Stimulation of Somatic Cell Reprogramming by ERas‐Akt‐FoxO1 Signaling Axis
Stimulation of Somatic Cell Reprogramming by ERas‐Akt‐FoxO1 Signaling Axis
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DOI：
10.1002/stem.1447
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发表时间：
2014-02
期刊：
影响因子：
5.2
通讯作者：
Yong Shen Yu;Dan Liang;Qing Tian;Xiaona Chen;Bowen Jiang;Bin-Kuan Chou;Ping Hu;Linzhao Cheng;Ping Gao;Jinsong Li;Gang Wang
中科院分区：
文献类型：
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作者：
Yong Shen Yu;Dan Liang;Qing Tian;Xiaona Chen;Bowen Jiang;Bin-Kuan Chou;Ping Hu;Linzhao Cheng;Ping Gao;Jinsong Li;Gang Wang
体细胞重编程为诱导多能干细胞（iPSC）与癌症起始过程有很多相似之处，这两个过程的分子机制仍有待阐明。在这里，我们报告了一种肿瘤或胚胎干细胞特异性Ras基因ERas，它编码一种组成型活性形式的GT3，及其下游磷酸肌醇-3激酶/Akt信号通路是体细胞重编程过程的重要促进因素。我们发现ERas的过表达增强了小鼠iPSC的诱导，而ERas的敲低则抑制了它。通过遗传或化学手段调节Akt信号转导极大地影响了重编程效率。组成型活性Akt 1基因的强制表达可以挽救由于ERas敲低而导致的效率降低，点突变分析进一步揭示ERas与Akt信号传导紧密耦合以增强重编程。从机制上讲，叉头转录因子FoxO 1可以作为iPSC诱导的屏障，Akt依赖性磷酸化导致FoxO 1失活在很大程度上解释了ERas-Akt信号转导对重编程的增强作用。总的来说，这些结果揭示了ERas-Akt-FoxO 1信号轴在iPSC生成中的重要性，表明体细胞重编程和癌症启动可能有共同的分子基础。干细胞2014;32：349-363
Reprogramming of somatic cells to induced pluripotent stem cells (iPSCs) shares much similarity to the cancer initiation process, and the molecular mechanisms underlying both processes remain to be elucidated. Here, we report that a tumor‐ or embryonic stem cell‐specific Ras gene ERas, which encodes a constitutively active form of GTPase, and its downstream Phosphoinositide‐3 kinase/Akt signaling pathway are important facilitators for the somatic reprogramming process. We found that overexpression of ERas retrovirally enhanced mouse iPSC induction while ERas knockdown repressed it. Modulation of Akt signaling by genetic or chemical means greatly impacted the reprogramming efficiency. Forced expression of a constitutively active Akt1 gene could rescue the reduced efficiency resulting from ERas knockdown, and point‐mutation analyses further revealed that ERas is tightly coupled with Akt signaling to enhance reprogramming. Mechanistically, the forkhead transcription factor FoxO1 can function as a barrier to the iPSC induction, and the inactivation of FoxO1 by Akt‐dependent phosphorylation largely accounts for the enhancing effect of ERas‐Akt signaling on reprogramming. Collectively, these results unravel the significance of the ERas‐Akt‐FoxO1 signaling axis in iPSC generation, suggesting a possibly shared molecular basis for both somatic reprogramming and cancer initiation. Stem Cells 2014;32:349–363