Inhibition of pluripotency networks by the Rb tumor suppressor restricts reprogramming and tumorigenesis

Cell Stem Cell. 2015 Jan 8;16(1):39-50. doi: 10.1016/j.stem.2014.10.019. Epub 2014 Nov 13.

Abstract

Mutations in the retinoblastoma tumor suppressor gene Rb are involved in many forms of human cancer. In this study, we investigated the early consequences of inactivating Rb in the context of cellular reprogramming. We found that Rb inactivation promotes the reprogramming of differentiated cells to a pluripotent state. Unexpectedly, this effect is cell cycle independent, and instead reflects direct binding of Rb to pluripotency genes, including Sox2 and Oct4, which leads to a repressed chromatin state. More broadly, this regulation of pluripotency networks and Sox2 in particular is critical for the initiation of tumors upon loss of Rb in mice. These studies therefore identify Rb as a global transcriptional repressor of pluripotency networks, providing a molecular basis for previous reports about its involvement in cell fate pliability, and implicate misregulation of pluripotency factors such as Sox2 in tumorigenesis related to loss of Rb function.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Carcinogenesis / metabolism
  • Carcinogenesis / pathology*
  • Cell Cycle
  • Cellular Reprogramming*
  • Chromatin / metabolism
  • Fibroblasts / metabolism
  • Homeodomain Proteins / metabolism
  • Humans
  • Induced Pluripotent Stem Cells / cytology
  • Induced Pluripotent Stem Cells / metabolism*
  • Mice
  • Nanog Homeobox Protein
  • Octamer Transcription Factor-3 / genetics
  • Protein Binding
  • Repressor Proteins / metabolism
  • Retinoblastoma Protein / deficiency
  • Retinoblastoma Protein / metabolism*
  • SOXB1 Transcription Factors / genetics

Substances

  • Chromatin
  • Homeodomain Proteins
  • Nanog Homeobox Protein
  • Nanog protein, mouse
  • Octamer Transcription Factor-3
  • Repressor Proteins
  • Retinoblastoma Protein
  • SOXB1 Transcription Factors

Associated data

  • GEO/GSE40594