and others is focused on identifying downstream effectors of KRAS signaling that may be therapeutic targets. miRNAs are powerful regulators of gene expression that can behave as oncogenes or tumor suppressors. Dysregulation of miRNA expression is commonly observed in human tumors, including PDAC. The mir-17~92 cluster of miRNAs is an established oncogene in a variety of tumor contexts, and members of the mir-17~92 cluster are upregulated in PDAC, but their role has not been explored in vivo. This dissertation encompasses two studies exploring the role of miRNAs in pancreatic tumorigenesis. In Chapter II, I demonstrate that deletion of the mir-17~92 cluster impairs PDAC precursor lesion formation and maintenance, and correlates with reduced ERK signaling in these lesions. mir-17~92 deficient tumors and cell lines are also less invasive, which I attribute to the loss of the miR-19 family of miRNAs. In Chapter III, I find that Dicer heterozygosity inhibits PDAC metastasis, and that this phenotype is attributable to an increased sensitivity to anoikis. Ongoing experiments will determine whether shifts in particular miRNA signatures between cell lines can be attributed to this phenotype. Together these findings illustrate the importance of miRNA biogenesis, and the mir-17~92 cluster in particular, in supporting PDAC development and progression.
26
Chadee, Deborah Natalie. "Involvement of histone H1 and H3 phosphorylation in oncogene-mediated cellular transformation." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk2/ftp02/NQ41604.pdf.
Full text
27
Wang, Hsiao-Hsien. "Cytotoxic effects of a novel nitric oxide donor compound and oncogenic transformation of a human urothelial cell line." Thesis, University of St Andrews, 1995. http://hdl.handle.net/10023/14088.
Full textAbstract:
Transitional cell carcinoma of the bladder is commonly encountered in urological practice. It affects people of a relatively young age causing economic and social distress to patients. In order to prevent the disease it is important to understand its pathogenesis. In this study, we have tumorigenically transformed a human urothelial cell by growing cells in a serum free, factor free, chemically defined culture. The tumorigenic property of the cell was determined by the generation of a tumor after inoculation into nude mouse. DNA fingerprinting analysis demonstrated the common back ground of the non-tumorigenic human urothelial cell and its tumorigenic transformant. This result also shows evidence of mutation occurring during transformation. By analysing conditioned medium, a significant reduction in the levels of soluble human stem cell factor and interleukin la were found in tumorigenic cell conditioned medium. A model derived from this evidence may suggest that tumor cells undergo further transformation under nutrient and growth factor deprived conditions. Intravesical chemotherapeutic agents in current use have shown moderate tumor-killing effects with some systemic or local side effects. Identification of a drug with better effect and less side effects is essential for the successful treatment of bladder tumors. Nitric oxide (NO) is a natural product of the human body with a role in tumor cell-killing. Thus by using NO as a chemotherapeutic agent we could at least expect limited side effects. Roussin's black salt (RBS) is a novel NO donor. Its cytotoxicity was tested on tumorigenic (T24) and non-tumorigenic (SV-HUC-1) human urothelial cells. The cytotoxicity of RBS was shown to be dose- and contact time- dependent. This cytotoxicity was enhanced by light irradiation and reduced in the presence of haemoglobin. The cytotoxic effect of RBS was also tested on CHO cells and the DNA repair deficient mutant xrs-5 cell line. Both colony forming and micronuclei forming assays demonstrated that xrs-5 cells are more sensitive to RBS than their counterpart. This result may indicate that NO is involved in the cytotoxicity of RBS and furthermore that DNA damage might be one possible mechanism by which the cytotoxic effect of RBS is expressed.
28
Palmer, Susan A. "The role of EVI-1 in cellular transformation and its biological activity in primary bone marrow cells." Thesis, University of Glasgow, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340250.
Full text
29
Sridhar, Joshi Pooja. "LOSS OF RAB25 COOPERATES WITH ONCOGENES IN THE TRANSFORMATION OF HUMAN MAMMARY EPITHELIAL CELLS (HMEC)." OpenSIUC, 2017. https://opensiuc.lib.siu.edu/theses/2150.
Full textAbstract:
The RAB guanosine triphosphates (RAS-related in brain) belong to the Ras superfamily of GTPases, and loss of RAB 25 expression has been reported in a number of breast cancer cases containing H-Ras point mutations, particularly triple negative breast cancers (TNBC), one of the most aggressive subtypes of breast cancer and associated with a poor prognosis. The mechanism involved in the progression of these tumors is poorly understood. In this study, we are trying to understand if loss of RAB25 expression in Human Mammary Epithelial Cell (HMEC) lines co-operates with H-Ras mutations and contributes to tumorigenesis. HMEC were immortalized by transduction with LXSN CDK4 R24C, a mutant form of cyclin-dependent kinase, followed by transduction with hTERT, catalytic subunit of the telomerase enzyme that permits the cells to exceed the Hayflick Limit and become immortal. We have found that with loss of RAB25 and over expression of mutant H-Ras61L, immortal HMEC undergo transformation. We have looked into the co-operativity between loss of Rab25 and H-Ras61L mutant by in-vitro studies to show their anchorage independent growth and increased ability to migrate. Furthermore, cells express low CD24, high CD44, and very low levels of Claudin indicating that cells acquire stem-like properties upon transformation. Loss of RAB25 and over-expression of H-ras61L resulted in increased expression of transcription markers Snail and Slug that drive these cells to lose E-cadherin and undergo Epithelial Mesenchymal Transition (EMT). This study shows that loss of RAB25 and over-expression of mutant H-Ras can transform HMEC and give rise to mesenchymal stem-like tumors. Our findings reveal that RAB25 functions as a tumor suppressor gene, and loss of RAB25 could serve as a novel biomarker in the prognosis of Claudin-low type of TNBC.
