Дисертації з теми "Mutant p53 gain of function"
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Vaughan, Catherine. "Investigation of Gain-of-Function Induced by Mutant p53." VCU Scholars Compass, 2015. http://scholarscompass.vcu.edu/etd/3965.
Повний текст джерелаTurrell, Frances Kathryn. "Gain-of-function and dominant-negative effects of distinct p53 mutations in lung tumours." Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/271848.
Повний текст джерелаHeath, Nikki. "An investigation into the role of microvesicles in mutant p53 invasive gain-of-function." Thesis, University of Glasgow, 2015. http://theses.gla.ac.uk/6895/.
Повний текст джерелаScian, Mariano J. "MODULATION OF GENE EXPRESSION BY TUMOR-DERIVED MUTANT p53. ROLE OF TRANSACTIVATION IN GAIN-OF-FUNCTION." VCU Scholars Compass, 2005. https://scholarscompass.vcu.edu/etd/5518.
Повний текст джерелаWülfing, Verena [Verfasser], and Jochen [Akademischer Betreuer] Dahm-Daphi. "Stimulation of Homologous Recombination by P53 gain-of-function mutant M237I / Verena Wülfing. Betreuer: Jochen Dahm-Daphi." Hamburg : Staats- und Universitätsbibliothek Hamburg, 2012. http://d-nb.info/1027574041/34.
Повний текст джерелаNapoli, Marco. "A Pin1/mutant p53 axis promotes aggressiveness in breast cancer." Doctoral thesis, Università degli studi di Trieste, 2011. http://hdl.handle.net/10077/4602.
Повний текст джерелаMutations in the TP53 gene are among the most frequent genetic alterations in human cancers. As a consequence of these mutations p53 loses its tumour suppressor functions and may acquire novel oncogenic activities (gain of function) sustaining tumour formation and progression. Many in vivo studies highlighted that mutant p53 gain of function is associated with elevated protein levels, supporting the notion that in tumour cells altered signalling could stabilize and activate mutant p53, with mechanisms similar to those required to stimulate wild-type p53. The aim of my PhD work was to investigate the mechanisms underlying mutant p53 gain of function, focusing on factors that might link cancer-related signalling with mutant p53 activity. An intriguing candidate for this role is the phosphorylationdependent prolyl isomerase Pin1, that transduces phosphorylation signalling into conformational changes affecting the functions of its substrates, as ours and other laboratories have reported for wild-type p53. Despite Pin1 supports wild-type p53 functions, Pin1 is frequently overexpressed in human tumours and has been shown to promote both Her2/Neu/Ras and Notch1 dependent transformation. So we reasoned that the physiological role of Pin1 as a component of checkpoint mechanisms might be subverted during tumourigenesis, thereby turning it into an essential partner of mutant p53 and a critical amplifier of its oncogenic functions. Indeed, we now demonstrate that Pin1 enhances tumourigenesis in a Li-Fraumeni mouse model and cooperates with mutant p53 in Ras-dependent cell transformation. In human breast cancer cells, Pin1 promotes both mutant p53 dependent inhibition of the anti-metastatic factor p63 and the induction of a mutant p53 transcriptional program to increase tumor aggressiveness. Accordingly, we have identified a transcriptional signature (the Pin1/mutant p53 signature) that is associated with poor prognosis in breast cancer and, in a cohort of patients, Pin1 over-expression influences the prognostic value of p53 mutation. Considering that TP53 mutation is more frequent in tumors with higher risk of recurrence such as triple-negative cases and that some of the Pin1/mutant p53 signature genes are over-expressed in triple negative breast cancers, our findings carry therapeutic implications for this kind of cancers and possibly also for other tumours bearing mutant p53 and high levels of Pin1.
XXII Ciclo
1983
Masood, Rubana. "The Effects of Gain of Function Mutant p53 and p63 on EPS8 and CXCL5 Expression in Head and Neck Squamous Cell Carcinoma." VCU Scholars Compass, 2013. http://scholarscompass.vcu.edu/etd/530.
Повний текст джерелаGadepalli, Venkat Sundar. "ISOLATION AND CHARACTERIZATION OF MULTIPOTENT LUNG STEM CELLS FROM p53 MUTANT MICE MODELS." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3644.
Повний текст джерелаChollat-Namy, Marie. "Effet de l’inactivation du gène suppresseur de tumeur p53 et de sa réactivation pharmacologique sur la réponse cytotoxique anti-tumorale The Pharmalogical Reactivation of p53 Function Improves Breast Tumor Cell Lysis by Granzyme B and NK Cells Through Induction of Autophagy Mutant P53 Gain of Function Stimulates PD-L1 Expression." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL032.
Повний текст джерелаImmune system plays an important role in the control and destruction of cancer cells. The major effectors of antitumor immune response are Natural Killer (NK) cells and the cytotoxic T lymphocytes, which recognize et destroy tumor cells by exocytosis of perforin and granzymes contained in cytotoxic granules. It has been previously shown in the laboratory that the tumor suppressor p53 plays an important role in this apoptotic pathway. However more than 50% of human tumors have p53 inactivating mutations which favor tumor development. Consequently, frequent p53 inactivation in human tumor could enable them to escape from destruction by cytotoxic immune cells. In this context, my thesis work has shown that the pharmacological reactivation of wild type p53 function in cancer cells expressing a mutated p53 increased their susceptibility to NK cell-mediated apoptosis cells through the induction of an autophagic process. Moreover, I tried to determine the link between p53 mutations and the expression of the immune checkpoint ligand PD-L1 which prevent efficient activation of cytotoxic cells and promote immune cells exhaustion. My work suggests that the expression of p53 mutants promotes an the expression of PD-L1 at the cancer cell surface. The study of the underlying mechanisms is still in progress
Choi, Sang H. "Study of p53 Gain of Function Mutations in p53-null Astrocytes." VCU Scholars Compass, 2000. http://scholarscompass.vcu.edu/etd/4420.
Повний текст джерелаJohnson, Thomas M. "p53 transactivation domain mutant knock-in mice provide novel insight into p53 tumor suppressor function /." May be available electronically:, 2007. http://proquest.umi.com/login?COPT=REJTPTU1MTUmSU5UPTAmVkVSPTI=&clientId=12498.
Повний текст джерелаJiang, Dadi. "Analysis of a p53 Gain-of-function Mutation in Transgenic Mouse Salivary Tumors." VCU Scholars Compass, 2007. http://scholarscompass.vcu.edu/etd_retro/103.
Повний текст джерелаGenevini, P. "ROLE OF MUTANT VAPB IN THE PATHOGENESIS OF AMYOTROPHIC LATERAL SCLEROSIS: GAIN OR LOSS OF FUNCTION?" Doctoral thesis, Università degli Studi di Milano, 2016. http://hdl.handle.net/2434/347511.
Повний текст джерелаOram, L. "The role of p53 gain-of-function mutations in the pathogenesis of basal-like breast cancer." Thesis, Queen's University Belfast, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.680241.
Повний текст джерелаBehrendt, Anna. "Proteomic and transcriptomic investigation of the mechanisms and consequences of p53 gain of function mutation in laryngeal squamous cell carcinoma." Thesis, University of Liverpool, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.569205.
Повний текст джерелаWang, Yifan. "A Gain of Function Senescence Bypass Screen Identifies the Homeobox Transcription Factor DLX2 as a Regulator of ATM-P53 Signaling." Thesis, Harvard University, 2016. http://nrs.harvard.edu/urn-3:HUL.InstRepos:26718730.
Повний текст джерелаMedical Sciences
Brachova, Pavla. "Oncomorphic Tp53 mutations in advanced serous ovarian carcinomas." Diss., University of Iowa, 2014. https://ir.uiowa.edu/etd/4581.
