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Kommagani, Ramakrishna. "DIFFERENTIAL REGULATION OF VITAMIN D RECEPTOR (VDR) BY p53, p63 AND p73." Wright State University / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=wright1239687284.
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Smolczyk, Yara [Verfasser], and Jörg [Akademischer Betreuer] Reichrath. "p53, Hautpigmentierung und Vitamin D : Untersuchungen zur Assoziation der Genvarianten (SNPs) von Mitgliedern der p53-Familie (p53, p63, p73) und der 25-Hydroxyvitamin- D-Serumkonzentration / Yara Smolczyk ; Betreuer: Jörg Reichrath." Saarbrücken : Saarländische Universitäts- und Landesbibliothek, 2017. http://d-nb.info/1173163158/34.
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Billant, Olivier. "Utilisation de la levure S. cerevisiae pour déchiffrer les mécanismes de l'effet dominant-négatif affectant la famille de gènes suppresseurs de tumeurs p53, p63 et p73." Thesis, Brest, 2016. http://www.theses.fr/2016BRES0055/document.
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P53 est un gène suppresseur de tumeur ubiquitaire qui empêche la prolifération de cellules malignes chez l’humain. En réponse à des dommages à l’ADN ou à des stress cellulaires, p53 entraine l’arrêt du cycle cellulaire et initie la réparation des lésions du génome. Si ces réparations échouent, p53 déclenche alors la mort de la cellule endommagée par apoptose. De plus, p53 présente une forte homologie avec deux autres gènes suppresseurs de tumeur : p63 et p73. Ces trois protéines forment une famille de facteurs de transcription qui protège l’organisme contre le développement de tumeurs. Ce système de défense est enrichi par les multiples isoformes de p53, p63 et p73 dont les rôles sont encore mal décrits. La neutralisation de la fonction de suppression de tumeur de p53, p63 et p73 est un mécanisme clef du développement tumoral auquel participent les mutants hotspots de p53 ainsi que certaines isoformes de p53, p63 et p73 par un effet dominant-négatif. Toutefois, de nombreuses zones d’ombre limitent notre compréhension de ce phénomène. Tout d’abord, l’identification des membres de la famille de p53 impliqués dans l’effet dominant-négatif reste incomplète. Ensuite, les mécanismes responsables de l’effet dominant-négatif sont débattus, suite notamment à l’émergence d’une nouvelle hypothèse impliquant un mécanisme de type prion. Enfin, l’effet dominant-négatif de la famille de p53 pourrait également être mis en cause dans d’autres types de pathologies comme les syndromes développementaux associés à des mutations de p63. Au cours de cette thèse, j’ai étudié l’impact fonctionnel des mutations hotspots de p53 ainsi que celui des principales isoformes de la famille de p53 sur l’activité transcriptionnelle des isoformes actives de p53, p63 et p73. En utilisant comme modèle d’étude un eucaryote simple, la levure S. cerevisiae, nous avons pu démontrer que l’effet dominant-négatif des mutants et isoformes de la famille de p53 repose sur la formation d’hétéro-tétramères entre formes actives et inactives de ces protéines et n’implique pas de mécanisme de type prion. De plus nos travaux ont montré que certains mutants de p53 interfèrent avec les isoformes actives de p63 et p73 par un mécanisme partiellement basé sur la tétramérisation. En outre, nos résultats préliminaires suggèrent que les mutants de p63 impliqués dans les syndromes développementaux EEC, ADULT et NSCL1 exercent également un effet dominant-négatif similaire à celui des mutants de p53. L’identification des mécanismes de l’effet dominant-négatif observé au sein de la famille de p53 permet d’envisager de nouvelles cibles thérapeutiques tant dans les cancers que dans certaines maladies rares du développement humainP53 is a ubiquitous tumor suppressor gene that prevents damaged cells from proliferating. Following DNA damage or cellular stress, p53 induces a cell cycle arrest and initiates an attempt to repair the lesions. If the repair fails, p53 triggers the apoptosis of the cell. p53 shares a high homology with two other tumor suppressor genes: p63 and p73. Together they form a family of transcription factors, which are actively protecting the organism from tumor development. This defense network is enriched by multiple N-terminal and C-terminal isoforms of p53, p63 and p73. The loss of p53, p63 and p73 tumor suppression function is a key step of cancer progression. Mutants of p53 and isoforms of p53, p63 and p73 often exhibit a dominant-negative behavior resulting in the loss of p53 tumor suppression activity. However, the extent of the dominant-negative effect within p53 family remains unclear. The mechanisms behind the dominant-negative effect are also debated due to the recent emergence of a prion-like hypothesis. Finally, the dominant-negative effect of p53 family members could be involved in other pathologies such as p63-related developmental syndromes During this PhD, I studied the functional consequences of hotspot mutations of p53 and of the main isoforms of the p53 family on the transcriptional activity of p53, p63 and p73. Using the naïve eukaryotic model S. cerevisiae we have demonstrated that the dominant-negative effect of mutants and isoforms of the p53 family relies on the formation of hetero-tetramers between functional and non-functional members of the family but not on a prion-like mechanism. In addition, certain p53 mutants are able to interfere with p63 and p73 isoforms though a mechanism that is only partially based on tetramerization. Of note, we obtained preliminary results suggesting that mutants of p63, which are involved in EEC, ADULT and NSCL1 developmental syndromes, behave like dominant-negative hotspot mutants of p53. The identification of the mechanisms of the dominant-negative effect occurring within p53 family could lead to new therapeutic targets both in cancer and in rare developmental syndromes.1 EEC : ectrodactyly, ectodermal dysplasia and cleft lip/palate syndrome, ADULT : acro-dermato-ungual-lacrimal-tooth syndrome, NSCL : non-syndromic cleft lip
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Huang, Vera. "Interactions of p53 and p73 with human promoters." Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2007. http://wwwlib.umi.com/cr/ucsd/fullcit?p3283559.
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Thesis (Ph. D.)--University of California, San Diego, 2007.Title from first page of PDF file (viewed November 21, 2007). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.
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Gillardin, Pierre. "Régulation épigénétique et protéique de p73 dans le Myélome Multiple." Thesis, Nantes, 2017. http://www.theses.fr/2017NANT1037/document.
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Les anomalies de TP53, que sont la délétion génique associée ou non à des mutations somatiques, demeurent un facteur de résistance au traitement dans le Myélome Multiple (MM) malgré l’introduction de nouveaux agents thérapeutiques. Pour contourner les anomalies de TP53, nous avons étudié la possibilité d’activer p73, un membre de la famille de p53, qui n’est pas fréquemment muté dans les cancers. Nous avons étudié l’expression, la méthylation et la régulation de TP73 dans une collection de lignées de MM sauvages ou déficientes pour p53. Nous montrons que TP73 est rarement exprimé et surtout dans les lignées TP53 sauvage. Nous avons étudié la méthylation de l’ilot CpG situé en amont du gène par MS-PCR et montré que l’absence d’expression correspond à son hyperméthylation, qui peut néanmoins être réversée par la décitabine, un inhibiteur de la méthylation. Malgré l’augmentation d’expression de TP73, la décitabine ne permet pas une expression protéique significative de p73. Pour étudier la régulation de p73, nous avons utilisé des agents alkylants, des inhibiteurs de MDM2 et du protéasome. Nous montrons que les nutlin3a et MG132, ne stabilisent pas p73 mais diminuent son expression constitutive. Les agents alkylants induisent une augmentation de p73 mais uniquement dans les lignées TP53 sauvage et l’extinction de p53 par ARN interférence inhibe cette régulation. Dans les lignées déficientes pour p53, la décitabine augmente l’expression génique mais le melphalan ne permet pas de stabilisation de la protéine. L’ensemble de nos résultats montre que TP73 n’apparaît pas être un bon candidat pour contourner les anomalies de TP53TP53 deficiency remains a major adverse event in Multiple Myeloma despite therapeutic progresses. p73, a member of p53 family, is very rarely mutated and has been poorly studied in myeloma. Using human myeloma cell lines with different TP53 status, we assessed methylation, expression and regulation of TP73. We report that TP73 is silenced by methylation and that decitabine increases its expression, which remains however insufficient for significant protein expression. Alkylating drugs increase expression of TP73 only in TP53wt cells and fail to synergize with decitabine in p53 deficient cells. On the other hand, MG132 and nutlin-3a don’t stabilize p73 in response to in TP53wt p73 positive cell lines. TP73 does not appear as a promising target for bypassing p53 deficiency in Multiple Myeloma
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Trnkus, Amanda. "Comparing wild-type p53 and a p53 isoform, p47." Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=107723.
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p53 is a tumor suppressor protein that is mutated in over 50% of human cancers. Although tightly regulated under normal conditions, this protein is quickly activated in response to a multitude of cellular stresses, inducing several downstream pathways such as cell cycle arrest, apoptosis, and senescence. p47 is an N-terminal truncated isoform made by alternative splicing of the p53 gene or from an alternative initiation site for translation, likely through cap-independent translation via an IRES. The objective of this study is to better understand the functions of p47 and to determine its structure and whether it can inhibit p53. p53 is part of a larger homologous family of proteins, including p63 and p73 – both of which contain their own N-terminally truncated isoforms. Having a complete understanding of all these proteins' roles is essential to better understand how cancer originates, progresses, and which pathways are affected. Whether p47 is a negative regulator of p53 or not is currently being disputed due to conflicting results. Evidence in this study suggests that, although p47 shares a structural conformation similar to mutant p53R175H, overall it does not negatively regulate p53. p47 is able to induce growth suppression of cancer cells and does not impair p53's suppression of growth or p53's induction of p21, nor does p47 alter the nuclear localization of p53. These results argue that p47 is not a negative regulator of p53.La protéine p53 est un gène suppresseur de tumeurs qui est muté dans plus de 50% des cancers humains. Quoique cette protéine soit étroitement contrôlée, elle peut être rapidement activée en réponse à une variété de stress cellulaires et mène à l'activation de plusieurs voies métaboliques telles que l'arrêt du cycle cellulaire, l'apoptose et la sénescence. p47 est un isoforme de p53 tronqué à l'extrémité N-terminale. La protéine p47 est générée soit par épissage alternatif de p53, soit par initiation de la traduction à un site alternatif, probablement par un mécanisme indépendant de la coiffe en 5' via un site d'entrée interne ribosomal (séquence IRES).Le but de ce projet est de mieux comprendre les fonctions de p47, notamment en déterminant sa structure et si p47 peut inhiber p53. p53 appartient à une grande famille de protéines homologues qui inclut p63 et p73, deux protéines qui ont leurs propres isoformes tronqués à l'extrémité N-terminale. Connaître le rôle de ces protéines est essentiel pour mieux comprendre comment le cancer apparaît, progresse, et les voies métaboliques qui y sont affectées. A cause de résultats contradictoires dans la littérature scientifique, il n'est pas clair si p47 peut inhiber p53. Les résultats présentés dans cette étude suggèrent que, bien que p47 a une structure semblable au mutant p53R175H de p53, p47 ne contrôle pas p53. p47 peut bloquer la croissance de cellules cancéreuses et n'affecte pas le blocage de croissance causé par p53, l'induction de p21 par p53, ni la localisation nucléaire de p53. Ces résultats indiquent que p47 n'est pas un régulateur négatif de p53.
