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Carcinogenesis Advance Access published online on January 6, 2009
Carcinogenesis, doi:10.1093/carcin/bgn291
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Epstein-Barr Virus Nuclear Antigen 2 Disrupts Mitotic Checkpoint and Causes Chromosomal Instability

Shih-Hsuan Pan1, Chia-Ching Tai1, Chang-Shen Lin2,5, Wei-Bin Hsu1, Shu-Fan Chou1, Chih-Chang Lai1, Jen-Yang Chen2, Hwei-Fang Tien3, Fen-Yu Lee4 and Won-Bo Wang1,*

1 Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei 100, Taiwan
2 National Health Research Institutes, Miaoli 350, Taiwan
3 Department of Internal Medicine
4 Department of Pathology, National Taiwan University Hospital, Taipei, Taiwan

* To whom correspondence should be addressed. Tel: +886-2-23123456 ext 88285, Fax: 886-2-23915293; Email: wbwang{at}ntu.edu.tw

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 compromise mitotic spindle checkpoint (MSC) induced by the spindle inhibitor nocodazole and cause chromosomal instability in HEp-2, U2-OS and BJAB cells. When EBNA2-expressing cells were treated with nocodazole, they exited mitosis prematurely and initiated another round of DNA synthesis. Nucleolocalization of EBNA2 was essential for EBNA2 to compromise MSC and to cause chromosomal instability. The metaphase chromosome spread data indicated that the EBNA2-expressing U2-OS cells showed a more heterogeneous chromosome number distribution than the vector-transfected and parental cells. The median chromosome number for EBNA2-expressing, vector-transfected, and parental U2-OS cells is 75, 65, and 64, respectively. EBNA2 was shown to be able to down-regulate MAD2 about 2-3 fold and up-regulate PLK1 about 2 fold. 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. Finally we show that EBNA2 could induce micronuclei and multinuclei formation in HEp-2 and U2-OS cells. Together, these studies reveal a new function of EBNA2 in cell cycle regulation and may shed light on the role of EBNA2 in EBV-mediated tumorigenesis.

Key Words: EBNA2 • genome instability • mitotic spindle checkpoint • endoreduplication

5 Current address: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan

Received June 1, 2008; revised December 5, 2008; accepted December 20, 2008.


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