Дисертації: "P53; tumour suppressor; cancer"

1

Webley, Katherine Mary. "p53 in colorectal cancer." Thesis, University of Sheffield, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286842.

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2

Marston, Nicola Jane. "Mutational analysis of the tumour suppressor protein, p53." Thesis, Imperial College London, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.387679.

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3

Burns, Alice Sin Ying Wai. "The role of the p53 tumour suppressor pathway in central primitive neuroectodermal tumours." Thesis, University of Newcastle Upon Tyne, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.300357.

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4

Scobie, Linda. "The role of p53 in cell transformation by BPV-4." Thesis, University of Glasgow, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.360279.

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5

Stuart, Debra. "The role of p53 in mouse skin keratinocytes." Thesis, University of Glasgow, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.364083.

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6

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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7

Froggatt, Nicola Jane. "Alterations to the tumour suppressor genes p53 and dcc in colorectal neplasia." Thesis, University of York, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.385322.

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8

Mee, Trevor Richard. "Analysis of the proteolytic cleavage reaction of the tumour suppressor protein p53." Thesis, University of York, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.310987.

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9

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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10

McArdle, Stephanie. "p53 epitopes as potential tumour targets for immunotherapy programmes against cancers." Thesis, University of Sheffield, 2000. http://etheses.whiterose.ac.uk/14459/.

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The tumour suppressor gene p53 is pivotal in the regulation of program cell death (apoptosis), and point mutations within the gene represent the most common genetic alterations in human cancers. This process can result in the overexpression and/or accumulation of mutated and/or wild-type p53 protein within the cell. Cytotoxic T lymphocytes (CTL) play a critical role in the immune defense by recognising peptide/MHC complexes on the surface of virally infected or tumour cells followed by lysis. Therefore, p53-derived peptides are potential candidates for immunisation strategies designed to induce anti-tumour CTL in patients.

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11

Fallows, Sarah Aileen Sharon. "A study of p53 in epithelial ovarian cancer." Thesis, Queen's University Belfast, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.263321.

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12

Rippin, Thomas Mark. "Mechanistic studies of the tumour suppressor p53 : a basis for rational anti-cancer drug design." Thesis, University of Cambridge, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621200.

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13

Maetens, Marion M. "Regulation of the tumor suppressor p53 by Mdm2 and Mdm4." Doctoral thesis, Universite Libre de Bruxelles, 2007. http://hdl.handle.net/2013/ULB-DIPOT:oai:dipot.ulb.ac.be:2013/210602.

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Mdm2 and Mdm4 are critical negative regulators of the p53 tumor suppressor. Mdm4-null mutants are severely anemic and exhibit impaired proliferation of the fetal liver erythroid lineage cells. This phenotype may indicate a cell-intrinsic function of Mdm4 in erythropoiesis. In contrast, red blood cell count was nearly normal in mice engineered to express low levels of Mdm2, suggesting that Mdm2 might be dispensable for red cell production. In the first part of the thesis, we further explore the tissue-specific functions of Mdm2 and Mdm4 in the erythroid lineage by crossing the conditional Mdm4 and Mdm2 alleles to an erythroid-specific-cre (EpoRGFP-Cre ) knock-in allele. Our data show that Mdm2 is required for rescuing erythroid progenitors from p53-mediated apoptosis during primitive erythropoiesis. In contrast, Mdm4 is only required for the high erythropoietic rate during embryonic definitive erythropoiesis. Thus, in this particular cellular context, interestingly, Mdm4 only contributes to p53 regulation at a specific phase of the differientation program.

Moreover, a large body of evidence indicates that aberrant expression of either MDM2 or MDM4 impairs p53 tumor suppression function and consequently favors tumor formation. Overexpression of MDM2 was observed in 10% of 8000 human cancers from various sites, including lung or stomach, and MDM4 was found amplified and/or overexpressed in 10-20% of over 800 diverse tumors including lung, colon, stomach and breast cancers. Remarkably, selective MDM4 amplification occurs in about 65% of human retinoblastomas. In contrast, MDM2 amplifications are relatively rare (about 5%) in retinoblastomas, indicating that depending on the tumor context (cell type, initiating oncogene, …), MDM4, rather than MDM2, overexpression might be selected for as a more efficient mean of suppression of p53 function. As part of a large effort to better understand why different cell types require distinct combinations of mutations to form tumours, we will examine the molecular basis for selective up-regulation of Mdm4 in retinoblastomas. In this context, we have successfully generated 2 conditional transgenic mouse lines expressing either mycMdm2 or mycMdm4 driven by the PCAGGs promoters in the ROSA26 locus. Since a cassette containing a floxed transcriptional stop element is inserted upstream of the transgenes, we can achieve tissue-specific expression and spatio-temporal regulation of the transgenes by using different Cre and CreER. By the use of N-terminal myc-tag fused with the transgenes, we are able to compare the expression levels of the transgenes. Finally, due to C-terminal IRES-GFP element, we can easily identify transgene expressing cells. One of our aims is to use this Mdm4 conditional transgenic mouse line as the first, non-chimeric, mouse model of retinoblastoma that can be used as an appropriate preclinical model to improve treatment of this disease.

Doctorat en Sciences
info:eu-repo/semantics/nonPublished

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14

Watterson, Jeanette Debbie. "Germline and novel double p53 mutations in canine skin and testicular cancer." Thesis, University of York, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.247026.

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15

Jooste, Lauren Sarah. "In vitro investigation of the ubiquitination and degradation of p53 by Murine Double Minute 2 (MDM2) and Retinoblastoma Binding Protein 6 (RBBP6)." University of the Western Cape, 2015. http://hdl.handle.net/11394/5051.