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Rutherford, Jodie. "Germline p53 mutations : characterisation and mechanisms of P53 dysfunction." Thesis, King's College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.252278.
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Tweddle, Deborah Anne. "The role of p53 and p53 regulated proteins in neuroblastoma." Thesis, University of Newcastle Upon Tyne, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.246680.
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Jaggi, Gaurav. "Rescuing p53 function : screening and characterization of p53 stabilizing drugs." Thesis, University of Cambridge, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.608405.
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Choi, Sang H. "Study of p53 Gain of Function Mutations in p53-null Astrocytes." VCU Scholars Compass, 2000. http://scholarscompass.vcu.edu/etd/4420.
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A number of recent studies suggest that expression of mutant p53 with mutations in certain codons show a gain of function and some of the characteristics of an oncoprotein. In order to study gain of function mutation and eliminate the potential of a dominant negative interaction with endogenous wild type p53 protein, p53 knockout mouse astrocytes were used. A retrovirus system was used to introduce mutant p53 genes into these p53-null astrocytes. Immunohistochemical staining and western blot experiments showed the expression of mutant p53 protein in these cells after infection with the mutant p53 retroviruses. Cell growth experiment did not suggest growth advantages for mutant p53 expressing astrocytes over vector control cells. Data from clonogenic survival assays following exposure to etoposide or cisplatin suggested that mutant p53 expressing cells with a point mutation at codon 273 may be resistant to apoptosis induced by etoposide. In contrast, p53 with a point mutation at codon 248 may sensitize cells to the apoptotic effects of etoposide and cisplatin.
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Esfandiari, Arman. "Modulation of p53 signalling and response to MDM2-p53 binding antagonists." Thesis, University of Newcastle upon Tyne, 2016. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.701153.
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Mutational inactivation of the p53 tumour suppressor protein, encoded by the TP53 gene, occurs in ≈50% of malignancies overall. Non-genotoxic activation of p53 signalling in the remaining TP53 wild-type malignancies is a promising therapeutic strategy. MDM2 inhibitors, such as Nutlin-3 and RG7388, can activate p53 in a nongenotoxic manner, mobilising p53-dependent signalling; however, sensitivity to these compounds varies widely among TP53 wild-type cell lines. In this study p53 signalling network components involved in the response to DNA damage and p53 homeostasis are investigated for their role as determinants of cellular sensitivity to MDM2 inhibitors. Deciphering determinants of sensitivity to this group of compounds will enable optimisation of their therapeutic potential. Chemical inhibition of kinases, ATM and DNA-PKcs, which are critical for DNA double strand break repair and activation of p53 signalling in response to DNA damage, did not affect the cellular sensitivity to Nutlin-3 in the absence of DNA damage. However, inhibition of these kinases enhanced the cellular sensitivity of TP53 wild-type cells to the combined effect of Nutlin-3 and DNA damage induced by ionising radiation, in a cell type dependent manner. In a neuroblastoma derived TP53 wild-type and mutant, otherwise isogenic, cell line pair, ionising radiation increased the growth inhibitory effect of Nutlin-3 in a p53-dependent manner and this was enhanced significantly in the presence of the DNA-PKcs inhibitor NU7441. In contrast, in the osteosarcoma derived TP53 wild-type and mutant, otherwise isogenic, cell line pair, exposure to ionising radiation decreased the growth inhibitory effect of Nutlin-3 in a p53-dependent manner and DNA-PKcs inhibition did not influence this protective effect. Given that ATM and DNA-PKcs activate p53 through phosphorylation of key residues, inhibition of the WIP1 phosphatase (encoded by the PPM1D gene) that dephosphorylates one such residue, was tested for the effect on cellular sensitivity to MDM2 inhibitors. Cellular growth/proliferation was assessed in TP53 wild-type and matched mutant/null cell line pairs, differing in their PPM1D genetic status, when treated with MDM2 inhibitors Nutlin-3/RG7388 + a highly selective WIP1 inhibitor GSK2830371 or transient siRNA knockdown of WIP1 expression. The effects of GSK2830371 and transient WIP1 siRNA knockdown on MDM2 inhibitor induced p53Ser15 phosphorylation, p53-mediated global transcriptional activity and apoptosis II were also investigated. WIP1 transient siRNA knockdown increased p53Ser15 phosphorylation and sensitivity to MDM2 inhibitors in TP53 wild-type parental cell lines. TP53 wild-type and mutant cell line pairs were relatively insensitive to single agent GSK2830371 regardless of their PPM1D status. However, a non-growth inhibitory dose of GSK2830371 markedly potentiated the response to MDM2 inhibitors in TP53 wild-type cell lines, most notably in those harbouring PPM1D activating mutations or copy number gain (up to 5.8-fold decrease in GI50). Potentiation also concurred with significant increase in MDM2 inhibitor induced cell death endpoints which were preceded by a marked increase in phosphorylated p53Ser15, a WIP1 negatively regulated substrate, and known to increase p53 transcriptional activity. Microarray-based gene expression profiling showed that the combination treatment increases the subset of early RG7388 induced p53-transcriptional target genes involved in growth inhibition and apoptosis. Increased mRNA and protein expression of WIP1 has been associated with poor clinical outcome in various malignancies in which MDM2 inhibitors are being considered as a potential therapeutic strategy. For neuroblastoma mining the Amsterdam microarray databank showed WIP1 mRNA expression to correlate with worse survival. Therefore, WIP1 protein expression was assessed by immunohistochemical (IHC) staining of neuroblastoma tissue microarrays. A wide range of WIP1 IHC staining was found, however there was no significant association between high WIP1 staining and clinical outcome. Overall these findings show that manipulating p53 post-translational modification following its activation by MDM2 inhibitors or DNA damaging agents can increase cellular sensitivity to this class of compounds. Furthermore, these observations provide evidence to support the inhibition of WIP1 phosphatase activity as a strategy for enhancing the efficacy of MDM2 inhibitors, particularly in TP53 wild-type, PPM1D overexpressing/overactive malignancies.
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Marini, Wanda. "Comparing mutant p53 and a wild-type p53 isoform, p47 : rationale for the selection of mutant p53 in tumours." Thesis, McGill University, 2009. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=116033.
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One of the major unresolved questions in cancer biology is why the majority of tumour cells express mutant p53 proteins. p53 is considered the prototype tumour suppressor protein, whose inactivation is the most frequent single genetic event in human cancer (Bourdon et al., 2005). Genetically-engineered p53-null knockout mice acquire multiple tumours very early on in life and human Li-Fraumeni families who carry germline mutations in p53 are highly cancer-prone (reviewed in Vousden and Lane, 2007). p53 mutant proteins have been found to acquire novel functions that promote cancer cell proliferation and survival, yet exactly why mutant p53s acquire oncogenic activity is still poorly understood. Mutant p53 has also been found to complex with wildtype p53, thus acting in a dominant negative way. However, this inhibition is incomplete since many cancers with mutant p53 alleles also have a loss of the second wild-type p53 allele and thus only express the mutant p53 (Baker et al., 1989). An N-terminal truncated p53 isoform, p47, arising from alternative splicing of the p53 gene (Ghosh et al., 2004) or by alternative initiation sites for translation (Yin et al. , 2002), has been described. Alternative splicing was found to be universal in all human multi-exon genes (Wang et al., 2008) and therefore determining the role of the p47 isoform with respect to the p53 gene is essential. Evidence in this study suggests that mutant p53 (p53RI75H) has a similar structure and function as p47, including the ability to complex with and impair both p53 and p73. Therefore, in addition to expressing a tumour suppressor protein, the p53 gene can also express an onco-protein (p47). This study therefore argues that tumours select for mutant p53 because it has gained the ability to function like p47, a wild-type p53 isoform.
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Bertagnolli, Angélica Cavalheiro. "Expressão de p63 e p53 em tumores mamários mistos de cadelas." Universidade Federal de Santa Maria, 2006. http://repositorio.ufsm.br/handle/1/10165.
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Conselho Nacional de Desenvolvimento Científico e TecnológicoThe p63 protein is expressed in the nuclei of the mammary myoepithelial cells and has synergisms or antagonisms with p53 tumor suppressor protein. The immunohistochemistry expression of p63 was studied for access the role of myoepithelial cells in histogenesis of the mixed tumors. Additionally, the possible association between p63 and p53 for access the biological aspects of this tumors was evaluated. Four specimens of the normal gland, 20 benign mixed tumors, 35 carcinomas in mixed tumors and 11 tubulopapilary carcinomas were evaluated. Myoepithelial cells forming layers periductals/periacinars continuous were reactive for protein p63 in normal gland and in benign mixed tumor. The carcinomas in mixed tumors and 72.7% (8/11) tubulopapilary carcinomas were reactive for p63. In the mixed tumors star and spindle shaped cells were reactive for p63. The p53 protein was expressed in 20.0% (4/20), 28.6% (10/35) and 36.7% (4/11), benign mixed tumors, carcinoma in mixed tumors and tubulopapilary carcinomas, respectively. There was not relation between p63 and p53 expression in none type of tumor. The present study point the participation of the mioepithelial cells in the histogenesis of the mixed tumors. The decrease in p63 expression in the basal myoepithelial cells of the carcinomas may be important for tumoral progression.
