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Molecular and Cellular Biology, August 2003, p. 5282-5292, Vol. 23, No. 15
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.15.5282-5292.2003

Involvement of Crm1 in Hepatitis B Virus X Protein-Induced Aberrant Centriole Replication and Abnormal Mitotic Spindles

Marshonna Forgues,1 Michael J. Difilippantonio,2 Steven P. Linke,1 Thomas Ried,2 Kunio Nagashima,3 Jeffrey Feden,4 Kristoffer Valerie,4 Kenji Fukasawa,5 and Xin W. Wang1*

Laboratory of Human Carcinogenesis,1 Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland 20892,2 NCI-Frederick, SAIC Frederick, Frederick, Maryland 21702,3 Department of Radiation Oncology, Medical College of Virginia, Virginia Commonwealth University, Richmond, Virginia 23298,4 Department of Cell Biology, University of Cincinnati College of Medicine, Cincinnati, Ohio 452675

Received 4 December 2002/ Returned for modification 26 January 2003/ Accepted 18 May 2003

Hepatitis B virus (HBV) includes an X gene (HBx gene) that plays a critical role in liver carcinogenesis. Because centrosome abnormalities are associated with genomic instability in most human cancer cells, we examined the effect of HBx on centrosomes. We found that HBx induced supernumerary centrosomes and multipolar spindles. This effect was independent of mutations in the p21 gene. Furthermore, the ability of HBV to induce supernumerary centrosomes was dependent on the presence of physiological HBx expression. We recently showed that HBx induces cytoplasmic sequestration of Crm1, a nuclear export receptor that binds to Ran GTPase, thereby inducing nuclear localization of NF-{kappa}B. Consistently, supernumerary centrosomes were observed in cells treated with a Crm1-specific inhibitor but not with an HBx mutant that lacked the ability to sequester Crm1 in the cytoplasm. Moreover, a fraction of Crm1 was found to be localized at the centrosomes. Immunocytochemical and ultrastructural examination of these supernumerary centrosomes revealed that inactivation of Crm1 was associated with abnormal centrioles. The presence of more than two centrosomes led to an increased frequency of defective mitoses and chromosome transmission errors. Based on this evidence, we suggest that Crm1 is actively involved in maintaining centrosome integrity and that HBx disrupts this process by inactivating Crm1 and thus contributes to HBV-mediated carcinogenesis.

* Corresponding author. Mailing address: Laboratory of Human Carcinogenesis, NCI, National Institutes of Health, 37 Convent Dr., MSC 4255, Building 37, Room 2C25, Bethesda, MD 20892-4255. Phone: (301) 496-2099. Fax: (301) 496-0497. E-mail: xw3u{at}nih.gov.

Molecular and Cellular Biology, August 2003, p. 5282-5292, Vol. 23, No. 15
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.15.5282-5292.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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