30
Li, Xingnan. "Regulation of [beta]-catenin by Gli1 in epithelial transformation." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2006. http://www.mhsl.uab.edu/dt/2007p/li_xingnan.pdf.
Full text
31
Fonti, Claire. "Caractérisation des altérations génétiques et épigénétiques associées aux étapes précoces de la transformation tumorale mammaire." Thesis, Montpellier 1, 2013. http://www.theses.fr/2013MON1T024.
Full textAbstract:
Les génomes des cellules cancéreuses subissent de profonds changements tant au niveau de leur structure, qu'au niveau épigénétique. Les tumeurs de sein présentent en particulier des profils d'anomalies génétiques et épigénétiques complexes et hétérogènes. Alors qu'une meilleure compréhension de la dynamique d'apparition des anomalies permettrait de mieux appréhender la complexité des tumeurs, peu d'informations sont disponibles à ce sujet. En effet la plupart des données, ont été, et sont produites à partir de tumeurs primitives ou de lignées cancéreuses établies et ne renseignent pas sur la séquence d'événements qui accompagnent le passage de l'état normal à cancéreux. De ce fait, nous nous sommes intéressés aux étapes précoces de la cancérogenèse. Nos travaux se basent sur l'utilisation d'un modèle de transformation progressive in vitro de cellules épithéliales mammaires primaires (HMEC). Les cellules, transduites de façon séquentielle à l'aide de constructions rétrovirales portant des shARN et différentes combinaisons d'oncogènes, ont été caractérisées à chaque étape au niveau cellulaire et moléculaire (CFH, MeDIP, Micro-array) afin de répondre aux questions suivantes : (1) Quelle est la séquence d'apparition des modifications épigénétiques et structurales au cours de la transformation tumorale ? (2) Les profils d'anomalies génétiques et épigénétiques sont-ils modulés en fonction de la voie oncogénique initialement activée dans la tumeur ? Contrairement aux données de la littérature, nous avons obtenu des cellules transformées grâce à l'expression de seulement deux éléments génétiques définis et non trois. Nos résultats indiquent que l'inactivation de p53 provoque la mise en place d'un terrain favorable à l'acquisition de nouvelles anomalies génomiques mais induit surtout d'importantes modifications du méthylome. De plus nous avons montré que les profils de remaniements génétiques et épigénétiques dépendent de l'oncogène initialement activé. Pour finir, nos résultats indiquent que la nature de l'oncogène initialement activé et responsable de la transformation, conditionne la dynamique de production et de sélection des anomalies et supportent l'hypothèse que l'hétérogénéité du cancer du sein peut être à l'origine de l'activation de voies oncogéniques distinctesThe genome of cancer cells undergoes profound changes at genetic and epigenetic level. Breast tumors exhibit in particular complex and heterogeneous genetic and epigenetic profiles. While a better understanding of the dynamics of these changes could allow a better understanding of tumor complexity, little information is available on this subject. In fact, most data have been, and are produced from primary tumors or established cancer cell lines and do not provide information on the sequence of events that accompany the transition from normal to cancerous state. Therefore, we have been interested in the early stages of carcinogenesis. To this aim, we have developed a stepwise transformation model of HMECs (human mammary epithelial cell) by sequential transduction of oncogenes and/or shRNA. Each cellular variant have been characterized at the cellular and molecular level (CGH, MeDIP, and Micro-array) in order to answer the following questions (1) what is the sequence of structural and epigenetic changes during malignant transformation? (2) The patterns of genetic and epigenetic abnormalities are they modulated according to the oncogenic pathway initially activated in the tumor? Contrary to the literature data, we have obtained transformed cells with the expression of only two defined genetic elements. Our results indicate that p53 inactivation promotes the acquisition of genomic alteration but mainly induces significant changes at the DNA methylation level. In addition, we have shown that the remodeling of genetic and epigenetic profiles depends on the oncogene initially activated. Finally, our results suggest that the nature of the oncogene initially activated and responible for the transformation affects the dynamics of production and selection of anomalies, and supports the hypothesis that the heterogeneity of breast cancer may be due to activation of different oncogenic pathways
32
Lucassen, Emy Marian. "The role of the neu oncogene in the transformation and differentiation of mammary epithelial cells." Thesis, Open University, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.276089.
Full text
33
Antczak, Michael Richard. "Growth factor- and oncogene-induced transformation in chicken embryo fibroblasts and normal diploid human fibroblasts." Case Western Reserve University School of Graduate Studies / OhioLINK, 1993. http://rave.ohiolink.edu/etdc/view?acc_num=case1057173851.
Full text
34
Pavlova, Natalya Nickolayevna. "A Role for PVRL4-Driven Cell-Cell Interactions in Tumorigenesis." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10722.
Full textAbstract:
Deciphering genetic determinants of tumorigenesis is the greatest challenge and promise of the present-day era of biomedical research. As extensive tumor genome characterization efforts of the past decade had revealed, tumor genomes harbor multiple point mutations and gene copy number alterations. This exquisite complexity brings forth the challenge of distinguishing numerous incidental alterations from those that are functionally relevant to tumorigenesis. During the past decade, functional genetic screens have shown their utility in identifying genetic changes that functionally contribute to tumor-specific hallmarks and thus hold a great potential for identifying promising new targets for the rational design of successful anticancer therapies. A key hallmark of cancer cells is their ability to escape signals that govern homeostasis of normal tissue. In normal epithelia, growth and survival of cells is dictated by their physical anchorage to the extracellular matrix, and disruption of proper cell-matrix anchorage triggers cell death. Tumors of epithelial origin develop ways to subvert anoikis signals, which enables both their uncontrollable expansion at the primary site as well as metastatic colonization of distant organs. Understanding the genetic determinants of matrix-independent growth of cancer cells is a promising approach to identify potent and selective anticancer targets. In the work presented in this dissertation, we use an unbiased functional genetic screening approach to test a large set of eight thousand human genes to identify those that are involved in inducing and maintaining resistance of mammary epithelial cells to matrix detachment-induced cell death. We show that a cell adhesion molecule PVRL4 promotes cell survival in the absence of matrix anchorage in normal epithelial cells and in cancer cells. Our work reveals that PVRL4 promotes anchorage-independent growth by promoting cell-to-cell attachment and matrix-independent c-Src activation. PVRL4 is focally and frequently amplified in several types of solid tumors. Growth of orthotopically implanted tumors in vivo is inhibited by blocking PVRL4-driven cell-to-cell attachment with monoclonal antibodies, demonstrating a novel strategy for targeted therapy of cancer.
35
Gu, Zhengming. "Studies on molecular mechanisms of transformation by human papillomavirus : the role of E6 and E5 oncogenes." Thesis, McGill University, 1996. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=40133.
Full textAbstract:
The ability of the HPV-18 E6 gene to impair p53-mediated transcriptional activity induced by DNA damaging agents was investigated. It is demonstrated that E6 can abolish DNA damage induced p53-mediated transcription and that a region from amino acid residue 113 to 117 of HPV-18 E6 protein was necessary for E6 to direct the degradation of p53. The biological importance of the E6/p53 interaction was then directly examined in HPV-16 containing cervical carcinoma derived cells by introducing the monomeric p53 mutant which is resistant to E6 mediated degradation. The two major observations made from this study were: (i) loss of p53 activity plays an important role in maintaining the malignant phenotype of these cells with respect to cell proliferation; (ii) the monomeric p53 mutant without its C-terminal regulatory region was biologically functional with respect to impairing cell proliferation in HPV-16 containing cervical carcinoma derived cells. Finally, it was revealed that the cellular MAP kinase signal transduction pathway was more active in cells expressing the HPV-16 E5 gene than in control cells or cells expressing E6 and E7. These observations help to define the mechanisms by which HPV oncogenes contribute to the development and maintenance of the neoplastic phenotype.
36
Kennah, Erin. "Identification of differentially expressed genes in AHI-1-mediated leukemic transformation in cutaneous t-cell lymphoma." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/962.
Full textAbstract:
The oncogene Ahi-1 was recently identified through provirus insertional mutagenesis in murine leukemias and lymphomas. Its involvement in human leukemogenesis is demonstrated by gross perturbations in its expression in several leukemic cells lines, particularly in cutaneous T-cell lymphoma (CTCL) cell lines (Hut 78 and Hut 102). Hut 78 is derived from a patient with Sezary syndrome, a common leukemic variant of the human CTCL mycosis fungoides. Aberrant expression of AHI-1 mRNA and protein has been found in CD4⁺CD7⁻ leukemic Sezary cells from patients with Sezary syndrome. Moreover, stable suppression of AHI-1 using retroviral-mediated RNA interference in Hut 78 cells inhibits their transforming activity in vitro and in vivo. In an effort to identify genes involved in AHI-1-mediated leukemic transformation in CTCL, microarray analysis was performed to compare six RNA samples from AHI-1 suppressed Hut 78/sh4 cells to five samples from Hut 78 control cells. Limma and dChip analyses identified 218 and 95 differentially expressed genes, respectively, using a fold change criteria of > or < 2 and a p-value threshold of ≤ 0.01. After evaluation of both analyses, 21 genes were selected based upon interesting structural and functional information, specificity to hematopoietic cells or T-cells, and previous connections to cancer. Expression patterns of these 21 genes were validated by qRT-PCR with p-values < 0.05 ranging from 1.97 x 10⁻¹⁰ to 6.55 x 10⁻³, with the exception of BRDG1 at 5.88 x 10⁻². The observed up-regulation of both BIN1 and HCK in AHI-1 suppressed Hut 78/sh4 cells as compared to control cells further confirmed at the protein level. The tumor suppressor BIN1 is known to physically interact with c-MYC, which also exhibits differential protein expression in these cells. Characterization of BIN1 identified 4 isoforms all of which contain exon 10 and demonstrate alternative splicing of exons 12A and 13. Additionally, qRT-PCR results from primary Sezary samples indicate there is clinical significance in the expression changes detected for BIN1, HCK, REPS2, BRDG1, NKG7 and SPIB. These findings identify several new differentially expressed genes that may play critical roles in AHI-1-mediated leukemic transformation of human CTCL cells.
37
Steinbrück, Lisa [Verfasser], and Dirk [Akademischer Betreuer] Eick. "The role of the herpesviral proteins LMP2A, K1, and K15 during oncogenic transformation of primary B cells / Lisa Steinbrück. Betreuer: Dirk Eick." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2012. http://d-nb.info/1020790709/34.
Full text
38
Morton, Jennifer P. "The role of Fas signalling and the c-MYC oncogene in T cell apoptosis and transformation." Thesis, University of Glasgow, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.390740.
Full text
39
McGarry, Lynn C. "Mediation of transformation by the v-fos oncogene : regulation of the invasive phenotype by histone deacetylases." Thesis, Open University, 2004. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.403835.
Full text
40
Pauker, Viktoria Isabella [Verfasser], Thomas C. [Gutachter] Mettenleiter, and Sonja [Gutachter] Härtle. "Proteome analysis of chicken lymphocytes after infection and transformation by the oncogenic Marek’s disease virus / Viktoria Isabella Pauker ; Gutachter: Thomas C. Mettenleiter, Sonja Härtle." Greifswald : Ernst-Moritz-Arndt-Universität, 2018. http://d-nb.info/1165227398/34.
Full text
41
Baffet, Georges. "Expression des oncogenes et des cytokeratines au cours de la differenciation et de la transformation des cellules hepatiques." Rennes 1, 1989. http://www.theses.fr/1989REN10087.
Full textAbstract:
Recherche de genes anormalement exprimes au cours du processus de cancerisation du foie; etablissement des relations entre ces alterations et des modifications de la forme et du cytosquelette des cellules, des communications intercellulaires, et des fonctions specifiques hepatocytaires. Etude de l'expression des oncogenes de la famille ras et du c-myc durant l'hepatocarcinogenese. Etude de l'expression des cytokeratines au cours de la differenciation cellulaire et de la transformation cellulaire
42
Quidute, Ana Rosa Pinto. "ExpressÃo dos genes GNAS e BTG2 e de um painel de microRNAs em somatotrofinomas esporÃdicos com e sem mutaÃÃo no gene GNAS." Universidade Federal do CearÃ, 2013. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=11346.
Full textAbstract:
nÃo hÃIntroduÃÃo: MutaÃÃes nos genes GNAS e AIP estÃo presentes em 35% e 3%, respectivamente, dos somatotrofinomas esporÃdicos. Recentemente, observa-se importÃncia biolÃgica crescente dos microRNAs (miRNAs) na tumorigÃnese hipofisÃria. Entretanto, mecanismos moleculares envolvidos na patogÃnese de 60% desses tumores permanecem nÃo elucidados. Objetivos: Identificar a prevalÃncia de mutaÃÃes nos genes GNAS e AIP em um grupo de somatotrofinomas esporÃdicos. Comparar parÃmetros clÃnicos e bioquÃmicos ao diagnÃstico como idade, tamanho tumoral e agressividade (escore Hardy), hormÃnio do crescimento (GH), prolactina (PRL) e Fator de Crescimento Insulin-Like I (IGF-1) e resposta as terapÃuticas entre os grupos com (gsp+) e sem (gsp-) mutaÃÃo no GNAS. Analisar a expressÃo dos genes GNAS e BTG2 e miRNAs entre somatotrofinomas e hipÃfises normais (HN) e a associaÃÃo entre a expressÃo com agressividade, a resposta à cirurgia e a todas as terapÃuticas adjuvantes disponÃveis. Material e MÃtodos: 26 pacientes com diagnÃstico de acromegalia. Tamanho tumoral foi avaliado por RNM/CT e o grau de invasibilidade pelo escore de Hardy (I a IV). GH basal ≤2.5μg/L ou nadir de GH apÃs o GTT≤1μg/L e IGF-1 normal para idade e sexo foram utilizados como critÃrio de cura apÃs cirurgia transesfenoidal (CTE). Como controle com o anÃlogo da somatostatina (AS), adotamos a normalizaÃÃo dos nÃveis de IGF-1 para idade e sexo. As amostras tumorais (n=26) foram obtidas durante a CTE, realizado histopatolÃgico e armazenadas a -70 ÂC, para estudos moleculares. HN (07) foram obtidas durante autÃpsias. RNA e DNA total foram extraÃdos pelo TRIzolÂ. Os cÃdons 201 e 227 do gene GNAS e o AIP completo foram sequenciados. ExpressÃo relativa dos genes GNAS e BTG2 e dos miRNAs let-7a, miR-16a, miR-21, miR-141, miR-143, miR-15a, miR-145, miR-23a, miR-23b e miR-24-2 foi avaliada por qPCR (sondas TaqMan), pelo mÃtodo 2-ΔΔCt. Resultados: A frequÃncia de mutaÃÃes no GNAS foi de 35% e no AIP 3,8%. NÃo houve diferenÃa entre as mÃdias de idade (39,0Â11,5 vs 43,6Â9,0 anos; p=0,32), nas concentraÃÃes plasmÃticas basais de GH (62,4Â128,1 vs 39,9Â48,3Âg/L; p=0,39), IGF-1 (435,5Â230,8 vs 556,9 238,3 %ULNR; p=0,32), PRL (25,7Â29,8 vs 30,9Â32,8 ng/L; p=0,69) e agressividade tumoral entre os gsp+ e gsp-(p=1,00). Ao analisar o uso do AS como terapÃutica adjuvante à CTE, observamos que 04/05 (80%) dos indivÃduos com somatotrofinoma gsp+ obtiveram controle da doenÃa, enquanto que no grupo gsp- 02/06 (33%) obtiveram controle (p=0,08). Quando associamos ao AS, os agonistas dopaminÃrgicos e/ou radioterapia externa, observamos que 05/05 (100%) dos pacientes gsp+ tiveram critÃrio de controle da doenÃa, contra (04/09) 44% no grupo gsp- (p=0,09). NÃo houve diferenÃa na expressÃo de GNAS entre os somatotrofinomas e as HN (1,07Â0,55 vs 0,98Â0,28; p=0,97), e entre os gsp+ e gsp- (1,04Â0,59 vs 1,10Â0,55; p=0,97, respectivamente). Os tumores Hardy I / II apresentaram maior expressÃo do GNAS do que os tumores classificados como III / IV (p=0,02). NÃo houve associaÃÃo entre a expressÃo do GNAS e o controle da doenÃa com cirurgia isolada ou com o uso de todas as terapÃuticas adjuvantes. Observamos hipoexpressÃo do BTG2 e dos miR-16a e miR-141 em somatotrofinomas quando foram comparados com as HN (p=0,002, fold=-6,63; p=0,01, fold=-10,00; p=0,0003, fold=-50,00, respectivamente) sem diferenÃas entre os gsp+ e gsp-. Houve hiperexpressÃo do miR-21 (p=0,02;fold=10,18) em somatotrofinomas (20,16Â18,48) quando comparado com as HN (2,52 Â3,56), sem diferenÃa entre os gsp + e gsp-. NÃo houve diferenÃa na expressÃo entre os grupos gsp+ e gsp- para os miRNAs let-7a, miR-21, miR-143, miR-15a, miR-23a e miR-24-2. Entretanto, miR-145 e miR-23b foram mais hipoexpressos no grupo gsp+ quando comparados ao gsp- (p=0,03, fold=-4,83 e p=0,02, fold=-2,77, respectivamente). NÃo houve associaÃÃo entre a expressÃo do BTG2 e o painel de miRNAs com agressividade e com o controle da doenÃa. ConclusÃo: Na presente sÃrie de somatotrofinomas, assumidos como esporÃdicos, a frequÃncia de mutaÃÃes nos genes GNAS (35%) e AIP (3,8%) foram semelhantes aos relatados na literatura. NÃo houve diferenÃas nas caracterÃsticas clÃnicas e bioquÃmicas, agressividade, resposta Ãs terapÃuticas, e na expressÃo diferencial do GNAS entre os pacientes com tumores gsp+ e gsp-. HipoexpressÃo de BTG2 (gene supressor tumoral relacionado Ãs vias de sinalizaÃÃo do p53 e do Rb), baixa expressÃo de miRNAs (supressores tumorais) e alta expressÃo de oncomirs em somatotrofinomas sugerem um papel desses na tumorigÃnese somatotrÃfica.