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>Magister Scientiae - MSc
P53 is one of the most important tumour suppressor proteins in the body which protects the cell against the tumourigenic effects of DNA damage by initiating processes such as apoptosis, senescence and cell cycle arrest. Regulation of p53 is key — so that the abovementioned processes are not initiated inappropriately. The principle negative regulator of p53 is Murine Double Minute 2 (MDM2), a RING finger-containing protein which catalyses the attachment of lysine48-linked poly-ubiquitin chains, targeting it for degradation by the 26S proteasome. It has been found to work in conjunction with the MDM2 homologue MDMX. Retinoblastoma Binding Protein 6 (RBBP6) is a RING finger-containing protein known to play a role in mRNA 3’-end processing, as well as interacting with p53 and another crucial tumour suppressor, pRb. It has previously been shown to cooperate with MDM2 in the ubiquitination and degradation of p53 in vivo and acts as a scaffold. The objectives of this project are to investigate the proposed role of RBBP6 in the MDM2-catalysed ubiquitination of p53 using a fully in vitro ubiquitination system. Due to the difficulty of expressing full length RBBP6 in bacteria, a shortened version, dubbed "R3" was used which includes the RING finger domain but excludes the domain identified in earlier studies as the p53-binding domain. Proteins required to set up the fully in vitro p53 ubiquitination assays – including E1 and E2 enzymes, MDM2, R3, p53 and ubiquitin - were all successfully expressed in bacteria. The active 26S proteasome was successfully purified out of human cell lysates using antibodies targeting the α2-subunit. Cloning, expression and purification results showed that p53, MDM2 and R3 were not very stable proteins to work with — with degradation being initiated almost immediately after expression and purification which progressed during the downstream processing of the proteins. Although levels of intact protein were not always high, they were sufficient for in vitro assays. MDM2 and GST-R3 were both capable of poly-ubiquitinating p53 independently in "partially in vitro" assays using human cell lysate. The fully in vitro ubiquitination of p53 using MDM2 and R3 was established based on the well-known MDM2/MDMX system. When acting together R3 and MDM2 was shown to produce poly-ubiquitination which is lysine-48 linked and recognised by the 26S proteasome leading to degradation. When the proteasome inhibitor MG132 was added, the poly-ubiquitinated p53 was rescued from degradation. R3 was also shown to successfully poly-ubiquitinate p53 independently of MDM2 and also interact with p53 in vitro. These results suggest R3 to be of the same order of importance as that of MDM2 — which is known to be the most important regulator of p53. It would also rule out the proposed model of RBBP6 functioning as a scaffold as it is able to poly-ubiquitinate p53 independent of MDM2. These results allow us to better understand the mechanism in which p53 is down-regulated by E3s.
National Research Foundation (NRF)

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16

Berggren, Petra. "Molecular changes in the tumour suppressor genes p53 and CDKN2A/ARF in human urinary bladder cancer /." Stockholm : [Karolinska institutets bibl.], 2002. http://diss.kib.ki.se/2002/91-7349-128-4.

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17

Hinnis, Adel Rady. "The tumour suppressor P53 and apoptotic regulatory proteins in breast cancer survival and response to therapy." Thesis, University of Leicester, 2005. http://hdl.handle.net/2381/29510.

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Many breast cancer patients receive chemotherapy as part of their treatment, but unlike hormonal therapy there are no specific markers for predicting response. Almost all cancer therapies induce cell death by apoptosis. Therefore, factors that control apoptosis such as the tumour suppressor p53 and other regulatory proteins could provide important clues.;Initially breast cell lines (MCF-7, T47-D, ZR-75, MDA-MB-231, MDA-MB-468, HBL-100 and MBA-MB-436) were characterised with regard to proliferation, apoptosis, p53 and phosphorylated p53, p21waf-1, ChK2, bcl-2, bax, bcl-x, survivin and XIAP, using immunocytochemistry and western blotting. The cells apart from HBL-100 and MDA-MB-436, were then treated with different doses and durations of doxorubicin and paclitaxel. Proliferation was suppressed and apoptosis induced mainly in cells with wild type p53. P53 was induced after treatment in both ZR-75 and MCF-7 cells. Strong staining for bcl-2 was found in ZR-75 cells and was down regulated with treatment. Bcl-x was strongly expressed in MCF-7, T47-D and MDA-MB-468. p21 waf-1 was higher in MCF-7 and ZR-75 cells, and was markedly induced after treatment, and to a lesser extent in the other cells. Bax, Survivin and XIAP were detected in all cell lines with some variation. Bax expression increased after treatment, Survivin decreased except in ZR-75 and XIAP decreased in MCF-7.;Breast cancers from patients who had all died from the disease and who had received either neo-adjuvant therapy or adjuvant chemotherapy and/or hormone therapy were examined for the same markers using immunohistochemistry, and related to clinicopathological factors. High proliferation index, the presence of phosphorylated p53, low expression of bcl-2 and over-expression of Survivin were associated with shorter duration of survival, with Survivin expression being independent of other factors. The presence of Survivin and being grade III significantly correlated with shorter survival in patients who received combined adjuvant chemotherapy and hormonal therapy.

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18

Lane, Trevor. "The influence of p53 on mutagenicity." Thesis, University of Oxford, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294357.

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19

Molinari, Marta. "Studies on the mechanisms of p53 stabilisation in vitro and in vivo." Thesis, University of York, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.387557.

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20

Bracey, Tim S. "The role of the p53 tumour suppressor gene and cell cycle checkpoints in #gamma#-radiation-induced apoptosis of human colorectal tumour cells in vitro." Thesis, University of Bristol, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.361164.

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21

Morton, Derrick J. Jr. "ID4 Acts as a Tumor Suppressor via p53: Mechanistic Insight." DigitalCommons@Robert W. Woodruff Library, Atlanta University Center, 2016. http://digitalcommons.auctr.edu/cauetds/21.

