1. Cancer Research Institute, University of California at San Francisco, 2340 Sutter Street, San Francisco, California 94143, USA
2. Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan
3. CRC Department of Medical Oncology, University of Glasgow, Garscube Estate, Switchback Road, Glasgow G61 1BD, UK
4. These authors contributed equally to this work

Correspondence to: Allan Balmain¹ Email: abalmain@cc.ucsf.edu

Abstract

The FBXW7/hCDC4 gene encodes a ubiquitin ligase implicated in the control of chromosome stability¹. Here we identify 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 small 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.

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