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Activated ROCK II by-passes the requirement of the CDK2 activity for centrosome duplication and amplification

Oncogene volume 30, pages 2188–2197 (2011)Cite this article

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Abstract

Initiation of centrosome duplication and DNA replication is coupled, which is primarily achieved by the late G1 phase-specific activation of cyclin-dependent kinase 2 (CDK2)-cyclin E, which triggers both centrosome duplication and DNA replication. Uncoupling of these two events contributes to overduplication of centrosomes, resulting in the presence of more than two centrosomes (centrosome amplification). Centrosome amplification, which is frequently observed in cancers, contributes to tumor development through destabilizing genomes. Nucleophosmin (NPM/B23) is one of the phosphorylation targets of CDK2-cyclin E for the initiation of centrosome duplication. It has been found that NPM/B23 phosphorylated on Thr199 by CDK2-cyclin E acquires a high binding affinity to ROCK II kinase. The Thr199-phosphorylated NPM/B23 physically interacts with and super-activates the centrosomally localized ROCK II, which is a critical event for centrosomes to initiate duplication. Here, we provide direct evidence for the activation of ROCK II as a primary and sufficient downstream event of CDK2-cyclin E for the initiation of centrosome duplication and for the induction of centrosome amplification.

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Acknowledgements

Cyclin E−/− MEFs lacking functional p53 were provided by Dr P Sicinski (Harvard Medical School), and p53−/− MEFs from Dr Donehower (Baylor College of Medicine). We thank M Crow, B Nepon-Sixt and M Rowland for technical assistance, and M Lloyd and J Johnson for technical assistance on microscopic analysis. This research is supported by the grants from the National Institutes of Health (CA90522 and GM87328) to KF and from AIRC2008 to MB.

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  1. Molecular Oncology Program, H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA

    K Hanashiro & K Fukasawa

  2. Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy

    M Brancaccio

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  1. K Hanashiro
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  2. M Brancaccio
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  3. K Fukasawa
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Correspondence to K Fukasawa.

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Hanashiro, K., Brancaccio, M. & Fukasawa, K. Activated ROCK II by-passes the requirement of the CDK2 activity for centrosome duplication and amplification. Oncogene 30, 2188–2197 (2011). https://doi.org/10.1038/onc.2010.607

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