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Molecular and Cellular Biology, April 2009, p. 1760-1773, Vol. 29, No. 7
0270-7306/09/$08.00+0     doi:10.1128/MCB.01124-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Molecular Dissection of the Centrosome Overduplication Pathway in S-Phase-Arrested Cells {triangledown} ,{dagger}

Suzanna L. Prosser, Kees R. Straatman, and Andrew M. Fry*

Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom

Received 16 July 2008/ Returned for modification 11 September 2008/ Accepted 1 January 2009

Cancer cells frequently exhibit overduplicated centrosomes that lead to formation of multipolar spindles, chromosome missegregation, and aneuploidy. However, the molecular events involved in centrosome overduplication remain largely unknown. Experimentally, centrosome overduplication is observed in p53-deficient cells arrested in S phase with hydroxyurea. Using this assay, we have identified distinct roles for Cdk2, microtubules, dynein, and Hsp90 in the overduplication of functional centrosomes in mammalian cells and show that Cdk2 is also required for the generation of centriolar satellites. Moreover, we demonstrate that nuclear export is required for centriolar satellite formation and centrosome overduplication, with export inhibitors causing a Cdk-dependent accumulation of nuclear centrin granules. Hence, we propose that centrosome precursors may arise in the nucleus, providing a novel mechanistic explanation for how nuclear Cdk2 can promote centrosome overduplication in the cytoplasm. Furthermore, this study defines a molecular pathway that may be targeted to prevent centrosome overduplication in S-phase-arrested cancer cells.

* Corresponding author. Mailing address: Department of Biochemistry, University of Leicester, Leicester LE1 9HN, United Kingdom. Phone: 44 116 229 7069. Fax: 44 116 229 7018. E-mail: amf5{at}le.ac.uk

{triangledown} Published ahead of print on 12 January 2009.

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

Molecular and Cellular Biology, April 2009, p. 1760-1773, Vol. 29, No. 7
0270-7306/09/$08.00+0     doi:10.1128/MCB.01124-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Klein, U. R., Nigg, E. A. (2009). SUMO-dependent regulation of centrin-2. J. Cell Sci. 122: 3312-3321 [Abstract] [Full Text]  


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