A proteína p63 é expressa no núcleo das células mioepiteliais da mama e apresenta funções sinérgicas ou antagonistas com a proteína de supressão tumoral p53. A expressão imuno-histoquímica de p63 foi estudada para acessar o papel das células mioepiteliais na histogênese dos tumores mistos. Adicionalmente, avaliou-se a possível relação entre expressão imuno-histoquímica de p63 e p53 com a finalidade de obter informações sobre a biologia desses tumores. Quatro amostras de mama normais, 20 tumores mistos benignos, 35 carcinomas em tumores mistos e 11 carcinomas tubulopapilares foram avaliados. Células mioepiteliais, formando camadas periductais/periacinares contínuas, foram imunoreativas para p63 na mama normal e nos tumores mistos benignos. Todos os carcinomas em tumores mistos e 72,7% (8/11) dos carcinomas tubulopapilares foram reativos para p63. A reatividade para p63 foi superior nos tumores mistos benignos quando comparada com os carcinomas. Nos tumores mistos, células mioepiteliais com formato fusiforme e estrelado, presentes no estroma mucinoso também foram reativas para p63. A proteína p53 foi expressa em 20,0% (4/20), 28,6% (10/35) e 36,4% (4/11) dos tumores mistos benignos, carcinomas em tumores mistos e carcinomas tubulopapilares, respectivamente. Não houve relação entre a expressão de p53 e p63 nos diferentes tipos tumorais. O presente estudo evidenciou a participação das células mioepiteliais na histogênese dos tumores mistos. A diminuição da expressão de p63 nas células mioepiteliais que compõem a camada basal dos carcinomas pode ser um evento importante para a progressão tumoral.
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Kim, Minsu. "Regulatory Interaction of the Class III PI3 Kinase Complex and p53." Thesis, Harvard University, 2012. http://dissertations.umi.com/gsas.harvard:10588.
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Autophagy is a catabolic pathway utilized by cells to maintain homeostasis. Dysregulation of this pathway often leads to various diseases, such as cancers and neurodegeneration. Therefore, autophagy must be tightly regulated by the extracellular environment or signaling pathways. The class III PI3 kinase complex, a lipid kinase complex functioning in converting phosphatidylinositol to phosphatidylinositol-3-phosphate, is a key regulator of autophagy that functions as a signaling hub where multiple regulatory signals converge. Here, we demonstrate that the class III PI3 kinase complex is negatively regulated by cyclin-dependent kinases (Cdks). The catalytic subunit of the kinase complex, Vps34, is phosphorylated by Cdk1 in mitotic cells and by Cdk5 in postmitotic cells. Phosphorylation on Vps34 results in its dissociation from a regulatory subunit Beclin 1, leading to decreased lipid kinase activity. As a result, autophagy is inhibited in dividing cells and postmitotic neuronal cells with elevated Cdk5 activity. Since dysfunction of autophagy has been shown to be implicated in cancers and neurodegeneration, which are characterized by abnormal activity of Cdk1 and Cdk5, respectively, our study provides a mechanism by which autophagy is modulated in those diseases. To further discover the regulatory mechanisms of autophagy, we used a novel autophagy inhibitor, spautin-1, identified in a small molecule screening. Spautin-1 inhibits autophagy by inhibiting Usp10/Usp13, which deubiquitinate and stabilize the class III PI3 kinase complex. Interestingly, Usp10/Usp13 are also stabilized by the class III PI3 kinase complex, suggesting that they are reciprocally regulated. These results led us to the observation that p53, a substrate of Usp10 is regulated by the class III PI3 kinase complex and spautin-1. We also report that A70, a more potent derivative of spautin-1, leads to the degradation of mutant p53 through the chaperone-mediated autophagy, whereas the wild-type p53 is degraded by the ubiquitin-proteasome system. Our study demonstrates an important regulatory interaction between the class III PI3 kinase complex and p53, suggesting a novel tumor suppressive function of the class III PI3 kinase complex.
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Vayssade, Muriel. "Implication de p53 et de ses homologues, p73 et p63 dans la chimiosensibilité des cellules de cancer du sein." Paris 6, 2002. http://www.theses.fr/2002PA066362.
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Becker, Marie-Christine. "Generierung und Charakterisierung von Makrophagen-Zelllinien aus CCR5-/-/p53-/- und p53-/- Mäusen." Diss., lmu, 2008. http://nbn-resolving.de/urn:nbn:de:bvb:19-80603.
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Wang, Qian. "p53 functional loss by mutation and p53 antagonizing proteins during tumor development /." Stockholm, 2000. http://diss.kib.ki.se/2000/20000525wang/.
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Di, Minin Giulio. "Functional analysis of novel interactors of mammalian p53 and p53-related proteins." Doctoral thesis, Università degli studi di Trieste, 2012. http://hdl.handle.net/10077/7356.
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2010/2011The tumor suppressor p53 plays a central role in the protection against DNA damage and other forms of stress, primarily by inducing cell cycle arrest or apoptosis. Mutation of p53, which is one of the most frequent genetic alterations detected in human cancers, inactivates these growth regulatory functions; in addition, very often mutant p53 acquires tumor-promoting activities (gain-of-function). A complete and thorough understanding of the signaling circuitry that regulates wild-type and mutant p53 functions is therefore a primary objective for basic cancer research, since it may lead to development of important tools for diagnosis and therapy of tumors. One crucial component of such knowledge is the protein interaction profile of p53. To gain novel insights on p53 interactions, we used a phylogenetic approach. We reasoned that a comprehensive map of the protein interaction profile of Drosophila p53 might reveal conserved interactions of the entire p53 family in man. Using a genome-scale in vitro expression cloning approach, we identified 91 previously unreported Dmp53 interactors. Next, we studied and characterized the interaction of human orthologs of newly identified Dmp53 interactors with all p53-family proteins, and it resulted in the identification of several novel interactants of this family of tumor suppressors (Part 1 of this Thesis). In parallel, we verified that many of the mammalian orthologs of Dmp53 interactors could also bind to an oncogenic p53 mutant (R175H), and therefore are potential novel targets or effectors of mut-53 gain of function activities. Among those proteins we focused our attention on DAB2IP, a tumor-suppressor gene that functions by counteracting the activation of multiple oncogenic pathways. There are evidences that mutant p53 has a stimulatory role in all the signaling pathways that are normally inhibited by DAB2IP; therefore, we propose that mutant p53 may bind and functionally inactivate DAB2IP as one of the mechanisms of its gain-of-function. Given the crucial role of DAB2IP in modulating cellular responses to TNF, we focus on the potential relevance of this interaction in the connection between inflammation and cancer (Part 2 of this Thesis).
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Gasperis, Alexia de. "Expression et fonctions biologiques de l’isoforme ΔNp63." Thesis, Lyon 1, 2011. http://www.theses.fr/2011LYO10275.
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Le gène TP63 fait partie de la famille du gène suppresseur de tumeur TP53. Il code plusieurs isoformes. L’une d’entre elles, tronquée dans la région amino-terminale et appelée ΔNp63, présente des propriétés oncogéniques. Elle est impliquée dans la progression tumorale et la chimiorésistance. Sa surexpression est fréquente dans certains types de cancers. La première partie de mes travaux a consisté à identifier les facteurs de transcription impliqués dans la régulation du promoteur de ΔNp63. J’ai montré que l’expression de cette isoforme est inhibée par p53 et activée par ΔNp63 elle-même et par la β-caténine, dans des lignées de carcinome hépatocellulaire et de carcinome épidermoïde de l’œsophage. Dans des conditions physiologiques, un des types cellulaires dans lequel ΔNp63 est exprimée est la cellule basale mammaire. Il est admis que les tumeurs mammaires dites basal-like sont issues des cellules basales. Certaines de ces tumeurs présentant une surexpression de ΔNp63, nous avons émis l’hypothèse que ΔNp63 serait impliquée dans la tumorigenèse des cellules basales. Dans la deuxième partie, j’ai montré que l’expression de ΔNp63 peut être augmentée en cultivant les cellules mammaires en présence de surnageant de fibroblastes embryonnaires humains. L’identification de facteurs solubles responsables est en cours. D’autre part, j’ai caractérisé les conséquences biologiques de cette augmentation en termes de prolifération, de motilité et de survie des cellules immatures mammaires normales et tumorales. Les plus grandes modifications observées concernent (i) l’état de différenciation, les cellules surexprimant ΔNp63 présentant un phénotype plus immature ; (ii) la balance entre migration et adhésion qui penche en faveur de cette dernière. ΔNp63 semble donc être au carrefour des mécanismes de prolifération, d’adhésion, de différenciation et de motilité, processus impliqués dans la formation et l’homéostasie des tissus, mais dont l’altération peut conduire à l’initiation et à la progression tumorale ainsi qu’à la dissémination métastatique. Mes travaux apportent des informations sur le rôle de cette protéine dans ces processus et devraient, à terme, permettre de mieux comprendre la genèse de certains cancers, en particulier les carcinomes basal-likeTP63 gene belongs to the TP53 tumor suppressor gene family. It encodes several isoforms. One of these, truncated in its amino-terminal end and called ΔNp63, displays oncogenic properties. It is involved in tumor progression and chemoresistance and is overexpressed in some tumor types. The first part of my work consisted of identifying the transcription factors involved in the regulation of the ΔNp63 promoter. I have shown that ΔNp63 expression is inhibited by p53 and activated by ΔNp63 itself and by β-catenin in hepatocellular carcinoma and esophageal squamous cell carcinoma cell lines. Under physiological conditions, one of the cell types in which ΔNp63 is expressed is the mammary basal cell. The “basal-like” mammary tumor sub-type seems to stem from basal cells. As some of these tumors exhibit overexpression of ΔNp63, we hypothesized that this isoform could be involved in the genesis of basal-like tumors. In the second part, I have shown that ΔNp63 expression can be increased in mammary cells cultivated in the presence of human embryonic fibroblast supernatant. Identifying the soluble factors responsible for this increase is in progress. In parallel, I have evaluated the biological consequences of ΔNp63 overexpression in terms of proliferation, cell motility and survival of normal and malignant immature mammary cells. The main modifications relate to (i) the differentiation status, ΔNp63-overexpressing cells exhibiting a more immature phenotype; (ii) the balance between migration and adhesion that is in favor of this latter. ΔNp63 seems to be at the crossroads of proliferation, adhesion, differentiation and motility, processes implicated in tissue formation and homeostasis, but whose alteration may lead to tumor initiation and progression and to metastatic dissemination. My work provides information on the role of this isoform in these processes and should allow better understanding of the genesis of some tumor types, in particular basal-like breast carcinomas
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Strefford, Jon C. "P53 and chromosome instability." Thesis, Swansea University, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.639125.
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This research project utilised methodologies from the fields of genetic toxicology and cytogenetic to accurately assess chromosome damage in p53-modified cell lines. Three primary diploid fibroblast cell lines were used; a control cell exhibited wild-type p53 characteristics, a mutant p53 cell line with a codon 143val-ala mutation, and a near null cell line containing transcripts for the E6 onco-fragments from the human papillomavirus type 16. These cell lines were characterised cytogenetically, and treated with genotoxic compounds so that the degree of chromosome damage could be assessed and correlated to p53 functional status. The mutant p53 plasmid induced significantly higher levels of spontaneous damage and premature centromeric division. After G1 and G2 chemical treatment, the E6 cell lines exhibited a significantly higher frequency of chromosome breakage, supporting the previous observations that p53 monitors these stages of the cell cycle. Chromosome painting and centromeric FISH for chromosome 1, 7 and 17 showed a shift towards abnormalities of chromosome 17 in the p53-modified cell lines. Post-treatment with a spindle poison, chromosome loss and non-disjunction were elevated in the p53 modified cell lines, implicating p53 as a monitoring protein in proper spindle formation. Treatment with Diazepam, showed ambiguous results, but suggested a limited role of p53 during centriole formation. This study demonstrated several p53-dependent monitoring capacities throughout cell cycle progression, several of which were novel observations. Premature centromeric division showed a clear correlation with changes in p53 functional status.
