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dc.contributor.authorWoodcock, Simon A
dc.contributor.authorRushton, Helen J
dc.contributor.authorCastañeda-Saucedo, Eduardo
dc.contributor.authorMyant, Kevin
dc.contributor.authorWhite, Gavin R M
dc.contributor.authorBlyth, Karen
dc.contributor.authorSansom, Owen J
dc.contributor.authorMalliri, Angeliki
dc.date.accessioned2010-08-10T14:18:55Z
dc.date.available2010-08-10T14:18:55Z
dc.date.issued2010-04-13
dc.identifier.citationTiam1-Rac signaling counteracts Eg5 during bipolar spindle assembly to facilitate chromosome congression. 2010, 20 (7):669-75 Curr Biolen
dc.identifier.issn1879-0445
dc.identifier.pmid20346677
dc.identifier.doi10.1016/j.cub.2010.02.033
dc.identifier.urihttp://hdl.handle.net/10541/109405
dc.description.abstractCentrosome separation, critical for bipolar spindle formation and subsequent chromosome segregation during mitosis, occurs via distinct prophase and prometaphase pathways. Kinesin-5 (Eg5), a microtubule (MT) motor, pushes centrosomes apart during bipolar spindle assembly; its suppression results in monopolar spindles and mitotic arrest. Forces that antagonize Eg5 in prophase are unknown. Here we identify a new force generating mechanism mediated by the guanine nucleotide exchange factor (GEF) Tiam1, dependent on its ability to activate the GTPase Rac. We reveal that Tiam1 and Rac localize to centrosomes during prophase and prometaphase, and Tiam1, acting through Rac, ordinarily retards centrosome separation. Importantly, both Tiam1-depleted cells in culture and Rac1-deficient epithelial cells in vivo escape the mitotic arrest induced by Eg5 suppression. Moreover, Tiam1-depleted cells transit more slowly through prometaphase and display increased chromosome congression errors. Significantly, Eg5 suppression in Tiam1-depleted cells rectifies not only their increased centrosome separation but also their chromosome congression errors and mitotic delay. These findings identify Tiam1-Rac signaling as the first antagonist of centrosome separation during prophase, demonstrate its requirement in balancing Eg5-induced forces during bipolar spindle assembly in vitro and in vivo, and show that proper centrosome separation in prophase facilitates subsequent chromosome congression.
dc.language.isoenen
dc.subject.meshAnimals
dc.subject.meshBase Sequence
dc.subject.meshCell Line
dc.subject.meshCentrosome
dc.subject.meshChromosome Segregation
dc.subject.meshDogs
dc.subject.meshGuanine Nucleotide Exchange Factors
dc.subject.meshKinesin
dc.subject.meshMice
dc.subject.meshMice, Inbred C57BL
dc.subject.meshMice, Transgenic
dc.subject.meshMitosis
dc.subject.meshMitotic Spindle Apparatus
dc.subject.meshModels, Biological
dc.subject.meshNeuropeptides
dc.subject.meshRNA Interference
dc.subject.meshSignal Transduction
dc.subject.meshrac GTP-Binding Proteins
dc.titleTiam1-Rac signaling counteracts Eg5 during bipolar spindle assembly to facilitate chromosome congression.en
dc.typeArticleen
dc.contributor.departmentCell Signalling Group, Cancer Research UK Paterson Institute for Cancer Research, The University of Manchester, Manchester, UK.en
dc.identifier.journalCurrent Biologyen
html.description.abstractCentrosome separation, critical for bipolar spindle formation and subsequent chromosome segregation during mitosis, occurs via distinct prophase and prometaphase pathways. Kinesin-5 (Eg5), a microtubule (MT) motor, pushes centrosomes apart during bipolar spindle assembly; its suppression results in monopolar spindles and mitotic arrest. Forces that antagonize Eg5 in prophase are unknown. Here we identify a new force generating mechanism mediated by the guanine nucleotide exchange factor (GEF) Tiam1, dependent on its ability to activate the GTPase Rac. We reveal that Tiam1 and Rac localize to centrosomes during prophase and prometaphase, and Tiam1, acting through Rac, ordinarily retards centrosome separation. Importantly, both Tiam1-depleted cells in culture and Rac1-deficient epithelial cells in vivo escape the mitotic arrest induced by Eg5 suppression. Moreover, Tiam1-depleted cells transit more slowly through prometaphase and display increased chromosome congression errors. Significantly, Eg5 suppression in Tiam1-depleted cells rectifies not only their increased centrosome separation but also their chromosome congression errors and mitotic delay. These findings identify Tiam1-Rac signaling as the first antagonist of centrosome separation during prophase, demonstrate its requirement in balancing Eg5-induced forces during bipolar spindle assembly in vitro and in vivo, and show that proper centrosome separation in prophase facilitates subsequent chromosome congression.


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