Watanabe S, Umehara H, Murayama K, Okabe M, Kimura T, Nakano T
Graduate School of Frontier Biosciences, Osaka University, Suita, Osaka, Japan.
Oncogene. 2006 May 4;25(19):2697-707. doi: 10.1038/sj.onc.1209307.
Embryonic stem (ES) cells can self-renew indefinitely without losing their differentiation ability to any cell types. Phosphoinositide-3 kinase (PI3K)/Akt signaling plays a pivotal role in various stem cell systems, including the formation of embryonic germ (EG) cells from primordial germ cells and self-renewal of neural stem cells. Here, we show that myristoylated, active form of Akt (myr-Akt) maintained the undifferentiated phenotypes in mouse ES cells without the addition of leukemia inhibitory factor (LIF). The effects of myr-Akt were reversible, because LIF dependence and pluripotent differentiation activity were restored by the deletion of myr-Akt. In addition, myr-Akt-Mer fusion protein, whose enzymatic activity is controlled by 4-hydroxy-tamoxifen, also maintained the pluripotency of not only mouse but also cynomolgus monkey ES cells. These results clearly demonstrate that Akt signaling sufficiently maintains pluripotency in mouse and primate ES cells, and support the notion that PI3K/Akt signaling axis regulates 'stemness' in a broad spectrum of stem cell systems.
胚胎干细胞（ES细胞）能够无限自我更新，且不丧失分化为任何细胞类型的能力。磷酸肌醇-3激酶（PI3K）/Akt信号传导在各种干细胞系统中发挥关键作用，包括原始生殖细胞形成胚胎生殖（EG）细胞以及神经干细胞的自我更新。在此，我们表明，在不添加白血病抑制因子（LIF）的情况下，肉豆蔻酰化的活性形式Akt（myr-Akt）维持了小鼠ES细胞的未分化表型。myr-Akt的作用是可逆的，因为通过缺失myr-Akt可恢复LIF依赖性和多能分化活性。此外，其酶活性受4-羟基他莫昔芬控制的myr-Akt-Mer融合蛋白，不仅维持了小鼠ES细胞的多能性，还维持了食蟹猴ES细胞的多能性。这些结果清楚地表明，Akt信号传导足以维持小鼠和灵长类ES细胞的多能性，并支持PI3K/Akt信号轴在广泛的干细胞系统中调节“干性”这一观点。