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Overexpression of tumor-derived mutant p53 is a common event in tumorigenesis, suggesting an advantageous selective pressure in cancer initiation and progression. Given that p53 is found to be mutated in 50% of all human cancers, restoration of mutant p53 to its wild type biological function has been a widely sought after avenue for cancer therapy. Most research efforts have largely focused on restoration of mutant p53 by artificial means given that p53 has some degree of conformational flexibility allowing for introduction of short peptides and artificial compounds. Recently, theoretical modeling and studies focused on restoration of mutant p53 by physiological means has raised the question of whether there are effective therapies worth exploring that focus on global physiological mechanisms of restoration of p53. Herein, we provide computational analysis of the thermodynamic stabilities of both wild-type and mutant p53 core domains by studying their respective minimum potential energies. Also, it is widely accepted that wild type p53 is modulated by various acetyl transferases as well as deactylases, but whether this mechanism of p53 modulation can be exploited for physiological restoration of mutant p53 remains under intense investigation. Using prostate cancer cell lines representative of varying stages of aggressiveness as a model, we show that ID4 dependent acetylation promotes mutant p53 DNA-binding capabilities to its wild type consensus sequence, thus regulating p53-dependent target genes leading to subsequent cell cycle arrest and apoptosis. Specifically, we identify that ID4 promotes acetylation of K373 and to a lesser extent K320, in turn regulating p53-dependent biological activities. Together, our data provides computational analysis of the core domain of certain mutant forms of p53 and a molecular understanding of ID4 dependent acetylation that suggests a strategy of enhancing p53 acetylation at sites K373 and K320, critical sites of post translational modification of p53, that may serve as a viable mechanism of physiological restoration of mutant p53 to its wild type biological function.

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22

Ehinger, Mats. "On the role of the tumor suppressor gene p53 in leukemic cell differentiation." Lund : Lund University, 1997. http://catalog.hathitrust.org/api/volumes/oclc/68945098.html.

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23

Tammemagi, Martin Carl. "Tobacco smoking, p53 tumour suppressor gene alterations, and clinicopathologic features and prognosis in non-small cell lung cancer." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape17/PQDD_0013/NQ35341.pdf.

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24

Grawenda, Anna Maria. "The identification and analysis of molecular biomarkers in the p53 tumour suppressor pathway that affect cancer progression in humans." Thesis, University of Oxford, 2013. http://ora.ox.ac.uk/objects/uuid:5a76b7ca-22f6-4f49-b715-5ad43f916984.

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The tumour suppressor p53 is at the centre of the signalling pathway that controls cellular processes crucial in tumourogenesis, cancer progression and tumour clearance. Alterations in the p53 pathway that lead to cancer progression can be good candidates for molecular biomarkers that would assist in the identification of patients with different prognoses, but also serve as good predictors of appropriate targeted therapies. Patient cohorts and cancer cell panels are utilised to seek associations with the attenuation of the p53 pathway and cancer progression. Firstly, the alternatively spliced transcript of the p53 inhibitor HDMX, which is frequently found in tumours with poor prognosis, is studied. The high ratio of the alternatively spliced HDMX-S transcript over the full-length HDMX-FL transcript (HDMX-S/FL) is demonstrated to associate with p53 pathway attenuation in cancer cells and breast carcinomas, and with faster metastatic progression of osteosarcoma and breast cancer patients. Secondly, inherited polymorphism in the HDMX gene is investigated and demonstrated as a unique and highly reproducible eQTL, which identifies patients with different prognoses for metastatic disease in breast cancer and melanoma cohorts. Lastly, a screening approach to identify novel inherited polymorphisms in the p53 pathway genes that associate with metastatic progression of melanoma is developed and implemented, and subsequently in silico and in vitro functional analyses are performed to investigate a mechanism behind the FOXO3 SNP, identified as the strongest candidate, whereby the experimental evidence demonstrate that the causal SNP in the FOXO3 haplotype is controlled by the GATA3 transcription factor. Together, the work presented in this thesis provides strong support for the role of the p53 pathway in the metastatic progression of cancer, and suggests that molecular biomarkers that can detect changes in the activity of p53 pathway genes could offer a robust set of biomarkers for cancer progression applicable to different types of cancer.

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25

Dang, Raymond K. B. "Molecular detection of minimal residual disease in breast cancer and leukaemias using p53 tumour suppressor gene mutations as markers." Thesis, University of Edinburgh, 2000. http://hdl.handle.net/1842/22132.

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The use of peripheral blood progenitor cell (PBPC) transplantation is an important advance in the treatment of breast cancer and acute leukaemias, and these conditions are among the commonest indications for this procedure. Inevitably, there is concern that malignant cells may contaminate progenitor cell harvests and be re-infused during transplantation and cause disease relapse. Various methods are available for the detection of such minimal residual disease (MRD), and the key aim of this project was to evaluate the feasibility of using a tumour-specific marker, namely mutations within the p53 gene, for this purpose. This provided a useful model to assess the feasibility of using subtle genetic changes to detect MRD within PBPC harvests from patients with malignant diseases. The first step involved the use of denaturing gradient gel electrophoresis (DGGE) to screen original tumour tissues for mutations to be used as disease markers, in 5 individually PCR-amplified DNA fragments (A to E) covering exons 5 to 8 of p53. The technique was first optimised using cell lines known to contain p53 mutations in each fragment. Optimisation was performed with respect to electrophoresis temperature, time, voltage and polyacrylamide cross-linker. The sensitivity of DGGE in detecting a mutation in a mixed cell population was determined by diluting tumour cells in wild type (WT) cells. Although the presence of a mutation could be demonstrated when tumour cells occurred as 5% of total, a representation of at least 40% was required for the mutant homoduplex to be isolated for sequencing. Clinical samples studied were from 51 breast cancer patients, 38 of whom had metastatic disease or at high risk of metastasis, and 13 had high risk stage II/III disease randomised in a clinical study investigating PBPC transplantation and adjuvant therapy, and from 29 patients with acute leukaemias. A positive result was obtained in 14 of 51 primary breast cancer patients (1 was positive in 2 different fragments) and 3 of 29 patients with acute leukaemias.

