Graduate School of Biological Sciences, Nara Institute of Science and Technology, Nara 630-0101, Japan.
Sci Rep. 2013;3:1054. doi: 10.1038/srep01054. Epub 2013 Jan 11.
The fifth component (CSN5) of the mammalian COP9 signalosome complex plays an essential role in cell proliferation and senescence, but its molecular mediator remains to be determined. Here, we searched for interactors among various cell cycle regulators, and found that CSN5, but not the CSN holo-complex, bound to CDK2 in vivo and in vitro. Depletion of CSN5 enhanced phosphorylation of CDK2 by Akt, resulting in cytoplasmic accumulation of CDK2 together with cyclin E in a leptomycin B-resistant manner, and impaired phosphorylation of the retinoblastoma protein. Additional knockdown of CDK2, which reduced the expression of cyclin E to the normal level, did not restore cell proliferation, but significantly suppressed senescence in CSN5-depleted cells. Enforced expression of cytoplasmic cyclin E induced premature senescence in immortalized cell lines. These results show that CSN5 functions through CDK2 to control premature senescence in a novel way, depending on cyclin E in the cytoplasm.
哺乳动物 COP9 信号小体复合物的第五个组成部分（CSN5）在细胞增殖和衰老中发挥着重要作用，但它的分子介质仍有待确定。在这里，我们在各种细胞周期调节剂中寻找相互作用蛋白，发现 CSN5 而不是 CSN 全复合物，在体内和体外与 CDK2 结合。CSN5 的耗竭增强了 Akt 对 CDK2 的磷酸化，导致 CDK2 与细胞周期蛋白 E 一起以莱普霉素 B 抗性的方式在细胞质中积累，并抑制视网膜母细胞瘤蛋白的磷酸化。另外敲低 CDK2，将细胞周期蛋白 E 的表达降低到正常水平，并没有恢复细胞增殖，但显著抑制了 CSN5 耗竭细胞的衰老。强制表达细胞质细胞周期蛋白 E 会导致永生化细胞系过早衰老。这些结果表明，CSN5 通过 CDK2 以一种新的方式控制细胞过早衰老，这种方式依赖于细胞质中的细胞周期蛋白 E。