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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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Preudhomme, Claude. "P53 et hemopathies malignes." Lille 2, 1995. http://www.theses.fr/1995LIL2P257.
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Pei, Lim-cho Steven, and 貝念祖. "Role(s) of p53/p63 in chondrocyte re-differentiation upon activation of ER stress." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2012. http://hdl.handle.net/10722/198926.
Full textAbstract:
Endoplasmic Reticulum (ER) stress signal is a cellular response to various insults including
abnormal protein folding load, activating the unfolded protein response. Under severe ER stress,
apoptosis will occur in most cell types. Interestingly, this does not happen in a disease model for
Metaphyseal chondrodysplasia type Schmid (MCDS), where ER stress was activated in the
hypertrophic zone of the growth plate where mutant collagen X proteins that cannot be folded
correctly is expressed. Instead of normal progression from proliferating chondrocytes (PCs) to
hypertrophic chondrocytes (HCs) and conversion to bone, HCs in MCDS mice undergo
re-differentiation to PCs as a survival strategy due to an activation of ER stress. Transcription
factors are known to be important in regulating differentiation. p53 family members, as
transcription factors, are known to play important roles in developmental processes including
cellular reprogramming, thus, we hypothesize that the ectopic expression of key transcription
factors, p53 and TAp63, which are activated by ER stress is involved in HC re-differentiation. p53
is normally expressed in late PCs, Pre-HCs, and upper HCs, while TAp63 is expressed in PCs and
Pre-HCs suggesting they may have roles in chondrocyte differentiation. p53 activated under ER
stress in HCs are nuclear localized in MCDS mice, but did not invoke the apoptotic programme.
In this project, using quantitative analyse to study the expression level of p53 and p63 isoforms, it
was confirmed that p53 and TAp63γ are in part transcriptionally activated upon ER stress. From
functional study by inactivating p53 in MCDS mice, it was shown that p53 alone was not sufficient
to mediate re-differentiation. Given that TAp63γ isoforms is also highly upregulated upon ER
stress, and the negative regulator, ΔNp63, is downregulated, this combination of change in gene
expression also need to be considered.
Furthermore, known regulators of p53 and p63 activity such as ASPP1 and iASPP are also
differentially expressed in HCs, and are altered upon activation of ER stress favouring cell survival.
Thus, it would be important to evaluate the combination of TAp63 in the re-differentiation process
from conditional inactivation of p63 or in combination with p53 to gain a clearer understanding of
the contribution and relationship of these transcription factors in the survival strategy of stressed
HCs.published_or_final_version
Biochemistry
Master
Master of Philosophy
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Liu, Yue. "Regulation of p53 and p73 function by PCAF and adenovirus E1B 55-kDa oncoprotein." Thèse, Sherbrooke : Université de Sherbrooke, 2002. http://savoirs.usherbrooke.ca/handle/11143/4172.
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Jo, Sebastien. "Discovering the p53 isoforms' code." Thesis, University of Dundee, 2017. https://discovery.dundee.ac.uk/en/studentTheses/9530ac6e-bce9-4515-9284-0198a7f41a9a.
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p53 has a key role in the maintenance of the genetic stability and, thus, in preventing tumour development. The current model is that the p53-dependent responses are solely driven by p53α. The uncovering that the TP53 gene physiologically expresses several p53 isoforms, challenges this paradigm. According to the data gathered about p53 isoforms in the past ten years, we hypothesise that the so-called p53 is a multi-protein system composed by the twelve isoforms and that a p53-mediated cell response is, in fact, the sum of the intrinsic activities of the co-expressed p53 isoforms. Here, we report that the TP53 gene always co-expresses several p53 protein isoforms in cells, tumour tissues and also in normal human tissues. Physiologically, the HPV E6 protein differentially regulates the expression of all p53 isoforms to command replication. Differentially modulating isoforms expression using siRNAs, without changing extra-cellular signals, alters the cell-fate outcome. Furthermore, we establish that the p53 pathway is still active in cell lines devoid of canonical p53α expression, but retaining expression of other isoforms. Mechanistically, we demonstrate that, depending on post-translational modifications, the isoforms co-expressed in a given cell type, oligomerise together and regulate target-gene transactivation in a promoter-dependent manner. Altogether, this study shows that p53 functions as a multi-protein system that is functional in the absence of canonical p53α. The cellular content in p53 isoforms defines the cell response. The isoforms oligomerise together, depending on post-translational modifications, to finely tune target-gene expression in a promoter-dependent manner. These data indicate that the p53 isoforms would compose a cellular code. Cracking “the p53 isoforms’ code” will, therefore, enable to define cell responses and to develop new therapeutic strategies.
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Boyd, Scott D. (Scott Dexter) 1970. "p53 nuclear localization control, and p53-dependent regulation of DNA repair gene transcripts." Thesis, Massachusetts Institute of Technology, 2004. http://hdl.handle.net/1721.1/30070.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2004."February 2004."
Includes bibliographical references.
The experiments presented in this thesis use mutation analysis, and study of the cells of mice with a deletion allele for the Trp53 gene, to explore both the regulation of p53, and its downstream functions mediated by specific activation of target genes. Chapter 2 addresses the regulation of nuclear localization of the p53 protein. Previous reports in the literature had suggested that the p53 negative regulator HDM2 was a nucleocytoplasmic shuttling protein that binds and carries p53 from the nucleus of the cell to the cytoplasm where it is destroyed by the proteasome. We determined that HDM2 with a mutated nuclear export sequence was still able to able to alter p53's cellular localization to a cytoplasmic pattern. The nuclear export sequence in the p53 C-terminus was required for this activity, as was the ability of HDM2 to ubiquitinate p53. Further studies indicated that ubiquitination of the p53 C-terminus was the basis for HDM2's ability to remove it from the nucleus and cause its efficient degradation. C-terminal ubiquitination causes the p53 nuclear export sequence to be activated or made more accessible to the nuclear export machinery of the cell. Chapter 3 summarizes cDNA microarray experiments in which Trp53-/- and Trp53+/+ fibroblasts were treated with a panel of genotoxic agents, and assayed for p53-dependent upregulation or downregulation of the approximately 15,000 gene sequences represented on the microarray. New candidate p53 target genes were revealed, among them the DNA repair gene ErccS, which encodes the xeroderma pigmentosum disease gene homolog Xpg, a participant in nucleotide excision repair and a mediator of base excision repair of oxidative DNA damage.
(cont.) Further analysis of most of the DNA repair genes in the mouse genome using real-time PCR indicated that a second gene, Polk, encoding the translesion DNA polymerase kappa, is also a p53-induced gene. Chapter 4 describes further characterizes the p53-dependent regulation of Ercc5, and shows that it is a directly-regulated p53 target gene with a p53-responsive site in its first intron. TrpS3-null cells show a modest reduction in the ability to repair an oxidatively-damaged DNA construct, and this defect is rescued by exogenous expression of retrovirally transduced XPG, indicating that the lower levels of this gene are likely responsible for the defect.
by Scott D. Boyd.
Ph.D.
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Cadot, Bruno. "P63alpha, membre de la famille de p53 : structure, interaction et importance du domaine SAM de p63alpha." Paris 6, 2005. http://www.theses.fr/2005PA066045.
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Cuella-Martin, Raquel. "Molecular regulation of p53-dependent tumour suppressor responses by the p53 binding protein 1." Thesis, University of Oxford, 2018. http://ora.ox.ac.uk/objects/uuid:7b2e64f3-bda4-4c3c-aeaf-d27393b7bc07.
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The tumour suppressor p53 binding protein 1 (53BP1), a fundamental node in DNA double strand break (DSB) repair, was identified as a p53-interacting protein over two decades ago. However, its contribution to p53-dependent responses has remained largely enigmatic. Here, using a combination of detailed structure-function approaches and in vivo analyses I aim to unravel this aspect of 53BP1 functionality. I showed 53BP1 to enhance genome-wide p53-dependent transactivation events in response to multiple stress stimuli. Oligomerised 53BP1 relies on the tandem BRCT domain, dispensable for 53BP1-driven DSB repair, to bridge dual interactions with p53 and the ubiquitin specific protease 28 (USP28). These interactions are both essential for 53BP1-dependent modulation of p53 functionality. Indeed, the cooperation between 53BP1 and USP28 is required for proficient p53-dependent G1/S checkpoint and senescence responses. Mechanistically, the action of the USP28-53BP1 complex involves differential ubiquitination events that ultimately stimulate p53's ability to bind the responsive elements (RE) in its target genes. Furthermore, I demonstrated 53BP1-driven p53 modulation to function independently of 53BP1's well-described DSB repair roles, and be separable by specific point mutations within 53BP1 architecture. Translation to in vivo mouse models revealed 53BP1-driven DSB repair to be responsible for 53BP1's role in the physiology of the immune system, while functional 53BP1-p53 connections result in effective quality control of chromosomal dosage upon defective mitotic division. Collectively, my findings define 53BP1 as an integral node in genome stability control, driving efficient DSB repair and mitotic surveillance mechanisms.
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Osadchuk, Olha. "Optimalizace izolace mutantního proteinu p53 a jeho DNA vazebné vlastnosti." Master's thesis, Vysoké učení technické v Brně. Fakulta chemická, 2020. http://www.nusl.cz/ntk/nusl-413550.
