The FBXW7/hCDC4 gene encodes a ubiquitin ligase implicated in the control of chromosome stability1. 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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Rajagopalan, H. et al. Inactivation of hCDC4 can cause chromosomal instability. Nature 428, 77–81 (2004)
Donehower, L. A. et al. Mice deficient for p53 are developmentally normal but susceptible to spontaneous tumours. Nature 356, 215–221 (1992)
Kemp, C. J., Wheldon, T. & Balmain, A. p53-deficient mice are extremely susceptible to radiation-induced tumorigenesis. Nature Genet. 8, 66–69 (1994)
Grigorian, M. et al. Tumour suppressor p53 protein is a new target for the metastasis-associated Mts1/S100A4 protein: functional consequences of their interaction. J. Biol. Chem. 276, 22699–22708 (2001)
Browes, C., Rowe, J., Brown, A. & Montano, X. Analysis of trk A and p53 association. FEBS Lett. 497, 20–25 (2001)
Strohmaier, H. et al. Human F-box protein hCdc4 targets cyclin E for proteolysis and is mutated in a breast cancer cell line. Nature 413, 316–322 (2001)
Moberg, K. H., Bell, D. W., Wahrer, D. C., Haber, D. A. & Hariharan, I. K. Archipelago regulates cyclin E levels in Drosophila and is mutated in human cancer cell lines. Nature 413, 311–316 (2001)
Spruck, C. H. et al. hCDC4 gene mutations in endometrial cancer. Cancer Res. 62, 4535–4539 (2002)
Calhoun, E. S. et al. BRAF and FBXW7 (CDC4, FBW7, AGO, SEL10) mutations in distinct subsets of pancreatic cancer: potential therapeutic targets. Am. J. Pathol. 163, 1255–1260 (2003)
Koepp, D. M. et al. Phosphorylation-dependent ubiquitination of cyclin E by the SCFFbw7 ubiquitin ligase. Science 294, 173–177 (2001)
Wu, G. et al. SEL-10 is an inhibitor of notch signaling that targets notch for ubiquitin-mediated protein degradation. Mol. Cell. Biol. 21, 7403–7415 (2001)
Oberg, C. et al. The Notch intracellular domain is ubiquitinated and negatively regulated by the mammalian Sel-10 homolog. J. Biol. Chem. 276, 35847–35853 (2001)
Gupta-Rossi, N. et al. Functional interaction between SEL-10, an F-box protein, and the nuclear form of activated Notch1 receptor. J. Biol. Chem. 276, 34371–34378 (2001)
Hoh, J. et al. The p53MH algorithm and its application in detecting p53-responsive genes. Proc. Natl Acad. Sci. USA 99, 8467–8472 (2002)
Kimura, T., Gotoh, M., Nakamura, Y. & Arakawa, H. hCDC4b, a regulator of cyclin E, as a direct transcriptional target of p53. Cancer Sci. 94, 431–436 (2003)
Tsunematsu, R. et al. Mouse Fbw7/Sel-10/Cdc4 is required for notch degradation during vascular development. J. Biol. Chem. 279, 9417–9423 (2004)
Tetzlaff, M. T. et al. Defective cardiovascular development and elevated cyclin E and Notch proteins in mice lacking the Fbw7 F-box protein. Proc. Natl Acad. Sci. USA 101, 3338–3345 (2004)
Ye, Q., Shieh, J. H., Morrone, G. & Moore, M. A. Expression of constitutively active Notch4 (Int-3) modulates myeloid proliferation and differentiation and promotes expansion of hematopoietic progenitors. Leukemia 18, 777–787 (2004)
Zhou, H. et al. Tumour amplified kinase STK15/BTAK induces centrosome amplification, aneuploidy and transformation. Nature Genet. 20, 189–193 (1998)
Miyoshi, Y., Iwao, K., Egawa, C. & Noguchi, S. Association of centrosomal kinase STK15/BTAK mRNA expression with chromosomal instability in human breast cancers. Int. J. Cancer 92, 370–373 (2001)
Meraldi, P., Honda, R. & Nigg, E. A. Aurora-A overexpression reveals tetraploidization as a major route to centrosome amplification in p53 - / - cells. EMBO J. 21, 483–492 (2002)
