The NEDD8 system is essential for cell cycle progression and morphogenetic pathway in mice.
The NEDD8 system is essential for cell cycle progression and morphogenetic pathway in mice.
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NEDD8系统对于小鼠的细胞周期进程和形态发生途径至关重要。
DOI：
10.1083/jcb.200104035
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发表时间：
2001-11-12
影响因子：
7.8
通讯作者：
Chiba, T
中科院分区：
文献类型：
--
作者：
Tateishi, K;Omata, M;Tanaka, K;Chiba, T
NEDD 8/Rub 1是一种泛素（Ub）样分子，通过类似于泛素化的酶级联反应与靶蛋白共价连接。已知该修饰剂靶向所有cullin（Cul）家族蛋白。后者是Skp 1/Cul-1/F-box蛋白（SCF）样Ub连接酶复合物的重要组成部分，在Ub介导的蛋白水解中起关键作用。为了确定NEDD 8系统在哺乳动物中的作用，我们产生了编码NEDD 8激活酶催化亚基的Uba 3基因缺陷的小鼠。Uba 3 − /−小鼠在围着床期死于子宫内。突变胚胎表现出选择性凋亡的内细胞团，但不是滋养层细胞。然而，突变的滋养层细胞无法进入核内复制周期的S期。这种细胞周期阻滞伴随着细胞周期蛋白E和p57 Kip 2的异常表达。这些结果表明，NEDD 8系统是必不可少的有丝分裂和核内复制细胞周期的进展。β-连环蛋白是Wnt/wingless信号通路的一种介质，通过SCF Ub连接酶在细胞质中持续降解，也在Uba 3 −/−细胞质和细胞核中积累。因此，NEDD 8系统对于参与细胞周期进展和形态发生的蛋白质降解途径的调节是必不可少的，这可能是通过Cul家族蛋白质的功能实现的。
NEDD8/Rub1 is a ubiquitin (Ub)-like molecule that covalently ligates to target proteins through an enzymatic cascade analogous to ubiquitylation. This modifier is known to target all cullin (Cul) family proteins. The latter are essential components of Skp1/Cul-1/F-box protein (SCF)–like Ub ligase complexes, which play critical roles in Ub-mediated proteolysis. To determine the role of the NEDD8 system in mammals, we generated mice deficient in Uba3 gene that encodes a catalytic subunit of NEDD8-activating enzyme. Uba3 − /− mice died in utero at the periimplantation stage. Mutant embryos showed selective apoptosis of the inner cell mass but not of trophoblastic cells. However, the mutant trophoblastic cells could not enter the S phase of the endoreduplication cycle. This cell cycle arrest was accompanied with aberrant expression of cyclin E and p57Kip2. These results suggested that the NEDD8 system is essential for both mitotic and the endoreduplicative cell cycle progression. β-Catenin, a mediator of the Wnt/wingless signaling pathway, which degrades continuously in the cytoplasm through SCF Ub ligase, was also accumulated in the Uba3 −/− cytoplasm and nucleus. Thus, the NEDD8 system is essential for the regulation of protein degradation pathways involved in cell cycle progression and morphogenesis, possibly through the function of the Cul family proteins.