The Effects of Epstein-Barr Virus Nuclear Antigen 2 on Cell Cycle and Chromosomal Stability

• Main Authors: Shih-Hsuan Pan, 潘仕軒
• Other Authors: Won-Bo Wang
• Format: Others
• Language: en_US
• Published: 2009
• Online Access: http://ndltd.ncl.edu.tw/handle/18100095082639998434

博士 === 國立臺灣大學 === 微生物學研究所 === 97 === The Epstein-Barr virus (EBV) nuclear antigen 2 (EBNA2) plays a key role in transformation of B-lymphocytes mediated by EBV and can induce tumor formation in transgenic mice. However, the precise mechanism underlying EBNA2-mediated tumorigenesis remains elusive. Here we report that EBNA2 can retard cell cycle at G2/M phase by disrupting CDK1-Cdc25C pathway. It is well known that dys- regulating cell cycle causes chromosomal instability and results in turmerigenesis. We found that EBNA2 can compromise mitotic spindle checkpoint (MSC) and cause polyploidy in HEp-2, U2-OS and BJAB cells. Because polyploidy is thought the route to aneuploidy, we also tested whether EBNA2 can induce aneuploidy. Indeed, by using karyotyping, we found aneuploidy is increased in EBNA2-expressing cells. Furthermore, EBNA2-expressing cells initiated another round of DNA synthesis during nocodazole-induced metaphase arrest by using BrdU incorporation assay. EBNA2 was shown to be able to down-regulate Mad2 and up-regulate Plk1. The dysregulation of Mad2 and Plk1 may lead to activation of APC/C and premature degradation of Securin. Indeed, we found that when MSC was induced by nocodazole, Securin was prematurely degraded in EBNA2-expressing cells. We also showed that EBNA2 could induce micronuclei and multinuclei formation in HEp-2 and U2-OS cells. Finally, we demonstrated that EBNA2-induced polyploidy is due to both DNA endo-replication and cytokinesis failure. Together, these studies reveal a new function of EBNA2 in cell cycle regulation and chromosomal instability, and may shed light on the role of EBNA2 in EBV-mediated tumorigenesis.