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

Mol Cancer. 2011 Oct 19;10:131. doi: 10.1186/1476-4598-10-131.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aurora Kinases
  • Azepines / pharmacology
  • Humans
  • Kinesin / antagonists & inhibitors
  • Kinesin / metabolism
  • Kinetochores / metabolism
  • Microtubules / metabolism*
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Serine-Threonine Kinases / antagonists & inhibitors*
  • Protein-Serine-Threonine Kinases / genetics
  • Protein-Serine-Threonine Kinases / metabolism*
  • Pyrimidines / pharmacology
  • RNA Interference
  • Spindle Apparatus / physiology*
  • Tumor Cells, Cultured

Substances

  • Azepines
  • KIF11 protein, human
  • MLN 8237
  • Protein Kinase Inhibitors
  • Pyrimidines
  • Aurora Kinases
  • Protein-Serine-Threonine Kinases
  • Kinesin