MYC Releases Early Reprogrammed Human Cells from Proliferation Pause via Retinoblastoma Protein Inhibition

Cell Rep. 2018 Apr 10;23(2):361-375. doi: 10.1016/j.celrep.2018.03.057.

Abstract

Here, we report that MYC rescues early human cells undergoing reprogramming from a proliferation pause induced by OCT3/4, SOX2, and KLF4 (OSK). We identified ESRG as a marker of early reprogramming cells that is expressed as early as day 3 after OSK induction. On day 4, ESRG positive (+) cells converted to a TRA-1-60 (+) intermediate state. These early ESRG (+) or TRA-1-60 (+) cells showed a proliferation pause due to increased p16INK4A and p21 and decreased endogenous MYC caused by OSK. Exogenous MYC did not enhance the appearance of initial reprogramming cells but instead reactivated their proliferation and improved reprogramming efficiency. MYC increased expression of LIN41, which potently suppressed p21 post-transcriptionally. MYC suppressed p16 INK4A. These changes inactivated retinoblastoma protein (RB) and reactivated proliferation. The RB-regulated proliferation pause does not occur in immortalized fibroblasts, leading to high reprogramming efficiency even without exogenous MYC.

Keywords: LIN41; MYC; immortalization; induced pluripotent stem cell; pluripotency; post-transcriptional regulation; proliferation; reprogramming; senescence.

MeSH terms

  • Antigens, Surface / metabolism
  • Cell Line
  • Cell Proliferation
  • Cellular Reprogramming*
  • Cyclin-Dependent Kinase Inhibitor p16 / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism
  • Phosphorylation
  • Proteoglycans / metabolism
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism*
  • RNA Interference
  • RNA, Small Interfering / metabolism
  • Retinoblastoma Protein / antagonists & inhibitors
  • Retinoblastoma Protein / metabolism*
  • Transcription Factors / genetics
  • Transcription Factors / metabolism
  • Tripartite Motif Proteins / metabolism
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • Antigens, Surface
  • Cyclin-Dependent Kinase Inhibitor p16
  • Proteoglycans
  • Proto-Oncogene Proteins c-myc
  • RNA, Small Interfering
  • Retinoblastoma Protein
  • TRA-1-60 antigen, human
  • Transcription Factors
  • Tripartite Motif Proteins
  • TRIM71 protein, human
  • Ubiquitin-Protein Ligases