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FBXW7 is the substrate recognition component of a SCF-type E3 ubiquitin ligase. It has multiple targets such as Notch1, c-Jun, and cyclin E that function in critical developmental and signalling pathways. Mutations in FBXW7 are often found in many types of cancer. In most cases, these mutations do not inactivate the protein, but are mono-allelic missense changes at specific arginine resides involved in substrate binding. We have hypothesized that FBXW7 mutations are selected in cancers for reasons other than haploinsufficiency or full loss-of-function. Given that the existing mutant Fbxw7 mice carry null alleles, we created a mouse model carrying one of the commonly occurring point mutations (Fbxw7(R482Q)) in the WD40 substrate recognition domain of Fbxw7. Mice heterozygous for this mutation apparently developed normally in utero, died perinatally due to a defect in lung development, and in some cases showed cleft palate and eyelid fusion defects. By comparison, Fbxw7(+/-) mice were viable and developed normally. Fbxw7(-/-) animals died of vascular abnormalities at E10.5. We screened known FBXW7 targets for changes in the lungs of the Fbxw7(R482Q/+) mice and found Tgif1 and Klf5 to be up-regulated. Fbxw7(R482Q) alleles are not functionally equivalent to heterozygous or homozygous null alleles, and we propose that they are selected in tumourigenesis because they cause a selective or partial loss of FBXW7 function.

Original publication

DOI

10.1002/path.2874

Type

Journal article

Journal

J Pathol

Publication Date

06/2011

Volume

224

Pages

180 - 189

Keywords

Abnormalities, Multiple, Alleles, Amino Acid Sequence, Animals, Arginine, Cell Cycle Proteins, Disease Models, Animal, F-Box Proteins, F-Box-WD Repeat-Containing Protein 7, Humans, Lung, Mice, Molecular Sequence Data, Neoplasm Proteins, Neoplasms, Point Mutation, Pulmonary Alveoli, Sequence Alignment, Transforming Growth Factor beta, Ubiquitin-Protein Ligases