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dc.contributor.authorGurden, MD
dc.contributor.authorAnderhub, SJ
dc.contributor.authorFaisal, A
dc.contributor.authorLinardopoulos, S
dc.date.accessioned2018-08-07T13:52:11Z
dc.date.accessioned2020-10-15T15:04:15Z
dc.date.issued2018-04
dc.identifier.citationOncotarget, 2018, 9 (28), pp. 19525 - 19542
dc.identifier.issn1949-2553
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4151
dc.identifier.eissn1949-2553
dc.identifier.doi10.18632/oncotarget.10657
dc.description.abstractAccurate chromosome segregation is dependent on the spindle assembly checkpoint (SAC). In current models, the key direct role of Aurora B in the SAC has been suggested to be to promote rapid kinetochore localisation of MPS1, allowing MPS1 to generate the checkpoint signal. However, Aurora B is also thought to play an indirect role in the SAC through the destabilisation of kinetochore-microtubule (KT-MT) attachments. Here, we demonstrate that Aurora B activity is not required for the kinetochore recruitment of the majority of SAC proteins. More importantly, we show that the primary role of Aurora B in the SAC is to prevent the premature removal of SAC proteins from the kinetochore, which is strictly dependent on KT-MT interactions. Moreover, in the presence of KT-MT interactions, Aurora B inhibition silences a persistent SAC induced by tethering MPS1 to the kinetochore. This explains the highly synergistic interaction between Aurora B and MPS1 inhibitors to override the SAC, which is lost when cells are pre-arrested in nocodazole. Furthermore, we show that Aurora B and MPS1 inhibitors synergistically kill a panel of breast and colon cancer cell lines, including cells that are otherwise insensitive to Aurora B inhibitors alone. These data demonstrate that the major role of Aurora B in SAC is to prevent the removal of SAC proteins from tensionless kinetochores, thus inhibiting premature SAC silencing, and highlights a therapeutic strategy through combination of Aurora B and MPS1 inhibitors.
dc.formatElectronic-eCollection
dc.format.extent19525 - 19542
dc.languageeng
dc.language.isoeng
dc.relation.replaceshttps://repository.icr.ac.uk/handle/internal/2282
dc.relation.replacesinternal/2282
dc.relation.replacesinternal/95
dc.relation.replaceshttps://repository.icr.ac.uk/handle/internal/95
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleAurora B prevents premature removal of spindle assembly checkpoint proteins from the kinetochore: A key role for Aurora B in mitosis.
dc.typeJournal Article
dcterms.dateAccepted2016-06-01
rioxxterms.versionofrecord10.18632/oncotarget.10657
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.licenseref.startdate2018-04
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfOncotarget
pubs.declined2018-08-07T14:24:14.873+0100
pubs.issue28
pubs.merge-frominternal/95
pubs.merge-fromhttps://repository.icr.ac.uk/handle/internal/95
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Drug Target Discovery
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Breast Cancer Research/Drug Target Discovery
pubs.publication-statusPublished
pubs.volume9
pubs.embargo.termsNot known
icr.researchteamDrug Target Discoveryen_US
dc.contributor.icrauthorLinardopoulos, Spyridonen
dc.contributor.icrauthorGurden, Marken


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Except where otherwise noted, this item's license is described as https://creativecommons.org/licenses/by/4.0