Tesi: "Tumour suppressor gene pten"

1

Vlachogiannis, G. "Investigation of unique dependencies of cells lacking the PTEN tumour suppressor gene". Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1395122/.

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Over the past ten years significant effort has been put in the identification of pharmacological targets that facilitate the selective targeting of cancer cells. The concept of synthetic lethality in combination with RNA interference (RNAi) technology provides an attractive platform for the identification of such drug targets. With this in mind I designed, set up, and executed a large-scale siRNA screen aiming at identifying genes that exhibit a synthetic lethal relationship with loss of the PI3K/AKT signalling cascade negative regulator PTEN. A PTEN-isogenic cell system derived from the breast epithelial cell line MCF10A was employed in this study, and screened with a siRNA library against the “Druggable genome”. Putative hits exhibiting a potential synthetic lethal relationship with loss of PTEN were identified by differential Z-score analysis, and validated in a panel of breast cancer cell lines segregated based on their PTEN status. This analysis identified several PTEN-loss synthetic lethal candidate genes whose further evaluation may reveal new insights in the biology of PTEN null cancer cells. The functional mechanism underlying one of the identified PTEN-loss synthetic lethal putative hits (CYTH1/PSCD1) was investigated in detail. Knockdown of CYTH1 selectively induced apoptosis in the PTEN-/- MCF10A cells, and biochemical and genetic evidence supported a potential synthetic lethal relationship with PI3K/AKT pathway activation due to loss of PTEN. Although definite confirmation that CYTH1 was the sole target mediating the identified PTEN-loss synthetic lethal interaction was not obtained, further investigation on the exact nature of the described PTEN-loss synthetic lethal relationship may have the potential to uncover previously unknown vulnerabilities of PTEN-deficient cancer cells that could be pharmacologically exploited.

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2

Snaddon, Jennifer A. M. "Molecular analysis of the tumour suppressor genes MXI1 and PTEN in human squamous cell carcinoma of the head and neck". Thesis, Glasgow Caledonian University, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340609.

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3

Crosland, Rachel. "Studies of the PTEN tumour suppressor in endometrial cancer". Thesis, Sheffield Hallam University, 2004. http://shura.shu.ac.uk/19515/.

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Somatic mutations in the PTEN gene (Phosphatase and Tensin Homologue Deleted on Chromosome Ten) have been found in many types of cancer, but most frequently in cancer of the endometrium. The PTEN gene encodes a D3 lipid phosphatase of the second messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3), which activates protein kinase B/Akt. Constitutive activation of Akt has been found in cells that lack functional PTEN, thus by dephosphorylating PIP3, this enzyme modulates several cellular functions e.g. proliferation, differentiation and migration. The PTEN protein comprises a 403 amino acid, 55KDa protein which is present in the cytoplasm but has also been detected in the nucleus of some cells. The function of nuclear versus cytoplasmic PTEN has not yet been determined. Little is known about modulation of PTEN expression by molecules such as hormones and cytokines. It has been reported, however, that NGF, BDNF and vitamin D3 analogues can up-regulate PTEN. The steroid hormones oestrogen and progesterone have been proposed as mediators of PTEN transcription, since their expression in endometrium reflects the menstrual cycle. The role of TGF-beta1 in PTEN expression of PTEN in human cells has been also investigated, but the results are contradictory. Compounds which stimulate up-regulation of PTEN represent potential anti-tumour therapies and therefore merit investigation. To further investigate the role of PTEN in endometrial cancer the following approaches were taken. The effect of TGF-beta1 on two endometrial carcinoma cell lines, HEC-1B and Ishikawa were investigated. The cell lines were stimulated with TGF-beta1 in the presence or absence of serum, and changes in mRNA and protein levels of PTEN and other genes analysed by RT-PCR and Western blotting. The morphology, cell number and cell viability were also assessed. Modest up-regulation of PTEN mRNA was detected in both cell lines, but little change in protein levels was observed. In accordance with published data, TGF-beta1 suppressed the growth of, and changed the morphology of both cell lines. To study PTEN sub-cellular localisation, full-length human PTEN cDNA was used in RT-PCR to generate a 1.2Kb fragment which was cloned into a green fluorescent protein expression vector pEGFP-N1 to create pRC-2. Sequencing of pRC-2 confirmed the in-frame cloning of wild-type PTEN. Lipid-basedtransfection was used to transiently transfect HEC-1B, Ishikawa and Cos-7 cells. Strong perinuclear and cytoplasmic localisation was detected in these cell lines, and localisation to the endoplasmic reticulum was observed. Stimulation with TGF-beta and 17-beta-estradiol had no discernable effect on sub-cellular localisation of PTEN in either HEC-1B or Ishikawa cell lines. A mutational study was performed using a large repository of archival endometrial carcinomas and normal cervical controls. PCR was used to amplify PTEN exons 5 and 8 from extracted DNA and the fragments separated by single-strand conformation polymorphism (SSCP) analysis. A number of samples exhibiting bandshifts were detected in both exons.

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4

Patel, Anjla Chhotubhai. "The role of fat tumour suppressor gene". Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.619808.

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5

Discenza, Maria Teresa. "Regulation of expression of the Wilms' tumour 1 tumour suppressor gene". Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=82855.

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Wilms' tumour, a pediatric kidney cancer that affects 1 in 10 000 children, is an excellent paradigm for studying the relationship between cancer and development. The Wilms' tumour suppressor 1 ( WT1) gene was identified through the study of hereditary cases of Wilms' tumour showing cytogenetic deletions at chromosome position 11p13. The WT1 gene encodes a zinc finger transcription factor necessary for the development of the genitourinary system. WT1 functions as an activator or a repressor, interacts with a number of different protein partners and regulates the expression of several genes important for cellular growth and differentiation. WT1 mRNA is present in tissues of mesodermal origin that undergo a mesenchymal to epithelial transition. Expression of WT1 is tightly regulated both temporally and spatially during development of the urogenital system.
We have identified a novel trans-acting factor, named complex D, which shows sequence specific binding to the WT1 promoter. By electrophoretic mobility shift assays (EMSA), we demonstrate that the transcription factor Sp1 binds the WT1 promoter at a site overlapping the complex D binding site. Molecular mass determination experiments and in situ UV crosslinking indicate that complex D is approximately 130 kDa and consists of at least two proteins. Transient transfection assays show that the integrity of the complex D binding site is necessary for maximal activation of a reporter gene, suggesting that complex D may function as an activator.
Similar to WT1, the ETS-domain transcription factor Pea3 is expressed in tissues where mesenchymal-epithelial interactions occur and both gene products are implicated in regulating the expression of genes necessary for the epithelialization of common organs. Transient transfection assays using WT1 promoter-reporter gene constructs identified a Pea3 responsive element in the WT1 promoter. Overexpression of Pea3 transactivates the WT1 promoter and the presence of the intact Pea3 responsive element is necessary for the transactivation. We demonstrate, by EMSA, the sequence specific binding of Pea3 to the responsive element.
WT1 and the paired box domain transcription factor Paired box 2 (Pax2) are expressed at the initial stages of metanephric kidney development and are critical for the initiation of nephrogenesis. We generated WT1/Pax2 compound heterozygous mutant mice to provide an in vivo model for studying the interplay between WT1 and Pax2 during nephrogenesis. WT1+/-/Pax2 1Neu/+ kidneys were 50% smaller that wild type kidneys and displayed a more severe underdevelopment of the medulla, renal calyces and renal pelvis compared to Pax21Neu/+ kidneys. We demonstrate that WT1 and Pax2 proteins physically interact in vitro and in vivo. Our data suggest that WT1 is a modifier of the Pax2 mutant phenotype and that both proteins may be implicated in a common pathway in the transcriptional network governing metanephric development.

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6

Zabkiewicz, Joanna. "In vivo modelling of tumour suppressor gene function". Thesis, Cardiff University, 2005. http://orca.cf.ac.uk/55388/.

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LKB1 has been implicated in a wide range of cellular functions and is associated with many potential substrates in in vitro studies, however the in vivo role of LKB1 remains unclear and its precise contribution to the prevention of intestinal tumours in the hereditary Peutz-Jegers syndrome is as yet uncharacterised. Conditional deletion of LKB1 in the murine small intestine resulted in significant disruption of intestinal homeostasis, particularly that of the differentiation process, suggesting LKB1 plays a key role in intestinal differentiation and it is loss of this function that predisposes to tumourigenesis

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7

Rohrig, A. E. "Role for tumour suppressor Merlin in gene expression". Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1415770/.

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The tumour suppressor Merlin is mutated in the familial cancer syndrome Neurofibromatosis Type 2 (NF2) and in various sporadic tumours. Several lines of evidence show a role for Merlin in mediating contact-dependent inhibition of proliferation. Contact inhibition is essential for normal tissue homeostasis and its deregulation is a hallmark of cancer. Despite extensive efforts the mechanism underlying tumour suppression by Merlin remains elusive. A proteomics approach led to the identification of novel Merlin interacting proteins several of which are involved in gene expression, in particular transcription elongation, RNA processing and histone modifications, and are also deregulated in cancer. Among those are the RNA PolymeraseII-associated factor1 complex (Paf1C), CHD1, TAT-SF1 and spliceosome components. These interactions have been validated and mapped to Merlin’s FERM domain and loss-of-function Merlin mutations found in tumours invariably disrupt these interactions. The interaction of Merlin with the Paf1C is modulated by cell density and is required for Merlin’s tumour suppressor function. We find a remarkable case of tumour suppressor gene hypersensitivity in Merlin-deficient cells that correlates with Merlin’s ability to regulate gene expression. Using genome-wide expression profiling we identify a gene signature associated with growth arrest by Merlin expression that is consistent with Merlin’s role in mediating contact inhibition and suggests a role for Merlin in innate immunity and communication with the microenvironment. By integrating re-expression and knockdown gene signatures a core Merlin signature has been defined that correlates with NF2 mutational status and suggests differential drug sensitivities and potential therapeutic targets for treatment of NF2-related tumours. Using genome-wide occupancy analysis we identify a subset of genes where Merlin expression regulates association of the Paf1C with chromatin of coding regions. Some of these regulated genes are known target genes of YAP, the transcriptional co-activator of the Hippo tumour suppressor pathway. Although YAP expression rescues growth arrest by Merlin, Merlin can regulate expression independently of YAP. A model is proposed where Merlin functions parallel to YAP to regulate gene expression at the elongation level through the Paf1C.

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8

Woodward, Emma Roisin. "Molecular genetic studies of the VHL tumour suppressor gene". Thesis, University of Cambridge, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.624312.

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9

Duarte, Antonio. "Regulation of gene expression by the Wilms' tumour suppressor, WT1". Thesis, University of Oxford, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.389178.

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10

Miranda, Alexandra de Sousa Montenegro. "Characterisation of LVI-1 (WDR76) as a candidate tumour suppressor gene". Thesis, University of Glasgow, 2006. http://theses.gla.ac.uk/4967/.

