Format

Send to

Choose Destination
Cancer Cell. 2003 Jan;3(1):51-62.

AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol.

Author information

1
CR UK Department of Oncology and The medical Research Council Cancer Cell Unit, Hutchison/MRC Research Centre, University of Cambridge, Hills Road, Cambridge CB2 2XZ, United Kingdom.

Abstract

The serine-threonine kinase gene AURORA-A is commonly amplified in epithelial malignancies. Here we show that elevated Aurora-A expression at levels that reflect cancer-associated gene amplification overrides the checkpoint mechanism that monitors mitotic spindle assembly, inducing resistance to the chemotherapeutic agent paclitaxel (Taxol). Cells overexpressing Aurora-A inappropriately enter anaphase despite defective spindle formation, and the persistence of Mad2 at the kinetochores, marking continued activation of the spindle assembly checkpoint. Mitosis is subsequently arrested by failure to complete cytokinesis, resulting in multinucleation. This abnormality is relieved by an inhibitory mutant of BUB1, linking the mitotic abnormalities provoked by Aurora-A overexpression to spindle checkpoint activity. Consistent with this conclusion, elevated Aurora-A expression causes resistance to apoptosis induced by Taxol in a human cancer cell line.

PMID:
12559175
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center