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Molecular Pharmacology Fast Forward
First published on November 8, 2007; DOI: 10.1124/mol.107.039024

0026-895X/08/7302-419-430$20.00
Mol Pharmacol 73:419-430, 2008

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BubR1 Is Required for a Sustained Mitotic Spindle Checkpoint Arrest in Human Cancer Cells Treated with Tubulin-Targeting Pyrrolo-1,5-BenzoxazepinesFormula

Lisa M. Greene, Giuseppe Campiani, Mark Lawler, D. Clive Williams, and Daniela M. Zisterer

School of Biochemistry and Immunology, Trinity College, Dublin, United Kingdom (L.M.G., D.C.W., D.M.Z.); Dipartimento Farmaco Chimico Tecnologico, Universita'degli Studi di Siena, Italy (G.C.); and Institute of Molecular Medicine, St. James's Hospital and Trinity College, Dublin, United Kingdom (M.L.)

Intrinsic or acquired resistance to chemotherapy is a major clinical problem that has evoked the need to develop innovative approaches to predict and ultimately reverse drug resistance. A prolonged G2M arrest has been associated with apoptotic resistance to various microtubule-targeting agents (MTAs). In this study, we describe the functional significance of the mitotic spindle checkpoint proteins, BubR1 and Bub3, in maintaining a mitotic arrest after microtubule disruption by nocodazole and a novel series of MTAs, the pyrrolo-1,5-benzoxazepines (PBOXs), in human cancer cells. Cells expressing high levels of BubR1 and Bub3 (K562, MDA-MB-231, and HeLa) display a prolonged G2M arrest after exposure to MTAs. On the other hand, cells with low endogenous levels of mitotic spindle checkpoint proteins (SK-BR-3 and HL-60) transiently arrest in mitosis and undergo increased apoptosis. The phosphorylation of BubR1 correlated with PBOX-induced G2M arrest in four cell lines tested, indicating an active mitotic spindle checkpoint. Gene silencing of BubR1 by small interfering RNA interference reduced PBOX-induced G2M arrest without enhancing apoptotic efficacy. Further analysis demonstrated that PBOX-treated BubR1-depleted cells were both mononucleated and multinucleated with a polyploid DNA content, suggesting a requirement for BubR1 in cytokinesis. Taken together, these results suggest that BubR1 contributes to the mitotic checkpoint induced by the PBOXs.

Received June 20, 2007; accepted November 8, 2007

Address correspondence to: Dr. Lisa Greene, School of Biochemistry and Immunology, Trinity College, Dublin 2, United Kingdom. E-mail: greeneli{at}tcd.ie






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