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Synergistic induction of centrosome hyperamplification by loss of p53 and cyclin E overexpression

Oncogene volume 19, pages 1635–1646 (2000)Cite this article

Abstract

Centrosome hyperamplification and the consequential mitotic defects contribute to chromosome instability in cancers. Loss or mutational inactivation of p53 has been shown to induce chromosome instability through centrosome hyperamplification. It has recently been found that Cdk2-cyclin E is involved in the initiation of centrosome duplication, and that constitutive activation of Cdk2-cyclin E results in the uncoupling of the centrosome duplication cycle and the DNA replication cycle. Cyclin E overexpression and p53 mutations occur frequently in tumors. Here, we show that cyclin E overexpression and loss of p53 synergistically increase the frequency of centrosome hyperamplification in cultured cells as well as in tumors developed in p53-null, heterozygous, and wild-type mice. Through examination of cells derived from Waf1-null mice, we further found that Waf1, a potent inhibitor of Cdk2-cyclin E and a major target of p53's transactivation function, is involved in coordinating the initiation of centrosome duplication and DNA replication, suggesting that Waf1 may act as a molecular link between p53 and Cdk2-cyclin E in the control of the centrosome duplication cycle.

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Acknowledgements

We thank Dr Philip Leder for Waf1−/− and Waf1+/+ MEFs, Dr Fred Mushinski for the mouse Waf1 cDNA, and Dr George Babcock and Mr Jim Cornelius for flow cytometric analysis. We also thank T Kim, T Hagerty and A Dierkers for technical assistance. We also thank Mr S Tyner for organizing and preparing the tumor samples. This work was supported in part by grants from American Cancer Society, and Cancer Research Challenge and Ruth Lyons Fund.

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Author notes

  1. Jeffrey G Mussman and Henning F Horn: JG Mussman and HF Horn contributed equally to this study

Authors and Affiliations

  1. Department of Cell Biology, University of Cincinnati College of Medicine, P.O. Box 670521, Cincinnati, 45267-0521, Ohio, OH, USA

    Jeffrey G Mussman, Henning F Horn, Patrick E Carroll, Masaru Okuda, Pheruza Tarapore & Kenji Fukasawa

  2. Division of Molecular Virology, Baylor College of Medicine, One Baylor Plaza, Houston, 77030-3498, Texas, TX, USA

    Lawrence A Donehower

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  1. Jeffrey G Mussman
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Mussman, J., Horn, H., Carroll, P. et al. Synergistic induction of centrosome hyperamplification by loss of p53 and cyclin E overexpression. Oncogene 19, 1635–1646 (2000). https://doi.org/10.1038/sj.onc.1203460

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