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J. Biol. Chem., Vol. 282, Issue 10, 6954-6964, March 9, 2007

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Caffeine Promotes Apoptosis in Mitotic Spindle Checkpoint-arrested Cells^*

From the Cancer Biology Program, Centre for Immunology and Cancer Research, University of Queensland, Brisbane, Queensland 4102, Australia

The spindle assembly checkpoint arrests cells in mitosis when defects in mitotic spindle assembly or partitioning of the replicated genome are detected. This checkpoint blocks exit from mitosis until the defect is rectified or the cell initiates apoptosis. In this study we have used caffeine to identify components of the mechanism that signals apoptosis in mitotic checkpoint-arrested cells. Addition of caffeine to spindle checkpoint-arrested cells induced >40% apoptosis within 5 h. It also caused proteasome-mediated destruction of cyclin B1, a corresponding reduction in cyclin B1/cdk1 activity, and reduction in MPM-2 reactivity. However, cells retained MAD2 staining at the kinetochores, an indication of continued spindle checkpoint function. Blocking proteasome activity did not block apoptosis, but continued spindle checkpoint function was essential for apoptosis. After systematically eliminating all known targets, we have identified p21-activated kinase PAK1, which has an anti-apoptotic function in spindle checkpoint-arrested cells, as a target for caffeine inhibition. Knockdown of PAK1 also increased apoptosis in spindle checkpoint-arrested cells. This study demonstrates that the spindle checkpoint not only regulates mitotic exit but apoptosis in mitosis through the activity of PAK1.

Received for publication, October 30, 2006 , and in revised form, December 19, 2006.

^* This work was supported by grants from National Health and Medical Research Council of Australia and the Queensland Cancer Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement"in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

² Present address: Dept. of Molecular Biology and Pharmacology, Washington University School of Medicine, St. Louis, MO 63110.

³ Senior Research Fellow for Lions Medical Research.

¹ Senior Research Fellow of the National Health and Medical Research Council of Australia. To whom correspondence should be addressed: Centre for Immunology and Cancer Research, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia. Fax: 61-7-3240-5946; E-mail: bgabrielli{at}cicr.uq.edu.au.

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