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Protein p53 je jednou z nejdůležitějších molekul v lidském těle. P53 reguluje celou řadu procesů v buňce, jako je například oprava DNA, buněčný cyklus nebo indukce apoptózy. Protein p53 je známý i jako „strážce genomu“. DNA vazebné schopnosti proteinu p53 jsou důležité pro normální vývoj a růst buňky. Mutace genu pro p53 mohou vést ke ztrátě jeho DNA vazebných vlastností a funkce nádorového supresoru, což muže způsobit rozvoj rakoviny. Teoretická část této diplomové práce je zaměřena na popis vlastností, funkce a mechanismus aktivace proteinu p53 a popis lokálních sekundárních struktur DNA. Hlavním cílem experimentální části byla produkce čtyř mutantních forem proteinů p53 a wild-type p53 proteinu a studium jejich vazebných vlastnosti s různými lokálními sekundárními strukturami DNA. Pomoci Gateway klonovacího systému byly připraveny čtyři expresní vektory, které byly použity pro produkci proteinů v bakteriálním expresním systému. Celkem byly úspěšně připraveny čtyři mutantní formy a wild-type p53 protein. Jejich vazebné vlastnosti byly studovány gelovou retardační analýzu. Výsledky naznačují různé DNA-vazebné vlastnosti wild-type p53 a studovaných mutantních forem tohoto proteinu. Všechny mutantní proteiny ztratily schopnost sekvenčně specificky vázat DNA, zatímco nespecifická interakce s DNA byla pozorována u tří ze čtyř mutantních forem. Jeden ze studovaných mutantních proteinů se vázal jenom na superhelikální formu DNA.
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Tomas, Fanny. "Caractérisation fonctionnelle de la relation entre le suppresseur de tumeur p53 et son isoforme Delta133p53 dans les cellules humaines normales." Thesis, Montpellier, 2018. http://www.theses.fr/2018MONTT085.
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La sénescence réplicative (SR) dans les fibroblastes humains primaires est causée par l’érosion des télomères et est contrôlée par p53. La régulation dynamique de l’activation de p53 est essentielle pour l’induction de la sénescence ; cependant, les mécanismes moléculaires sous-jacents ne sont pas clairement établis. Nous montrons, dans les cellules surexprimant les isoformes Δ133/Δ160p53, que ces isoformes s’oligomérisent avec p53, conduisant ainsi à la stabilisation d’une forme inactive de p53. A l’inverse, l’inactivation des isoformes endogènes Δ133/Δ160p53 induit l’accumulation de la protéine p53 et l’activation de son activité transcriptionnelle. La surexpression de Δ133/Δ160p53 inhibe les fonctions de p53, en particulier son activité transcriptionnelle et son rôle dans l’arrêt du cycle après un dommage à l’ADN. Nous avons remarqué que les protéines Δ133/Δ160p53 et p53 sauvage possédaient des conformations différentes. Les protéines Δ133/Δ160p53 sont reconnues pas l’anticorps Pab40 : elles adopteraient une conformation similaire à un mutant de conformation de p53. Enfin, nous observons qu’une faible expression de l’ARNm Δ133/Δ160TP53 coïnciderait avec la durée de l’activation transcriptionnelle de p53 lors de la SR, indiquée par l’accumulation de l’ARNm d’un effecteur majeur de p53, p21. L’augmentation de l’expression de Δ133/Δ160TP53 à un temps tardif au cours de la SR est corrélée à l’accumulation du marqueur de sénescence p16INK4a et à celle de la cytokine pro-inflammatoire IL-6. En conséquence, les isoformes Δ133/Δ160p53 contrôleraient l’activité de p53 dans l’arrêt du cycle et sur le phénotype sécrétoire des cellules sénescentesTelomere attrition in primary human fibroblasts induces replicative senescence by activation of the tumour suppressor p53. Fine-tuned activation of p53 is essential for senescence induction; however, the mechanisms underlying the regulation of p53 activity during senescence have not been clearly established yet. We report here that in cells that express the Δ133/Δ160p53 isoforms, these p53 isoforms oligomerize with p53, leading to the stabilization of the transcriptionally inactive form of p53. Conversely, endogenous Δ133/Δ160p53 silencing increases the level of p53 and p53-dependent transcriptional activity to promote cell cycle arrest. Overexpressed Δ133/Δ160p53 repress p53 functions, including gene transcription activation and growth inhibition, upon DNA damage. We also found that Δ133/Δ160p53 and wild-type p53 have different structural conformations. Δ133/Δ160p53 adopt a more unfolded conformation recognized by the Pab240 antibody, indicating that these p53 isoforms have a p53 mutant-like conformation. Finally, we observed that low level of Δ133/Δ160TP53 mRNA coincided with the duration of p53 transcriptional activation in replicatively senescent fibroblasts, as indicated by the upregulation of CDKN1A (p21) mRNA expression, a downstream effector of p53. Δ133/Δ160p53TP53 was upregulated at a later stage when the senescence marker p16INK4a and the pro-inflammatory interleukin-6 (IL-6) were also induced. Therefore, p53 activity on growth suppression and senescence-associated secretory phenotype may be differentially regulated by its Δ133/Δ160p53 isoforms
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Mitchell, Geoffrey C. "The p53 homolog p63 modulates acute and chronic damage in irradiated salivary glands." Diss., The University of Arizona, 2010. http://hdl.handle.net/10150/194089.
Full textAbstract:
Head and neck cancer is diagnosed in more than 50,000 Americans each year, resulting in roughly 11,000 deaths. For this disease, a typical therapeutic regimen involves cisplatin, a radiosensitizer, given alongside targeted irradiation. While technological advances such as IMRT have been useful in sparing normal tissues from radiotherapy, the salivary glands occupy much of the head and neck and surround several lymph nodes, and thus, non-diseased salivary glands are often damaged. This causes reduced salivary output, damaged oral mucosa, dysphagia, malnutrition and tooth decay. Often, these side-effects are so severe that patients discontinue treatment, however, in many cases, salivary gland damage is permanent, and treatment options are palliative. Specifically, muscarinic-cholinergic agonists are used to enhance secretion from remaining salivary cells, although due to non-specific action, these drugs have a number of ill-effects. It is clear that therapies are needed to prevent radiation-induced salivary gland damage, as well as to restore glandular function in patients who are already suffering.Previous work from our group has shown that salivary gland dysfunction results from loss of acinar cells to radiation-induced apoptosis. Importantly, a single intravenous dose of IGF1 can prevent apoptosis and preserve salivary output when given immediately prior to irradiation. Because of its broad effects, however, IGF1 may never be a viable clinical option. Instead, our goal is to identify signaling events that mediate the radioprotective effects of IGF1 downstream of Akt. Because radiation-induced apoptosis in salivary glands is p53-dependent, we assessed the contributions of the p53 homologs p63 and p73 to the DNA damage response. Here, we show that IGF1 enhances cell cycle arrest following irradiation by reducing inhibitory binding of deltaNp63 to the p21 promoter. We hypothesize that IGF1-induced cell cycle arrest may allow time for DNA repair, thus preventing apoptosis and maintaining salivary function. In addition, we indicate chronic signaling events downstream of p63 that may contribute to permanent loss of salivary function by blocking differentiation of salivary progenitor cells. Together, these results indicate that p63 may be a valid therapeutic target for both prevention of damage and restoration of function in irradiated salivary glands.
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Beitzinger, Michaela [Verfasser], and Michael [Akademischer Betreuer] Schön. "Regulierung der Telomerase durch das p53-Homolog p73 / Michaela Beitzinger. Betreuer: Michael Schön." Würzburg : Universität Würzburg, 2006. http://d-nb.info/1099603676/34.
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Schumacher, Björn. "The C. elegans p53 pathway." Diss., lmu, 2004. http://nbn-resolving.de/urn:nbn:de:bvb:19-19806.
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Ogi, François-Xavier. "Regulation of p53 by Rad23." Karlsruhe : FZKA, 2005. http://bibliothek.fzk.de/zb/berichte/FZKA7180.pdf.
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Constantinou, Constantina. "Regulation of translation by p53." Thesis, St George's, University of London, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.423184.
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Saundh, Harpal. "Targeting mutant p53 in cSCCs." Thesis, University of Dundee, 2016. https://discovery.dundee.ac.uk/en/studentTheses/29e37f0d-5ed7-483c-9a92-87212934d72b.
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Cutaneous squamous cell carcinoma (cSCC) is a type of non-melanoma skin cancer that is the 4th most common cancer registration in Scotland after BCC, lung and breast cancer. Over 30,000 cSCC incidences are reported each year in the United Kingdom. In addition, around 1 in 4 skin cancer deaths in the UK are due to cSCCs. Amongst those highly prone to developing cSCCs include organ transplant recipient, immunosuppressed, recessive dystrophic epidermolysis bullosa (RDEB) and Xeroderma Pigmentosum (XP) patients. cSCC patients that display regional metastasis have a 5-year survival rate of 25-50%, whilst this rate is close to 0% in RDEB patients with multiple cSCCs. Wild-type p53 (wt-p53) has been shown to prevent cSCC development and induce tanning and sunburn responses in skin cells. However, TP53 mutations are found in over half of all human cancers and cSCC is no exception as TP53 mutational frequency in cSCCs is around 64-87.5% (Durinck et al, 2011; South et al, 2014). The majority of TP53 mutations in cSCCs are UV-signature missense mutations, highlighting UV-radiation as one of the main risk factors for cSCC development. Mutant p53 proteins can lose wt-p53 functions, have dominant-negative effects against wt-p53 and acquire gain of function (GOF) activities. Mutant p53 GOF activity is induced by the accumulation of mutant p53 in tumour cells. Mutant p53 accumulation is not due to intrinsic properties of the mutants but requires other cellular events, possibly those known to stabilise wt-p53 under cellular stress. It is known that the TP53 mutations and mutant p53 accumulation are early steps in cSCC development. This makes skin an excellent system to investigate the early changes to p53. We have investigated the potential of targeting mutant p53 for cSCC therapy and mechanisms that promote mutant p53 accumulation in cSCCs. We selected low-passage cSCC cell lines that express hotspot mutant p53 proteins, in cSCCs and in general, by analysing TP53 mutational data from the IARC database and next generation sequencing studies performed on cSCC primary tumours by Dr South at Ninewells Hospital, Dundee. cSCC cell lines were generated from immunocompetent, transplant and RDEB patients by Dr South’s group at Ninewells Hospital, Dundee. We found that: 1. PRIMA-1MET, a small molecule reported to restore wt-p53 activity, lacked tumour selectivity as it is able to reduce cell viability in both normal skin and cSCC cells with similar potency. cSCC cell lines are relatively resistant to PRIMA-1MET compared to cell lines derived from other tumour types. 2. Mutant p53 knockdown studies performed on cSCC cell lines suggest that some p53 mutants play a pro-proliferative role. However, there is no evidence for a pro-migratory role of mutant p53 in cSCC. 3. There are no clear alterations in DNA-damage response pathways or the general ubiquitin proteasome system that could contribute to mutant p53 stabilisation in cSCC. 4. Heat shock factor 1 (HSF-1) is upregulated in cSCC compared to normal human keratinocytes (NHK). HSP90 inhibitors, 17-AAG and 17-DMAG, reduce mutant p53 protein levels suggesting that HSP90 plays a role in stabilising mutant p53 in cSCCs. 5. PR-619, a broad range deubiquitinating enzyme (DUB) inhibitor, reduces mutant p53 protein levels in a range of cSCC cell lines. This is rescued by the addition of bortezomib suggesting that DUBs can play a role in protecting mutant p53 from proteasomal degradation. Expression of HAUSP and USP10, which have been shown to stabilise wild-type p53, is generally elevated in cSCC compared to NHK. However, knockdown of these DUBs does not reduce protein levels of mutant p53 in cSCC cell lines. 6. A potential isoform of MDMX (51 kDa) is strongly upregulated in all cSCC cell lines examined. There is an association between the ability of MDMX siRNAs to deplete the 51 kDa protein and reduce mutant p53 protein levels and stability. Furthermore we show that the protein can form complexes with MDM2 in vitro and in cSCC cells. We propose that the MDMX isoform is able to stabilise mutant p53 in cSCC cells through this interaction with MDM2.
