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© The Rockefeller University Press, 0021-9525/2003/4/281 $5.00
The Journal of Cell Biology, Volume 161, Number 2, 281-294

The small molecule Hesperadin reveals a role for Aurora B in correcting kinetochore–microtubule attachment and in maintaining the spindle assembly checkpoint

¹ Research Institute of Molecular Pathology, 1030 Vienna, Austria
² Laboratory for Cell Regulation, Wadsworth Center for Laboratories and Research, Albany, NY 12201
³ Boehringer Ingelheim Pharma KG, 88397 Biberach/Riss, Germany
⁴ Boehringer Ingelheim Austria, 1121 Vienna, Austria

Address correspondence to Jan-Michael Peters, Research Institute of Molecular Pathology, Dr. Bohr-Gasse 7, 1030 Vienna, Austria. Tel.: 43-1-797-30-886. Fax: 43-1-798-71-53. E-mail: peters{at}imp.univie.ac.at

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.

Key Words: mitosis; chromosome segregation; kinetochores; spindle assembly checkpoint; chemical biology

^* Abbreviations used in this paper: APC, anaphase-promoting complex; NEB, nuclear envelope breakdown; RNAi, RNA interference; siRNA, small inhibitory RNA.

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• Vader, G., Medema, R. H., Lens, S. M.A. (2006). The chromosomal passenger complex: guiding Aurora-B through mitosis. JCB 173: 833-837 [Abstract] [Full Text]  
• Klein, U. R., Nigg, E. A., Gruneberg, U. (2006). Centromere Targeting of the Chromosomal Passenger Complex Requires a Ternary Subcomplex of Borealin, Survivin, and the N-Terminal Domain of INCENP. Mol. Biol. Cell 17: 2547-2558 [Abstract] [Full Text]  
• Pinsky, B. A., Kotwaliwale, C. V., Tatsutani, S. Y., Breed, C. A., Biggins, S. (2006). Glc7/Protein phosphatase 1 regulatory subunits can oppose the ipl1/aurora protein kinase by redistributing glc7.. Mol. Cell. Biol. 26: 2648-2660 [Abstract] [Full Text]  
• Lens, S. M.A., Rodriguez, J. A., Vader, G., Span, S. W., Giaccone, G., Medema, R. H. (2006). Uncoupling the Central Spindle-associated Function of the Chromosomal Passenger Complex from Its Role at Centromeres. Mol. Biol. Cell 17: 1897-1909 [Abstract] [Full Text]  
• Rosa, J., Canovas, P., Islam, A., Altieri, D. C., Doxsey, S. J. (2006). Survivin Modulates Microtubule Dynamics and Nucleation throughout the Cell Cycle. Mol. Biol. Cell 17: 1483-1493 [Abstract] [Full Text]  
• Wang, I-C., Chen, Y.-J., Hughes, D., Petrovic, V., Major, M. L., Park, H. J., Tan, Y., Ackerson, T., Costa, R. H. (2005). Forkhead Box M1 Regulates the Transcriptional Network of Genes Essential for Mitotic Progression and Genes Encoding the SCF (Skp2-Cks1) Ubiquitin Ligase. Mol. Cell. Biol. 25: 10875-10894 [Abstract] [Full Text]  
• Ruiz-Cortes, Z. T., Kimmins, S., Monaco, L., Burns, K. H., Sassone-Corsi, P., Murphy, B. D. (2005). Estrogen Mediates Phosphorylation of Histone H3 in Ovarian Follicle and Mammary Epithelial Tumor Cells via the Mitotic Kinase, Aurora B. Mol. Endocrinol. 19: 2991-3000 [Abstract] [Full Text]  
• Huang, H.-K., Bailis, J. M., Leverson, J. D., Gomez, E. B., Forsburg, S. L., Hunter, T. (2005). Suppressors of Bir1p (Survivin) Identify Roles for the Chromosomal Passenger Protein Pic1p (INCENP) and the Replication Initiation Factor Psf2p in Chromosome Segregation. Mol. Cell. Biol. 25: 9000-9015 [Abstract] [Full Text]  
• Monaco, L., Kolthur-Seetharam, U., Loury, R., Murcia, J. M.-d., de Murcia, G., Sassone-Corsi, P. (2005). Inhibition of Aurora-B kinase activity by poly(ADP-ribosyl)ation in response to DNA damage. Proc. Natl. Acad. Sci. USA 102: 14244-14248 [Abstract] [Full Text]  
• Emanuele, M. J., McCleland, M. L., Satinover, D. L., Stukenberg, P. T. (2005). Measuring the Stoichiometry and Physical Interactions between Components Elucidates the Architecture of the Vertebrate Kinetochore. Mol. Biol. Cell 16: 4882-4892 [Abstract] [Full Text]  
• Yuce, O., Piekny, A., Glotzer, M. (2005). An ECT2-centralspindlin complex regulates the localization and function of RhoA. JCB 170: 571-582 [Abstract] [Full Text]  
• Morrow, C. J., Tighe, A., Johnson, V. L., Scott, M. I.F., Ditchfield, C., Taylor, S. S. (2005). Bub1 and aurora B cooperate to maintain BubR1-mediated inhibition of APC/CCdc20. J. Cell Sci. 118: 3639-3652 [Abstract] [Full Text]  
• Godl, K., Gruss, O. J., Eickhoff, J., Wissing, J., Blencke, S., Weber, M., Degen, H., Brehmer, D., Orfi, L., Horvath, Z., Keri, G., Muller, S., Cotten, M., Ullrich, A., Daub, H. (2005). Proteomic Characterization of the Angiogenesis Inhibitor SU6668 Reveals Multiple Impacts on Cellular Kinase Signaling. Cancer Res. 65: 6919-6926 [Abstract] [Full Text]  

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