title: HBXIP, cellular target of hepatitis B virus oncoprotein, is a regulator of centrosome dynamics and cytokinesis.
abstract: Hepatitis B virus accounts for more than 1 million cancer deaths annually, but the mechanism by which this virus promotes hepatocellular carcinoma remains unclear. The hepatitis B virus genome encodes an oncoprotein, HBx, which binds various cellular proteins including HBXIP. We show here that HBXIP is a regulator of centrosome duplication, required for bipolar spindle formation in HeLa human carcinoma cells and primary mouse embryonic fibroblast cells. We found that most cells deficient in HBXIP arrest in prometaphase with monopolar spindles whereas HBXIP overexpression causes tripolar or multipolar spindles due to excessive centrosome replication. Additionally, a defect in cytokinesis was seen in HBXIP-deficient HeLa cells, with most cells failing to complete division and succumbing eventually to apoptosis. Expression of viral HBx in HeLa cells mimicked the effects of HBXIP overexpression, causing excessive centrosome replication, resulting in tripolar and multipolar spindles and defective cytokinesis. Immunolocalization and fluorescent protein tagging experiments showed that HBXIP associates with microtubules of dividing cells and colocalizes with HBx on centrosomes. Thus, viral HBx and its cellular target HBXIP regulate centrosome dynamics and cytokinesis affecting genetic stability. In vivo experiments using antisense oligonucleotides targeting HBXIP in a mouse model of liver regeneration showed a requirement for HBXIP for growth and survival of replicating hepatocytes. Thus, HBXIP is a critical regulator of hepatocyte cell growth in vivo, making it a strong candidate for explaining the tumorigenic actions of viral HBx.
authors.affiliation: Burnham Institute for Medical Research, La Jolla, California and ISIS Pharmaceuticals, Inc., Carlsbad, California, USA.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Fujii
authors.forename: Changjun
authors.initials: C
authors.lastname: Zhu
authors.forename: Yunfei
authors.initials: Y
authors.lastname: Wen
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Marusawa
authors.forename: Beatrice
authors.initials: B
authors.lastname: Bailly-Maitre
authors.forename: Shu-ichi
authors.initials: S
authors.lastname: Matsuzawa
authors.forename: Hong
authors.initials: H
authors.lastname: Zhang
authors.forename: Youngsoo
authors.initials: Y
authors.lastname: Kim
authors.forename: C Frank
authors.initials: CF
authors.lastname: Bennett
authors.forename: Wei
authors.initials: W
authors.lastname: Jiang
authors.forename: John C
authors.initials: JC
authors.lastname: Reed
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D018385:Centrosome / Q000502:physiology*; D006367:HeLa Cells; D022781:Hepatocytes / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008115:Liver Regeneration; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008870:Microtubules / Q000378:metabolism; D008938:Mitosis / Q000502:physiology; D008941:Spindle Apparatus / Q000502:physiology; D015534:Trans-Activators / Q000378:metabolism*; D014162:Transfection; D054334:Viral Regulatory and Accessory Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C110719:LAMTOR5 protein, human; D015534:Trans-Activators; D054334:Viral Regulatory and Accessory Proteins; C057628:hepatitis B virus X protein