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The central aim of this study was to characterise the expression of the candidate tumour suppressor gene, LV/-J (lentivirus integration-I) and its products. The LVI-J gene (WDR76) was discovered as a target for disruption by proviral insertional mutagenesis in a case of pre-B cell lymphoma in a FIV infected cat {Beatty, 1998 5 lid; Beatty, 2002 7 lid}. As LV/-J is highly conserved, my work focused on the human and murine orthologues to take advantage of the superior resources available for these species. My work showed potentially important differences in expression of the human and mouse genes with respect to promoter use and length of 3' untranslated sequences. The murine gene is transcribed mainly from the distal PI promoter, which appears to be a bi-directional element shared with the adjacent MJapJ gene, while the human gene transcripts are derived exclusively from the proximal P2 promoter. Direct analysis by RT-PCR showed that the murine gene could also be expressed from the P2 promoter. These findings have significant implications for Lvi-l protein expression as the P2 transcripts are predicted to express larger proteins with a distinct N-terminal sequence. To characterise the LV/-J gene products, rabbit polyclonal antisera were raised to GST fusion proteins expressed in bacteria. Use of the murine anti-ml.vi-I antiserum in Western blotting identified a protein of the expected size (58 kDa) based on translation of the major mRNA species from the PI promoter. Immunofluorescence and confocal microscopy suggested that this protein is localised mainly in the cytoplasm. Although the function of LVI-I is unknown, its closest relative in the human genome is DDB2, a protein involved in repair of UV-induced DNA damage. Regulation of LVI-I expression was examined after UV irradiation, providing preliminary evidence of responses at transcriptional and post-transcriptional levels. Further leads were followed by analogy with the yeast orthologue of LVI-I, YDLI56W, but no evidence of a complex between LVI-I and MSH6 was found. In conclusion, while function of the LVI-I gene remains to be establishes, it provides the basis for future characterisation of this highly conserved and potentially important eukaryotic gene.

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11

O'Neill, Vincent John. "Characterisation of a novel multi-tissue tumour suppressor gene in mouse". Thesis, University of Glasgow, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366186.

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12

Mason, Susan. "Investigating pathological mutations in the neurofibromatosis type 2 tumour suppressor gene". Thesis, University of Newcastle Upon Tyne, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.245083.

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13

Papaconstantinou, Maria Campos Ana Regina. "Functional characterization of the Mnn1 tumour suppressor gene in Drosophila melanogaster". *McMaster only, 2007.

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14

Bright-Thomas, Rachel Marie. "Corrective gene therapy in a murine model of familial adenomatous polyposis : a study of the efficacy of gene transfer and the resultant phenotypic effects". Thesis, University College London (University of London), 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.274918.

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15

Lucas, Christopher H. "The role of the Wilms tumour suppressor gene (WTI) during human decidualization". Thesis, Swansea University, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.678325.

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16

Chinswangwatanakul, Wimol. "Role of p16 in chronic myeloid leukaemia and normal haemopoiesis". Thesis, Imperial College London, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.313953.

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17

Andrews, H. N. "Role played by BRCA1 in regulating the interferon gamma mediated antiproliferative response". Thesis, Queen's University Belfast, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.269159.

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18

McWilliams, Stewart. "BRCA1 regulates the interferon gamma mediated antiproliferative response". Thesis, Queen's University Belfast, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246464.

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19

Fidler, Carrie. "Molecular analysis of the 5q- syndrome". Thesis, Open University, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.338608.

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20

Asimakopoulos, Fotios A. "Molecular analysis of chromosome 20q deletions associated with myeloproliferative disorders and myelodysplastic syndromes". Thesis, University of Cambridge, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388490.

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21

McKenna, Sarah Mary Michelle. "The role played by BRCA1 in mediating the cytotoxic effect of antimicrotubule agents". Thesis, Queen's University Belfast, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246470.

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22

Li, Li. "Molecular analysis of the homeobox gene BarX2, a candidate tumour-suppressor gene in ovarian cancer". Thesis, University of Edinburgh, 2001. http://hdl.handle.net/1842/23088.

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The objective of this study is to investigate the role of BarX2 gene as a candidate tumour-suppressor gene in human epithelial ovarian cancer. Active work on this project was commenced by the candidate on 4^th January 1998. The scope of the project thus far has involved the following: 1) using PCR based polymorphic microsatellites to further refine the region of frequent loss of heterozygosity on chromosome 11q24 in DNA blood/tumour pairs from patients with ovarian cancer and colorectal cancer which confirms that BarX2 region is subject to LOH in clinical cancers; 2) using RT - PCR and Northern blot to detect the expression pattern of Barx2 in cancer cell lines and cancer tissues; 3) Mutation analysis using SSCP, DHPLC and Fluorescence DNA sequencing to define the molecular basis of BarX2 gene in cancer cell lines and blood/tumour pairs from patients with ovarian and colorectal cancer; 4) performing functional studies of BarX2 by using an expression vector for this genein ovarian cancer cell lines; 5) using drug- sensitivity testing in vitro to detect whether introduction of Barx5 gene into a platinum resistant ovarian cancer cell line affects the sensitivity of this cell line to Cis-platinum. Preliminary results showed that: 1) Barx2 gene has downregulated expression in at least some ovarian cancer cells and is associated with disease progression in ovarian cancer as well; 2) Altered transcript size is seen in some ovarian cancer cell; 3) The Barx2 gene can suppress the growth of ovarian cancer cell lines and tumour cell invasion in matrigel; 3) Introduction of Barx2 into a platinum resistant ovarian cancer cell line increases the sensitivity of this cell line to Cisplatinum. These results suggest that Barx2 gene may play a important role as tumour suppressor gene in carcinogenesis. Further work will focus on mutation analysis and methylation studies in cell lines and clinical samples in order to define the physical molecular basis of BarX2 abnormalities; and dissection of the matrigel invasion phenotype using cell migration and cell adhesion assays for BarX2 transfected cells.

