Please use this identifier to cite or link to this item: http://hdl.handle.net/10077/10114
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dc.contributor.advisorDel Sal, Gianninoit_IT
dc.contributor.authorComel, Annait_IT
dc.date.accessioned2014-07-08T10:51:06Z-
dc.date.available2015-04-28T04:01:28Z-
dc.date.issued2014-04-28it_IT
dc.identifier.urihttp://hdl.handle.net/10077/10114-
dc.description2012/2013it_IT
dc.description.abstractCancer and neurodegeneration are linked by a relation of inverse comorbidity, cancer patients being at lower risk for neurodegenerative disorders and vice versa. Interestingly, many cellular processes and factors contribute to both pathologies, and a central role is played by the transcription factor p53. Best known for its antiproliferative activities following transformation-related stimuli, p53 acts to maintain genetic stability and prevent tumour onset by transcriptional and non-transcriptional mechanisms. Recently, a contribution of p53 also in neuronal development and death was unveiled. In the case of Huntington’s Disease (HD), p53 mediates cytotoxicity in HD cells and animal models, whereas its inhibition prevents this phenotype. On these premises, we were prompted to investigate the signalling pathways and protein interactions that modulate p53 activation in both cancer and neurodegeneration with the aim of identifying critical hubs as new targets for therapeutic intervention. We discovered that expression of HD causative agent, i.e. mutant Huntingtin (mHtt) protein, behaves like a genotoxic stimulus in inducing phosphorylation of p53 on Ser46, that leads to its modification by phosphorylation-dependent prolyl-isomerase Pin1 and consequent induction of apoptotic target genes. Inhibition of Ser46 phosphorylation by targeting HIPK2, PKCδ, or ATM kinases, as well as inhibition of Pin1, prevented mHtt-dependent apoptosis of neuronal cells. These results provide a rationale for the use of inhibitors of stress-responsive kinases and Pin1 as a potential therapeutic strategy for HD treatment. On the other hand, we investigated the contribution of BRD7, a protein involved in epigenetic regulation, to the p53 pathway. We found that BRD7 is required for the onset of oncogene-induced senescence, a main tumour suppressive p53 activity. In addition, we found that upon oncogene activation BRD7 restrains, independently of p53, the acquisition of malignant phenotypes, such as migration/invasion and stem cell traits. We observed a strong induction of inflammatory genes after depletion of BRD7, whose contribution to this process is still under investigation. BRD7 takes part into SWI/SNF and PRC2 chromatin remodelling complexes, whose pleiotropic roles in tumorigenesis make them appealing targets for cancer therapy. We will discuss how this new generated knowledge could be exploited for the treatment of neurodegenerative diseases, in which chromatin alterations are now recognized as drivers of pathogenesis.it_IT
dc.language.isoenit_IT
dc.publisherUniversità degli studi di Triesteit_IT
dc.rights.urihttp://www.openstarts.units.it/dspace/default-license.jsp-
dc.subjectp53it_IT
dc.subjectBRD7it_IT
dc.subjectbreast cancerit_IT
dc.subjectHuntington's Diseaseit_IT
dc.subjectNeurodegenerationit_IT
dc.subjectSenescenceit_IT
dc.subject.classificationSCUOLA DI DOTTORATO DI RICERCA IN BIOMEDICINA MOLECOLAREit_IT
dc.titlep53 at the crossroads between cancer and neurodegeneration: unveiling molecular circuitries involved in tumorigenesis and neuronal cell deathit_IT
dc.typeDoctoral Thesis-
dc.subject.miurBIO/13 BIOLOGIA APPLICATAit_IT
dc.description.cycleXXV Cicloit_IT
dc.rights.statementEMBARGO 2015-04-28it_IT
dc.identifier.nbnurn:nbn:it:units-12536-
dc.description.birth1983-
item.grantfulltextopen-
item.languageiso639-1other-
item.fulltextWith Fulltext-
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