Actions for Epstein-Barr virus latency-associated proteins regulate multiple pathways to promote B cell proliferation and survival

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Epstein-Barr virus latency-associated proteins regulate multiple pathways to promote B cell proliferation and survival

Author
Bowman, Emily
Published
[University Park, Pennsylvania] : Pennsylvania State University, 2015.
Physical Description
1 electronic document
Additional Creators
Sample, Clare
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Open Access.
Summary
Epstein-Barr virus (EBV) is a DNA tumor virus associated with persistent latent infection of B lymphocytes. Upon initial infection in B cells, EBV expresses a repertoire of 9 latency-associated proteins (EBNA1, -2, -3A, -3B, -3C, -LP, LMP1, -2A, and -2B) to modulate host cellular pathways, promoting survival and proliferation of EBV-infected B cells. Lifelong infection is achieved by expressing a series of latency programs in which latency genes are progressively downregulated to avoid immune surveillance and ensure persistent infection. EBV contributes to both lymphoid and epithelial cell malignancies, and is notably linked to the development of Burkitt lymphoma (BL). This dissertation investigates contributions of EBV latency-associated proteins to the pathogenesis of EBV infection. Our studies focused on the Epstein-Barr virus nuclear antigen 3A (EBNA3A), and in particular, the mechanisms by which EBNA3A drives proliferation of a unique and aggressive subset of BL tumors that exhibit a W promoter-restricted form of latency (Wp-R). Using shRNA-mediated knock-down, we determined that EBNA3A is essential for growth of Wp-R, as EBNA3A knock-down results in abrupt G0/G1 cell cycle arrest followed by induction of apoptosis. Increased expression of the cell cycle inhibitor p21WAF1/CIP1 was detected, correlating with the onset of cell cycle arrest. EBNA3A-mediated repression of p21 was required to maintain hyperphosphorylation of Rb and promote cell cycle progression. Additionally, EBNA3A repressed p53-dependent transcriptional activation of p21. Whereas typical BL (Latency I) displays mutant p53, Wp-R BL contains wild-type p53. EBNA3A counteracted the wild-type status of p53 in Wp-R and inhibited induction of p53-responsive gene products. EBNA3A did not alter p53 transcription, but rather protein expression of p53 was elevated following EBNA3A knock-down. EBNA3A likely regulates p53 protein stability via interactions with HDM2. Both EBNA3A and the related family member, EBNA3C, were required for proliferation of lymphoblastoid cell lines (LCLs), but we found EBNA3C was dispensable for proliferation of Wp-R and did not affect p21 levels. Additionally, EBNA3A, but not EBNA3C, activated expression of the oncogenic microRNA, microRNA-155 (miR-155), which may contribute to p21 repression. Here we identify a unique role for EBNA3A in repressing transcriptional activation of p53 target genes, including p21, to promote cell cycle progression.
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Dissertation Note
Ph.D. Pennsylvania State University, 2015.
Reproduction Note
Microfilm (positive). 1 reel ; 35 mm. (University Microfilms 107-59887)
Technical Details
The full text of the dissertation is available as an Adobe Acrobat .pdf file ; Adobe Acrobat Reader required to view the file.
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