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23

Franklin, R. J. "The role of the BRCA1 tumour suppressor gene : from biochemistry to function". Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.599182.

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BRCA1 is an important tumour suppressor gene involved in hereditary breast and ovarian cancer. Since 1994 much research has focussed on what the normal functions of this gene are at the molecular, cellular and organismal level. BCRA1 has been implicated in a number of different cellular processes many of which act to maintain genome stability. However the molecular mechanisms by which BRCA1 acts have remained elusive. Recently BRCA1 has been shown to exhibit E3 ubiquitin ligase activity, a biochemical activity which may explain how the protein functions at the molecular level. The work described in this dissertation sets out to determine the relationship between the biochemical activities of BRCA1 (including ubiquitin ligase activity) and its most well defined functions at the cellular level. The chief conclusion from this work is that ubiquitin ligase activity is not required for mediating some of BRCA1’simportant functions. Instead the BRCT domains and the formation of a complex with another protein, BARD1, are essential for function.

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24

Trueman, Lisa Ann. "The neurofibromatosis Type 2 tumour suppressor gene : further characterisation and pathological mutations". Thesis, University of Newcastle Upon Tyne, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246094.

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25

Dowell, Stephanie Patricia. "Studies of the p53 tumour suppressor gene and related proteins in cytopathology". Thesis, King's College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.336432.

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26

Ajayi, A. A. "Investigation of a tumour suppressor gene at chromosome 10q23.3 in prostate carcinoma". Thesis, University College London (University of London), 2006. http://discovery.ucl.ac.uk/1445295/.

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Using various molecular genetic techniques, attempts have been made to identify a tumour suppressor gene (TSG) in prostate carcinoma. This gene will act as a genetic marker to identify patients at risk of disease progression from prostate cancer. The region at chromosome 10q23-24 is postulated to contain a TSG that plays an important role in the development and progression of tumours as it is deleted in a number of cancers including glioblastomas, endometrial and prostate cancer. In glioblastomas, chromosome 10 is partially or entirely deleted in approximately 90% of tumours. The TSG called Pten has been identified on chromosome 10 in the region 10q23.3. The significance of loss of the Pten gene in prostate cancer is unknown. In this thesis, the clinical significance of single nucleotide polymorphisms (SNP'S) in the chromosomal region 10q23-24 was evaluated. Comparisons in the distribution of polymorphisms between Ninety-five prostate cancer patients and forty-three non-prostate cancer patients were made. Three intronic polymorphism markers within the Pten gene were used: a single-base A >G substitution in intron A, 96 bp upstream of exon 2. A 5-bp ATCTT insertion / deletion in intron D, 110 bp downstream of exon 4 and a single-base T >G substitution in intron H, 32 bp downstream of exon 8. This study did not isolate any particular trend in polymorphism distribution in the Pten gene when comparisons were made between the two study groups. The significance of loss of Pten gene in thirty-four prostate cancer patients was evaluated using four highly informative microsatellite markers: D10S541, D10S2492, D10S1765 and AFMa086wg9 located within and around the Pten locus. DNA was extracted from prostate cancer cells following microdissection of archival paraffin embedded radical prostatectomy specimens. Loss of heterozygousity (LOH) studies was performed on matching blood/tissue DNA using these four microsatellite markers. For these case specimens, frequency of allele loss of 48% was found at the D10S541 locus 39% at D10S1765 32% at D10S2492 and 22% at the AFMa086wg9 locus. At all four microsatellite, the mean (range) LOH was 35.25% (22%-48%). Of the 34 case specimens 17(50%) showed LOH in at least one of the informative marker sites. Correlating the significance of this region of LOH with pathological staging and known prognostic indicators in prostate cancer showed that the loss of the Pten gene was associated with late stage disease and likely to be involved in disease progression in prostatic adenocarcinoma.

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27

Zhu, Yong-Ming. "Studies on expression of tumour suppressor genes in acute myeloblastic leukaemia". Thesis, Nottingham Trent University, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297012.

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28

Reynolds, Paul Andrew. "Localization of a novel t(1;7) translocation associated with Wilms' tumour". Thesis, University of Bristol, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.388159.

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29

Wiegand, Kimberly Charlotte. "Clear cell ovarian carcinoma and emergence of the novel tumour suppressor gene ARID1A". Thesis, University of British Columbia, 2013. http://hdl.handle.net/2429/44697.

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30

Sigglekow, Nicholas David Garvan Institute of Medical Research Faculty of Medicine UNSW. "Mutated in colorectal cancer (MCC): a putative tumour suppressor gene in colorectal cancer". Publisher:University of New South Wales. Garvan Institute of Medical Research, 2009. http://handle.unsw.edu.au/1959.4/43617.

