A transgenic approach to investigate the role of Epstein-Barr virus encoded RNA1 in lymphomagenesis

Repellin, Claire E (2005) A transgenic approach to investigate the role of Epstein-Barr virus encoded RNA1 in lymphomagenesis. PhD thesis, University of Glasgow.

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Epstein-Barr Virus (EBV) is associated with several human cancers including Burkitt's lymphoma (BL), Hodgkin's disease and nasopharyngeal carcinoma amongst others. In these cancers, a different subset of the viral latent genes are expressed, but all express the EBV small encoded RNAs: EBERl and EBER2. The EBERs are polymerase III (pol III) genes but do not fall neatly into any of the 3 promoter types as they combine both pol II (Spl, ATF and TATA-like box) and pol III elements (A and B boxes). The EBERs have been shown to confer resistance to interferon (IFN)-alpha-induced apoptosis via binding of the IFN-inducible, double-stranded (ds) RNA-activated protein kinase PKR and inhibition of its activation by phosphorylation. Evidence has also suggested an oncogenic role of the EBERs in BL cells, indicating their possible contribution to the disease process of EBV-associated tumours. In order to investigate the potential role of EBER1 as an oncogenic RNA in vivo, 13 lines of transgenic mice designed to express EBER1 in lymphoid cells using three variant transgenes were generated. The transgenes incorporate a novel combination of tissue-specific RNA pol II and pol III elements. The efficacy of transgene expression was confirmed in culture. Mice of 10 of the transgenic lines were shown to express EBER1 in lymphoid tissues and the expression varied between the lines. The phenotypic consequences of EBER1 expression in vivo were examined and lymphoid expansion in mice of several lines was observed at a young age as well as the development of B-cell lymphoma in one of the lines. Cross-breeding programmes were undertaken and have shown that EBER1 does not cooperate in lymphomagenesis with EBNAl. However cooperation was observed in B-cell lymphomagenesis between EBER1 and N-myc although not with c-Myc. This might suggest that the oncogenic mechanism is elicited through cell survival. The role of EBER1 in response to dsRNA stimulation was analysed in vivo and results indicate an inhibition of Statl expression and activation by EBER1, This might reflect downstream actions of blockade of the IFN pathway or a new pathway. The results in this study support the hypothesis that EBER1 has oncogenic properties, the first pol III RNA described as such. This implicates the RNA in the pathogenesis of EBV associated lymphoma in addition to its role in immune evasion.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Additional Information: Adviser: Joanna Wilson
Keywords: Immunology, Virology, Genetics
Date of Award: 2005
Depositing User: Enlighten Team
Unique ID: glathesis:2005-74106
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 23 Sep 2019 15:33
Last Modified: 23 Sep 2019 15:33
URI: https://theses.gla.ac.uk/id/eprint/74106

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