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

• Published in: Molecular cancer Vol. 10; no. 1; p. 131
• Main Authors: Asteriti, Italia A, Giubettini, Maria, Lavia, Patrizia, Guarguaglini, Giulia
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 19.10.2011; BioMed Central; BMC
• Subjects: Aurora Kinases; Aurora-A; Azepines - pharmacology; Cancer; Cancer therapies; Cell division; Cellular biology; ch-TOG; Chromosomes; Eg5; Experiments; Genetic aspects; Humans; Kinases; Kinesin - antagonists & inhibitors; Kinesin - metabolism; Kinetochores - metabolism; Medical research; Microtubules - metabolism; Mitosis; mitotic spindle forces; MLN8237; multipolar spindles; Nuf2; Osteosarcoma; 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; Italy
• ISSN: 1476-4598; 1476-4598
• DOI: 10.1186/1476-4598-10-131

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. 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. 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.