Stimulation of somatic cell reprogramming by ERas-Akt-FoxO1 signaling axis

Yong Yu, Dan Liang, Qing Tian, Xiaona Chen, Bo Jiang, Bin Kuan Chou, Ping Hu, Linzhao Cheng, Ping Gao, Jinsong Li, Gang Wang

Research output: Contribution to journalArticlepeer-review

Abstract

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.

Original languageEnglish (US)
Pages (from-to)349-363
Number of pages15
JournalStem Cells
Volume32
Issue number2
DOIs
StatePublished - Feb 2014
Externally publishedYes

Keywords

  • Akt
  • ERas
  • FoxO1
  • Induced pluripotent stem cells
  • Reprogramming

ASJC Scopus subject areas

  • Molecular Medicine
  • Developmental Biology
  • Cell Biology

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