title: The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint.
abstract: The proper segregation of sister chromatids in mitosis depends on bipolar attachment of all chromosomes to the mitotic spindle. We have identified the small molecule Hesperadin as an inhibitor of chromosome alignment and segregation. Our data imply that Hesperadin causes this phenotype by inhibiting the function of the mitotic kinase Aurora B. Mammalian cells treated with Hesperadin enter anaphase in the presence of numerous monooriented chromosomes, many of which may have both sister kinetochores attached to one spindle pole (syntelic attachment). Hesperadin also causes cells arrested by taxol or monastrol to enter anaphase within <1 h, whereas cells in nocodazole stay arrested for 3-5 h. Together, our data suggest that Aurora B is required to generate unattached kinetochores on monooriented chromosomes, which in turn could promote bipolar attachment as well as maintain checkpoint signaling.
authors.affiliation: Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, 1030 Vienna, Austria.
authors.forename: Silke
authors.initials: S
authors.lastname: Hauf
authors.forename: Richard W
authors.initials: RW
authors.lastname: Cole
authors.forename: Sabrina
authors.initials: S
authors.lastname: LaTerra
authors.forename: Christine
authors.initials: C
authors.lastname: Zimmer
authors.forename: Gisela
authors.initials: G
authors.lastname: Schnapp
authors.forename: Rainer
authors.initials: R
authors.lastname: Walter
authors.forename: Armin
authors.initials: A
authors.lastname: Heckel
authors.forename: Jacques
authors.initials: J
authors.lastname: van Meel
authors.forename: Conly L
authors.initials: CL
authors.lastname: Rieder
authors.forename: Jan-Michael
authors.initials: JM
authors.lastname: Peters
mesh_terms: D000705:Anaphase / Q000187:drug effects / Q000235:genetics; D024422:Aneugens / Q000494:pharmacology*; D000818:Animals; D064107:Aurora Kinase B; D064127:Aurora Kinases; D018797:Cell Cycle Proteins / Q000187:drug effects / Q000235:genetics; D020090:Chromosome Segregation / Q000187:drug effects / Q000235:genetics; D010450:Endopeptidases; D005057:Eukaryotic Cells / Q000166:cytology / Q000187:drug effects / Q000201:enzymology*; D018816:Genes, cdc / Q000187:drug effects / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D018386:Kinetochores / Q000187:drug effects / Q000201:enzymology*; D008870:Microtubules / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D008938:Mitosis / Q000187:drug effects / Q000235:genetics*; D015739:Nocodazole / Q000494:pharmacology; D017239:Paclitaxel / Q000494:pharmacology; D010641:Phenotype; D011123:Polyploidy; D011494:Protein Kinases / Q000187:drug effects / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011743:Pyrimidines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D064247:Separase; D008941:Spindle Apparatus / Q000187:drug effects / Q000201:enzymology* / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology*; D013871:Thiones / Q000494:pharmacology
chemical_list: D024422:Aneugens; D018797:Cell Cycle Proteins; D007211:Indoles; D011743:Pyrimidines; D034741:RNA, Small Interfering; D013449:Sulfonamides; D013871:Thiones; C400223:monastrol; D011494:Protein Kinases; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; D010450:Endopeptidases; D064247:Separase; D017239:Paclitaxel; C474723:hesperadin; D015739:Nocodazole