title: 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.
authors.affiliation: Cancer Research Institute, University of California at San Francisco, 2340 Sutter Street, San Francisco, California 94143, USA.
authors.forename: Jian-Hua
authors.initials: JH
authors.lastname: Mao
authors.forename: Jesus
authors.initials: J
authors.lastname: Perez-Losada
authors.forename: Di
authors.initials: D
authors.lastname: Wu
authors.forename: Reyno
authors.initials: R
authors.lastname: Delrosario
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Tsunematsu
authors.forename: Keiichi I
authors.initials: KI
authors.lastname: Nakayama
authors.forename: Ken
authors.initials: K
authors.lastname: Brown
authors.forename: Sheila
authors.initials: S
authors.lastname: Bryson
authors.forename: Allan
authors.initials: A
authors.lastname: Balmain
mesh_terms: D000818:Animals; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002471:Cell Transformation, Neoplastic / Q000473:pathology / Q000528:radiation effects; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D000073979:F-Box-WD Repeat-Containing Protein 7; D005260:Female; D005347:Fibroblasts; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor / Q000502:physiology*; D019656:Loss of Heterozygosity / Q000235:genetics; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D000073979:F-Box-WD Repeat-Containing Protein 7; C513273:FBXW7 protein, human; C513272:Fbxw7 protein, mouse; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases