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Inhibitors of Polo-like kinase reveal roles in spindle-pole maintenance

McInnes, Campbell; Mazumdar, Aveek; Mezna, Mokdad; Meades, Christopher; Midgley, Carol; Scaerou, Fred; Carpenter, Lee; Mackenzie, Mairi; Taylor, Paul; Walkinshaw, Malcolm; Fischer, Peter M. and Glover, David (2006). Inhibitors of Polo-like kinase reveal roles in spindle-pole maintenance. Nature Chemical Biology, 2(11) pp. 608–617.

URL: http://www.nature.com/nchembio/journal/v2/n11/full...
DOI (Digital Object Identifier) Link: http://dx.doi.org/10.1038/nchembio825
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Abstract

Polo-like kinases (Plks) have several functions in mitotic progression and are upregulated in many tumor types. Small-molecule Plk inhibitors would be valuable as tools for studying Plk biology and for developing antitumor agents. Guided by homology modeling of the Plk1 kinase domain, we have discovered a chemical series that shows potent and selective Plk1 inhibition. The effects of one such optimized benzthiazole N-oxide, cyclapolin 1 (1), on purified centrosomes indicate that Plks are required to generate MPM2 epitopes, recruit gamma-tubulin and enable nucleation of microtubules. The compound can also promote loss of centrosome integrity and microtubule nucleating ability apparently through increased accessibility of protein phosphatases. We show that treatment of living S2 cells with cyclapolin 1 leads to collapsed spindles, in contrast to the metaphase-arrested bipolar spindles observed after RNAi. This different response to protein depletion and protein inhibition may have significance in the development of antitumor agents.

Item Type: Journal Article
Copyright Holders: 2006 Nature Publishing Group
ISSN: 1552-4450
Keywords: anaphase-promoting complex; early mitotic inhibitor-1; kinesin-like protein; checkpoint proteins; cytostatic factor; metaphase arrest; m-phase; drosophila; phosphorylation; plk1; polo-like kinase
Academic Unit/Department: Science > Life, Health and Chemical Sciences
Interdisciplinary Research Centre: Biomedical Research Network (BRN)
Item ID: 29606
Depositing User: Carol Midgley
Date Deposited: 27 Sep 2011 10:17
Last Modified: 07 Mar 2014 13:30
URI: http://oro.open.ac.uk/id/eprint/29606
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