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J. Biol. Chem., Vol. 283, Issue 5, 2793-2803, February 1, 2008

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Interaction of Hepatitis B Viral Oncoprotein with Cellular Target HBXIP Dysregulates Centrosome Dynamics and Mitotic Spindle Formation^*

Yunfei Wen, Vladislav S. Golubkov, Alex Y. Strongin, Wei Jiang^¶, and John C. Reed¹

From the Program on Apoptosis and Cell Death Research, Program on Cell Adhesion and Extracellular Matrix Biology, and ^¶Program on Cancer Genetics and Epigenetics, Burnham Institute for Medical Research, La Jolla, California 92037

Hepatitis B virus infection is associated with hepatocellular carcinoma, claiming 1 million lives annually worldwide. To understand the carcinogenic mechanism of hepatitis B virus-encoded oncoprotein HBx, we explored the function of HBx interaction with its cellular target HBXIP. Previously, we demonstrated that viral HBx and cellular HBXIP control mitotic spindle formation, regulating centrosome splitting. By using various fragments of HBx, we determined that residues ¹³⁷CRHK¹⁴⁰ within HBx are necessary for binding HBXIP. Mutation of the ¹³⁷CRHK¹⁴⁰ motif in HBx abolished its ability to bind HBXIP and to dysregulate centrosome dynamics in HeLa and immortal diploid RPE-1 cells. Unlike wild-type HBx, which targets to centrosomes as determined by subcellular fractionation and immunofluorescence microscopy, HBx mutants failed to localize to centrosomes. Overexpression of viral HBx wild-type protein and knockdown of endogenous HBXIP altered centrosome assembly and induced modifications of pericentrin and centrin-2, two essential proteins required for centrosome formation and function, whereas HBXIP nonbinding mutants of HBx did not. Overexpression of HBXIP or fragments of HBXIP that bind HBx neutralized the effects of viral HBx on centrosome dynamics and spindle formation. These results suggest that HBXIP is a critical target of viral HBx for promoting genetic instability through formation of defective spindles and subsequent aberrant chromosome segregation.

Received for publication, October 10, 2007 , and in revised form, November 19, 2007.

The nucleotide sequence(s) reported in this paper has been submitted to the GenBank^TM/EBI Data Bank with accession number(s) NM_006402 and U55762.

^* This work was supported by National Institutes of Health Grants CA 112053 (to J. C. R.) and AG 15402 (to J. C. R.) and a Susan G. Komen for the Cure postdoctoral fellowship (to Y. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1 and Movies 1-4.

¹ To whom correspondence should be addressed: 10901 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: 858-795-5300; Fax: 858-646-3194; E-mail: reedoffice{at}burnham.org.

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