AURORA-A amplification overrides the mitotic spindle assembly checkpoint, inducing resistance to Taxol.
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.
Anand
Shubha
S
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.
Penrhyn-Lowe
Sue
S
Venkitaraman
Ashok R
AR
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D064096:Aurora Kinase A; D064127:Aurora Kinases; D015153:Blotting, Western; D002478:Cells, Cultured; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004622:Embryo, Mammalian; D005347:Fibroblasts; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D005784:Gene Amplification; D018816:Genes, cdc; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D008938:Mitosis / Q000502:physiology*; D009154:Mutation; D017239:Paclitaxel / Q000494:pharmacology; D011494:Protein Kinases / Q000235:genetics; D017346:Protein Serine-Threonine Kinases / Q000096:biosynthesis / Q000235:genetics*; D008941:Spindle Apparatus / Q000502:physiology; D014162:Transfection
D000972:Antineoplastic Agents, Phytogenic; D011494:Protein Kinases; C576918:Aurka protein, mouse; D064096:Aurora Kinase A; D064127:Aurora Kinases; C584277:BUB1 protein, human; C584281:Bub1 protein, mouse; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases; D017239:Paclitaxel