AuroraA overexpression overrides the mitotic spindle checkpoint triggered by nocodazole, a microtubule destabilizer.
AuroraA, a mitotic kinase, is reported to be amplified and overexpressed in a variety of human tumors. Active mutants of AuroraA can transform mouse fibroblasts and form tumors in nude mice. However, the mechanism behind this oncogenic potential remains elusive. In this study, we investigated the consequences of AuroraA overexpression and showed that increased AuroraA levels compromise the mitotic spindle checkpoint triggered by nocodazole, a microtubule polymerization inhibitor. This is accomplished by disrupting the proper assembly of the mitotic checkpoint complex at the level of the Cdc20-BubR1 interaction. As a result, the spindle checkpoint complex fails to form and cells progress through mitosis without proper arrest in response to nocodazole. This ability to override the mitotic spindle checkpoint was found to be independent of AuroraA kinase activity. We conclude that maintenance of a functional balance between AuroraA and mitotic checkpoint proteins is essential for the proper progression through mitosis. This study therefore offers a possible explanation of how deregulation of AuroraA can contribute to genetic instability and tumorigenesis.
Jiang
Ying
Y
DNAX Research Inc., Palo Alto, CA 94304, USA.
Zhang
Yongke
Y
Lees
Emma
E
Seghezzi
Wolfgang
W
D064127:Aurora Kinases; D018797:Cell Cycle Proteins; D002460:Cell Line; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic; D006801:Humans; D008870:Microtubules / Q000187:drug effects*; D015739:Nocodazole / Q000494:pharmacology*; D011494:Protein Kinases / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases; D008941:Spindle Apparatus; D029867:Xenopus Proteins
D018797:Cell Cycle Proteins; D029867:Xenopus Proteins; D011494:Protein Kinases; C112134:AURKA protein, Xenopus; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases; D015739:Nocodazole