2004
DOI: 10.1038/nature03155
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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 tumo… Show more

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Cited by 352 publications
(423 citation statements)
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“…Fbw7 regulates p53-dependent induction of Lats2 and p21 cip1 and elevated levels of Lats2 can inhibit drug-induced polyploidization Together with a study describing the emergence of Fbw7 mutations during tumorigenesis in p53 þ /À but not p53 À/À mice (Mao et al, 2004), our results suggest a molecular cross talk between Fbw7 and p53. Previous studies have placed Fbw7 downstream of p53 (Kimura et al, 2003).…”
Section: Fbw7 Activity Prevents Drug-induced Polyploidy S Finkin Et Alsupporting
confidence: 70%
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“…Fbw7 regulates p53-dependent induction of Lats2 and p21 cip1 and elevated levels of Lats2 can inhibit drug-induced polyploidization Together with a study describing the emergence of Fbw7 mutations during tumorigenesis in p53 þ /À but not p53 À/À mice (Mao et al, 2004), our results suggest a molecular cross talk between Fbw7 and p53. Previous studies have placed Fbw7 downstream of p53 (Kimura et al, 2003).…”
Section: Fbw7 Activity Prevents Drug-induced Polyploidy S Finkin Et Alsupporting
confidence: 70%
“…Lesions in the Fbw7 gene have been observed in a large list of cancers (Moberg et al, 2001;Strohmaier et al, 2001;Spruck et al, 2002;Cassia et al, 2003;Ekholm-Reed et al, 2004;Rajagopalan et al, 2004;Kwak et al, 2005). Its classification as a tumor suppressor is further underscored by experimental evidence demonstrating that the development of radiation-induced tumors in mice heterozygous for Fbw7 is greater than that in mice expressing two normal alleles (Mao et al, 2004). Moreover, tumors derived from irradiated p53-heterozygous mice acquire mutations in the Fbw7 gene whereas tumors derived from p53 null mice do not (Mao et al, 2004), suggesting a p53-dependent selective pressure for Fbw7 inactivation.…”
Section: Introductionmentioning
confidence: 99%
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“…However, genes whose protein products appear, at least in some tumour types, to contribute to the neoplastic phenotype continue to be identified. While it is the case that mutations are crucial to the role of many oncogenes and tumour suppressor genes in neoplasia, it is becoming increasingly apparent that the neoplastic phenotype can be a consequence of alterations in gene expression, with haploinsufficiency being an increasingly common theme (Mao et al, 2004), coupled with environmental factors, often having a multifaceted spatial (Orimo et al, 2005) and temporal interplay (Cook et al, 2005). Furthermore, the surprising revelation of how relatively few genes we have in the human genome and the extent of alternate splicing that exists, highlights the possibility that the range of genes whose products will have a role in neoplasia will continue to grow as we develop a more detailed understanding of the molecular events that regulate cells.…”
Section: Resultsmentioning
confidence: 99%
“…Multiple regulators of Aurora-A kinase stability have been described recently (Mao et al, 2004;Yu et al, 2005). Most of them target Aurora-A through Ubdependent and proteasome-dependent degradation pathway.…”
Section: Discussionmentioning
confidence: 99%