Повний текст джерелаFiorini, Claudia. "“Molecular mechanisms induced by p53 reactivating molecules in p53 mutant pancreatic adenocarcinoma cell lines”." Doctoral thesis, 2014. http://hdl.handle.net/11562/706761.
Повний текст джерелаTP53 gene mutations compromising p53 transcriptional function occur in more than 50% of human cancers, including pancreatic adenocarcinoma, and render cancer cells more resistant to conventional therapy. In the last few years, many efforts have been addressed to identify p53-reactivating molecules able to restore the wild-type transcriptionally competent conformation of the mutated proteins. In the present thesis, we show that two of these compounds, CP-31398 and RITA, can induce cell growth inhibition, apoptosis, and autophagy by activating p53/DNA binding and p53 phosphorylation (Ser15), without affecting the total amount of p53. These effects occur in both wild-type and mutant p53 (mutp53) pancreatic adenocarcinoma cell lines, whereas they are much less pronounced in normal human primary fibroblasts. Furthermore, CP-31398 and RITA regulate the axis SESN1- 2/AMPK/mTOR by inducing AMPK phosphorylation in Thr172, which has a crucial role in the autophagic response. The protective role of autophagy in cell growth inhibition by CP-31398 and RITA is supported by the finding that the AMPK inhibitor compound C or the autophagy inhibitors chloroquine or 3-methyladenine sensitize pancreatic adenocarcinoma cell lines to the apoptotic response induced by p53-reactivating molecules. Our results demonstrate for the first time a survival role for autophagy induced by p53 reactivating molecules in p53 mutant cancer cells. Mutp53 proteins not only lose their tumor suppressive function but also gain new oncogenic properties known as “gain-of-function” (GOF). Generally, mutp53 proteins are over-expressed in cancer cells and promote GOF activities enhancing the proliferation of cells and their resistance to a variety of chemotherapeutic drugs commonly used in the clinical practice. GOF activities are carried out because mutp53 proteins behave as oncogenic transcription factors by interacting with other transcriptional regulators, such as E2F1, NF-Y and VDR. Moreover, these p53 mutant proteins can also interact with oncosuppressor proteins inhibiting their function. Here, we show that the standard drug gemcitabine (GEM) strongly activates mutp53 by stimulating both its phosphorylation (Ser15) and nuclear translocation. These events result in the stimulation of mutp53 GOF in cancer cells bearing mutant p53, as revealed by the stimulation of cell cycle promoting genes, as Cdk1 and CCNB1, after GEM treatment. Furthermore, we demonstrate that silencing of mutp53 strongly increases sensitivity of cancer cells to GEM and that the addition of CP-31398 or RITA to GEM treatment can synergistically induce apoptotic cell death in both wt and mutant p53 pancreatic adenocarcinoma cell lines, whereas these effects are missing in p53-null cancer cells. This drug combination strongly induces p53 phosphorylation in Ser15 (without affecting the total amount of p53), apoptosis, and autophagosome formation. Furthermore, we demonstrate that autophagy stimulation by GEM/CP-31398 has a protective role for cancer cells. In fact, the addition of the autophagy inhibitors, chloroquine or 3-methyladenine, increases apoptosis induced by GEM/CP-31398 treatment. Our results support the development of an anti-tumoral strategy based on autophagy inhibition associated to the combined treatment of p53-reactivating molecules with standard chemotherapy, for both wild-type and mutant p53 pancreatic adenocarcinoma cell types.
Freed-Pastor, William Allen. "Gain-of-Function Effects of Mutant p53 Explored Using a Three-Dimensional Culture Model of Breast Cancer." Thesis, 2012. https://doi.org/10.7916/D8ZK5Q1M.
Повний текст джерелаNoll, Jacqueline Elise. "An investigation of mutant p53 function." Thesis, 2011. http://hdl.handle.net/2440/95872.
