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Roles of cyclins A and E in induction of centrosome amplification in p53-compromised cells

Oncogene volume 27, pages 5288–5302 (2008)Cite this article

Abstract

Abnormal amplification of centrosomes, which occurs frequently in cancers, leads to high frequencies of mitotic defect and chromosome segregation error, profoundly affecting the rate of tumor progression. Centrosome amplification results primarily from overduplication of centrosomes, and p53 is involved in the regulation of centrosome duplication partly through controlling the activity of cyclin-dependent kinase (CDK) 2-cyclin E, a kinase complex critical for the initiation of centrosome duplication. Thus, loss or mutational inactivation of p53 leads to an increased frequency of centrosome amplification. Moreover, the status of cyclin E greatly influences the frequency of centrosome amplification in cells lacking functional p53. Here, we dissected the roles of CDK2-associating cyclins, namely cyclins E and A, in centrosome amplification in the p53-negative cells. We found that loss of cyclin E was readily compensated by cyclin A for triggering the initiation of centrosome duplication, and thus the centrosome duplication kinetics was not significantly altered in cyclin E-deficient cells. It has been shown that cells lacking functional p53, when arrested in either early S-phase or late G2 phase, continue to reduplicate centrosomes, resulting in centrosome amplification. In cells arrested in early S phase, cyclin E, but not cyclin A, is important in centrosome amplification, whereas in the absence of cyclin E, cyclin A is important for centrosome amplification. In late G2-arrested cells, cyclin A is important in centrosome amplification irrespective of the cyclin E status. These findings advance our understandings of the mechanisms underlying the numeral abnormality of centrosomes and consequential genomic instability associated with loss of p53 function and aberrant expression of cyclins E and A in cancer cells.

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Acknowledgements

We thank C French, A Wilson and M Crowe for technical assistance, and Drs Z Andrysik and S Schwemberger for FACS analysis. This research is supported by the grants from National Institutes of Health, USA (CA90522 to KF and CA108950 to PS).

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Authors and Affiliations

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

    K Hanashiro, M Kanai & K Fukasawa

  2. Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA, USA

    Y Geng & P Sicinski

  3. Department of Pathology, Harvard Medical School, Boston, MA, USA

    Y Geng & P Sicinski

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  1. K Hanashiro
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  2. M Kanai
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  3. Y Geng
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  4. P Sicinski
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  5. K Fukasawa
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Correspondence to K Fukasawa.

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Hanashiro, K., Kanai, M., Geng, Y. et al. Roles of cyclins A and E in induction of centrosome amplification in p53-compromised cells. Oncogene 27, 5288–5302 (2008). https://doi.org/10.1038/onc.2008.161

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