Multiple functions of Jab1 are required for early embryonic development and growth potential in mice
Multiple functions of Jab1 are required for early embryonic development and growth potential in mice
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DOI：
10.1074/jbc.m406559200
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发表时间：
2004-10-08
影响因子：
4.8
通讯作者：
Kato, Y
中科院分区：
文献类型：
--
作者：
Tomoda, K;Yoneda-Kato, N;Kato, Y
Jab1与多种信号分子相互作用，调节它们在哺乳动物细胞中的稳定性。作为COP9信号体(CSN)复合体的第五组分，Jab1(CSN5)在Skp1-cullin-F box蛋白泛素连接酶复合体cullin亚基的降解中起着核心作用。此外，还提出了Jab1不依赖于CSN的功能，但还没有得到很好的描述。为了阐明Jab1的功能，我们通过在小鼠胚胎干细胞中进行同源重组来定位Jab1基因。Jab1基因缺失的胚胎在植入后不久就死亡。缺乏其他CSN成分的Jab1/-胚胎细胞表达较高水平的p27、P53和Cyclin E，导致增殖受阻和加速细胞凋亡。Jab1杂合子小鼠是健康和可生育的，但比它们的野生型小鼠小。Jab1/-小鼠胚胎成纤维细胞中含有Jab1的小亚复合体数量选择性减少，增殖较差，在G(1)期p27表达下调，从G(0)期向S期的进程较野生型细胞延迟3h。最有趣的是，在Jab1/-小鼠胚胎成纤维细胞中，Cyclin E和去dydlated Cul1的水平没有变化，也没有诱导P53的表达。因此，Jab1通过调节多个细胞周期信号通路来控制细胞周期进程和细胞存活。
Jab1 interacts with a variety of signaling molecules and regulates their stability in mammalian cells. As the fifth component of the COP9 signalosome (CSN) complex, Jab1 (CSN5) plays a central role in the deneddylation of the cullin subunit of the Skp1-Cullin- F box protein ubiquitin ligase complex. In addition, a CSN-independent function of Jab1 is suggested but is less well characterized. To elucidate the function of Jab1, we targeted the Jab1 locus by homologous recombination in mouse embryonic stem cells. Jab1-null embryos died soon after implantation. Jab1-/- embryonic cells, which lacked other CSN components, expressed higher levels of p27, p53, and cyclin E, resulting in impaired proliferation and accelerated apoptosis. Jab1 heterozygous mice were healthy and fertile but smaller than their wild-type littermates. Jab1-/- mouse embryonic fibroblast cells, in which the amount of Jab1-containing small subcomplex, but not that of CSN, was selectively reduced, proliferated poorly, showed an inefficient down-regulation of p27 during G(1), and was delayed in the progression from G(0) to S phase by 3 h compared with the wild-type cells. Most interestingly, in Jab1-/- mouse embryonic fibroblasts, the levels of cyclin E and deneddylated Cul1 were unchanged, and p53 was not induced. Thus, Jab1 controls cell cycle progression and cell survival by regulating multiple cell cycle signaling pathways.