title: The chromosomal passenger complex controls spindle checkpoint function independent from its role in correcting microtubule kinetochore interactions.
abstract: The chromosomal passenger complex (CPC) is a critical regulator of chromosome segregation during mitosis by correcting nonbipolar microtubule-kinetochore interactions. By severing these interactions, the CPC is thought to create unattached kinetochores that are subsequently sensed by the spindle assembly checkpoint (SAC) to prevent premature mitotic exit. We now show that spindle checkpoint function of the CPC and its role in eliminating nonbipolar attachments can be uncoupled. Replacing the chromosomal passenger protein INCENP with a mutant allele that lacks its coiled-coil domain results in an overt defect in a SAC-mediated mitotic arrest in response to taxol treatment, indicating that this domain is critical for CPC function in spindle checkpoint control. Surprisingly, this mutant could restore alignment and cytokinesis during unperturbed cell divisions and was capable of resolving syntelic attachments. Also, Aurora-B kinase was localized and activated normally on centromeres in these cells, ruling out a role for the coiled-coil domain in general Aurora-B activation. Thus, mere microtubule destabilization of nonbipolar attachments by the CPC is insufficient to install a checkpoint-dependent mitotic arrest, and additional, microtubule destabilization-independent CPC signaling toward the spindle assembly checkpoint is required for this arrest, potentially through amplification of the unattached kinetochore-derived checkpoint signal.
authors: Department of Medical Oncology, University Medical Center, 3584 CG Utrecht, The Netherlands.
authors: Gerben
authors: G
authors: Vader
authors: Carin W A
authors: CW
authors: Cruijsen
authors: Tanja
authors: T
authors: van Harn
authors: Martijn J M
authors: MJ
authors: Vromans
authors: René H
authors: RH
authors: Medema
authors: Susanne M A
authors: SM
authors: Lens
mesh_terms: D064107:Aurora Kinase B; D064127:Aurora Kinases; D045744:Cell Line, Tumor; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism; D002875:Chromosomes / Q000378:metabolism*; D017353:Gene Deletion; D006801:Humans; D018386:Kinetochores / Q000378:metabolism*; D008870:Microtubules / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D015398:Signal Transduction; D008941:Spindle Apparatus / Q000378:metabolism*
chemical_list: D002868:Chromosomal Proteins, Non-Histone; C083767:INCENP protein, human; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases
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