Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene

Jian Hua Mao, Jesus Perez-Iosada, Di Wu, Reyno DelRosario, Ryosuke Tsunematsu, Kelichi I. Nakayama, Ken Brown, Sheila Bryson, Allan Balmain

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Abstract

The FBXW7/hCDC4 gene encodes a ubiquitin ligase implicated in the control of chromosome stability. Here we identity the mouse Fbxw7 gene as a p53-dependent tumour suppressor gene by using a mammalian genetic screen for p53-dependent genes involved in tumorigenesis. Radiation-induced lymphomas from p53+/- mice, but not those from p53-/- mice, show frequent loss of heterozygosity and a 10% mutation rate of the Fbxw7 gene. Fbxw7 +/- mice have greater susceptibility to radiation-induced tumorigenesis, but most tumours retain and express the wild-type allele, indicating that Fbxw7 is a haploinsufficient tumour suppressor gene. Loss of Fbxw7 alters the spectrum of tumours that develop in p53 deficient mice to include a range of tumours in epithelial tissues such as the lung, liver and ovary. Mouse embryo fibroblasts from Fbxw7-deficient mice, or wild-type mouse cells expressing Fbxw7 smali interfering RNA, have higher levels of Aurora-A kinase, c-Jun and Notch4, but not of cyclin E. We propose that p53-dependent loss of Fbxw7 leads to genetic instability by mechanisms that might involve the activation of Aurora-A, providing a rationale for the early occurrence of these mutations in human cancers.

Original languageEnglish
Pages (from-to)775-779
Number of pages5
JournalNature
Volume432
Issue number7018
DOIs
Publication statusPublished - Dec 9 2004

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Mao, J. H., Perez-Iosada, J., Wu, D., DelRosario, R., Tsunematsu, R., Nakayama, K. I., ... Balmain, A. (2004). Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene. Nature, 432(7018), 775-779. https://doi.org/10.1038/nature03155