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26

Campbell, Christine. "The role of tumour suppressor gene P53 in non-melanoma skin cancer and in the cellular response to ultraviolet radiation." Thesis, University of Newcastle Upon Tyne, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.260075.

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27

Daniels, Paula Rosamund. "Characterisation of HPV type 16 E6 interactions with p53 and E6-associated protein in vitro and ex vivo." Thesis, University of York, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.387558.

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28

Worrall, Erin G. "Novel concepts in MDM2 protein regulation." Thesis, University of Edinburgh, 2009. http://hdl.handle.net/1842/3889.

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The tumour suppressor p53 has evolved a MDM2-dependent feedback loop that has a dual role as either a stimulator of p53 protein translation through mRNA binding or a stimulator of p53 protein degradation through the ubiquitin-proteasome system. A unique pseudo-substrate motif or “lid” in MDM2 is adjacent to its N-terminal hydrophobic drug-binding pocket and we have evaluated whether the lid of MDM2 is a physiological regulator of this dual function of MDM2. Deletion of this flexible pseudosubstrate motif inhibits MDM2 indicating that this peptide stretch can function as a positive regulatory motif. Phospho-mimetic mutation in the pseudo-substrate motif at codon 17 (MDM2S17D) stabilizes the binding of MDM2 towards p53. Molecular modeling orientates the pseudo-substrate motif over a charged surface patch on the MDM2 surface at Arg97/Lys98 and mutation of these residues to the MDM4 equivalent reverses the activating effect of the phosphomimetic mutation. Transient or inducible low level expression of MDM2WT can promote an increase in p53 protein steady-state levels whilst the expression of MDM2S17D in cells results in p53 protein de-stabilization. Phospho-specific antibodies to the MDM2 lid demonstrate two physiological conditions that alter lid phosphorylation: (i) lid hypo-phosphorylation occurs after DNA damage where p53 protein is stabilized and (ii) lid hyper-phosphorylation occurs at high cell density under conditions where p53 protein is de-stabilized. Expression of MDM2S17D in cells also de-stabilizes hyperubiquitinated mutant p53 under conditions where MDM2WT has no effect on mutant p53 protein degradation. The lid functions as a flexible regulatory motif whose phosphorylation switches MDM2 from a synthesis mode to a degradation mode with implications for defining the physiological signals that control the MDM2-p53 feedback regulatory loop.

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29

Ryk, Charlotta. "Influence of genetic polymorphisms on DNA repair, p53 mutations and cancer risk /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-940-8/.

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30

Sagne, Charlotte. "Polymorphisms in G-quadruplex regions of the TP53 tumour suppressor gene : Impact on cancer susceptibility and expression of p53 N-terminal isoforms." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA11T072/document.

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Le gène TP53 est extrêmement polymorphique avec 85 polymorphismes décrits. Certains de ces polymorphismes sont associés à une augmentation du risque de cancer, par exemple rs10425222 peut moduler les fonctions de p53. Cependant, pour d’autres, comme le rs17878362 qui est le polymorphisme intronique le plus étudié, leur association avec une augmentation du riques au cancer est controversée.Pour analyser l’association entre le polymorphisme rs17878362 et la susceptibilité au cancer, nous avons analysé son rôle dans des contextes de cancers sporadiques et familiaux. Les résultats obtenus pour le polymorphisme rs17878362 sont paradoxaux avec une augmentation des cancers sporadiques associée avec le génotype A2A2 alors que l’allèle A2 est associé avec un effet « protectif » chez les patients atteints du syndrome de Li-Fraumeni porteurs d’une mutation germinale de TP53 situé sur l’haplotype A1. Ces observations suggèrent que des haplotypes spécifiques de TP53 pourraient moduler les capacités suppressives de p53. Une hypothèse possible est que les différents haplotypes de TP53 présenteraienrt des mutations somatiques à des fréquences différentes dans la population.De plus, le gène TP53 exprime différentes isoformes, comme le D40p53, inhibant l’activité suppressive de p53. Le D40p53 peut être produite par le maintien de l’intron 2 par épissage alternatif. Nous avons montré que les G-quadruplexes, des structures tridimensionnelles formées dans des régions riches en G, sont formés dans l’intron 3 et régulent la rétention de l’intron 2 et la formation du transcrit p53I2. Nous avons aussi observé que le polymorphisme rs1652785 (localisé dans l’intron 2) semble réguler la stabilité du p53I2. Ces résultats suggèrent que les polymorphismes de TP53 localisés dans une région de 412 pb située entre l’exon 2 et l’exon 4 régulent l’expression des isoformes de p53 dans une séquence temporelle d’évènements en modulant la formation des pré-ARNm (rs17878362), la stabilité des ARNm (rs1642785) et les fonctions protéiques (rs10425222).L’expression des isoformes de p53 est donc finement régulée par des mécanismes impliquant les polymorphismes de TP53 qui sont aussi associés avec une altération dans la susceptibilité au cancer
The TP53 gene is a highly polymorphic gene with 85 polymorphisms described. Some of these have been associated with an increase of cancer susceptibility, for example rs10425222 that can modulate certain p53 activities. However for others such as rs17878362, the most studied intronic polymorphism, the association with cancer risk is more controversial. To investigate the influence of rs17878362 on cancer susceptibility, we analysed its role in sporadic and familial contexts. The results are paradoxical with an increase of sporadic cancer associated with the rs17878362 A2A2 genotype whereas the rs17878362 A2 allele is associated with a “protective” effect in the context of Li-Fraumeni patients carrying a TP53 germline mutation on an A1 haplotype. These observations suggest that specific TP53 haplotypes could modulate p53’s tumour suppression capacities. A possible hypothesis to explain this could be that somatic mutations are carried on different haplotypes of TP53 present at different allele frequencies in the population. In addition, TP53 is expressed as several protein isoforms, such as D40p53, which inhibits p53’s suppressive activity. D40p53 can be produced from an alternative spliced transcript that retains intron 2. We have shown that G-quadruplexes, tri-dimensional structures formed in G-rich sequences, are formed in intron 3 and regulate the retention of intron 2 and the formation of the p53I2 transcript. We also observed that rs1642785 (located in intron 2) could regulate p53I2’s stability. These results suggest that the TP53 polymorphisms located in a 412 bp region located between exon 2 and exon 4 regulate the expression of p53 isoforms in a temporal sequence of events by modulating the pre-mRNA formation (rs17878362), mRNA stability (rs1642785) and protein functions (rs1042522).p53 isoforms’ expression is thus finely regulated by mechanisms involving TP53 polymorphisms, which are also associated with altered cancer susceptibility

