MRC Cancer Cell Unit, Hutchison/MRC Research Centre, Hills Road, Cambridge CB2 0XZ, UK.
Curr Biol. 2011 Apr 26;21(8):692-9. doi: 10.1016/j.cub.2011.03.026. Epub 2011 Apr 14.
Geminin is an essential cell-cycle protein that is only present from S phase to early mitosis in metazoan somatic cells. Genetic ablation of geminin in the mouse results in preimplantation embryonic lethality because pluripotent cells fail to form and all cells differentiate to trophoblast. Here we show that geminin is present in G1 phase of mouse pluripotent cells in contrast to somatic cells, where anaphase-promoting complex/cyclosome (APC/C)-mediated proteasomal destruction removes geminin in G1. Silencing geminin directly or by depleting the APC/C inhibitor Emi1 causes loss of stem cell identity and trophoblast differentiation of mouse embryonal carcinoma and embryonic stem cells. Depletion of cyclins A2 or B1 does not induce this effect, even though both of these APC/C substrates are also present during G1 of pluripotent cells. Crucially, geminin antagonizes the chromatin-remodeling protein Brg1 to maintain expression of Oct4, Sox2, and Nanog. Our results define a pluripotency pathway by which suppressed APC/C activity protects geminin from degradation in G1, allowing sustained expression of core pluripotency factors. Collectively, these findings link the cell cycle to the pluripotent state but also raise an unexplained paradox: How is cell-cycle progression possible in pluripotent cells when oscillations of key regulatory proteins are lost?
生殖细胞核蛋白是一种必需的细胞周期蛋白，仅存在于后生动物体细胞的 S 期到早期有丝分裂期。在小鼠中敲除生殖细胞核蛋白会导致胚胎植入前致死，因为多能细胞无法形成，所有细胞都分化为滋养层。在这里，我们发现生殖细胞核蛋白存在于小鼠多能细胞的 G1 期，而体细胞中，有丝分裂促进复合物/细胞周期蛋白（APC/C）介导的蛋白酶体降解会在 G1 期去除生殖细胞核蛋白。直接沉默生殖细胞核蛋白或耗尽 APC/C 抑制剂 Emi1 会导致小鼠胚胎癌细胞和胚胎干细胞丧失干细胞特性并分化为滋养层。尽管这两种 APC/C 底物在多能细胞的 G1 期也存在，但耗尽细胞周期蛋白 A2 或 B1 不会诱导这种效应。至关重要的是，生殖细胞核蛋白拮抗染色质重塑蛋白 Brg1 以维持 Oct4、Sox2 和 Nanog 的表达。我们的研究结果定义了一种多能性途径，即受抑制的 APC/C 活性在 G1 期保护生殖细胞核蛋白免受降解，从而允许核心多能性因子的持续表达。总的来说，这些发现将细胞周期与多能状态联系起来，但也提出了一个未解决的悖论：当关键调节蛋白的振荡丢失时，多能细胞的细胞周期如何进行？
