Deletion of the CuI1 gene in mice causes arrest in early embryogenesis and accumulation of cyclin E
Deletion of the CuI1 gene in mice causes arrest in early embryogenesis and accumulation of cyclin E
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DOI：
10.1016/s0960-9822(00)80024-x
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发表时间：
1999-10-21
期刊：
影响因子：
9.2
通讯作者：
Tyers, M
中科院分区：
文献类型：
--
作者：
Wang, YS;Penfold, S;Tyers, M
许多蛋白质的稳定性由泛素蛋白水解系统控制，该系统通过E3泛素连接酶的作用识别特异性底物[1]。SCF是最近描述的一类遍在蛋白连接酶，其靶向许多细胞周期调节剂和其他蛋白质以在酵母和哺乳动物细胞中降解[2-6]。每个SCF复合物由核心蛋白亚基Skp 1、Rbx 1和Cul 1组成（在酵母中称为Cdc 53），和被称为F-box蛋白的底物特异性衔接子亚基[2-4]，为了了解SCF复合物在哺乳动物细胞中的生理作用，我们产生了携带Cull基因缺失的小鼠。Cul 1（-/-）胚胎在原肠胚形成开始前的胚胎第6.5天（E6.5）左右停滞。在突变胚胎的所有细胞中，细胞周期蛋白E蛋白，但不是mRNA，高度升高。Cul 1（-/-）囊胚的生长在体外具有有限的增殖能力，并且在所有细胞中积累了细胞周期蛋白E。在Cul 1（-/-）胚泡培养，滋养层巨细胞继续内循环，尽管细胞周期蛋白E水平升高。这些结果表明，细胞周期蛋白E丰度是由SCF活性，可能通过SCF依赖性降解细胞周期蛋白E。
The stability of many proteins is controlled by the ubiquitin proteolytic system, which recognizes specific substrates through the action of E3 ubiquitin ligases [1]. The SCFs are a recently described class of ubiquitin ligase that target a number of cell cycle regulators and other proteins for degradation in both yeast and mammalian cells [2-6], Each SCF complex is composed of the core protein subunits Skp1, Rbx1 and Cul1 (known as Cdc53 in yeast), and substrate-specific adaptor subunits called F-box proteins [2-4], To understand the physiological role of SCF complexes in mammalian cells, we generated mice carrying a deletion in the Cull gene. Cul1(-/-) embryos arrested around embryonic day 6.5 (E6.5) before the onset of gastrulation. In all cells of the mutant embryos, cyclin E protein, but not mRNA, was highly elevated. Outgrowths of Cul1(-/-) blastocysts had limited proliferative capacity in vitro and accumulated cyclin E in all cells. Within Cul1(-/-) blastocyst cultures, trophoblast giant cells continued to endocycle despite the elevated cyclin E levels. These results suggest that cyclin E abundance is controlled by SCF activity, possibly through SCF-dependent degradation of cyclin E.