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31

Xie, Tian. "Scintillation proximity assay (SPA) measuring p53 DNA binding and total p53 level in human thyroid cancer cell line ARO." Diss., Online access via UMI:, 2007.

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32

OGDEN, STACEY KATHRYN. "HBx-MEDIATED DISRUPTION OF p53 TUMOR SUPPRESSOR PROTEIN FUNCTION LEADING TO RE-ACTIVATION OF A SILENCED TUMOR MARKER GENE." University of Cincinnati / OhioLINK, 2002. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1014751166.

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33

Nakade, Koji. "Functional interaction between p53, a tumor suppressor and Net, an intermediate of signalling by the Ras oncogene." Université Louis Pasteur (Strasbourg) (1971-2008), 2003. http://www.theses.fr/2003STR13178.

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34

Awad, Keytam Salem. "Inhibition of human papilloma virus E6 oncogene function by mammalian lignans activates the p53 tumor suppressor protein and induces apoptosis in cervical cancer cells." [Kent, Ohio] : Kent State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=kent1183405761.

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Thesis (Ph.D.)--Kent State University, 2007.
Title from PDF t.p. (viewed July 8, 2009). Advisor: Angelo L. DeLucia. Keywords: human papilloma virus, mammalian lignans, p53, E6 oncogene. Includes bibliographical references (p. 133-149).

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Serra, Kátia Piton 1979. "Subtipos clínico-patológicos de carcinoma de mama e sua relação com a expressão da COX2 e da p53 = Clinico-pathological subtypes of breast cancer related to COX2 and p53." [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/313100.