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Abstract (sommario):

Colorectal cancer (CRC) remains a significant burden in contemporary society due to an aging population, unhealthy dietary choices and an increasingly sedentary lifestyle. While the underlying defects for many hereditary forms of CRC have been determined, many genetic and epigenetic changes promoting common sporadic CRCs have yet to be identified. The Mutated in Colorectal Cancer (MCC) gene, identified in 1991, was initially thought to be responsible for the hereditary form of CRC, familial adenomatous polyposis, before the discovery of the susceptibility gene Adenomatous Polyposis Coli (APC), which then became the focus of intense research. Recent data, however, suggests that MCC may also be important in the development of CRC. I have investigated the mechanism of MCC gene silencing, the putative structure, and multiple functions of MCC. MCC was frequently silenced by promoter hypermethylation in CRC cell lines and primary tumours. MCC methylation showed strong molecular and clinicopathological associations with hallmarks of the serrated neoplasia pathway. Furthermore, MCC methylation was more frequent in serrated precursor lesions compared with adenomas, thus occurring early during carcinogenesis. MCC is highly conserved in complex multicellular organisms. Re-introduction of MCC in CRC cell lines resulted in partial G1 to S phase, and G2/M phase cell cycle blocks, potentially by upregulating cell cycle inhibitor gene transcription and interfering with the process of mitotic checkpoints and division, respectively. Changes in MCC levels also modulated NF?B pathway signalling, the pathway required for maintaining cell viability and proliferation in colonic epithelial cells. In particular, MCC overexpression suppressed both TNF? and LPS-induced NF?B activation, decreasing both the magnitude and rate of cellular responses. Overexpression also resulted in downregulation of proteins involved in canonical NF?B pathway signalling, while increasing the transcription of non-canonical NF?B genes. Therefore, MCC may direct activation of this pathway to a specific subset of NF?B-regulated genes. These data provide a molecular basis for the role of MCC as a tumour suppressor gene in CRC. MCC may have multiple functions, regulating cell cycle progression and modulating NF?B pathway signalling, either through direct involvement in pathway signalling cascades, or by providing a scaffold on which signalling events can occur.

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31

Huddleston, J. E. "Mechanisms regulating the imprinted tumour suppressor gene DIRAS3 in normal development and cancer". Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.604715.

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In this thesis I have extended previous work on DNA methylation of DIRAS3 using quantitative methods and studied a broad range of tissues. This leads to identification of a probable germline DMR. I have identified CTCF and cohesion binding sites in the DIRAS3 locus and shown that these factors positively regulate DIRAS3 expression. Methylation changes in cancer at DIRAS3 prevents CTCF binding leading to silencing of DIRAS3. This silencing can be reversed using demethylating agents. I have identified putative enhancer regions by their chromatin signature and tested them for enhancer activity using luciferase assays. I have proposed models for regulation of DIRAS3 via allele specific higher order chromatin structures mediated by CTCF/cohesion. I have identified a long non-coding RNA that is associated with the DIRAS3region. The long non-coding RNA is not a ‘classical’ imprinted gene as the promoter is unmethylated, however the genomic organisation of the long non-coding RNA relative to DIRAS3 bears some similarities to the imprinted retrogenes. The non-coding RNA is alternatively spliced, and some splice variants are imprinted and maternally expressed. This may represent a novel mechanism by which an imprinted gene can affect splicing patterns of an associated gene. I hypothesised that the non-coding RNA might have a role in setting up maternal methylation imprints at DIRAS3 and made a mouse model to test the role of transcription through the DIRAS3 DMRs in the germline.

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32

Quinn, Anthony G. "Chromosome loss and tumour suppressor gene inactivation in human non-melanoma skin cancer". Thesis, University of Newcastle Upon Tyne, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.260068.

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33

Camargo, Romera Paula. "Isoform 2 of DLG2 gene as a possible candidate tumour suppressor of neuroblastoma". Thesis, Högskolan i Skövde, Institutionen för biovetenskap, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:his:diva-20234.

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Abstract (sommario):

Neuroblastoma (NB) is the most frequent extracranial solid tumour in childhood. The clinical diagnosis of NB is difficult due to the age of the patient and the vague appearance of the symptoms. Moreover, there are two groups of aggressive NBs, one with MYCN amplification and the other with an 11q deletion. Some genes could be a candidate suppressor for NB, e.g., the DLG2 gene that resides within the 11q-deleted region. The DLG2 gene has a large number of exons and multiple isoforms depending on the alternative splicing process. Moreover, these isoforms can include the L27 domain or not. This study aimed to analyse, by applying bioinformatic tools, if isoform 2, which does not have L27 domain, could be a candidate suppressor for this disease. RNA-seq samples from different human cell lines were collected from NCBI and a quality analysis was performed. The filtered samples were run in R and Python programs to do a visualization of the exon expression level and the prediction of Rsubread for exon-exon junctions. The results showed that isoform 2 of DLG2 gene was not expressed in the samples of NB, which is a promising result for being a candidate suppressor of NB. Furthermore, the prediction of exon-exon junctions by Rsubread was confirmed to be very accurate. In conclusion, this study shows that isoform 2 of DLG2 gene could be a candidate tumour suppressor in NB that could, in the future, be used as a target to help to detect earlier the presence of NB and increase the life expectancy of children who suffer from this disease.

There are other digital material (eg film, image or audio files) or models/artifacts that belongs to the thesis and need to be archived.

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34

Janczar, Szymon Lech. "WWOX, tumour suppressor and modifier gene, as a regulator of gene expression and apoptosis in ovarian cancer". Thesis, Imperial College London, 2010. http://hdl.handle.net/10044/1/5859.