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Tournillon, Anne-Sophie. "The p53-MDM2-MDMX interplay." Paris 7, 2014. http://www.theses.fr/2014PA077233.
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P53 est un gène suppresseur de tumeur majeur muté dans plus de 50% des cancers. Les deux régulateurs principaux de p53 sont MDM2 et MDMX et les modèles murins n'exprimant pas MDM2 ou MDMX décèdent lors de l'embryogénèse de manière p53 dépendante. Étant donné leur fonction centrale dans la tumorigénèse, il est essentiel de comprendre comment ces protéines régulent l'expression et l'activité de p53. Dans ce manuscrit de thèse, je présente mon travail sur la boucle de régulation entre ces 3 partenaires et d'un point de vu plus large comment ces données prennent place dans un modèle thermodynamique général. Contrairement à la capacité de p53 à lier l'ADN, peu de choses sont connus sur celle à lier l'ARN et son importance physiologique. Lors de mon étude, j'ai utilisé p53 et l'ARN de mdmx comme modèle afin de caractériser la capacité de p53 à lier l'ARN. J'ai démontré que l'expression de p53 supprime la synthèse de MDMX en se liant à l'ARNm de mdmx. De plus j'ai pu monté que p53 se lie spécifiquement au 5'UTR de mdmx. Des analyses de mutants de délétions et de mutants ponctuels ont montré que le domaine de liaison à l'ADN de p53 se lie spécifiquement au 5'UTR de mdmx et que le domaine N-terminal de p53 régule son activité de trans-suppression. Mes résultats ont montrés que les capacités de p53 à lier l'ADN et l'ARN se chevauchent mais avec des caractéristiques distinctes. Lors de ce projet, nous avons également identifié un nouvel isoforme de MDMX qui ne possède pas le domaine N-terminal. L'isoforme MDMXP6° ne lie pas p53 mais régule l'activité E3 ligase de MDM2. Ainsi les résultats de ma thèse mettent en lumière de nouveaux mécanismes de régulations entre p53, MDM2 , et MDMXP53 is a major tumor suppressor gene mutated in more than 50% of cancers. The two main non-redundant regulators of p53 are MDM2 and MDMX and mice lacking either MDMX or MDM2 die early during embryogenesis in a p53-dependent fashion. Given their central function in tumourgenesis, it is essential to understand how these proteins are regulating p53 expression and activity. In this thesis manuscript I present my work on the regulatory loop between these 3 partners and from a broader point of view how these data could fit in a general thermodynamic model. Unlike its DNA binding capacity, little is known on p53's RNA binding capacity and its physiological relevance. During my study, I used the p53-mdmx mRNA as a model to characterize the RNA binding capacity of p53. I demonstrate that expression of p53 suppresses MDMX synthesis by binding to mdmx mRNA. Furthermore, I could show that p53 specifically binds to mdmx 5'UTR. Deletion and mutation analysis have revealed that the DNA binding domain of p53 binds to mdmx 5'UTR with high specificity and that the N-terminus domain of p53 regulates its trans-suppression activity. My data show that the RNA and DNA binding capacities of p53 to a large extend overlap but with some distinct features. During the course of this project we also identified an alternative translated isoform of MDMX, which Jacks the N-terminus. The MDMXP6° isoform has a unique property in that it does not bind the p53 protein but regulates MDM2 E3 ligase activity. Hence the outcome of my 4-year study is shedding light on new regulatory loops between p53, MDM2 and MDMX
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Radakovič, Jozef. "Predikce vazebních míst proteinu p53." Master's thesis, Vysoké učení technické v Brně. Fakulta informačních technologií, 2015. http://www.nusl.cz/ntk/nusl-234992.
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Protein p53 which is encoded by gene TP53 plays crucial role in cell cycle as a regulator of transcription of genes in cases when cell is under stress. Therefore p53 acts like tumor suppressor. Understanding the pathway of p53 regulation as well as predicting its binding sites on p53 regulated genes is one of the major concerns of modern research in genetics and bioinformatics. In first part of this project we aim to introduce basics from molecular biology to better understand the p53 protein pathway in gene transcription and introduction to analysis of prediction of p53 binding sites. Second part is about implementation and testing of tool which would be able to predict transcription factor binding sites for protein p53.
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Marques, Candeias Marco. "RNA-Dependent regulation of p53." Paris 7, 2007. http://www.theses.fr/2007PA077077.
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La protéine suppresseur de tumeur p53 est impliquée dans la régulation de la croissance et de la survie des cellules en réponse à une multitude de facteurs de stress cellulaires. Son activation a pour conséquence des modifications de l'expression d'un grand nombre de gènes. Son régulateur principal est la protéine Mdm2, une E3 ubiquitine-ligase qui lie p53 et conduit à sa dégradation par la voie protéasomale. Cependant, la façon dont p53 peut reconnaître spécifiquement différents stimuli de stress et y répondre en induisant des voies alternatives de régulation menant soit à un arrêt du cycle cellulaire, soit à l'apoptose ou encore au vieillissement prématuré, n'est pas encore clairement établi. Le groupe de Fahraeus a décrit l'existence d'une protéine p53 tronquée de la partie N-terminale (p53/47) et issue d'une traduction alternative au niveau d'un second site d'initiation de la traduction dans TARN messager (ARNm) de p53. Cette protéine n'interagit pas directement avec Mdm2 et induit des changements de stabilité et de trans-activation des formes tétramèriques de p53. Les résultats présentés dans cette thèse montrent que l'ARNm de p53 participe à la régulation de l'activité de p53 par le biais de trois mécanismes différents de contrôle de l'expression de p53 (FLp53), de p53/47 et de Mdm2. Des modifications de la synthèse de FLp53 ou de p53/47 sont induites par différents facteurs de stress cellulaires agissant sur des régions distinctes de l'ARNm de p53, ainsi que par des mécanismes de traduction coiffe-dépendants et -indépendants. En outre, la région de l'ARNm de p53 codant pour le domaine de liaison avec Mdm2 interagit directement avec le domaine RING de Mdm2, ce qui conduit à la diminution de l'activité ubiquitine-ligase de Mdm2, à l'augmentation de la traduction de p53 et à son activation, le tout ayant pour conséquence une augmentation des niveaux protéiques de p53 et de Mdm2. Des ARNm de p53 comportant des mutations silencieuses localisées dans cette région ont été identifié. Il est démontré également que l'expression de p53/47 diversifie l'activité de p53 d'une façon stress-dépendante. L'ensemble des résultats présentés indique que, par la régulation des mécanismes alternatifs de la traduction et par sa liaison à Mdm2, l'ARNm de p53 induit différents niveaux d'expression et d'activité des isoformes de p53, ce qui aide à déterminer le devenir biologique des cellules en réponse à différents types de stress cellulairesP53 controls the growth and survival of cells by acting in response to a multitude of cellular stresses. Activation of p53 results in changes in the expression of a large number of gene products. Its focal regulator is the E3 ubiquitin-ligase Mdm2, which binds and targets p53 for proteasomal degradation. However, it is not yet fully understood how p53 can distinguish the different stress stimuli and induce alternative pathways leading to either cell-cycle arrest, apoptosis or premature ageing. Fahraeus' group and others have described an N-terminally truncated p53 protein (p53/47) originating from a second translation initiation site in the p53 messenger RNA (mRNA) which does not directly interact with Mdm2 and imposes altered stability and transactivation properties to p53 tetramers. Results presented in this thesis show that the p53 mRNA helps in the regulation of the p53 activity by using three different mechanisms to control the expression of the full-length p53 protein (FLp53), p53/47 and Mdm2. Changes in synthesis of FLp53 or p53/47 are regulated by distinct cell stress-induced pathways acting through separate regions of the p53 mRNA and through both cap-dependent and -independent mechanisms. Furthermore, the p53 mRNA region coding for the Mdm2-binding domain interacts with the RING domain of Mdm2 and this results in the impairment of Mdm2's E3 ligase action and supports p53 mRNA translation and activation resulting in high levels of both p53 and Mdm2. P53 mRNAs with silent mutations in this region were found in cancers and are shown to have less aptitude to bind Mdm2 and express a smaller amount of active p53 protein. It is also reported that expression of p53/47 diversifies p53 activity in a stress-dependent fashion. Altogether, the presented data indicate that by regulating alternative mechanisms of translation and by binding to Mdm2, the p53 mRNA gives rise to different levels of the p53 isoforms which help to orchestrate the cell biological outcome of p53 activation in response to different types of cell stress
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Harms, Kelly Lynn. "Mechanisms of P53-mediated apoptosis." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2009r/harms.pdf.
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Gaitonde, Supriya Vishwaraj. "Mechanisms involved in p53 regulation." Diss., The University of Arizona, 2000. http://hdl.handle.net/10150/298798.
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Inactivation of the tumor suppressor protein p53 is a very important and common step in the process of carcinogenesis. The overall purpose of this project was to gain a better understanding of the mechanisms involved in the regulation of p53 function. To gain insight into these mechanisms, we chemically mutagenized A1-5 cells expressing high levels of temperature sensitive p53 val135 (tsp53) and selected for clones that were capable of growth at the permissive temperature for p53 activation. The clones generated, called ALTR (for A&barbelow;1-5 L&barbelow;ow T&barbelow;emperature R&barbelow;esistant), could grow at the permissive temperature. Using the ALTR cell system and the parent A1-5 cells, we determined that nuclear translocation of p53 could result in a change in the conformation from mutant to wild-type but that these may be two separable events. We also investigated, in depth, the mechanism by which p53 was inactivated in one ALTR cell line, ALTR 9. We identified calpain mediated degradation of p53 as a partial mechanism of p53 inactivation in these cells. Our results suggest that degradation of p53 by calpain can lead to the functional inactivation of p53 and that this degradation can be regulated by genomic stress. To gain insight into the significance of cytoplasmically sequestered p53 protein in tumors, we chose a neuroblastoma derived cell line, SK-N-SH, that expresses a wild-type but cytoplasmically sequestered p53 protein. We report here, that down regulation of p53 by HPV-16 E6 resulted in the morphological conversion of SK-N-SH cells to substrate-adherent fibroblast-like S-type cells. The morphologic conversion was accompanied by a loss of neurofilament expression, a marker for the neuronal N-type cells, an increase in the expression of vimentin, a lack of responsiveness to RA induced neuronal differentiation, and loss of anchorage independent growth. These results suggest that p53 is required for the maintenance of the neuroblastic tumorigenic phenotype. Both the ALTR cell system and the SK-N-SH cells provided us with insight into the mechanisms involved in p53 inactivation resulting in tumor formation.
