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

S. Finkin, Y. Aylon, S. Anzi, M. Oren, E. Shaulian*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

41 Scopus citations

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.

Original languageAmerican English
Pages (from-to)4411-4421
Number of pages11
JournalOncogene
Volume27
Issue number32
DOIs
StatePublished - 24 Jul 2008

Bibliographical note

Funding Information:
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).

Keywords

  • Fbw7
  • Polyploidy
  • Spindle inhibitors
  • p53

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