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WWOX is a tumour suppressor gene, as demonstrated by increased neoplasia incidence in Wwox-knock-out animals, and is frequently disrupted in human cancers. WWOX expression reconstitution abolishes xenograft growth of lung, pancreatic, breast, ovarian and prostate cancer cells. The tumoursuppressive function of WWOX is suggested to be related to pro-apoptotic effects or interactions with potentially oncogenic transcription factors leading to their cytoplasmic sequestration and trans-activity inhibition. In physiology WWOX might be involved in metabolism. Our group demonstrated that WWOX reconstitution in ovarian cancer cells inhibits xenograft growth but this was not accompanied by altered in vitro growth or apoptosis rates. Rather, WWOX transfection reduced cancer cell adhesion to extracellular matrix due to reduction of integrin α3 binding. Additionally, our group postulated that natural polymorphic variants of WWOX are linked to ovarian cancer clinicopathological features. The hypotheses behind this work were that WWOX regulates gene expression or promotes apoptosis in ovarian cancer. Further, this project aimed at confirming the associations of WWOX polymorphisms. I demonstrate no link between WWOX status and the subcellular localization of putative WWOX-binding transcription factors or the expression of their target genes in ovarian cancer cells. The phenotypic consequences of WWOX expression manipulation do not appear to be explained by transcriptional changes. I show that WWOX increases apoptosis rates in ovarian cancer cells exposed to the chemotherapy agent paclitaxel, but not cisplatin. This is independent of the anti-mitotic function of taxanes and unrelated to integrin regulation. Rather, WWOX promotes cell death during taxane-induced endoplasmic reticulum stress. I propose WWOX-driven cell death during endoplasmic reticulum stress might be also linked to anti-tumorigenic effects in vivo. A validation study did not confirm the link between WWOX genetic variants and ovarian cancer pathology. There is also no link between WWOX polymorphisms and bone metabolism, a trait affected in WWOX-knock-out animals.

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35

Lapinskas, Erika Jane. "ELF5 is an epithelial-specific member of the Ets oncogene/tumour suppressor gene family". Monash University, Centre for Functional Genomics and Human Disease, 2003. http://arrow.monash.edu.au/hdl/1959.1/5672.

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36

Lee, Kwok. "RPS6KA2 (RSK3) is a candidate imprinted tumour suppressor gene involved in epithelial ovarian cancer". Thesis, University of Oxford, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.422658.

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37

Liu, Ying. "Isolation of a tumour suppressor gene on chromosome 6q26-27 in epithelial ovarian cancer". Thesis, University of Oxford, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.249544.

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38

Okon, Imoh S. "Elucidating functional mechanisms of OPCML : a tumour suppressor gene lost in epithelial ovarian cancer". Thesis, Imperial College London, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.522833.

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Opioid binding protein cell adhesion molecule-like (OPCML) is a tumour suppressor gene (TSG), originally found to be silenced in epithelial ovarian cancer. Initial functional analysis highlighted both in vitro and in vivo suppression of tumour growth upon constitutive OPCML expression the SKOV-3 ovarian cancer cell line. Increased cell-to-cell adhesion and reduced chemotactic migration was also demonstrated. However, evidence demonstrating possible mechanisms by which OPCML mediates these functions was non-existent. Stable transfection of OPCML into SKOV-3 cells resulted in the inhibition of phospho-ERK1&2 proteins. This result, in addition to earlier observations, provided further clues of possible upstream signal attenuation by OPCML. Subsequent experiments demonstrated upregulation of OPCML (mRNA and protein levels) upon EGF stimulation. Upregulation of OPCML expression correlated with the inhibition of EGFR and ErbB2 proteins, suggesting a negative feedback modulatory mechanism. Ablation of ErbB2 protein level on Western blots was further supported by confocal microscopy in OPCML expressing lines. OPCML expression correlated with increased ErbB2 poly-ubiquitination and proteasomal degradation. Further experiments employing GST-OPCML fusion protein confirmed a direct interaction between the third Ig-domain of OPCML and ErbB2 (but not EGFR). Specific inhibitors directed against the receptors (EGFR/ErbB2) were used to explore the therapeutic potential of OPCML. Results demonstrated increased sensitisation of OPCML-transfected SKOV-3 cells to lapatinib and trastuzumab. In summary, OPCML acts as a 'signalling modulator' that co-ordinately regulates a specific repertoire of receptor tyrosine kinases (RTKs) (mainly ErbB2) resulting in the negative regulation of specific downstream signalling pathways.

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39

Neill, Graham William. "Protein interactions mediated by the product of the tumour suppressor gene neurofibromatosis type 2". Thesis, Institute of Cancer Research (University Of London), 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.369248.

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40

Hurlstone, Adam Felix Lloyd. "Cloning of a multi-tissue tumour suppressor/replicative senescence gene on human chromosome 7q31". Thesis, University of Glasgow, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266461.

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41

Sawan, Ali Sadek. "Tumour suppressor and anti-metastatic gene expression in human breast cancer : an immunohistochemical study". Thesis, University of Newcastle Upon Tyne, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.239797.

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42

Bergman, Lee Melissa. "Molecular and cellular biology of the multiple endocrine neoplasia type 1 tumour suppressor gene /". St. Lucia, Qld, 2001. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe16539.pdf.

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43

Fawole, Adeshina Sergei. "Evidence for a novel tumour suppressor gene at 10q21 chromosome in sporadic colorectal adenocarcinoma". Thesis, Keele University, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.421667.