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D'Alessandro, Alba. "p53 regulates Mevalonate Metabolic pathway." Doctoral thesis, Universita degli studi di Salerno, 2014. http://hdl.handle.net/10556/1461.
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2012-2013The mevalonate pathway is an important metabolic pathway implicated in multiple aspects of tumorigenesis. In this study, I provided evidences about genetic and pharmacologic perturbation of p53, which directly influenced expression of mevalonate pathway enzymes, including 3’-Hydroxy-3’-Methylglutaryl - CoenzymeA Reductase, Mevalonate Kinase, Farnesyl Diphosphate Synthase, Farnesyl Diphosphate Farnesyl Transferase 1. Three different cell lines have been considered, U343 MG (U343) and U251 MG (U251) glioma cells, both classified as IV grade glioblastoma cell lines, with two different malignancy grade, and Normal Human Astrocytes (NHA),their normal counterpart. In particular, NHA and U343 cells have wild type p53 (wtp53) while U251bearing mutation (R273H)p53. This mutation affects p53 DNA binding site, preventing transcriptional function of the protein. Different basal expression level of the mevalonate pathway’s genes have found among the different cell lines considered and I hypothesized that this could be ascribable to p53 mutation status and function. Indeed, I observed that functional and active p53 recognized specific p53 Responsive Elements (p53REs) present in MVA enzymes gene-sequences. p53 bound to these regions correlated with increased transcription levels of mentioned genes and such effect has abolished in cells bearing mut(R273H)p53 or by site-directed mutagenesis of p53REs. These new findings expose another facet of p53 functions, unrelated to tumor suppression, and render it a novel regulator of mevalonate pathway providing insight into the role of this pathway in cancer progression. [edited by author]
XII n.s.
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Johnson, Jodi L. "The p53 family interacting pathways in carcinogenesis and cellular response to DNA damage." Oregon Health & Science University, 2007. http://content.ohsu.edu/u?/etd,628.
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Ph.D.Molecular and Medical Genetics
The objective of this study is to examine, in light of the expression of multiple p53 family member isoforms, the specific role of p73 in malignant conversion, cellular response to DNA damage, and direct or indirect cooperation with other p53 family members in a clonal model of epidermal carcinogenesis. We first focused on the role of p73 in malignant conversion. Whether sporadic or siRNA induced, loss of p73 in initiated p53+/+ keratinocytes lead to conversion to squamous cell carcinoma (SCC) in vivo which was reversible upon reconstitution of TAp73α but not ΔNp73α. Second, we investigated the cellular response to ionizing radiation (IR) in the presence and absence of p73, showing that loss of p73 at malignant conversion was associated with resistance to IR in vitro. The loss of radiation sensitivity and malignant conversion was characterized by reduced steady state DNA binding levels of transcriptionally active p63 isoforms to the p21 promoter, failure to induce specific p53 family transcriptional targets, and failure to arrest in G1. Reconstitution of TAp73α, but not ΔNp73α, increased steady state DNA binding capabilities of TAp63β, TAp63γ, and ΔNp63γ, and steady state levels of p53 family target mRNA, but did not restore cellular sensitivity to IR. We thus uncovered a functional cooperation between TA isoforms of p73 and p63 and showed that p73-mediated DNA damage response was uncoupled from its tumor suppressive role. We observed preferential DNA binding of the inhibitory ΔNp63α isoform both in vitro and invivo in SCC suggesting that in the absence of TAp73α a balance is tipped toward DNA binding of the inhibitory isoforms. Third, we studied the role of the p53 family inkeratinocyte response to UVB. Tumorigenic cells lacking p73 that were resistant to IR remained sensitive to UVB, accompanied by DNA binding of the TAp63γ isoform, suggesting that keratinocyte response to UVB is not dependent upon p73 and suggesting a hierarchy of p53 family member responses to DNA damage. Finally, we examined TAp73α interaction with the p53 family inhibitor Mdm2. Mdm2 was in complex with DNA-bound p53 family members in malignant cells, but reconstitution of cells withTAp73α correlated with removal of Mdm2 from the complex, making them more like primary keratinocytes or initiated cells. Like the initiated cells, cells expressing TAp73α were refractory to treatment with the Mdm2-p53 inhibitor Nutlin-3 while cells lacking p73 expression or expressing ΔNp73α were sensitive. Thus, we suggest that p73 may be acting as a molecular shield to keep p53 family member inhibitors, such as ΔNp63α andMdm2, at bay. Further understanding of p53 family interplay in tumor development and DNA damage response could lead to new therapies or optimization of current therapeutic strategies in solid tumors of epithelium, particularly where deregulation or loss of p63 and p73 expression is associated with increased tumor invasiveness, treatment resistance, and poor patient prognosis.
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Chao, Connie. "Functional role of p53 N-terminal phosphorylation in regulating the p53 response to DNA damage." Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2006. http://wwwlib.umi.com/cr/ucsd/fullcit?p3208105.
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Thesis (Ph. D.)--University of California, San Diego, 2006.Title from first page of PDF file (viewed June 2, 2006). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references.
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Lee, Anna F. "P53-dependent and independent mechanisms by which the p53-related protein, ANp73, promotes neuronal survival." Thesis, McGill University, 2005. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=85930.
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The survival of neurons during nervous system development depends on the interaction of neurotrophins with cell surface receptors, of which the Trk tyrosine kinase family mediates survival and the p75 neurotrophin receptor (p75NTR) mediates apoptosis. Within the cell, these receptors generate functionally antagonistic signal transduction cascades, and the relationship between Trk and p75NTR signaling determines whether a neuron will ultimately survive or die. Downstream of these receptors, the p53 family, which includes p53, p63, and p73, has been shown to be critical mediators of neuronal survival. Like Trk and p75NTR, pro- and anti-apoptotic p53 family members are functionally antagonistic. The p53 tumour suppressor protein is essential for mediating neuronal apoptosis during development. In contrast, the related protein p73, expressed in neurons as an N-terminal-truncated, anti-apoptotic isoform (DeltaNp73), is essential for neuronal survival. The mechanisms by which DeltaNp73 promotes neuronal survival are the subject of this thesis.In the first part of this thesis, we showed that DeltaNp73 promotes sympathetic neuron survival through p53-dependent and independent mechanisms. Our genetic data demonstrated that loss of p53 partially rescued the sympathetic neuron loss seen in p73-/- mice. We confirmed this biochemically by showing that DeltaNp73 acts at multiple levels of the neuronal apoptotic pathway both upstream and downstream of p53. DeltaNp73 inhibited p53-dependent processes such as Apaf-1 and p21 induction, caspase-3 cleavage, and mitochondrial cytochrome c release. DeltaNp73 also inhibited p53-independent induction of Bim and JNK, the latter possibly through an interaction with JNK. We also found a role for p73 in regulating cell size, through mechanisms that do not involve its interactions with p53.
In the second part of this thesis, we investigated DeltaNp73's actions on the JNK pathway, which is activated very early in apoptosis, and found that DeltaNp73 acted at or above the level of the JNK kinase MKK4. We also found evidence that the PI3-kinase/Akt survival pathway, a major Trk effector, was involved in regulation of DeltaNp73 levels.
Together, these studies suggested that DeltaNp73, through its regulation by the PI3-kinase/Akt survival pathway, acts at multiple levels of the neuronal apoptotic pathway to inhibit apoptosis.
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Yu, Miao. "Cancer preventive mechanisms by exercise: activation of p53 and p53-related IGF-1 pathway regulators." Thesis, Kansas State University, 2016. http://hdl.handle.net/2097/32219.
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Master of ScienceDepartment of Human Nutrition
Weiqun Wang
Exercise has been previously reported to lower cancer risk through reducing circulating IGF-1 and IGF-1-dependent signaling in mouse skin cancer models. This study is to investigate the underlying mechanisms by which exercise might impact IGF-1 pathway regulated by p53 and p53-related proteins in mouse skin epidermis. Female SENCAR mice were pair fed an AIN-93 diet with or without 10-week treadmill exercise at 20 m/min for 60 min daily. Animals were topically treated with TPA or vehicle control 2 hours before sacrifice and the target proteins in the epidermis were assessed by immunohistochemistry and Western blotting. Under TPA or vehicle treatment, MDM2 was significantly reduced in exercised mice compared with sedentary control. Meanwhile, p53 was significantly increased. In addition, p53 transcription target proteins p21, IGFBP-3, and PTEN were elevated in response to exercise. An interaction between exercise and TPA was observed on the decrease of MDM2 and increase of p53, but not p53 down-regulated proteins. Taken together, exercise appears to activate p53 by reducing MDM2 suppression, resulting in enhanced expression of p21, IGFBP-3 and PTEN that might further induce a negative regulation of IGF-1 pathway and therefore contribute to the observed cancer prevention by exercise in this mouse skin cancer model.
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Johnson, 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.
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Jemaâ, Mohamed. "Chimiothérapie ciblant les cellules cancéreuses p53 déficientes." Thesis, Paris 11, 2012. http://www.theses.fr/2012PA11T040/document.
