Establishment and analysis of a novel mouse line carrying a conditional knockin allele of a cancer-specific FBXW7 mutation.
Establishment and analysis of a novel mouse line carrying a conditional knockin allele of a cancer-specific FBXW7 mutation.
复制标题
DOI：
10.1038/s41598-018-19769-1
复制
发表时间：
2018-01-31
影响因子：
4.6
通讯作者：
Furukawa Y
中科院分区：
文献类型：
--
作者：
Ikenoue T;Terakado Y;Zhu C;Liu X;Ohsugi T;Matsubara D;Fujii T;Kakuta S;Kubo S;Shibata T;Yamaguchi K;Iwakura Y;Furukawa Y
F-box和WD 40结构域蛋白7（FBXW 7）是SKP 1-CUL 1-F-box蛋白（SCF）复合物的组分，其介导多种致癌靶蛋白的泛素化。FBXW 7突变在人类原发性癌症中的探索揭示了WD 40结构域中保守精氨酸残基（Arg 465，Arg 479和Arg 505）的三个突变热点，这对底物识别至关重要。为了研究人FBXW 7 R465 C（人恶性肿瘤中最常见的突变）的功能，我们产生了对应于人FBXW 7 R465 C的鼠FBXW 7 R468 C的新的条件性敲入小鼠系。Fbxw 7 R468 C突变的系统性杂合敲入导致由于肺发育缺陷导致的围产期死亡，偶尔引起出生时睁眼表型和腭裂。此外，携带肝脏特异性杂合和纯合Fbxw 7 R468 C等位基因的小鼠与致癌Kras突变合作，分别在出生后8个月内表现出胆管增生，在出生后8周内表现出胆管癌样病变。此外，受突变体Fbxw 7影响的底物在胚胎、胚胎成纤维细胞和成人肝脏之间存在差异。这一新的条件性敲入Fbxw 7 R468 C系将有助于更深入地了解FBXW 7突变相关的致癌作用。
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 (Arg465, Arg479, and Arg505) in the WD40 domain, which are critical for substrate recognition. To study the function of human FBXW7R465C, the most frequent mutation in human malignancies, we generated a novel conditional knockin mouse line of murine Fbxw7R468C corresponding to human FBXW7R465C. Systemic heterozygous knockin of the Fbxw7R468C 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 Fbxw7R468C 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 Fbxw7R468C line should be useful to gain a more profound understanding of carcinogenesis associated with mutation of FBXW7.
登录
查看更多内容
影响因子：
64.8
作者：
Inuzuka, Hiroyuki;Shaik, Shavali;Onoyama, Ichiro;Gao, Daming;Tseng, Alan;Maser, Richard S.;Zhai, Bo;Wan, Lixin;Gutierrez, Alejandro;Lau, Alan W.;Xiao, Yonghong;Christie, Amanda L.;Aster, Jon;Settleman, Jeffrey;Gygi, Steven P.;Kung, Andrew L.;Look, Thomas;Nakayama, Keiichi I.;DePinho, Ronald A.;Wei, Wenyi
通讯作者：
Wei, Wenyi
影响因子：
64.8
作者：
Strohmaier, H;Spruck, CH;Reed, SI
通讯作者：
Reed, SI
DOI：
10.1073/pnas.0307875101
发表时间：
2004-03-09
影响因子：
11.1
作者：
Tetzlaff, MT;Yu, W;Elledge, SJ
通讯作者：
Elledge, SJ
影响因子：
5.3
作者：
Wu, GY;Lyapina, S;Kitajewski, J
通讯作者：
Kitajewski, J
影响因子：
56.9
作者：
Nateri, AS;Riera-Sans, L;Behrens, A
通讯作者：
Behrens, A