Nateri, A. S., Riera-Sans, L., Da Costa, C. & Behrens, A. The ubiquitin ligase SCFFbw7 antagonizes apoptotic JNK signaling. Science 303, 1374–1378 (2004)
Fero, M. L., Randel, E., Gurley, K. E., Roberts, J. M. & Kemp, C. J. The murine gene p27Kip1 is haplo-insufficient for tumour suppression. Nature 396, 177–180 (1998)
Tang, B. et al. Transforming growth factor-β1 is a new form of tumour suppressor with true haploid insufficiency. Nature Med. 4, 802–807 (1998)
Artandi, S. E. et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers in mice. Nature 406, 641–645 (2000)
Liu, G. et al. High metastatic potential in mice inheriting a targeted p53 missense mutation. Proc. Natl Acad. Sci. USA 97, 4174–4179 (2000)
Hanks, S. et al. Constitutional aneuploidy and cancer predisposition caused by biallelic mutations in BUB1B. Nature Genet. 36, 1159–1161 (2004)
Frenkel, J. et al. Accentuated apoptosis in normally developing p53 knockout mouse embryos following genotoxic stress. Oncogene 18, 2901–2907 (1999)
Linardopoulos, S. et al. Deletion and altered regulation of p16INK4a and p15INK4b in undifferentiated mouse skin tumors. Cancer Res. 55, 5168–5172 (1995)
Brummelkamp, T. R., Bernards, R. & Agami, R. A system for stable expression of short interfering RNAs in mammalian cells. Science 296, 550–553 (2002)
We thank the staff of the CRUK Beatson Institute and UCSF Comprehensive Cancer Center animal house for animal husbandry; L. Heath (Laboratory Animal Resource Center, UCSF) for analysing the histological slides from tumors; and J. Hoh (Laboratories of Statistical Genetics and Cancer Biology of The Rockefeller University, New York, USA) for providing the p53MH algorithm program. The UCSF Cancer Center Genome Core was essential for the sequencing and study design of the Taqman assay. These studies were initially supported by the Commission of the European Communities and the Cancer Research Campaign (UK), and subsequently by an NCI grant and a DOE grant to A.B. J.H.M. is the recipient of a Leukemia & Lymphoma Society Fellowship. J.P.L. has a Fellowship from the ‘Ministerio de Educacion y Ciencia’ of Spain. A.B. is the recipient of the Barbara Bass Bakar Chair in Cancer Genetics.
The authors declare that they have no competing financial interests.
Contains Supplementary Methods and legends for Supplementary Figures S1–S5. (DOC 32 kb)
LOH detected by microsatellite analysis, distribution of microsatellite markers used to detect LOH by PCR. (PDF 6 kb)
LOH detected by microsatellite analysis, representative LOH pattern (PDF 77 kb)
Identification of mutations in Fbxw7 in lymphomas from p53+/- mice. (PDF 8 kb)
FACS analysis of aneuploidy in MEFs expressing Fbxw7 RNAi (PDF 82 kb)
Expression of p53 detected by Western blotting in MEFs with or without Fbxw7 RNAi. (PDF 23 kb)
Proposed scheme for the sequence of events in radiation induced lymphoma in p53 deficient mice (PDF 6 kb)
Putative p53 DNA-responsive elements within 10 Kb promoter region of mouse Fbxwα, β and γ. (PDF 7 kb)
Supplementary Table 2: list of D3MA markers. Supplementary Table 3: primer for DNA sequencing Fbxw7 . Supplementary Table 4: primer for RT-PCR and sequencing Fbxw7. (PDF 86 kb)
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Mao, JH., Perez-losada, J., Wu, D. et al. Fbxw7/Cdc4 is a p53-dependent, haploinsufficient tumour suppressor gene. Nature 432, 775–779 (2004). https://doi.org/10.1038/nature03155
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