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Molecular and Cellular Biology, May 2006, p. 3853-3863, Vol. 26, No. 10
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.10.3853-3863.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

RNA Interference-Mediated Silencing of Mitotic Kinesin KIF14 Disrupts Cell Cycle Progression and Induces Cytokinesis Failure{dagger}

Michael Carleton,1,{ddagger}* Mao Mao,1,{ddagger} Matthew Biery,1 Paul Warrener,1 Sammy Kim,1 Carolyn Buser,2 C. Gary Marshall,2,§ Christine Fernandes,2,¶ James Annis,1 and Peter S. Linsley1

Rosetta Inpharmatics LLC, 401 Terry Ave. N, Seattle, Washington 98109,1 Merck Research Laboratories, West Point, Pennsylvania 194862

Received 6 December 2005/ Returned for modification 23 December 2005/ Accepted 12 February 2006

KIF14 is a microtubule motor protein whose elevated expression is associated with poor-prognosis breast cancer. Here we demonstrate KIF14 accumulation in mitotic cells, where it associated with developing spindle poles and spindle microtubules. Cells at later stages of mitosis were characterized by the concentration of KIF14 at the midbody. Time-lapse microscopy revealed that strong RNA interference (RNAi)-mediated silencing of KIF14 induced cytokinesis failure, causing several rounds of endoreduplication and resulting in multinucleated cells. Additionally, less efficacious KIF14-specific short interfering RNAs (siRNAs) induced multiple phenotypes, all of which resulted in acute apoptosis. Our data demonstrate the ability of siRNA-mediated silencing to generate epiallelic hypomorphs associated with KIF14 depletion. Furthermore, the link we observed between siRNA efficacy and phenotypic outcome indicates that distinct stages during cell cycle progression are disrupted by the differential modulation of KIF14 expression.

* Corresponding author. Mailing address: Rosetta Inpharmatics, 401 Terry Ave., N. Seattle, WA 98109. Phone: (206) 802-6380. Fax: (206) 802-6388. E-mail: michael_carleton{at}merck.com.

{dagger} Supplemental material for this article may be found at http://mcb.asm.org/.

{ddagger} These authors contributed equally to this work.

§ Present address: Merck Research Laboratories, Boston, MA 02115.

Present address: GlaxoSmithKline Pharmaceuticals, Collegeville, PA 19426.

Molecular and Cellular Biology, May 2006, p. 3853-3863, Vol. 26, No. 10
0270-7306/06/$08.00+0     doi:10.1128/MCB.26.10.3853-3863.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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