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Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy

Oncogene volume 27, pages 4411–4421 (2008)Cite this article

Abstract

Fbw7 is a tumor suppressor that is mutated in numerous cancers. It encodes an E3 ubiquitin ligase, whose ability to decrease the levels of pivotal regulators of cell growth and proliferation underlies its tumor suppressor function. Here, we explore the consequences of Fbw7 inactivation on the outcome of chemotherapeutic treatments. When exposed to spindle toxins such as vinblastine and taxol, Fbw7-deficient cells undergo extensive mitotic slippage and endoreduplication, rendering them polyploid. A combined deregulation of several Fbw7 target proteins is required for this phenotype. Specifically, elevated expression of cyclin E and Aurora A in Fbw7-deficient cells is required for drug-induced polyploidy. However, overexpression of either cyclin E or Aurora A alone is not sufficient for drug-induced polyploidy. In addition, we demonstrate that Fbw7 deficiency limits the ability of p53 to respond to mitotic toxins but not to DNA damage. Furthermore, Fbw7 expression regulates the p53-dependent induction of genes such as Lats2 and p21 in response to vinblastine. Hence, we suggest that Fbw7 serves as a master regulator of the mitotic and tetraploidy checkpoints.

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Acknowledgements

We thank B Vogelstein, K Nakayama, B Clurman and M Madryj for providing us with valuable reagents. This work was supported by grant number 492/05 from the Israeli Science Foundation and grant number 3702 from the Nadia Shaskin Foundation, Public Committee for Allocation of Estate Funds, Ministry of Justice and the Ministry of Health, Israel (to ES) and grant R37 CA40099 from the National Cancer Institute and EC FP6 grant LSHC-CT-2004-503576 (to MO).

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  1. S Finkin and Y Aylon: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Experimental Medicine and Cancer Research, Hebrew University Medical School, Jerusalem, Israel

    S Finkin, S Anzi & E Shaulian

  2. Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel

    Y Aylon & M Oren

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  1. S Finkin
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Correspondence to E Shaulian.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Finkin, S., Aylon, Y., Anzi, S. et al. Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy. Oncogene 27, 4411–4421 (2008). https://doi.org/10.1038/onc.2008.77

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