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Etude fonctionnelle de l'Ubinucléine, partenaire cellulaire du facteur de transcription EB1 du virus d'Epstein-Barr et inhibition du cycle lytique viral

Abstract : Discovered in 1964, Epstein-Barr virus belongs to the Gamma-herpesvirus family. This DNA virus shows an important prevalence (90% of the adult population is infected). It was the first virus identified as associated with cancers (Hodgkin and Burkitt lymphomas, Gastric and oropharyngal carcinomas). It presents two distinct cycles: Latency and Lytic cycle (viral particle production). Viral transcription EB1 (or Zebra) is a key element for lytic cycle initiation and seems to be an important target for future treatment development. A first part of this work concerned the characterization of the cellular protein Ubinuclein that inhibits EB1 activity. This protein travels between nucleus and tight junctions. It belongs to the “NACos” (nuclear and adhesion complex components) protein family. Ubinuclein function is not known and its proteomic was performed when it was localized at tight junction. Next, functional studies showed that Ubinuclein interacts with various cellular partners and goes though the clathrin dependent endocytosis pathway. It's localisation (nuclear or at tight junction) changes with PKA activity. In the second part of this work, we focus on viral transcription factor EB1 inhibitors. After high-throughput screening of compounds (EMBL-Heidelberg), in-vitro assays allowed to select one molecule for in-vivo experiments. This compound inhibits the activity of the transcription factor EB1 and stops early lytic cycle establishment in Burkitt lymphoma cells. Further work needs to be done to increase efficacy and specificity of this molecule.
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https://tel.archives-ouvertes.fr/tel-00819882
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Audrey Conti. Etude fonctionnelle de l'Ubinucléine, partenaire cellulaire du facteur de transcription EB1 du virus d'Epstein-Barr et inhibition du cycle lytique viral. Sciences agricoles. Université de Grenoble, 2012. Français. ⟨NNT : 2012GRENV059⟩. ⟨tel-00819882⟩

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