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IC261, a specific inhibitor of the protein kinases casein kinase 1-delta and -epsilon, triggers the mitotic checkpoint and induces p53-dependent postmitotic effects

Oncogene volume 19, pages 5303–5313 (2000)Cite this article

Abstract

The p53-targeted kinases casein kinase 1δ (CK1δ) and casein kinase 1ε (CK1ε) have been proposed to be involved in regulating DNA repair and chromosomal segregation. Recently, we showed that CK1δ localizes to the spindle apparatus and the centrosomes in cells with mitotic failure caused by DNA-damage prior to mitotic entry. We provide here evidence that 3-[(2,4,6-trimethoxyphenyl)methylidenyl]-indolin-2-one (IC261), a novel inhibitor of CK1δ and CK1ε, triggers the mitotic checkpoint control. At low micromolar concentrations IC261 inhibits cytokinesis causing a transient mitotic arrest. Cells containing active p53 arrest in the postmitotic G1 phase by blockage of entry into the S phase. Cells with non-functional p53 undergo postmitotic replication developing an 8N DNA content. The increase of DNA content is accompanied by a high amount of micronucleated and apoptotic cells. Immunfluorescence images show that at low concentrations IC261 leads to centrosome amplification causing multipolar mitosis. Our data are consistent with a role for CK1δ and CK1ε isoforms in regulating key aspects of cell division, possibly through the regulation of centrosome or spindle function during mitosis.

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Acknowledgements

We are grateful to our colleages Merl Hoekstra and Toni DeMaggio (ICOS Corporation, USA) who have kindly provided the CK1δ/ε specific inhibitor IC261. In addition, we thank Biny Mathew for technical assistance and Sonja Wolff for stimulating discussion. This work is supported by grants from the Deutsche Krebshilfe, Dr. Mildred Scheel Stiftung, to Uwe Knippschild (10-1285-Kn I) and from the Medical Research Council (UK) to David Meek. The Heinrich-Pette-Institut is financially supported by Freie und Hansestadt Hamburg and Bundesministerium für Gesundheit. The work is part of the PhD thesis of Lars Behrend, Fachbereich Biologie at the University of Hamburg.

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  1. L E Campbell

    Present address: Department of Anatomy and Physiology, Wellcome Trust Building, University of Dundee, Dundee, DD1 4HN, UK

Authors and Affiliations

  1. Heinrich-Pette-Institut für Experimentelle Virologie und Immunologie, Martinstrasse 52, Hamburg, D-20251, Germany

    L Behrend, M Stöter, W Deppert & U Knippschild

  2. Biomedical Research Centre, Ninewells Hospital and Medical School, University of Dundee, Dundee, DD1 9SY, UK

    D M Milne, L E Campbell & D W Meek

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Behrend, L., Milne, D., Stöter, M. et al. IC261, a specific inhibitor of the protein kinases casein kinase 1-delta and -epsilon, triggers the mitotic checkpoint and induces p53-dependent postmitotic effects. Oncogene 19, 5303–5313 (2000). https://doi.org/10.1038/sj.onc.1203939

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