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This thesis sought to define deletions of chromosome lOin sporadic colorectal adenocarcinoma and determine their role in colorectal tumorigenesis. This thesis has shown a region of frequent loss of heterozygosity (LOH) in the region lOql1-21 centring on the marker D10S1790 at lOq21 suggesting this is the most likely locus of a putative tumour suppressor gene in this region. It has also been shown that LOH at this marker (D10S1790) is significantly associated with earlier presentation of patients. Analysis of adenomas revealed a low frequency of LOH in this region with only two of nine severely dysplastic adenomas showing LOH and none of those with mild or moderate dysplasia. This suggests that loss of the putative tumour suppressor gene at this locus is a late event in colorectal tumorigenesis. Furthermore, deletions at the chromosome 17 locus containing the known tumour suppressor gene, pS3, were examined together with pS3 expression by immunohistochemistry, which are also known to occur late in colorectal tumorigenesis. The frequency of LOH at the pS3 locus as well as pS3 expression were similar to previous studies and there was no significant association with losses at lOq suggesting that loss of a putative tumour suppressor gene at 10q occurs independently of loss of p53 function. LOH at lOq21 was also found not to be associated with LOH at the APe gene locus on 5q21-22 which occurs in up to 50% of sporadic colorectal adenocarcinomas. This thesis suggests that loss of the putative tumour suppressor genets) on lOq provides a selective advantage for clonal expansion in the somatic evolutionary process of colorectal tumorigenesis. Elucidation of the tumour suppressor genets) at this site will further help our understanding of the series of genetic mutations that occur in the evolution of colorectal cancer and will contribute to the efforts in the prevention, early detection and treatment of this prevalent disease.

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44

Wojnarowicz, Paulina Maria. "Chromosome 17 and epithelial ovarian cancer: evidence of genomic loss, altered gene expression, and tumour suppressor gene candidates". Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=110350.

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Epithelial ovarian cancer (EOC) is frequently diagnosed at advanced stage, which is associated with poor outcome. The etiology of this disease is largely unknown, hindering the development of effective disease detection strategies and treatment options. Cytogenetic and molecular genetic analyses have frequently reported chromosome 17 anomalies in EOC. Loss of heterozygosity (LOH) analyses have found loss of chromosome 17 often involving an entire chromosome 17 homologue, as well as recurrent patterns of LOH of specific regions of chromosome 17, such as 17q25. Based on Alfred G. Knudson's "two-hit model" and the paradigm of the classical tumour suppressor gene (TSG), LOH may be indicative of a TSG-containing genomic region. The hypothesis of this thesis research states that there exist as yet unidentified TSGs mapping to chromosome 17 that contribute to EOC tumourigenesis. LOH analysis was performed to refine a previously identified minimal region of deletion (MRD) at 17q25 and identify TSG candidates. Refinement of the MRD to a 65 Kb interval found three candidate genes that mapped to this region. Gene expression analysis of the candidate genes found RHBDF2 and CYGB to be underexpressed in EOC samples, relative to primary cultures of normal ovarian surface epithelial cells (NOSE) samples. These two candidate genes were investigated for DNA sequence mutations and evidence of promoter methylation, which are classical mechanisms of TSG inactivation. No mutations were identified in either gene, however evidence of promoter methylation was found for CYGB. Thus based on their expression profiles, and in the case of CYGB, evidence of promoter methylation, both RHBDF2 and CYGB have emerged as TSG candidates in EOC warranting further investigation to test their TSG candidacy. An alternate approach for identifying regions of LOH, whole-genome genotyping analysis using single nucleotide polymorphism (SNP) arrays, was performed on high-grade ovarian serous carcinoma (HGOSC) samples to characterize the genomic content of these samples. In that analysis LOH of the entirety of chromosome 17 was observed in nearly 100% of samples analysed, suggesting that LOH of this chromosome is a near-ubiquitous feature of these cancers. Gene expression microarray analysis was performed to identify chromosome 17 genes that are differentially expressed in HGOSC samples relative to the primary cultures of NOSE samples. This analysis found 253 differentially expressed genes, where five genes, ADORA2B, CCL2, ACLY, WIPI1, and SLC16A3, were found underexpressed at least three-fold in all HGOSC samples analysed, relative to the primary cultures of NOSE samples. Underexpression may be indicative of an inactivated TSG, thus a "functional" complementation approach was used to test whether "re-expressing" one of these five genes would suppress tumourigenicity. An expression vector containing the coding region of CCL2 was transfected into the tumourigenic EOC cell line OV-90, which does not express CCL2, to generate stable CCL2-expressing clones. Injection of the CCL2¬-expressing clones into SCID mouse xenograft tumour models resulted in increased tumour latency and increased survival, relative to mice injected with the parental cell line. Thus expression of CCL2 appears to contribute to increased tumour latency, suggesting that this gene contributes to inhibiting tumourigenesis. This thesis research found that chromosome 17 loss and underexpression of chromosome 17 genes is common in HGOSC, suggesting that several chromosome 17 genes may be involved in TSG pathways, and that the genes RHBDF2, CYGB and CCL2 are candidate TSGs warranting further investigation in EOC.
Le cancer épithélial de l'ovaire (CEO) est fréquemment diagnostiqué à un stade avancé de la maladie ce qui l'associe à une issue défavorable. L'étiologie de la maladie reste en grande partie inconnue, ce qui nuit au développement de stratégies de dépistage efficaces ainsi qu'au développement de nouveaux traitements. Le chromosome 17 présente de fréquentes anomalies dans les CEO. Des analyses de pertes d'hétérozygotie (LOH) ont mis en évidence la perte allélique de régions spécifiques du chromosome 17 et même la perte du chromosome 17 dans son intégralité. Selon la théorie des deux évènements de Alfred G. Knudson et le paradigme des gènes suppresseurs de tumeurs (TSG) classiques, ces LOH présentes sur le chromosome 17 suggèrent la présence de régions abritant des TSG. Ce travail de thèse se base sur l'hypothèse qu'il existe au moins un TSG, encore non identifié, localisé sur le chromosome 17 qui contribuerait à l'initiation ou au développement du CEO. Une analyse LOH a été effectuée pour affiner la cartographie d'une région minimale de délétion (RMD), déjà déterminée dans la région 17q25, et identifier de nouveaux TSG. L'affinement des frontières de la RMD a réduit à 65 Kb l'intervalle et a identifié trois gènes candidats. L'analyse de l'expression de ces gènes a montré une répression transcriptionnelle de RHBDF2 et de CYGB dans des échantillons de CEO, comparativement à des cultures primaires ce cellules épithéliales de l'ovaire normal (EON). Ces deux gènes candidats ont fait l'objet d'analyses génétiques pour la détection des mécanismes classiques d'inactivation des TSG. Aucune mutation ne fut trouvée dans ces deux gènes, en revanche, le promoteur de CYGB est apparu méthylé. En s'appuyant sur leurs profils d'expression génique, et dans le cas de CYGB, sur la méthylation du promoteur, RHBDF2 and CYGB apparaissent comme de sérieux candidats. Une approche alternative pour identifier les régions présentant des LOH, le génotypage à l'échelle du génome entier par puces à marqueurs SNP (Polymorphismes à Simple Nucléotide), a été utilisée sur des d'échantillons de carcinomes ovariens séreux de haut grade (COSHG) pour caractériser leur contenu génomique. Les résultats montrent qu'une LOH du chromosome 17 dans son intégralité est observée dans 100% des cas analysés, suggérant que le LOH pour ce chromosome est ubiquitaire dans ce type de cancer. L'analyse de l'expression génique par puce à ADN a été effectuée pour identifier les gènes du chromosome 17 qui sont différentiellement exprimés dans les COSHG, comparativement aux EON. Cette analyse a révélé 253 gènes différentiellement exprimés, et parmi eux, ADORA2B, CCL2, ACLY, WIPI1, et SLC16A3, ont été trouvés transcriptionnellement réprimés dans tous les COSHG. Cette répression transcriptionnelle pouvant indiquer l'inactivation d'un TSG. Une approche fonctionnelle de complémentation a été utilisée pour tester si la réexpression d'un des ces gènes pourrait supprimer la tumorigénicité dans les COSHG. Un vecteur d'expression contenant la région codante du CCL2 a été transfecté dans OV-90, une lignée cellulaire de CEO qui n'exprime pas CCL2, afin de générer des clones stables exprimant CCL2. L'injection de ces clones dans des souris SCID a montré une latence dans la formation de tumeurs et une prolongation de la survie des souris, comparativement à celles injectées avec OV-90. L'expression de CCL2 semble donc induire une latence dans la formation tumorale, ce qui suggère que ce gène participe à l'inhibition de la tumorigénèse. Ce travail de thèse a montré que la perte allélique du chromosome 17 ainsi que la répression transcriptionnelle des gènes du chromosome 17 sont des évènements fréquents dans les COSHG. Les résultats obtenus suggèrent que plusieurs gènes sur ce chromosome pourraient être impliqués dans la tumorigénèse ovarienne, et que RHBDF2, CYGB et CCL2 sont de candidats pour être des TSG, méritant de faire l'objet d'analyses plus approfondies sur leurs fonctions dans les CEO.

