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J. Biol. Chem., Vol. 281, Issue 15, 9987-9995, April 14, 2006

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Inhibition of S/G₂ Phase CDK4 Reduces Mitotic Fidelity^*

Andrew Burgess¹, Matthew Wigan, Nichole Giles, Wanda DePinto, Paul Gillespie^¶, Frankie Stevens, and Brian Gabrielli²

From the Cancer Biology Program, Centre for Immunology and Cancer Research, University of Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia and Discovery Oncology and ^¶Discovery Chemistry, Hoffmann-La Roche Inc., Nutley, New Jersey 07110

Cyclin-dependent kinase 4 (CDK4)/cyclin D has a key role in regulating progression through late G₁ into S phase of the cell cycle. CDK4-cyclin D complexes then persist through the latter phases of the cell cycle, although little is known about their potential roles. We have developed small molecule inhibitors that are highly selective for CDK4 and have used these to define a role for CDK4-cyclin D in G₂ phase. The addition of the CDK4 inhibitor or small interfering RNA knockdown of cyclin D3, the cyclin D partner, delayed progression through G₂ phase and mitosis. The G₂ phase delay was independent of ATM/ATR and p38 MAPK but associated with elevated Wee1. The mitotic delay was because of failure of chromosomes to migrate to the metaphase plate. However, cells eventually exited mitosis, with a resultant increase in cells with multiple or micronuclei. Inhibiting CDK4 delayed the expression of the chromosomal passenger proteins survivin and borealin, although this was unlikely to account for the mitotic phenotype. These data provide evidence for a novel function for CDK4-cyclin D3 activity in S and G₂ phase that is critical for G₂/M progression and the fidelity of mitosis.

Received for publication, November 29, 2005 , and in revised form, January 17, 2006.

^* This work was supported in part by grants from the Queensland Cancer Fund and the National Health and Medical Research Council of Australia. 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 Table 1.

¹ Current address: CNRS-CRBM, Montpellier 34293, France.

² An National Health and Medical Research Council Senior Research Fellow. To whom correspondence should be addressed. Fax: 61-7-3240-5946; E-mail: bgabrielli{at}cicr.uq.edu.au.

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