HBXIP, Cellular Target of Hepatitis B Virus Oncoprotein, Is a Regulator of Centrosome Dynamics and Cytokinesis
- 15 September 2006
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 66 (18), 9099-9107
- https://doi.org/10.1158/0008-5472.can-06-1886
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. (Cancer Res 2006; 66(18): 9099-107)Keywords
This publication has 29 references indexed in Scilit:
- Use of a Chemically Modified Antisense Oligonucleotide Library to Identify and Validate Eg5 (Kinesin-Like 1) as a Target for Antineoplastic Drug DevelopmentCancer Research, 2006
- Recruitment of MKLP1 to the spindle midzone/midbody by INCENP is essential for midbody formation and completion of cytokinesis in human cellsBiochemical Journal, 2005
- Functional Analysis of Human Microtubule-based Motor Proteins, the Kinesins and Dyneins, in Mitosis/Cytokinesis Using RNA InterferenceMolecular Biology of the Cell, 2005
- Hepatitis B virus X protein (HBx)‐induced apoptosis in HuH‐7 cells: influence of HBV genotype and basal core promoter mutationsScandinavian Journal of Gastroenterology, 2004
- Involvement of Crm1 in Hepatitis B Virus X Protein-Induced Aberrant Centriole Replication and Abnormal Mitotic SpindlesMolecular and Cellular Biology, 2003
- Antisense Oligonucleotide Blockade of Tumor Necrosis Factor-α in Two Murine Models of ColitisJournal of Pharmacology and Experimental Therapeutics, 2003
- The Hallmarks of CancerCell, 2000
- Characterization of the p22 Subunit of Dynactin Reveals the Localization of Cytoplasmic Dynein and Dynactin to the Midbody of Dividing CellsThe Journal of cell biology, 1998
- Hepatitis B Virus ImmunopathogenesisAnnual Review of Immunology, 1995
- Efficient selection for high-expression transfectants with a novel eukaryotic vectorGene, 1991