| First Author | Ikenoue T | Year | 2018 |
| Journal | Sci Rep | Volume | 8 |
| Issue | 1 | Pages | 2021 |
| PubMed ID | 29386660 | Mgi Jnum | J:258194 |
| Mgi Id | MGI:6144352 | Doi | 10.1038/s41598-018-19769-1 |
| Citation | Ikenoue T, et al. (2018) Establishment and analysis of a novel mouse line carrying a conditional knockin allele of a cancer-specific FBXW7 mutation. Sci Rep 8(1):2021 |
| abstractText | F-box and WD40 domain protein 7 (FBXW7) is a component of the SKP1-CUL1-F-box protein (SCF) complex that mediates the ubiquitination of diverse oncogenic target proteins. The exploration of FBXW7 mutations in human primary cancer has revealed three mutation hotspots at conserved arginine residues (Arg(465), Arg(479), and Arg(505)) in the WD40 domain, which are critical for substrate recognition. To study the function of human FBXW7 (R465C) , the most frequent mutation in human malignancies, we generated a novel conditional knockin mouse line of murine Fbxw7 (R468C) corresponding to human FBXW7 (R465C) . Systemic heterozygous knockin of the Fbxw7 (R468C) mutation resulted in perinatal lethality due to defects in lung development, and occasionally caused an eyes-open at birth phenotype and cleft palate. Furthermore, mice carrying liver-specific heterozygous and homozygous Fbxw7 (R468C) alleles cooperated with an oncogenic Kras mutation to exhibit bile duct hyperplasia within 8 months of birth and cholangiocarcinoma-like lesions within 8 weeks of birth, respectively. In addition, the substrates affected by the mutant Fbxw7 differed between the embryos, embryonic fibroblasts, and adult liver. This novel conditional knockin Fbxw7 (R468C) line should be useful to gain a more profound understanding of carcinogenesis associated with mutation of FBXW7. |
