Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene.
Nature
; 432(7018): 775-9, 2004 Dec 09.
Article
em En
| MEDLINE
| ID: mdl-15592418
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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Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Genes Supressores de Tumor
/
Proteína Supressora de Tumor p53
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Proteínas de Ciclo Celular
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Ubiquitina-Proteína Ligases
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Proteínas F-Box
Limite:
Animals
Idioma:
En
Revista:
Nature
Ano de publicação:
2004
Tipo de documento:
Article