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45

Parry, David Alun. "Biochemical and functional analyses of p16INK4a, an inhibitor of cyclin D-dependent kinases". Thesis, Imperial College London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.243499.

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46

Gleeson, Catherine M. "The molecular genetics of adenocarcinoma of the oesophagus and gastric cardia". Thesis, Queen's University Belfast, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.387932.

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47

Suaeyun, Ratchada. "The cellular roles of MDM2 and its alternatively spliced variants". Thesis, University of Newcastle Upon Tyne, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340667.

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48

Ouboussad, Lylia. "Identification of novel tumour suppressor genes involved in the development of cutaneous malignant melanoma". Thesis, Brunel University, 2009. http://bura.brunel.ac.uk/handle/2438/4393.

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Skin cancer is one of the most common forms of adult solid tumour. The incidence is increasing rapidly making skin cancer a major health problem in several countries. Cutaneous Malignant Melanoma (CMM) is the least common but the most life threatening type of skin cancers and is responsible for 90% of all skin malignancy associated deaths. The precise cellular and molecular etiology of malignant melanoma is quite complex and the molecular events directly related to melanoma progression are yet to be elucidated. However, recent advances in molecular biology have resulted in a clearer understanding of the cellular and molecular events of skin cancer development. The best-characterized locus associated with CMM development is the CDKN2A that maps to chromosome 9p21 and encodes for the cell cycle regulator p16 tumour suppressor gene (TSG), and is frequently inactivated in melanoma tumours. In addition to p16, other loci located in 9p21 appear to be important in CMM development and functional evidence for the presence of TSG(s) has been provided (Parris et al., 1999). The aim of our study is to contribute to the understanding of CMM development by isolating and characterising novel TSG(s) at this location. In order to pursue identifying potential TSG(s), we have developed several monochromosome hybrids using microcell mediated chromosome transfer, and evaluated the tumourigenicity of the constructed hybrids by anchorage independent growth in soft agar. For the molecular biology aspects, expression analysis of the genes in the 9p21 region was carried out by reverse transcription PCR. Potential candidate tumour suppressor genes were then carefully evaluated by generating expression profiles via conducting real time PCR. Experimental evidence is provided which supports the candidacy of interferon alpha 1 (IFNA1) as a tumour suppressor gene for melanoma development.

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49

Bristow, Robert Glen. "The role of the p53 tumour suppressor gene as a determinant of intrinsic cellular radiosensitivity". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1997. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape16/PQDD_0011/NQ27609.pdf.

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50

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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