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HBV X protein targets hBubR1, which induces dysregulation of the mitotic checkpoint.

Authors
Kim, S; Park, SY; Yong, H; Famulski, JK; Chae, S; Lee, JH; Kang, CM; Saya, H; Chan, GK; Cho, H
Citation
Oncogene, 27(24):2357-2364, 2008
Journal Title
Oncogene
ISSN
0950-92321476-5594
Abstract
Accurate chromosomal segregation is monitored by the mitotic checkpoint, and an increased rate of chromosomal missegregation leads to chromosomal instability (CIN). Here, we demonstrate that the HBV X protein (HBx) binds BubR1, a component of the mitotic checkpoint complex and co-localizes with BubR1 at the kinetochores. HBx binding to BubR1 attenuates the association between BubR1 and CDC20, an activator of the anaphase-promoting complex/cyclosome (APC/C) and induces slippage of mitotic arrest in the presence of microtubule poisons. In addition, HBx binding to BubR1 results in the accumulation of lagging chromosomes and chromosome bridges. In contrast, a C-terminally truncated HBx mutant (HBx(1-100)) fails to bind BubR1 and does not cause aberrant chromosomal segregation. This provides a novel mechanism for dysregulation of the mitotic checkpoint by a viral pathogen linking it to the accumulation of chromosomal instability in HBV-associated hepatocarcinogenesis.
MeSH terms
Blotting, WesternCarcinoma, Hepatocellular/geneticsCarcinoma, Hepatocellular/metabolism*Cell Cycle Proteins/metabolismChromosomal Instability*Chromosome SegregationChromosomes, Human/geneticsFluorescent Antibody TechniqueHela CellsHumansImmunoprecipitationKinetochoresLiver Neoplasms/geneticsLiver Neoplasms/metabolismMicrotubules/drug effectsMitosis/physiology*Mitotic Spindle ApparatusProtein-Serine-Threonine Kinases/geneticsProtein-Serine-Threonine Kinases/metabolism*Saccharomyces cerevisiaeTrans-Activators/geneticsTrans-Activators/metabolism*TransfectionTwo-Hybrid System TechniquesUbiquitin-Protein Ligase Complexes/metabolismUbiquitin-Protein Ligase Complexes/physiology
DOI
10.1038/sj.onc.1210998
PMID
18193091
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Biochemistry & Molecular Biology
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