Regulation of Cdk inhibitor p27 by Jab1.

Jab 1也被称为COP 9信号体（CSN）的第五组分，在包括细胞周期控制在内的许多生物学过程中发挥重要作用。CSN复合物的核心由八个亚基（CSN 1 -8）组成，并且一个组分的破坏导致整个复合物的损失。到目前为止，已知两种酶活性与CSN相关。一种是蛋白激酶（酪蛋白激酶II、蛋白激酶D和5/6激酶），它们通过直接磷酸化来调节蛋白质如c-Jun和p53的稳定性。另一个是金属蛋白酶活性，其通过从cullin亚基去除共价偶联的泛素样肽Nedd 8来调节SCF泛素连接酶。除了450-550-kDa的CSN复合物，Jab 1也被发现作为一个较小的（约100 kDa）胞质复合物。目前还不清楚哪种酶活性和哪种形式的复合物负责与Jab 1相关的各种生物学反应。 关于我们 b1在体内，我们在小鼠ES细胞中通过同源重组靶向Jab 1位点。在不同Job 1杂合子杂交的186只后代中，没有一只空合子小鼠活产，杂合子小鼠与野生型小鼠的比例为2.0：1，表明Jab 1的丢失是胚胎致死的。对从胚胎第8.5天到早至E3.5天的定时杂合杂交中分离的胚胎的分析表明，Jab 1-/-胚胎存活至胚泡Jab 1-null胚胎细胞，其也缺乏其他CSN组分，表达更高水平的p27、p53和细胞周期蛋白E，对TUNEL测定呈阳性，并且掺入的BrdU很少，表明Jab 1和CSN复合物的缺失导致增殖受损和由于多种细胞周期调节剂的失调而加速的凋亡。有趣的是，Jab 1杂合子小鼠，虽然它们是健康和可生育的，但比野生型同窝出生的小鼠要小。这是由于p53、细胞周期蛋白E和neddylated Cull的水平数量较少所致。在这些细胞中，选择性地减少了含Jab 1的小复合物的量，但没有减少CSN的量。同步化MEFs的细胞周期分析表明，Jab 1 +/-MEFs未能有效地下调G1期的p27，并延迟进入S期3小时。因此，这些结果表明，Jab 1控制细胞周期的进展，在CSN依赖和独立的方式。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