Disruption of the COP2 signalosome Csn2 subunit in mice causes deficient cell proliferation, accumulation of p53 and cyclin E, and early embryonic death
Disruption of the COP2 signalosome Csn2 subunit in mice causes deficient cell proliferation, accumulation of p53 and cyclin E, and early embryonic death
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DOI：
10.1128/mcb.23.19.6790-6797.2003
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发表时间：
2003-10-01
影响因子：
5.3
通讯作者：
Wei, N
中科院分区：
文献类型：
--
作者：
Lykke-Andersen, K;Schaefer, L;Wei, N
Csn 2（Trip 15/Cops 2/Alien）编码COP 9信号体（CSN）的第二亚基，CSN是与26 S蛋白酶体的lid亚复合物同源的八亚基异聚复合物。CSN是SCF（Skp 1-cullin-F-box蛋白）遍在蛋白连接酶的调节剂，主要通过将遍在蛋白样蛋白Ndd 8与SCF Cull组分去偶联的酶活性来实现。此外，CSN与靶向p53、c-Jun和IkappaB磷酸化的蛋白激酶活性相关。Csn 2还与核激素受体的一个子集相互作用并调节，被认为是一种新的辅阻遏物。我们报告说，有针对性地破坏Csn 2在小鼠引起的胚胎发育在围着床期的逮捕。Csn 2（-/-）囊胚在培养中未能长出，并且在内细胞团中表现出细胞增殖缺陷，伴随着10月4日的轻微减少。此外，Csn 2的缺乏破坏了CSN复合物，导致细胞周期蛋白E的急剧增加，支持CSN与SCF-泛素-蛋白酶体系统合作调节蛋白质周转的作用。此外，Csn 2（-/-）胚胎含有升高水平的p53和p21，这可能有助于突变体的细胞周期提前停滞。
Csn2 (Trip15/Cops2/Alien) encodes the second subunit of the COP9 signalosome (CSN), an eight-subunit heteromeric complex homologous to the lid subcomplex of the 26S proteasome. CSN is a regulator of SCF (Skp1-cullin-F-box protein) ubiquitin ligases, mostly through the enzymatic activity that deconjugates the ubiquitin-like protein Nedd8 from the SCF Cull component. In addition, CSN associates with protein kinase activities targeting p53, c-Jun, and IkappaB for phosphorylation. Csn2 also interacts with and regulates a subset of nuclear hormone receptors and is considered a novel corepressor. We report that targeted disruption of Csn2 in mice caused arrest of embryo development at the peri-implantation stage. Csn2(-/-) blastocysts failed to outgrow in culture and exhibited a cell proliferation defect in inner cell mass, accompanied by a slight decrease in Oct4. In addition, lack of Csn2 disrupted the CSN complex and resulted in a drastic increase in cyclin E, supporting a role for CSN in cooperating with the SCF-ubiquitin-proteasome system to regulate protein turnover. Furthermore, Csn2(-/-) embryos contained elevated levels of p53 and p21, which may contribute to premature cell cycle arrest of the mutant.