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Vol. 18, Issue 10, 4024-4036, October 2007

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Use of the Novel Plk1 Inhibitor ZK-Thiazolidinone to Elucidate Functions of Plk1 in Early and Late Stages of Mitosis

Anna Santamaria^*, Rüdiger Neef^,, Uwe Eberspächer, Knut Eis, Manfred Husemann, Dominik Mumberg, Stefan Prechtl, Volker Schulze, Gerhard Siemeister, Lars Wortmann, Francis A. Barr^,||, and Erich A. Nigg^*

*Department of Cell Biology and Intracellular Protein Transport, Independent Junior Research Group, Max-Planck Institute of Biochemistry, Martinsried, 82152 Germany; and Bayer Schering Pharma AG, Global Drug Discovery, Berlin, 13342 Germany

Submitted June 1, 2007; Revised July 20, 2007; Accepted July 25, 2007
Monitoring Editor: Mark Solomon

Polo-like kinase 1 (Plk1) is a key regulator of mitotic progression and cell division in eukaryotes. It is highly expressed in tumor cells and considered a potential target for cancer therapy. Here, we report the discovery and application of a novel potent small-molecule inhibitor of mammalian Plk1, ZK-Thiazolidinone (TAL). We have extensively characterized TAL in vitro and addressed TAL specificity within cells by studying Plk1 functions in sister chromatid separation, centrosome maturation, and spindle assembly. Moreover, we have used TAL for a detailed analysis of Plk1 in relation to PICH and PRC1, two prominent interaction partners implicated in spindle assembly checkpoint function and cytokinesis, respectively. Specifically, we show that Plk1, when inactivated by TAL, spreads over the arms of chromosomes, resembling the localization of its binding partner PICH, and that both proteins are mutually dependent on each other for correct localization. Finally, we show that Plk1 activity is essential for cleavage furrow formation and ingression, leading to successful cytokinesis.

The online version of this article contains supplemental material at MBC Online (http://www.molbiolcell.org).

Present addresses: Micromet AG, Process Development, Staffelseestrasse 2, 81477 München, Germany;

^|| University of Liverpool Cancer Studies Centre, 200 London Road, Liverpool L3 9TA, United Kingdom.

Address correspondence to: Erich A. Nigg (nigg{at}biochem.mpg.de)

Abbreviations used: GEF, guanine nucleotide exchange factor; K-fiber, kinetochore fiber; -TuRC, -tubulin ring complex; PBD, Polo-box domain; Plk1, Polo-like kinase; Plk1 KD, Plk1 kinase dead; Plk1 WT, Plk1 wild type; SAC, spindle assembly checkpoint; TAL, ZK-Thiazolidinone.

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