Fbw7 regulates the activity of endoreduplication mediators and the p53 pathway to prevent drug-induced polyploidy.
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.
Finkin
S
S
Department of Experimental Medicine and Cancer Research, Hebrew University Medical School, Jerusalem, Israel.
Aylon
Y
Y
Anzi
S
S
Oren
M
M
Shaulian
E
E
D064127:Aurora Kinases; D018797:Cell Cycle Proteins / Q000502:physiology*; D019927:Cyclin E / Q000502:physiology; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000502:physiology; D004261:DNA Replication; D044783:F-Box Proteins / Q000502:physiology*; D000073979:F-Box-WD Repeat-Containing Protein 7; D045325:HCT116 Cells; D006801:Humans; D008938:Mitosis / Q000187:drug effects; D011123:Polyploidy; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*; D014747:Vinblastine / Q000494:pharmacology
C493956:CDKN1A protein, human; D018797:Cell Cycle Proteins; D019927:Cyclin E; D050759:Cyclin-Dependent Kinase Inhibitor p21; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D014747:Vinblastine; D044767:Ubiquitin-Protein Ligases; C406449:LATS2 protein, human; D064127:Aurora Kinases; D017346:Protein Serine-Threonine Kinases