title: Uncoupling the central spindle-associated function of the chromosomal passenger complex from its role at centromeres.
abstract: Survivin is a component of the chromosomal passenger complex (CPC) that plays a role in maintenance of an active spindle checkpoint and in cytokinesis. To study whether these different functions can be attributed to distinct domains within the Survivin protein, we complemented Survivin-depleted cells with a variety of point- and deletion-mutants of Survivin. We show that an intact baculovirus IAP repeat (BIR) domain is required for proper spindle checkpoint functioning, but dispensable for cytokinesis. In line with this, mutants lacking an intact BIR domain localized normally to the central spindle, but their localization to inner centromeres was severely perturbed. Consequently, these mutants failed to recruit Aurora B, Borealin/Dasra B, and BubR1 to centromeres and kinetochores, but they had retained the ability to recruit Aurora B and Borealin/Dasra B to the midzone and midbody. Thus, the C terminus of Survivin is sufficient for central spindle localization and execution of cytokinesis, but the additional presence of a functional BIR domain is essential for centromere targeting and spindle checkpoint function. Importantly, our data show that the function of the CPC at the centromere can be separated from its function at the central spindle and that execution of cytokinesis does not require prior concentration of the CPC at centromeres.
authors.affiliation: Department of Medical Oncology, University Medical Center Utrecht, 3584 CG Utrecht, The Netherlands. s.m.a.lens@med.uu.nl
authors.forename: Susanne M A
authors.initials: SM
authors.lastname: Lens
authors.forename: Jose A
authors.initials: JA
authors.lastname: Rodriguez
authors.forename: Gerben
authors.initials: G
authors.lastname: Vader
authors.forename: Simone W
authors.initials: SW
authors.lastname: Span
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Giaccone
authors.forename: René H
authors.initials: RH
authors.lastname: Medema
mesh_terms: D064107:Aurora Kinase B; D064127:Aurora Kinases; D018797:Cell Cycle Proteins / Q000378:metabolism; D002503:Centromere / Q000737:chemistry / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000032:analysis / Q000378:metabolism; D002877:Chromosomes, Human / Q000378:metabolism; D048749:Cytokinesis / Q000235:genetics; D004252:DNA Mutational Analysis; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins; D018386:Kinetochores / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000032:analysis / Q000235:genetics / Q000378:metabolism*; D017354:Point Mutation; D011494:Protein Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000032:analysis / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics / Q000494:pharmacology; D017384:Sequence Deletion; D008941:Spindle Apparatus / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D000077022:Survivin
chemical_list: C107489:BIRC5 protein, human; C490157:CDCA8 protein, human; D018797:Cell Cycle Proteins; D002868:Chromosomal Proteins, Non-Histone; C083767:INCENP protein, human; D051034:Inhibitor of Apoptosis Proteins; D008869:Microtubule-Associated Proteins; D009363:Neoplasm Proteins; D034741:RNA, Small Interfering; D000077022:Survivin; D011494:Protein Kinases; C576921:AURKB protein, human; D064107:Aurora Kinase B; D064127:Aurora Kinases; C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases