Abstract
BackgroundAurora-A is an oncogenic kinase playing well-documented roles in mitotic spindle organisation. We previously found that Aurora-A inactivation yields the formation of spindles with fragmented poles that can drive chromosome mis-segregation. Here we have addressed the mechanism through which Aurora-A activity regulates the structure and cohesion of spindle poles.ResultsWe inactivated Aurora-A in human U2OS osteosarcoma cells either by RNA-interference-mediated silencing or treating cultures with the specific inhibitor MLN8237. We show that mitotic spindle pole fragmentation induced by Aurora-A inactivation is associated with microtubule hyperstabilisation. Silencing of the microtubule-stabilising factor ch-TOG prevents spindle pole fragmentation caused by inactivation of Aurora-A alone and concomitantly reduces the hyperstabilisation of microtubules. Furthermore, decreasing pole-directed spindle forces by inhibition of the Eg5 kinesin, or by destabilisation of microtubule-kinetochore attachments, also prevents pole fragmentation in Aurora-A-inactivated mitoses.ConclusionsOur findings indicate that microtubule-generated forces are imbalanced in Aurora-A-defective cells and exert abnormal pressure at the level of spindle poles, ultimately causing their fragmentation. This study therefore highlights a novel role of the Aurora-A kinase in regulating the balance between microtubule forces during bipolar spindle assembly.
Highlights
Aurora-A is an oncogenic kinase playing well-documented roles in mitotic spindle organisation
We previously reported that RNA interference (RNAi)-mediated inactivation of Aurora-A yielded an abnormal accumulation of ch-TOG at spindle poles
Aurora-A inactivation yields hyperstabilisation of mitotic spindle MTs Aurora-A can be effectively silenced by RNAi in human cells, providing a useful tool to unravel the biological functions of this kinase [22,23,24,32]
Summary
Aurora-A is an oncogenic kinase playing well-documented roles in mitotic spindle organisation. Microtubule (MT)-generated forces drive the dynamic movements of centrosomes, chromosomes and MTs themselves and are essential players in the build-up of the mitotic bipolar spindle (see [1,2,3] for reviews). Novel molecules with Aurora-A-inhibitory activity are being designed in many laboratories, some of which have yielded promising results in pre-clinical studies and are under evaluation in phase I and II clinical trials (see [12] for a recent review). These observations highlight the importance of unraveling Aurora-A downstream processes. They call for increasing attention on elucidating potentially adverse consequences of Aurora-A inactivation on cell division
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