Introduction: Mutations in GNAS and AIP genes are present in 35% and 3%, respectively, of the sporadic somatotropinomas. Recently, increased biological importance of microRNAs (miRNAs) has been observed in pituitary tumorigenesis. However, the molecular mechanisms involved in the pathogenesis of 60% of these tumors remain to be elucidated. Objectives: To identify the prevalence of mutations in GNAS and AIP genes in a series of sporadic somatotropinomas. Compare clinical, bioquimical parametrer at diagnosis as age, tumor size and theirs aggressiveness, pre-operative growth hormone (GH), prolactin (PRL) and insulin-like growth factor-I (IGF-1) levels and treatment responsiveness between somatotropinomas with (gsp+) and without (gsp-) GNAS mutation.To analyze the expression of GNAS and BTG2 genes and a panel of miRNAs between somatotrofinomas and normal pituitaries (NP) and the association between the expression of these genes and miRNAs with aggressiveness, as well as disease control with surgery or control with all adjuvant therapeutic approaches. Material and Methods: 26 patients with acromegaly. GH basal ≤2.5μg/L or nadir after OGTT ≤1μg/L and normal IGF-I matched for age and sex were used as diagnosis and for cure criteria after transsphenoidal surgery (TS). As control after somatostatin analogues (SA), we adopted the normalization of IGF-I matched for age and sex. Tumor size was evaluated by MRI/CT and the degree of invasiveness by Hardy score (I to IV).Tumor samples (26) were obtained during TS, processed for histopathology and stored at -70ÂC for molecular studies. NP (07) were obtained during autopsy. Total DNA and RNA were extracted by TRIzolÂ. Codons 201 and 227 of the GNAS gene and the whole AIP gene were sequenced. Relative expression of BTG2 and GNAS genes and miRNAs let-7a, miR-16a, miR-21, miR-141, miR-143, miR-15a, miR-145, miR-23a, miR-23b, and miR-24-2 was measured by qPCR (TaqMan probes) using 2-ΔΔCt method. Results: Frequencies of GNAS and AIP mutations were 35% and 3.8%, respectively. There was no difference between the mean age (39.0 Â 11.5 vs 43.6 Â 9.0 years, p=0.32), basal GH (62.4Â128.1 vs 39.9 Â 48.3 μg/L; p=0.39), IGF-I (435.5 Â 230.8 vs. 556.9 Â 238.3; p=0.32) and PRL (25.7 Â 29.8 vs. 30.9 Â 32.8 ng/L, p=0.69) in plasma concentration, and tumor aggressiveness (p=1.00) between (gsp+) and (gsp-) groups. We observed that 80% (04/05) of gsp+ whereas 33% (02/06) of the gsp- achieved control (p=0.07) after SA therapy adjuvant to TS. When SA, dopamine agonists and/or external radiotherapy were associated 100% (05/05) of gsp+ group and 44% (04/09) of gsp- group (p=0.08) showed disease control.There was no difference in GNAS expression between somatotropinomas and NP (1.07 Â 0.55 vs 0.98 Â 0.28, p=0.97) as well as between somatotropinomasgsp+ and gsp- (1.04 Â 0.59 vs 1.10 Â 0.55, p=0.97, respectively). Hardy I/II tumors showed higher GNAS expression than Hardy III/IV (p=0.02), but there was no association between GNAS expression and disease control with surgery alone or associated with other adjuvant therapies. We observed hypoexpression of BTG2 and miR-16a and miR-141 in somatotropinomas compared with NP (-6.6 fold, p=0.002; -10.0 fold, p=0.01; and -50.0 fold, p=0.0003, respectively) with no difference between gsp+ and gsp- somatotropinomas. There was miR-21 overexpression in somatotropinomas compared with NP (20.2 Â 18.5 vs 2.5 Â 3.6; 10.2 fold, p=0.02), with no difference between gsp+ and gsp- somatotropinomas. However, miR-145 and miR-23b were more hipoexpressed in gsp+ compared to gsp- (-4.8fold, p=0.03 and-2.7 fold, p=0.02). There was no association between the expression of BTG2 and a panel of miRNAs with aggressiveness or disease control. Conclusion: In this series of assumed sporadic somatotopinomas, the frequencies of mutations in GNAS (35%) and AIP (3.8%) were similar to the literature. There were no differences in clinical and biochemical characteristics, aggressiveness, response to therapy, and GNAS expression in patients with gsp+ and gsp- somatotropinomas. Hypoexpression of BTG2, a tumor suppressor gene related to p53 and Rb signaling pathways, low expression of tumor suppressor miRNAs and high expression of oncomirs in somatotropinomas suggest a role in the somatotrophic tumorigenesis.
43
Chaix, Amandine. "Les spécificités de la signalisation oncogénique par rapport à la signalisation physiologique : le modèle de KIT, un récepteur à activité tyrosine kinase." Thesis, Aix-Marseille 2, 2010. http://www.theses.fr/2010AIX22079/document.
Full textAbstract:
Le système de communication SCF/KIT est impliqué dans le développement et l’homéostasie de plusieurs lignages cellulaires. Des dysfonctionnements de la voie sont à l’origine de pathologies affectant ces compartiments. En particulier, des mutations gain-de-fonction, qui entraînent l’activation constitutive du récepteur à activité tyrosine kinase KIT, sont responsables de néoplasies chez l’homme.L’objectif des travaux réalisés durant cette thèse était d’étudier certaines spécificités de la signalisation de formes oncogéniques de KIT, ceci dans le modèle du mastocyte transformé par l’oncogène KIT-D816V. Cette étude a été menée au niveau proximal sur le récepteur lui-même ainsi qu’au niveau distal sur la voie STAT ,une des voies de signalisation spécifiquement activée de manière constitutive par le récepteur mutant.Au niveau proximal, nous avons pu montrer que le motif dityrosine Y568-Y570situé dans le domaine juxtamembranaire de hKIT est une plateforme majeure de recrutement des effecteurs de la signalisation intracellulaire avec au moins 15partenaires différents recrutées. Par ailleurs l’étude de modèles cellulaires dans des analyses liées aux fonctions physiologiques du récepteur réalisés in vitro et in vivo ont révélé que le site est impliqué dans la régulation négative du signal transformant issu de l’oncogène KIT-D816.Au niveau distal, nous avons analysé les mécanismes de phosphorylation des protéines STAT1, -3 et -5 ainsi que l’importance fonctionnelle de leur activation dans la transformation dépendante de KIT-D816. Nous avons ainsi étudié la contribution de différentes kinases dans les phosphorylations activatrices des STATs sur tyrosine et serine. Nos résultats suggèrent que seul STAT5 a une activité transcriptionnelle dans nos modèles suggérant une implication potentielle non canonique des STAT1et -3 dans la transformation dépendante de KIT-D816.L’ensemble de nos travaux contribue à une meilleure compréhension des mécanismes de l’oncogenèse dépendante de KIT-D816, un point critique dans le développement raisonné de thérapeutiques anticancéreuses cibléesThe receptor tyrosine kinase KIT and its ligand, the stem cell factor (SCF), are implicated both in the development and the homeostasis of multiple cell lineages. Dysfunctions in the KIT/SCF pathway are involved in several pathologies affecting these compartments. In particular, gain-of-function mutations that lead to constitutive activation of the receptor KIT are found in human neoplasia.The purpose of this thesis project was to investigate some differences between normal and oncogenic signalling of KIT receptor using mast cells transformed by the KIT-D816 oncogene as a model. This question was analysed at aproximal level on the oncogenic receptor itself and at a more distal level on the STAT signal transduction pathway, which is specifically and constitutively activated by theKIT-D816 mutant.At the proximal level, we show that the juxtamembrane dityrosine motif Y568-Y570 of KIT is the major platform of recruitment of intracellular signalling partnerswith more than 15 interactors found in mast cells. Furthermore, the analysis ofcellular models in both in vitro and in vivo assays related to KIT physiological functions has revealed the negative role of the motif in KIT-D816-mediated cell transformation. At the distal level, we have analysed the mechanisms of phosphorylation ofSTAT1, -3 and -5 proteins and the functional relevance of their activation in KITD816-mediated transformation. We describe the contribution of different kinases inthe phosphorylation of STATs on both serine and tyrosine residues. Our results suggest that only STAT5 is transcriptionaly active whereas STAT1 and STAT3 are not, suggesting a non conventional implication of their activation in celltransformation. Our work contributes to a better understanding of the mechanisms of KITD816-mediated oncogenesis and could be used to improve the rational developmentof new targeted cancer therapies
44
Freudenberger, Nora [Verfasser], and Thomas [Akademischer Betreuer] Dobner. "Role of minor core protein V during productive infection with human adenovirus type 5 and the proteins relevance to oncogenic transformation processes / Nora Freudenberger ; Betreuer: Thomas Dobner." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2017. http://d-nb.info/1139492837/34.
Full text
45
Mortreux, Franck. "Aspects moleculaires des etapes precoces de la transformation maligne a travers l'etude de l'histoire replicative du retrovirus oncogene htlv-1." Paris 7, 2001. http://www.theses.fr/2001PA077045.
Full textAbstract:
Le retrovirus htlv-1 est l'agent de la leucemie t de l'adulte (atl) et de la paraparesie spastique tropicale (tsp) chez 5% des individus infectes. Alors que la majorite des retrovirus se replique essentiellement par transcription inverse (rt), la replication de htlv-1 repose essentiellement sur l'expansion clonale des cellules infectees. De par son activite activatrice de la proliferation cellulaire et son potentiel mutagene, la proteine virale tax joue un role clef dans la profileration de la cellule infectee. Htlv-1 se replique donc essentiellement par l'immortalisation de sa cellule hote dans un contexte d'instabilite genetique genere par tax. L'etude du tempo replicatif de htlv-1 chez le singe ecureuil, experimentalement infecte, a permis de montrer que la rt et l'expansion clonale appartenaient a deux etapes distinctes de l'histoire naturelle de l'infection. La replication virale par rt ne constitue en effet qu'une premiere etape transitoire et precoce de l'infection suivie de l'expansion clonale persistante des cellules infectees, l'accroissement de la charge provirale au cours du temps etant correlee au degre de proliferation des cellules infectees et non au nombre de cellules infectees de novo. Chez l'homme, l'etude de la variabilite genetique du provirus a permis de montrer qu'il existait des phenomenes de mutations somatiques (ms) accompagnant la mitose des cellules hotes. Quel que soit le statut clinique des individus, l'essentiel de la variabilite genetique de htlv-1 resulte de ms plutot que de rearrangements lies aux erreurs de rt. La frequence elevee de ces mutations, retrouvee egalement au niveau du genome hote, est correlee au degre de proliferation des cellules infectees. Les clones de grande ampleur etant plus abondant chez les patients atteints d'atl ou de tsp, les ms ont ete plus frequemment detectees chez les sujets symptomatiques. Ces resultats decrivent un nouveau mode de variabilite des retrovirus et suggerent qu'une proliferation accrue des cellules infectees par htlv-1 est susceptible d'entrainer une accumulation de mutations propices a l'acquisition du phenotype malin.
46
Bechade, Catherine. "Role des oncogenes v-mil et v-myc dans la multiplication et la transformation des cellules embryonnaires de neuroretine en culture." Paris 7, 1989. http://www.theses.fr/1989PA077176.
Full textAbstract:
Le retrovirus aviaire mh2 induit la multiplication et la transformation des cellules de neuroretine (nr) d'embryons de poulet qui normalement ne se divisent pas. Le genome du virus mh2 contient deux oncogenes: v-mil et v-myc. L'isolement de mutants de mh2, deletes dans v-mil ou v-myc, nous a permis de preciser les proprietes biologiques de chacun des oncogenes et d'analyser les relations entre l'induction de la division cellulaire et la transformation. Le gene v-mil est responsable de la division des cellules de nr. Par contre, il induit un phenotype de transformation reduit dans les cellules infectees. La transformation des cellules de nr par mh2 necessite, donc, l'expression des deux oncogenes v-mil et v-myc. Le gene v-myc n'a pas d'effet mitogene ni transformant dans les cellules de nr quiescentes. Par contre, ce gene peut transformer des cellules de nr dont la division a ete induite soit par des oncogenes viraux, tels que v-src ou v-mil, soit par l'utilisation de milieux enrichis. L'expression des proprietes transformantes de v-myc dans les cellules de nr depend donc de leur etat de division. Les cellules de nr peuvent egalement etre induites a se diviser apres infection par un retrovirus depourvu d'oncogenes: le rav-1. Cette proliferation resulte, dans certains cas, de l'activation et de la transduction du gene cellulaire c-mil
47
Hartmann, Thomas [Verfasser], Stefan [Akademischer Betreuer] Engelhardt, and Claus [Akademischer Betreuer] Schwechheimer. "Role of the Cullin-RING E3 ubiquitin ligase 7 in oncogenic transformation by simian virus 40 large T-antigen / Thomas Hartmann. Gutachter: Stefan Engelhardt ; Claus Schwechheimer. Betreuer: Stefan Engelhardt." München : Universitätsbibliothek der TU München, 2014. http://d-nb.info/1053761996/34.
Full text
48
AHMED, FADLALLAH MINA. "Etude des effets anti/apoptotiques des oncogenes bcr/abl par utilisation des modeles de transformation hematopoietiques in vitro implication potentielle des molecules stat." Paris 7, 1999. http://www.theses.fr/1999PA077002.
Full textAbstract:
Le sujet de ce travail est l'etude des effets anti-apoptotiques de bcr-abl par utilisation des modeles de transformation hematopoietiques in vitro. Dans le modele de transformation de la lignee murine ba/f3, nous avons montre que bcr-abl et le cepo-r induisaient une autonomie de croissance mais seul bcr-abl etait capable d'inhiber l'apoptose induite par deprivation de serum et presence d'etoposide, et activer de maniere constitutive les molecules stat1, 5 et 6. A l'inverse, dans la lignee myelomonocytaire a croissance autonome u937, bcr-abl etait incapable d'inhiber l'apoptose induite par divers stimuli. Cette absence d'effet anti-apoptotique etait correlee a l'absence d'activation constitutive de stat5, qui a ete par ailleurs detectee sous une forme tronquee dans cette lignee. La surexpression de stat5b murin dans u937 n'etait pas suffisante pour complementer l'absence d'effet anti-apoptotique de bcr-abl. Enfin, nous avons utilise la lignee hematopoietique pluripotente ut-7 pour montrer qu'il existe une correlation significative entre les niveaux d'expression de bcr-abl et son effet anti-apoptotique, avec par ailleurs, une diminution du potentiel de differenciation de cette lignee dans un clone exprimant des quantites fortes de bcr-abl.
49
Bchini-Hooft, van Huijsduijnen Olfa. "Influence de l'hormone de croissance et des oncogenes RAS et MYC sur le developpement et la transformation des cellules epitheliales mammaires de souris transgeniques." Université Louis Pasteur (Strasbourg) (1971-2008), 1990. http://www.theses.fr/1990STR13228.
Full text
50
Mouly, Vincent. "Heterogeneite des cellules musculaires apparaissant au cours du developpement embryonnaire chez les oiseaux : isolement de lignees par l'utilisation d'un virus oncogene." Paris 7, 1988. http://www.theses.fr/1988PA077125.
Full textAbstract:
Le tissu musculaire est forme par l'association de cellules mononuclees en elements plurinucles, les myotubes, euxmemes associes en fibre musculaire. La mise en culture des myoblastes et l'etude des proteines exprimees dans les myotubes a permis de montrer que trois types de differenciation se succedent au cours des developpements du bourgeon de patte: le premier (4-5eme jour) est caracterise par la formation de petits myotubes exprimant les chaines legeres de la myosine de type mlc::(1f) et mlc::(2s); le deuxieme (6-7eme jour) presentent de grands myotubes exprimant les 4 types de chaines legeres et le troisieme (9-12eme jour) exprime les formes rapides (mlc::(1f) et mlc::(2f)). La reassociation in vitro des myoblastes dissocies provoque l'expression dans les myotubes des marqueurs exprimes in vivo, montrant l'importance des contacts intercellulaires pour l'expression d'un programme complet de differenciation