State Key Laboratory of Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
Stem Cells. 2014 Feb;32(2):349-63. doi: 10.1002/stem.1447.
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.
体细胞重编程为诱导多能干细胞（iPSCs）与癌症起始过程有许多相似之处，而这两个过程的分子机制仍有待阐明。在这里，我们报告称，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 GTPase，及其下游的 Phosphoinositide-3 kinase/Akt 信号通路是体细胞重编程过程的重要促进剂。我们发现，过表达 ERas 逆转录病毒增强了小鼠 iPSC 的诱导，而 ERas 敲低则抑制了它。通过遗传或化学手段调节 Akt 信号对重编程效率有很大影响。强制表达组成型活性 Akt1 基因可以挽救 ERas 敲低导致的效率降低，而点突变分析进一步表明，ERas 与 Akt 信号紧密耦合并增强重编程。在机制上，叉头转录因子 FoxO1 可以作为 iPSC 诱导的障碍，而 Akt 依赖性磷酸化使 FoxO1 失活，这在很大程度上解释了 ERas-Akt 信号对重编程的增强作用。总之，这些结果揭示了 ERas-Akt-FoxO1 信号轴在 iPSC 生成中的重要意义，表明体细胞重编程和癌症起始可能具有共同的分子基础。
