title: Cancer-Specific requirement for BUB1B/BUBR1 in human brain tumor isolates and genetically transformed cells.
abstract: To identify new candidate therapeutic targets for glioblastoma multiforme, we combined functional genetics and glioblastoma network modeling to identify kinases required for the growth of patient-derived brain tumor-initiating cells (BTIC) but that are dispensable to proliferating human neural stem cells (NSC). This approach yielded BUB1B/BUBR1, a critical mitotic spindle checkpoint player, as the top-scoring glioblastoma lethal kinase. Knockdown of BUB1B inhibited expansion of BTIC isolates, both in vitro and in vivo, without affecting proliferation of NSCs or astrocytes. Mechanistic studies revealed that BUB1B's GLE2p-binding sequence (GLEBS) domain activity is required to suppress lethal kinetochore-microtubule (KT-MT) attachment defects in glioblastoma isolates and genetically transformed cells with altered sister KT dynamics, which likely favor KT-MT instability. These results indicate that glioblastoma tumors have an added requirement for BUB1B to suppress lethal consequences of altered KT function and further suggest that sister KT measurements may predict cancer-specific sensitivity to BUB1B inhibition and perhaps other mitotic targets that affect KT-MT stability.
  
  
  CONCLUSIONS
  Currently, no effective therapies are available for glioblastoma, the most frequent and aggressive brain tumor. Our results suggest that targeting the GLEBS domain activity of BUB1B may provide a therapeutic window for glioblastoma, as the GLEBS domain is nonessential in untransformed cells. Moreover, the results further suggest that sister KT distances at metaphase may predict sensitivity to anticancer therapeutics targeting KT function.
authors.affiliation: Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington 98109, USA.
authors.forename: Yu
authors.initials: Y
authors.lastname: Ding
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Hubert
authors.forename: Jacob
authors.initials: J
authors.lastname: Herman
authors.forename: Philip
authors.initials: P
authors.lastname: Corrin
authors.forename: Chad M
authors.initials: CM
authors.lastname: Toledo
authors.forename: Kyobi
authors.initials: K
authors.lastname: Skutt-Kakaria
authors.forename: Julio
authors.initials: J
authors.lastname: Vazquez
authors.forename: Ryan
authors.initials: R
authors.lastname: Basom
authors.forename: Bin
authors.initials: B
authors.lastname: Zhang
authors.forename: Jennifer K
authors.initials: JK
authors.lastname: Risler
authors.forename: Steven M
authors.initials: SM
authors.lastname: Pollard
authors.forename: Do-Hyun
authors.initials: DH
authors.lastname: Nam
authors.forename: Jeffery J
authors.initials: JJ
authors.lastname: Delrow
authors.forename: Jun
authors.initials: J
authors.lastname: Zhu
authors.forename: Jeongwu
authors.initials: J
authors.lastname: Lee
authors.forename: Jennifer
authors.initials: J
authors.lastname: DeLuca
authors.forename: James M
authors.initials: JM
authors.lastname: Olson
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Paddison
mesh_terms: D000818:Animals; D001253:Astrocytes / Q000166:cytology / Q000378:metabolism; D001665:Binding Sites / Q000235:genetics; D015153:Blotting, Western; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D018797:Cell Cycle Proteins; D002460:Cell Line; D002461:Cell Line, Transformed; D049109:Cell Proliferation; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D008941:Spindle Apparatus / Q000378:metabolism; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured
chemical_list: C584278:Bub1b protein, mouse; D018797:Cell Cycle Proteins; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases