@article {146, title = {Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene.}, journal = {Nature}, volume = {432}, year = {2004}, month = {2004 Dec 9}, pages = {775-9}, 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.

}, keywords = {Animals, Base Sequence, Cell Cycle Proteins, Cell Transformation, Neoplastic, F-Box Proteins, Female, Fibroblasts, Gene Deletion, Genes, Tumor Suppressor, Loss of Heterozygosity, Male, Mice, Mice, Knockout, Mutation, Neoplasms, RNA, Messenger, RNA, Small Interfering, Survival Rate, Tumor Suppressor Protein p53, Ubiquitin-Protein Ligases}, issn = {1476-4687}, doi = {10.1038/nature03155}, author = {Jiang-Hua Mao and Perez-Losada, Jesus and Wu, Di and DelRosario, Reyno and Tsunematsu, Ryosuke and Nakayama, Keiichi I and Brown, Ken and Bryson, Sheila and Balmain, Allan} }