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Orientadores: Sophie Fraçoise Mauricette Derchain, Luís Otávio Zanatta Sarian
Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
Made available in DSpace on 2018-08-26T00:11:32Z (GMT). No. of bitstreams: 1 Serra_KatiaPiton_D.pdf: 3794654 bytes, checksum: ce5565714883e2e12d99e6f9ed0ca141 (MD5) Previous issue date: 2014
Resumo: Introdução: Na última década, doferentes subtipos moleculares de cancer de mama foram propostos. A classificação clinic-patológicas dos subtipos vem comprovando ser estratégica para predizer sobrevida e resposta ao tratamento. Modificação recente da classificação considera a avaliação semiquantitativa da expressão dos RP no curso clínico e resposta ao tratamento. Embora exista associação apreciável com o prognóstico e indicação de terapia citotóxica e endócrina, os subtipos parecem falhar em explicar completamente o comçortamento da doença e a resposta ao tratamento. Moléculas como as da família das cicloxigenases (COX), composta por três entidades (COX 1, 2 e 3) vem demonstrando associação com a carcinogênese mamária, e a análise da expressão da p53 nos tumores de mama pode também oferecer informações adicionais para determinação do prognóstico. Objetivos: Foi avaliada a associação entre os subtipos clinic-patológicos do cancer de mama com o prognóstico e fatores preditivos em uma relativamente grande casuística de pacientes Brasileiras com câncer de mama, que foram acompanhadas por cerca de quatro anos. Foram discutidas as vantagens e possíveis ressalvas relacionadas à nova classificação. Também foi mensurada a expressão da COX2 e da p53 em relação aos subtipos clínico-patológicos e avaliada se a expressão destas molécular poderia explicar a variabilidade no prognóstico ainda encontrada entre os subtipos clínico-patológicos do câncer de mama. Metodologia: Um total de 183 amostras de cancer de mama foram obtidas de mulheres tratadas no Hospital da Mulher da Universidade Estadual de Campinas, Campinas, Brasil, entre Junho de 2008 e Janeiro de 2011. Tissue microarrays (TMA) foram construídos dos blocos originais de parafina para realização de imunoistoquímica (IQ) e hibridização fluorescente in situ (FISH). IQ foi realizada para detecção da expressão de RE, RP, ki67, COX2 e p53; o status do HER2 foi avaliado por FISH nas 183 amostras. Os tumores foram classificados em cinco categorias de acordo com a definição correspondente clinic-patológica dos dos subtipos intrínsecos do câncer de mama, definida durante a 13th St Gallen International Breast Cancer Conference (2013). As características clínicas e patológicas das pacientes e seus tumors e a sobrevida foi avaliada em relação aos subtipos clínico-patológicos, a COX2 e a p53. O tempo médio de seguimento foi 2,94 anos (90% faixa central = 0,93 a 4,1 anos). Resultados: Aproximadamente 75% dos tumors foram classificados como luminais-like. OS HER2 positivos (não luminais) somaram 9,3% dos casos e os Triplos-negativos 13,1%. Os Luminais B-like e HER2 positivos (não luminais) foram associados a alto grau histológico quando comparados aos Luminais A-like (p<0,01). Os Luminais A-like associaram-se significativamente com melhor sobrevida global e livre de doença quando comparados aos HER2 positivos (não luminais) e Triplos-negativos. Não houve tendência à expressão de COX2 relacionada aos subtipos de Luminal A-like a Triplo-negativo. Em contraste, a p53 se expressou em cerca de 67% dos tumores Luminais A-like, 50% dos Luminais B-like HER2 positivos, 60,9% dos Luminais B-like HER2 negativos, 82% dos HER2 positivos (não luminais) e 87% dos Triplos-negativos (p para tendências = 0.06). Houve uma significativa expressão de COX2 nos tumors (66,9%) quando a p53 eram também positive, comparada àqueles tumors que não expressavam p53 (em cujo caso apenas 18,0% dos tumores foram positivos para COX2; p<0,001). Nem a COX2, nem a p53 se relacionaram à sobrevida das pacientes. Conclusões: O critério mais estrito para definer os tumors Luminais A-like aumentou a acurácia da classificação para selecionar tumors que partilhem um bom prognóstico e respondam a terapia endócrina. Parece haver uma associação positive entre a expressão da COX2 e da p53. Por outro lado, nem a expressão da COX2 nem a da p53 se associaram aos subtipos clínico-patológicos, características clínicas e do tumor e ao prognóstico. Parece ser muito cedo para eleger a detecção de COX2 usando IQ como ferramenta de prognóstico ou preditiva, mas evidências incipientes apontam para um possível papel para o marcador
Abstract: Background: In the last decade, different molecular subtypes of breast cancer have been proposed. The clinico-pathological surrogate subtypes of breast cancer classification has been proven as straightforward strategy to predict patient survival and response to treatment. Recent modifications to the classification considered the semi quantitative evaluation of the expression of PR in the clinical course and response to treatment. Although displaying appreciable association with disease prognosis and the prognostic value of cytotoxic and endocrine therapeutic modalities, the subtypes seem to fail at completely explaining disease behavior and response to treatment. Molecules such as those of the cyclocooxigenase (COX) family, currently composed of three entities (COX 1, 2 and 3) have been shown to be associated with breast carcinogenesis, and the analysis of p53 expression in breast tumors may also offer some additional prognostic clues. Objectives: We tested the association of the current clinico-pathological surrogate subtypes of breast cancer with the main prognostic and predictive factors in a relatively large dataset of breast cancer Brazilian patients, which were followed up for almost four years. We discuss the advantages and possible caveats related to this new classification. Our study also assessed COX2 and p53 expression in these clinico-pathological subtypes, and evaluated whether the expression of these molecules could help further explain the variability in prognosis still found within the surrogate molecular groups of breast cancer. Methods: A total of 183 breast cancer samples were obtained from women treated at the Women's Hospital of Campinas State University, Campinas, Brazil, between June 2008 and January 2011. Tissue microarrays (TMA) were constructed from the original paraffin blocks for immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) analyses. Immunohistochemistry was performed to detect the expression of ER, PR, ki67, COX2, and p53; the HER2 status of the 183 specimens was assessed using FISH. Tumors were subtyped into five distinct categories according to the Clinico-Pathological surrogate definitions of intrinsic subtypes of breast cancer defined during the 13th St Gallen International Breast Cancer Conference (2013). Clinical and pathological features of patients and their tumors, and patients¿ survival were assessed in relation to the surrogate subtypes, COX2 and p53. Mean follow-up time was 2.94 years (90% central range = 0.93 to 4.1 years). Results: Approximately 75% of the tumors were classified as luminal-type-like. HER2 positive (non-luminal) tumors accounted for 9.3% of the cases and Triple-negative tumors for the remainder 13.1%. Luminal B-like and HER2 positive (non-luminal) tumors were associated with higher histological grades when compared to Luminal A-like tumors (p<0.01). Luminal A-like tumors were significantly associated with better disease free and overall survival when compared to HER2 positive (non-luminal) and Triple-negative tumors. There was no trend in COX2 overexpression from Luminal A to Triple-negative subtypes. By contrast, p53 was expressed in roughly 67% of the Luminal A-like tumors, 50% of the Luminal B-like HER2 positive tumors, 60.9% of the Luminal B-like HER2 negative, approximately 82% of the HER2 positive (non-luminal) and 87% of the Triple-negative tumors (p for trends = 0.06). There was a significantly higher proportion of COX2 positive tumors (66.9%) when p53 was also positive compared to when the tumor was negative for p53 (in which case only 18.0% of the tumors were positive for COX2; p<0.001). Neither COX2 nor p53 were found to be associated with patients¿ survival. Conclusions: The more strict criteria to define Luminal A-like tumors increased the accuracy of the classification by selecting tumors that share a good prognosis and response to endocrine therapy.There seems to be a positive association between the expressions of COX2 and p53. On the other hand, neither the expression of COX nor that of p53 was associated with clinic-pathological subtypes, tumor features and prognosis. It seems to be too early to elect the detection of COX2 using IHC as prognostic or predictive tool, but incipient evidence points towards a possible role for the marker
Doutorado
Oncologia Ginecológica e Mamária
Doutora em Ciências da Saúde

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Murph, Mandi Michelle. "A characterization of the human G protein-coupled receptor, lysophosphatidic acid1 its intracellular trafficking and signaling consequences on the tumor suppressor, P53 /." Diss., Available online, Georgia Institute of Technology, 2005, 2005. http://etd.gatech.edu/theses/available/etd-03222005-105717/unrestricted/murph%5Fmandi%5Fm%5F200505%5Fphd.pdf.

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Thesis (Ph. D.)--Biology, Georgia Institute of Technology, 2005.
Merrill, Alfred, Committee Member ; Mills, Gordon, Committee Member ; McCarty, Nael, Committee Member ; Kubanek, Julia, Committee Member ; Radhakrishna, Harish, Committee Chair. Includes bibliographical references.

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Ponnada, Srikanth. "Glycine nitrosation and signature mutations in the p53 tumour suppressor gene : a molecular link between diet and cancers of the gastro-intestinal tract." Thesis, Open University, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.437806.

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Enane, Francis Obunyakha. "HEPATOCYTE DIFFERENTIATION AND HEPATOCELLULAR CARCINOMA: RATIONALE FOR P53 INDEPENDENT THERAPY." Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case1491570319727552.