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L’altération génétique et/ou fonctionnelle de p53 est très répondue dans les cancers humains et est répertoriée dans plus d’un cas sur deux. Les traitements et molécules utilisés en chimiothérapie anticancéreuse induisent pour la plupart l’apoptose dépendante de p53 ce qui confère une résistance particulière aux tumeurs p53 déficientes. Nous avons développé des techniques se basant sur la vidéomicroscopie à haut débit et l’utilisation de cellules fluorescentesTP53+/+ et TP53-/- pour mettre en évidence des agents chimiques qui ciblent les cellules p53 déficientes. Nous avons identifié SP600125, un inhibiteur de kinases dont MPS1, Aurora A et Aurora B, et qui tue préférentiellement les cellules tumorales TP53-/- . Cette cytotoxicité sélective a été confirmée sur de nombreux modèles de cellules déficientes en p53 in vitro et in vivo sur des xénogreffes TP53+/+ et TP53-/- injectés à des souris nudes. Nous avons utilisé une autre molécule qui a un spectre d’inhibition semblable à SP600125, la reversine, et nous avons aussi trouvé qu’elle a une cytotoxicité sélective envers les cellules p53 déficientes.L’analyse vidéomicroscopique des cellules traitées nous révèle que la mort préférentielle des cellules P53 déficientes est intimement liée à un mécanisme de polyploïdisation. En effet, les cellules TP53-/- (contrairement à celles TP53+/+) traitées effectuent des mitoses aberrantes sans karyokinèse ni cytokinèse qui ne sont pas contrôlées par un arrêt du cycle cellulaire. Ces cellules succombent par catastrophe mitotique après activation de la voie mitochondriale de l’apoptose.Cette observation concorde avec le fait que l’inhibition des protéines anti-apoptotiques de la famille Bcl-2 sensibilise les cellules traitées alors que l’inhibition des protéines BAX, APAF-1 et les caspases protège les cellules TP53-/- de l’effet cytotoxique de SP600125 et la reversine.Ces résultats nous permettent d’envisager ces drogues (ou dérivées) dans la prévention des cas de tumeurs pré malignes et/ou dans le traitement des cas de cancers p53 déficientsThe genetic and/or functional alterations of p53 are highly prevalent in cancer and are reported for more than a half of all human cancers. Classic chemotherapy leads p53 mediated apoptosis conferring a drug resistance for p53 deficient cells. We developed in the laboratory a technique based on high-content videomicroscopy and fluorescent TP53+/+ and TP53-/- cells for the screening of molecules that targets p53 deficient cells. We discovered that SP600125, a kinase inhibitor, including MPS1, Aurora A and Aurora B, kills p53-deficient cells more efficiently than their p53-proficient counterparts. This selective cytotoxicity was confirmed in vivo in mice carrying p53-deficient and -proficient human xenografts. Than after we used an another inhibitor with a similar broad-spectrum kinase, reversine, and we found that this molecule have a selective toxicity for TP53-/- cells and this result was confirmed in vitro for both molecule.Videomicroscopy-based cell fate profiling revealed that the p53-deficient cell death is coupled to hyperploïdy mechanism. Indeed, TP53-/- (but not TP53+/+) undergo successive round of abortive mitosis and failed to arrest the cell cycle in response to treatment and cells became polyploidy and progressively succumbed to mitochondrial apoptosis. In line with this notion, the depletion of anti-apoptotic proteins of the BCL-2 family sensitized TP53-/- cells to the toxic effects of SP600125 and reversine. Moreover, the knockdown of BAX or APAF-1, as well as the chemical inhibition of caspases, limited the death of TP53-/- cells.Hence, SP600125 or reversine (and its analogues/derivatives) might be used for cancer chemoprevention (for eliminating pre-malignant cells that have inactivated p53) or chemotherapy of p53-deficient cancers
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Saidj, Djamel. "Alteration of p53 and NF-kB pathways by E7 protein from cutaneous Human Papillomavirus type 38." Thesis, Lyon 1, 2013. http://www.theses.fr/2013LYO10237/document.
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Les infections virales sont responsables de 15 à 20 % des cancers humains. L étude des mécanismes moléculaires avec lesquels les virus oncogènes induisent la transformation cellulaire est essentielle pour la compréhension des cancers qui en résultent. Cela permettra également la découverte de nouveaux mécanismes pouvant être impliqués dans le développement de cancers, qui peuvent être ciblés par des approches thérapeutiques. Les virus du papillome humain (HPV) sont des petit virus à ADN qui futs isolés de la peau de patients souffrants de Epidermodysplasia Verruciformis (EV) qui cause un risque élevé d'infection par les HPV et le développement de cancer de la peau non mélanique (NMSC). Certains HPV cutanés, tels que HPV5, 8 et 38, sont suspectés de jouer un rôle dans de développement du cancer de la peau. Cependant, le lien direct entre les HPV cutanés et l'étiologie du cancer n'est pas encore clairement établi. Des études de notre laboratoire ont montré que les oncoprotéines HPV38 E6 et E7 sont capables d'immortaliser des kératinocytes primaires humains in vitro et in vivo. Pour immortaliser des cellules, d'importantes voies de signalisations, telles que les voies de p53 et celle de NF-KB, doivent être affectées. Dans cette étude, nous avons cherché à mettre en évidence les mécanismes moléculaires menant à la dérégulation de p53 et de NF-KB par E6 et E7 de HPV38, dans des kératinocytes humains. Nous avons montré que HPV38 E6 et E7 induisent la formation d'un complexe protéique incluant IKKβ, ΔNp73α, EZH2 et DNMT1. La formation de ce groupement protéique corrèle avec l'inhibition de la transcription de certains gènes cibles de p53, tel que PIG3. Nous avons également mis en évidence l'activation de la voie NF-KB par les oncoprotéins E6 et E7 de HPV38. Cette activation est importante par le rôle joué par NF-KB dans la protection des cellules de l apoptose induite par TNF-α et par l'exposition aux rayonnements UVB. De plus nous avons observé que E7 est la principale oncoprotéine de HPV38 responsable de la dérégulation des voies p53 et NF-KB. Nos études mettent en évidence de nouveaux mécanismes moléculaires qui peuvent être essentiels dans le processus de transformation cellulaire par HPV38Viral infections contribute to 15–20% of all human cancers. Studying the mechanisms employed by the oncogenic viruses to induce cellular transformation is essential for a better understanding of the resulting cancers and the discovery of new mechanisms involved in cancer development which can be targeted in therapeutic approaches. Human papillomaviruses (HPVs) are small dsDNA viruses which have been clearly associated with certain cancers. They were first isolated from the skin of patients suffering from Epidermodysplasia Verruciformis (EV) having an increased susceptibility to infection by specific HPV types and to the development of non-melanoma skin cancer (NMSC). Certain cutaneous HPV types, such as 5, 8, and 38, are suspected to play a role in skin cancer development. However the direct role of cutaneous HPV in the etiology of cancer is still under debate. Previous studies from our laboratory have reported that HPV38 E6 and E7 proteins are able to immortalize human primary keratinocytes in vitro and in vivo. Cellular immortalization can be achieved through the deregulation of important signaling pathways including p53 and NF-KB. In the present work, we have investigated the molecular mechanisms of p53 and NF-KB pathways deregulation by E6 and E7 oncoproteins from HPV38 in human keratinocytes. We show here that HPV38 E6E7 induce the formation of a transcription repressor complex including IKKβ, ΔNp73α, and polycomb group members EZH2 and DNMT1. The formation of this protein complex correlates with the inhibition of several p53-target genes, such as PIG3. We also report in these studies that HPV38 E6E7 activate NF KB pathway, which plays an important role in the survival of HPV38 E6E7-immortalized human keratinocytes upon TNF-α– and UVB-mediated apoptosis. In addition our data highlight E7 being the main HPV38 protein mediating p53 and NF-KB deregulation. Our studies shed light on novel molecular mechanisms that could be important for HPV38-mediated cellular transformation
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Tomas, Fanny. "Caractérisation fonctionnelle de la relation entre le suppresseur de tumeur p53 et son isoforme Delta133p53 dans les cellules humaines normales." Electronic Thesis or Diss., Montpellier, 2018. http://www.theses.fr/2018MONTT085.
Full textAbstract:
La sénescence réplicative (SR) dans les fibroblastes humains primaires est causée par l’érosion des télomères et est contrôlée par p53. La régulation dynamique de l’activation de p53 est essentielle pour l’induction de la sénescence ; cependant, les mécanismes moléculaires sous-jacents ne sont pas clairement établis. Nous montrons, dans les cellules surexprimant les isoformes Δ133/Δ160p53, que ces isoformes s’oligomérisent avec p53, conduisant ainsi à la stabilisation d’une forme inactive de p53. A l’inverse, l’inactivation des isoformes endogènes Δ133/Δ160p53 induit l’accumulation de la protéine p53 et l’activation de son activité transcriptionnelle. La surexpression de Δ133/Δ160p53 inhibe les fonctions de p53, en particulier son activité transcriptionnelle et son rôle dans l’arrêt du cycle après un dommage à l’ADN. Nous avons remarqué que les protéines Δ133/Δ160p53 et p53 sauvage possédaient des conformations différentes. Les protéines Δ133/Δ160p53 sont reconnues pas l’anticorps Pab40 : elles adopteraient une conformation similaire à un mutant de conformation de p53. Enfin, nous observons qu’une faible expression de l’ARNm Δ133/Δ160TP53 coïnciderait avec la durée de l’activation transcriptionnelle de p53 lors de la SR, indiquée par l’accumulation de l’ARNm d’un effecteur majeur de p53, p21. L’augmentation de l’expression de Δ133/Δ160TP53 à un temps tardif au cours de la SR est corrélée à l’accumulation du marqueur de sénescence p16INK4a et à celle de la cytokine pro-inflammatoire IL-6. En conséquence, les isoformes Δ133/Δ160p53 contrôleraient l’activité de p53 dans l’arrêt du cycle et sur le phénotype sécrétoire des cellules sénescentesTelomere attrition in primary human fibroblasts induces replicative senescence by activation of the tumour suppressor p53. Fine-tuned activation of p53 is essential for senescence induction; however, the mechanisms underlying the regulation of p53 activity during senescence have not been clearly established yet. We report here that in cells that express the Δ133/Δ160p53 isoforms, these p53 isoforms oligomerize with p53, leading to the stabilization of the transcriptionally inactive form of p53. Conversely, endogenous Δ133/Δ160p53 silencing increases the level of p53 and p53-dependent transcriptional activity to promote cell cycle arrest. Overexpressed Δ133/Δ160p53 repress p53 functions, including gene transcription activation and growth inhibition, upon DNA damage. We also found that Δ133/Δ160p53 and wild-type p53 have different structural conformations. Δ133/Δ160p53 adopt a more unfolded conformation recognized by the Pab240 antibody, indicating that these p53 isoforms have a p53 mutant-like conformation. Finally, we observed that low level of Δ133/Δ160TP53 mRNA coincided with the duration of p53 transcriptional activation in replicatively senescent fibroblasts, as indicated by the upregulation of CDKN1A (p21) mRNA expression, a downstream effector of p53. Δ133/Δ160p53TP53 was upregulated at a later stage when the senescence marker p16INK4a and the pro-inflammatory interleukin-6 (IL-6) were also induced. Therefore, p53 activity on growth suppression and senescence-associated secretory phenotype may be differentially regulated by its Δ133/Δ160p53 isoforms