Functional compensation between Myc and PI3K signaling supports self-renewal of embryonic stem cells

Stem Cells. 2015 Mar;33(3):713-25. doi: 10.1002/stem.1893.


c-Myc and phosphatidylinositol 3-OH kinase (PI3K) both participate in diverse cellular processes, including cell cycle control and tumorigenic transformation. They also contribute to preserving embryonic stem cell (ESC) characteristics. However, in spite of the vast knowledge, the molecular relationship between c-Myc and PI3K in ESCs is not known. Herein, we demonstrate that c-Myc and PI3K function cooperatively but independently to support ESC self-renewal when murine ESCs are cultured under conventional culture condition. Interestingly, culture of ESCs in 2i-condition including a GSK3β and MEK inhibitor renders both PI3K and Myc signaling dispensable for the maintenance of pluripotent properties. These results suggest that the requirement for an oncogenic proliferation-dependent mechanism sustained by Myc and PI3K is context dependent and that the 2i-condition liberates ESCs from the dependence of this mechanism.

Keywords: Embryonic stem cells; MAPK; Myc; PI3K; Pluripotency.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / biosynthesis
  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics
  • Cell Differentiation / physiology
  • Cell Proliferation / physiology
  • Embryonic Stem Cells / cytology*
  • Embryonic Stem Cells / metabolism*
  • MAP Kinase Signaling System
  • Mice
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / genetics
  • Mitogen-Activated Protein Kinases / metabolism
  • NF-E2-Related Factor 2 / biosynthesis
  • NF-E2-Related Factor 2 / genetics
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Pluripotent Stem Cells / cytology
  • Pluripotent Stem Cells / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*


  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • Myc protein, mouse
  • NF-E2-Related Factor 2
  • Nfe2l2 protein, mouse
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-myc
  • Max protein, mouse
  • Mitogen-Activated Protein Kinases