Epstein-Barr Virus Nuclear Antigen 3A Promotes G1/S Cell Cycle Progression
Open Access
- Author:
- Tursiella, Melissa Lynne
- Graduate Program:
- Microbiology and Immunology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- January 25, 2013
- Committee Members:
- Clare E Sample, Dissertation Advisor/Co-Advisor
Clare E Sample, Committee Chair/Co-Chair
Jeffery Thomas Sample, Committee Member
Richard James Courtney, Committee Member
Jianming Hu, Committee Member
John Michael Flanagan Jr., Committee Member - Keywords:
- Epstein-Barr virus
EBNA-3A
Burkitt lymphoma
cell cycle
p21
LCLs
Rb
p53 - Abstract:
- The DNA tumor virus, Epstein-Barr virus (EBV), is associated with persistent latent infection in B cells, and upon initial infection expresses all 9 latent proteins (known as Type III latency), including the EBV-nuclear antigen-3 family of proteins (EBNA-3s). The overall aim of this project was to evaluate the role of EBNA-3A in the pathogenesis of EBV infection, specifically within a newly characterized subset of Burkitt Lymphoma (BL) exhibiting a W promoter-restricted form of latency (Wp-R BL), and in lymphoblastoid cell lines (LCLs) that express Type III latency. By using RNAi, we found that EBNA-3A was essential for the proliferation of both Wp-R BL and LCLs, such that knock-down of EBNA-3A resulted in rapid loss of proliferation proceeded by progressive apoptosis. Following EBNA-3A knock-down, the expression of the cell cycle inhibitor p21 increased, and correlated with the onset of G0/G1 cell cycle arrest. Importantly, the related viral protein, EBNA-3C, was not essential for the proliferation of Wp-R BL, whereas it has been shown by other laboratories to be essential for LCL proliferation, with no effect on p21. Furthermore, knock-down of EBNA-3A in these two different latently infected cell lines resulted in hypophosphorylation of the Retinoblastoma protein (Rb), which is indicative of its activation, and over time, resulted in its depletion. Notably, in the literature, elevated p21 expression is associated with hypophosphorylation and depletion of Rb, suggesting that in our system p21 may be responsible for these effects on Rb. Thus, we concluded that EBNA-3A contributes to the pathogenesis of EBV by repressing p21, inactivating Rb and promoting cell proliferation. Importantly, this is the first unique function identified for EBNA-3A that is distinct from EBNA-3C.