Regulation of Cdk inhibitor p27 by Jab1.

Jab1也被称为COP9信号体(CSN)的第五组分，在包括细胞周期调控在内的许多生物学过程中发挥着重要作用。CSN复合体的核心由8个亚基(CSN1-8)组成，一个组分的破坏会导致整个复合体的损失。到目前为止，已知有两种酶活性与CSN有关。一种是蛋白激酶(酪蛋白激酶II、蛋白激酶D和5/6激酶)，它通过直接磷酸化来调节c-jun和p53等蛋白质的稳定性。另一个是金属蛋白酶活性，它通过从cullin亚基上去除共价偶联的泛素样肽Nedd8来调节SCF泛素连接酶。除了450-550 kDa的CSN复合体外，Jab1还是一个较小的(约100 kDa)细胞质复合体。Ja…的哪种酶活性和哪种形式的复合体对JA1相关的多种生物学反应起作用还有待确定。在体内，我们通过同源重组在小鼠ES细胞中靶向了Jab1基因。在不同Job1杂合子杂交的186只小鼠中，无一只出生，杂合子小鼠与野生型小鼠的比例为2.0：1，表明Jab1基因的缺失是胚胎致死的。对从胚胎8.5天到E3.5天的定时杂合杂交分离的胚胎的分析表明，Jab1/-胚胎存活到囊胚Jab1-空胚胎细胞，Jab1-空胚胎细胞也缺乏其他CSN成分，表达较高水平的p27、P53和Cyclin E，TUNEL检测呈阳性，BrdU掺入较少，表明Jab1和CSN复合体的缺失导致多细胞周期调节障碍，导致增殖受阻和加速细胞凋亡。有趣的是，Jab1杂合子小鼠虽然健康且多产，但比野生型小鼠要小。这是由于较少的P53、Cyclin E和neddylated cull的水平没有变化。在这些细胞中，含有Jab1的小分子复合体的数量选择性地减少，但不包括CSN。细胞周期分析显示，Jab1+/-MEFS不能有效下调G1期p27的表达，并使进入S期的时间推迟3h。因此，这些结果表明，Jab1以CSN依赖和非依赖的方式控制细胞周期进程。较少

Jab1, also known as the fifth component of the COP9 signalosome(CSN), plays an important role in a number of biological processes including cell cycle control. The core of the CSN complex is composed of eight subunits (CSN1-8), and disruption of one component results in loss of the whole complex. So far, two enzymatic activities are known to be associated with CSN. One is protein kinases (casein kinase II, protein kinase D, and 5/6 kinase), which regulate the stability of proteins such as c-Jun and p53 by direct phosphorylation. The others is a metalloprotease activity, which regulates the SCF ubiquitin ligase by removing the covalently-coupled, ubiquitin-like peptide, Nedd8, from the cullin subunit. Besides the 450-550-kDa CSN complex, Jab1 is also found as a smaller (ca 10 0 kDa)cytoplasmic complex. It remains to be determined which enzymatic activity and which form of the complex is responsible for a variety of biological responses connected to Jab1.To investigate the function of Ja … More b1 in vivo, we targeted the Jab1 locus by homologous recombination in mouse ES cells. No nullizygous mice were born live among 186 offspring of different Job1 heterozygous intercrosses, and the ratio of heterozygous mice to wild-type mice was 2.0 to 1, indicating that loss of Jab1 was embryonic lethal. Analysis of the embryos isolated from timed heterozygous intercrosses from embryonic day 8.5 to as early as E3.5 indicated that Jab1-/-embryos survived to the blastocyst Jab1-null embryonic cells, which also lacked other CSN components, expressed higher levels of p27, p53, and cyclin E, were positive for TUNEL assay and poorly incorporated BrdU, indicating that loss of Jab1 and the CSN complex results in impaired proliferation and accelerated apoptosis due to dysregulation of multiple cell cycle regulators. Interestingly, Jab1 heterozygous mice, although they were healthy and fertile, were smaller than the wild-type littermates. This was party due to less number of levels of p53, cyclin E and neddylated Cull were not changed. In these cells, the amount of Jab1-containing small complex but not that of CSN was selectively reduced. Cell cycle analysis of the synchronized MEFs showed that Jab1+/-MEFs failed to efficiently downregulate p27 during G1 and delayed the entry into S phase by 3 hours. Thus, these results suggest that Jab1 controls cell cycle progression in CSN-dependent and-independent ways. Less