title: Bub1 overexpression induces aneuploidy and tumor formation through Aurora B kinase hyperactivation.
abstract: High expression of the protein kinase Bub1 has been observed in a variety of human tumors and often correlates with poor clinical prognosis, but its molecular and cellular consequences and role in tumorigenesis are unknown. Here, we demonstrate that overexpression of Bub1 in mice leads to near-diploid aneuploidies and tumor formation. We found that chromosome misalignment and lagging are the primary mitotic errors responsible for the observed aneuploidization. High Bub1 levels resulted in aberrant Bub1 kinase activity and hyperactivation of Aurora B kinase. When Aurora B activity is suppressed, pharmacologically or via BubR1 overexpression, chromosome segregation errors caused by Bub1 overexpression are largely corrected. Importantly, Bub1 transgenic mice overexpressing Bub1 developed various kinds of spontaneous tumors and showed accelerated Myc-induced lymphomagenesis. Our results establish that Bub1 has oncogenic properties and suggest that Aurora B is a critical target through which overexpressed Bub1 drives aneuploidization and tumorigenesis.
authors.affiliation: Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN 55905, USA.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Ricke
authors.forename: Karthik B
authors.initials: KB
authors.lastname: Jeganathan
authors.forename: Jan M
authors.initials: JM
authors.lastname: van Deursen
mesh_terms: D000782:Aneuploidy; D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D045744:Cell Line, Tumor; D020090:Chromosome Segregation; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D015996:Survival Rate; D014018:Tissue Distribution
chemical_list: C584278:Bub1b protein, mouse; D018797:Cell Cycle Proteins; C576921:AURKB protein, human; C576924:Aurkb protein, mouse; D064107:Aurora Kinase B; D064127:Aurora Kinases; C584277:BUB1 protein, human; C584281:Bub1 protein, mouse; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases