The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore-microtubule attachment and in maintaining the spindle assembly checkpoint.
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.
Hauf
Silke
S
Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, 1030 Vienna, Austria.
Cole
Richard W
RW
LaTerra
Sabrina
S
Zimmer
Christine
C
Schnapp
Gisela
G
Walter
Rainer
R
Heckel
Armin
A
van Meel
Jacques
J
Rieder
Conly L
CL
Peters
Jan-Michael
JM
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
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