Повний текст джерелаThesis (Ph.D.) -- University of Adelaide, School of Medicine, 2011
Lin, Shyuan-Ling, and 林瑄翎. "p53 mutant mediates CXCR7 expression and function in breast cancer progression." Thesis, 2011. http://ndltd.ncl.edu.tw/handle/43999812932189422991.
Повний текст джерела中國醫藥大學
基礎醫學研究所碩士班
99
CXCR7 was identified as a novel, alternate receptor for CXCL12 that promotes tumor growth and metastasis in breast cancer and other malignancies. However, the expression and function of CXCR7 in tumor progression is controversial. This issue may be due to complex genetic alterations. Here, we show that two human breast tumor cell lines (MCF-7 and MDA-MB-231) have different expression levels of CXCR7. The poorly invasive MCF-7 cell line was up-regulation of CXCR7, whereas the highly invasive MDA-MB-231 cell line was down-regulation of CXCR7. The p53 levels are associated with CXCR7 expression. The p53 gain-of-function mutation in MDA-MB-231 cells suppressed CXCR7 expression via up-regulation of hypermethylated in cancer 1 (HIC1), a transcriptional repressor of CXCR7. Knockdown of p53 in MDA-MB-231 cells decreased HIC1 expression and further increased CXCR7 expression. However, overexpresion of p53 in MCF-7 increased HIC1 expression and further decreased CXCR7 expression. To investigate the function role of CXCR7 in breast cancer progression, Lentiviral expression and knockdown systems were used to overexpress CXCR7 in MDA-MB-231 cells and knockdown CXCR7 in MCF-7 cells, respectively. We observed that overexpression of CXCR7 in MDA-MB-231 cells promoted cell proliferation and migration whereas knockdown of CXCR7 in MCF-7 decreased the chemotaxis ability. Interestingly, the invasion ability was increased by knockdown of CXCR7 in MCF-7. Taken together, these results suggest that p53 mutant mediates CXCR7 expression and CXCR7 has multiple roles in breast cancer progression.
Cluis, Corinne Pamela. "Functional characterization of a gain-of-function mutant of AtMKK9 in Arabidopsis thaliana." Thesis, 2006. http://hdl.handle.net/2429/17512.
Повний текст джерелаScience, Faculty of
Botany, Department of
Graduate
Chuang, Jing-Yuan, and 莊淨媛. "A movable and regulable inactivation function within the central region of a temperature-sensitive p53 mutant." Thesis, 1996. http://ndltd.ncl.edu.tw/handle/72829787018745760912.
Повний текст джерела國立臺灣大學
病理學研究所
84
p53 is one of the most frequently mutated genes in human cancer. Naturally occurring mutations of p53 are mainly located within a region containing residues 100 to 300, and are predominantly of missense type, resulting in loss of the protein''s DNA-binding activity. Here we show that some p53 mutations also represses the p53 N-terminal activation domain. The repression activity is conformational dependent. Interestingly, the central region of a temperature-sensitive mutant p53N247I possesses a movable and regulable inacti- vation function. It represses other activities present on the same polypeptide chain without strict regard to the configuration of that polypeptide at the non-permissive temperature (37℃)butnot at the permissive one (30℃). Furthermore, this mutant p53 region exhibits no other activity and its function is independent of endogenous p53 status. Among those of human temperature-sensitive p53 mutants, the central region of p53N247I is optimal in demonstrating such an autonomous inactivation function. By deletion studies, the minimal region containing the activity is mapped to residues 101-298 of p53N247I. The central region of p53N247I appears to function in a manner that is intramolecular distance-dependent and does not alter the subcellular compartmentalization of the GAL4 fusion protein. Furthermore, de novo protein synthesis is not required for the activity of the central region of p53N247I. These results strongly suggest that the central region can be used as a movable regulatory cassette, a powerful tool for thermal regulation of chimeric proteins.
Freitas, Ana Maria Salgueiro. "Effects of ataxins-3 loss and gain of function : characterization of neuronal cell lines overexpressing wild-type and mutant forms of mutant ataxin-3." Master's thesis, 2013. http://hdl.handle.net/1822/27817.
