Fbxw8 Is Essential for Cul1-Cul7 Complex Formation and for Placental Development
Fbxw8 Is Essential for Cul1-Cul7 Complex Formation and for Placental Development
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DOI：
10.1128/mcb.00595-06
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发表时间：
2006-08
影响因子：
5.3
通讯作者：
R. Tsunematsu;Masaaki Nishiyama;Shuhei Kotoshiba;T. Saiga;T. Kamura;K. Nakayama
中科院分区：
文献类型：
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作者：
R. Tsunematsu;Masaaki Nishiyama;Shuhei Kotoshiba;T. Saiga;T. Kamura;K. Nakayama
基于Cullin的泛素连接酶（E3）是E3家族中最大的成员之一。Fbxw 8（也称为Fbw 6或Fbx 29）是一种F-box蛋白，与Cul 7组装成SCF样E3复合物。在这里，我们表明，Cul 7形成一个异二聚体复合物与Cul 1的方式依赖于Fbxw 8。我们产生了Fbxw 8缺陷的小鼠，发现Cul 7在这些小鼠的细胞中不与Cul 1结合。三分之二的Fbxw 8 −/−胚胎在子宫内死亡，而剩下的三分之一是活着出生并长大成人。Fbxw 8 −/−胚胎表现出宫内生长迟缓和胎盘发育异常，其特征是海绵滋养层厚度减少和迷路层血管结构异常。虽然Fbxw 8 −/−小鼠的胎盘表型与Cul 7 −/−小鼠相似，但Cul 7 −/−小鼠的其他异常在Fbxw 8 −/−小鼠中并不明显。这些结果表明，Cul 7为基础的SCF样E3复合物具有Fbxw 8依赖和Fbxw 8独立的功能。
ABSTRACT Cullin-based ubiquitin ligases (E3s) constitute one of the largest E3 families. Fbxw8 (also known as Fbw6 or Fbx29) is an F-box protein that is assembled with Cul7 in an SCF-like E3 complex. Here we show that Cul7 forms a heterodimeric complex with Cul1 in a manner dependent on Fbxw8. We generated mice deficient in Fbxw8 and found that Cul7 did not associate with Cul1 in cells of these mice. Two-thirds of Fbxw8−/− embryos die in utero, whereas the remaining one-third are born alive and grow to adulthood. Fbxw8−/− embryos show intrauterine growth retardation and abnormal development of the placenta, characterized by both a reduced thickness of the spongiotrophoblast layer and abnormal vessel structure in the labyrinth layer. Although the placental phenotype of Fbxw8−/− mice resembles that of Cul7−/− mice, other abnormalities of Cul7−/− mice are not apparent in Fbxw8−/− mice. These results suggest that the Cul7-based SCF-like E3 complex has both Fbxw8-dependent and Fbxw8-independent functions.