Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene
Abstract
The FBXW7/hCDC4 gene encodes a ubiquitin ligase implicated in the control of chromosome stability. 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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FBXW7 β-isoform is induced by p53.
“FBXW7 ubiquitin ligase is a component of the SCF complex and mediates degradation of several cell cycle proteins,158 and its β-isoform is induced by p53.159”
From Census and evaluation of p53 target genes (2017) · cites this paper as [159]
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- Authors
- Mao, J.-H., Perez-losada, J., Wu, D., DelRosario, R., Tsunematsu, R., Nakayama, K. I., Brown, K., Bryson, S., & Balmain, A.
- Affiliations
- University of California, San Francisco (US)
- Kyushu University (JP)
- University of Glasgow (GB)
- Corresponding author
- Balmain, Allan
- Venue
- Nature
- Published
- 2004-12
- Volume
- 432
- Issue
- 7018
- Pages
- 775-779
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- OpenAlex
- W2084910801
- Cited by
- 390
- References
- 30
- Citations by year
- 2026: 1 · 2025: 10 · 2024: 9 · 2023: 19 · 2022: 19 · 2021: 29 · 2020: 19 · 2019: 14 · 2018: 14 · 2017: 12 · 2016: 22 · 2015: 30 · 2014: 18 · 2013: 22 · 2012: 19
- FWCI
- 8.80
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- Funders
- U.S. Department of Energy
- Cancer Research UK
- University of California, San Francisco
- Beatson Institute for Cancer Research
- National Cancer Institute
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- FBXW7, Cdc4, haploinsufficiency, ubiquitin ligase, chromosome stability, genomic instability, radiation-induced lymphoma, loss of heterozygosity, AURKA, Notch4, c-Jun, carcinogenesis, mouse embryonic fibroblasts
- MeSH terms
- F-Box-WD Repeat-Containing Protein 7, Animals, Base Sequence, Cell Transformation, Neoplastic, Female, Fibroblasts, Male, Mutation, Neoplasms, RNA, Messenger, Survival Rate, Genes, Tumor Suppressor, Tumor Suppressor Protein p53, Gene Deletion, Mice, Knockout, Cell Cycle Proteins, Loss of Heterozygosity, RNA, Small Interfering, Ubiquitin-Protein Ligases, F-Box Proteins, Mice
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