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Awad, Keytam Salem. "INHIBITON OF HUMAN PAPILLOMA VIRUS E6 ONCOGENE FUNCTION BY MAMMALIAN LIGNANS ACTIVATES THE P53 TUMOR SUPPRESSOR PROTEIN AND INDUCES APOPTOSIS IN CERVICAL CANCER CELLS." Kent State University / OhioLINK, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=kent1183405761.

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Zhuang, Linhan [Verfasser], and Frank [Akademischer Betreuer] Rösl. "Regulation of tumor suppressor p53 under hypoxia in human papillomavirus type 16 (HPV16)-positive cervical cancer cells / Linhan Zhuang ; Betreuer: Frank Rösl." Heidelberg : Universitätsbibliothek Heidelberg, 2021. http://d-nb.info/1228234264/34.

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Carr, Michael I. "The Role of MDM2 Phosphorylation in P53 Responses to DNA Damage and Tumor Suppression: A Dissertation." eScholarship@UMMS, 2016. http://escholarship.umassmed.edu/gsbs_diss/847.

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The p53 tumor suppressor protein is upregulated in response to DNA damage and other stress signals. The upregulation of p53 involves freeing it from negative regulation imposed by Mdm2 and MdmX (Mdm4). Accumulating evidence indicates that phosphorylation of Mdm proteins by different stress-activated kinases such as ATM or c-Abl significantly impacts p53 functions. We have previously shown that ATM phosphorylation of Mdm2 Ser394 is required for robust p53 stabilization and activation following DNA damage. This dissertation describes in vivo examination of the mechanism by which Mdm2 Ser394 phosphorylation impacts p53 activities and its contribution to suppression of oncogene and DNA damage-induced tumors. We determine that phosphorylation of Mdm2 Ser394 regulates p53 activity by modulating Mdm2 stability and paradoxically delays Myc-driven lymphomagenesis while increasing lymphomagenesis in sub-lethally irradiated mice. c-Abl phosphorylates the residue neighboring Mdm2 Ser394, Mdm2 Tyr393. This dissertation describes the generation of a novel Mdm2Y393F mutant mouse to determine if c-Abl phosphorylation of Mdm2 regulates p53-mediated DNA damage responses or tumor suppression in vivo. Mdm2Y393F mice develop accelerated spontaneous and oncogene-induced tumors, yet display no defects in p53 stabilization and activity following acute genotoxic stress. Furthermore, the effects of these phosphorylation events on p53 regulation are not additive, as Mdm2Y393F/S394A mice and Mdm2S394A mice display similar phenotypes. The studies presented herein further our understanding of the mechanisms by which DNA damage-associated kinases stabilize and activate p53, and influence p53-dependent responses and tumor suppression. A better understanding of the in vivo effects of Mdm2 phosphorylation may facilitate the development of novel therapeutics capable of stimulating p53 anti-tumor activity or alleviating p53- dependent toxicities in non-malignant tissues.

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Beaucourt, Séverine. "Etude de 2 gènes cibles de la protéine P53 : siah (seven in absentia human homologue) et tsap6 (tumor suppressor activated pathway 6)." Phd thesis, Université Paris Sud - Paris XI, 2005. http://tel.archives-ouvertes.fr/tel-00157749.

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Notre travail a consisté à étudier 2 gènes impliqués dans la réversion tumorale et régulés par P53.
Nous avons identifié dans le promoteur du gène siah-1b une séquence sur laquelle P53 se lie in vitro et in vivo. De plus, nous avons montré la fonctionnalité de cet élément de réponse suite à l'induction de P53.
La particularité de ce site, dont la structure diffère fortement du consensus de liaison de P53 à l'ADN, ouvre de nouvelles perspectives dans l'analyse des mécanismes régulés par P53.
L'étude de la protéine TSAP6 murine a permis de caractériser son expression au niveau tissulaire et intracellulaire. La fonction de TSAP6 n'étant pas bien connue, nous avons entrepris de l'analyser dans des modèles animaux portant un gène tsap6 muté ou invalidé.
La mutation du gène tsap6 Gln-395-Lys induit l'apparition d'une microcytose et d'un emphysème pulmonaire chez la souris. La caractérisation des mécanismes conduisant à ces phénotypes est en cours et nous permettra de mieux comprendre la fonction de TSAP6.

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Rahko, E. (Eeva). "Evaluation of tumor suppressor gene p53, oncogene c-erbB-2 and matrix-metalloproteinase-9 as prognostic and predictive factors in breast carcinoma." Doctoral thesis, University of Oulu, 2007. http://urn.fi/urn:isbn:9789514284571.

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Abstract Breast carcinoma is the most common malignancy in females in western countries. Classical prognostic factors such as the size of a primary tumor and the presence or absence of axillary lymph node metastases, malignancy grade and hormone receptor status reflect the subsequent risk of disease recurrence after primary therapy and the need for adjuvant therapies. However, most breast carcinomas are detected in the early stage of the disease and the value of these classical prognostic factors is limited. There is also a great need to find new factors predicting the clinical efficacy of the anticancer drugs available. In this thesis tumor suppressor gene p53, oncogene c-erbB-2 and matrix metalloproteinase-9 were evaluated for their prognostic relevance in breast carcinoma patients treated in Oulu University Hospital, and matrix metalloproteinase-9 was also analyzed in women with premalignant lesions in the breast tissue in order to examine its role in breast carcinogenesis. Histological analyses were carried out from formalin-fixed, paraffin-embedded primary tumor specimens and p53, c-erbB-2 and matrix metalloproteinase-9 (MMP-9) statuses were systematically analyzed by immunohistochemistry. P53 expression correlated with disease-free survival and overall survival in patients with early-stage breast carcinoma, regardless of adjuvant antiestrogen therapy. The co-expression of p53 and c-erbB-2 characterizes a tumor type with a clinically aggressive course of breast carcinoma. The clinical efficacy of anthracyline-based chemotherapy in metastatic carcinoma might be limited in patients with p53 expression in a primary tumor. When postmenopausal patients with lymph node metastases and receiving adjuvant antiestrogen therapy were examined, MMP-9 expression indicated a slightly greater risk of breast carcinoma recurrence in patients with estrogen receptor negative tumors. Hyperplastic breast tissue and invasive breast carcinoma lesions expressed some MMP-9 immunopositivity. However, the strongest positivity was seen in ductal carcinoma in situ samples, suggesting that MMP-9 participates in breast carcinogenesis in the preinvasive phase.

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DelBove, Jessica Nachel Weissman Bernard E. "Characterization of the tumor suppressor capabilities of SWI/SNF complex member BAF155 in cancer cell lines and cooperation of SNF5 and p53 pathways." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2007. http://dc.lib.unc.edu/u?/etd,1220.

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Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2007.
Title from electronic title page (viewed Mar. 26, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Department of Pathology and Laboratory Medicine." Discipline: Pathology and Laboratory Medicine; Department/School: Medicine.

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Allen, Kristi Lynne. "Therapeutic reactivation of the p53 tumor suppressor protein in HPV-positive cervical cancer cells by the creosote bush lignan 3'-O-methyl-nordihydroguaiaretic acid." [Kent, Ohio] : Kent State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=kent1176432164.

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Thesis (Ph.D.)--Kent State University, 2007.
Title from PDF t.p. (viewed Mar. 11, 2009). Advisor: Angelo L. DeLucia. Keywords: human papillomavirus, E6 oncogene, lignan, p53, apoptosis. Includes bibliographical references (p. 132-144).

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Alkawar, Abdulrhaman Mohammed Mohammed. "Insulin-like growth factor-1 (IGF-1) impacts p53-regulated gene products in UVB-irradiated human keratinocytes and skin epidermis." Wright State University / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=wright1588119867567084.

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Love, Ian M. "Critical and Independent Roles of the P/CAF Acetyltransferase in ARF-p53 Signaling: A Dissertation." eScholarship@UMMS, 2011. https://escholarship.umassmed.edu/gsbs_diss/663.

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For 30 years, the tumor suppressor p53 has been a subject of intense research in nearly every discipline of scientific inquiry. While numerous surprising roles for p53 in health and disease are uncovered each year, the central role of its activation in preventing neoplastic transformation has been and will remain at the forefront of p53 research as investigators work to address an unexpectedly complex question—precisely how does p53 integrate upstream stress signals to coordinate activation of its target genes in response to stress? One manner in which to address this question is at the level of transcription initiation—after upstream signals converge on p53 and produce a number of pools of post-transcriptionally modified p53, how exactly are specific target promoters activated in such a sensitive, context-specific manner? The work presented herein aims to address the role of histone acetylation at the p21 promoter—a critical mediator of G1/S arrest—by the P/CAF acetyltransferase in response to a variety of p53-activating stresses. We show that depletion of P/CAF strongly inhibits p21 expression in response to a variety of stresses, despite normal stabilization of p53 and recruitment to target promoters. This defect in p21 expression correlates closely with abrogation of stress-induced cell-cycle arrest. Strikingly, a p53 allele lacking putative P/CAF acetylation sites was still able to direct p21 expression, which was still dependent upon P/CAF. We show further that histone acetylation at H3K14 at the p21 promoter following stress is dependent upon P/CAF. Rescue of p21 expression with wild-type P/CAF or a ∆HAT point mutant indicates that P/CAF requires an intact HAT domain, suggesting that histone acetylation at H3K14 is catalyzed by P/CAF HAT activity, not the molecular bridging of a heterologous HAT by P/CAF. Furthermore, RNA polymerase II (RNAP II) was present at the p21 proximal promoter under all basal and stress conditions, but elongation of RNAP II after stress required the presence of P/CAF. These data indicate that H3K14 acetylation by P/CAF closely correlates with the activation status of the p21 promoter, and may be necessary for activation of a larger subset of p53-responsive promoters. In addition to its critical role in p21 expression, we noted that p53 stabilization and cell-cycle arrest in response to p14ARF, but not other p53-stabilizing stresses, were also dependent on P/CAF. Cell-cycle arrest induced by p16INK4A was intact after P/CAF ablation, indicating a role for P/CAF in cell-cycle arrest specific to p14ARF-p53 signaling. Basal MDM2 levels were unaffected by P/CAF knockdown, as were p53- MDM2 and ARF-MDM2 complexes. A preliminary analysis of MDM2 localization was inconclusive, due to vastly different quantities of MDM2 in different conditions making analysis of subcellular localization difficult; however, the role of P/CAF in the relocalization of MDM2 to the nucleolus by p14ARF could potentially explain the defect in p53 stabilization, and should be explored further. These observations, underscored by recent reports that P/CAF undergoes loss of heterozygosity in several tumor types, suggest that P/CAF plays a critical role in p53-mediated cell-cycle arrest through multiple, independent mechanisms. Further study should clarify whether P/CAF is lost in tumors maintaining wild-type p53, and whether its reintroduction into these tumors confers any potential therapeutic benefit.

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Rayburn, Elizabeth R. "Novel immunomodulatory oligonucleotides for cancer therapy." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2009r/rayburn.pdf.

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Quandt, Jasmin [Verfasser], and Philipp [Akademischer Betreuer] Beckhove. "Common mutations in the tumor suppressor p53 & the oncogene Kras as targets for long peptide anti-cancer vaccination / Jasmin Quandt ; Akademischer Betreuer: Philipp Beckhove." Heidelberg : Universitätsbibliothek Heidelberg, 2014. http://d-nb.info/1181240956/34.

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Gamsby, Joshua John. "Study of the roles of LRBA in cancer cell proliferation and SHIP-1 in NK cell function." [Tampa, Fla] : University of South Florida, 2005. http://purl.fcla.edu/usf/dc/et/SFE0001317.

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Дисертації з теми "P53; tumour suppressor; cancer"

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