Повний текст джерелаMachado-Joseph Disease (MJD), also known as spinocerebellar ataxia type 3 (SCA3), is an autosomal dominant neurodegenerative disorder which involves the cerebellar, pyramidal, extrapyramidal, motor neuron and oculomotor systems. MJD is caused by an expanded CAG repeat in the coding region of the ataxin-3 gene; for this reason it belongs to the group of polyglutamine (polyQ) associated diseases. The normal function of the ataxin-3 protein (ATXN3) remains mostly unknown, although there are some data suggesting a role for this protein in the modulation of protein degradation (either by the UPS or through autophagy) in association with its deubiquitylase (DUB) activity. Other evidence suggests a role in transcription regulation, in the cellular response(s) to stress and in the cytoskeleton organization as well as in cellular adhesion. In this work we studied the normal function of ATXN3 in neurons, using a novel neuroblastoma SH-SY5Y cell-based approach. We characterized all the different cell lines, assessing cell differentiation and survival, morphology, adhesion and cytoskeleton features, in cells overexpressing wild-type (ATXN3_28Q) and expanded (ATXN3_83Q) ATXN3 as well as cells expressing a catalytic mutant version of this protein (ATXN3_C14A). We also evaluated the transcriptomic profile and protein expression of the cell lines and further investigated the pathways underlying the cellular changes and cytoskeletal regulators. Moreover, in cells expressing both mutant and expanded ATXN3, we found a decreased expression of α-5 integrin (ITGA5) and inhibition of its downstream partners’ activity. The findings described in this study led us to hypothesize that the DUB activity of ATXN3 underlie the neuronal phenotype regulation and also that the expansion of the polyQ tract causes partial loss of function.
A doença de Machado-Joseph (DMJ), também conhecida como ataxia espinocerebelar 3, é uma desordem autossómica dominante que envolve os sistemas cerebelar, piramidal, extrapiramidal, motor neuronal e oculomotor. A DMJ é causada por uma expansão no codão CAG na região codificante do gene da ataxina-3; por esta razão, pertence ao grupo das doenças associadas às poliglutaminas (poliQ). A função normal da proteína ataxina-3 permanece desconhecida, embora alguns dados sugiram um papel da modulação da degradação proteica (quer pelo UPS ou por autofagia) em associação com a sua actividade como deubiquitilase (DUB). Outras evidências apontam para funções relacionadas com regulação da transcrição, como resposta celular ao stress, no citoesqueleto e adesão celular. Neste trabalho estudámos a função normal da ATXN3 em neurónios, usando uma nova abordagem com uma linha neuronal SY5Y de neuroblastoma. Caracterizámos as diferentes linhas celulares, nomeadamente diferenciação celular e sobrevida, morfologia, propriedades de adesão e citoesqueleto em células sobreexpressando a estirpe selvagem da ATXN3 (ATXN3_28Q), a forma expandida (ATXN3_83Q) assim como células sobre-expressando uma versão catalítica mutante (ATXN3_C14A) desta proteína. Avaliámos as diferenças na expressão transcripcional e proteica entre as linhas celulares e investigámos quais as vias de sinalização envolvidas nas alterações celulares observadas e reguladores do citoesqueleto. As células sobre-expressando ambas as formas mutante e expandida, da proteína apresentaram uma expressão diminuída da α5 integrina (ITGA5) bem como uma inibição da actividade desta proteína ao longo da via. As evidências resultantes deste estudo levaram-nos a colocar a hipótese que a actividade DUB da ATXN3 está na base da regulação do fenótipo neuronal e também que a expansão do tracto de poliglutaminas causa uma perda parcial da função da ataxina-3.
Wefers, Benedikt [Verfasser]. "The role of ERK-MAPK signalling in emotional behaviour : studies on Braf knockout and gain-of-function mutant mice / Benedikt Wefers." 2011. http://d-nb.info/1011493829/34.
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