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

Jeffrey G. Mussman, Henning F. Horn, Patrick E. Carroll, Masaru Okuda, Pheruza Tarapore, Lawrence A. Donehower, Kenji Fukasawa

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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.

Original languageEnglish
Pages (from-to)1635-1646
Number of pages12
Issue number13
Publication statusPublished - 23 Mar 2000
Externally publishedYes



  • Cancer
  • Cdk2
  • Centrosome hyperamplification
  • Cyclin E
  • P53

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Mussman, J. G., Horn, H. F., Carroll, P. E., Okuda, M., Tarapore, P., Donehower, L. A., & Fukasawa, K. (2000). Synergistic induction of centrosome hyperamplification by loss of p53 and cyclin E overexpression. Oncogene, 19(13), 1635-1646.