Aurora-A inactivation causes mitotic spindle pole fragmentation by unbalancing microtubule-generated forces.

Abstract:

BACKGROUND:Aurora-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. RESULTS:We 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. CONCLUSIONS:Our 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.

journal_name

Mol Cancer

journal_title

Molecular cancer

authors

Asteriti IA,Giubettini M,Lavia P,Guarguaglini G

doi

10.1186/1476-4598-10-131

subject

Has Abstract

pub_date

2011-10-19 00:00:00

pages

131

issn

1476-4598

pii

1476-4598-10-131

journal_volume

10

pub_type

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