p53-independent upregulation of miR-34a during oncogene-induced senescence represses MYC

Cell Death Differ. 2010 Feb;17(2):236-45. doi: 10.1038/cdd.2009.109. Epub 2009 Aug 21.

Abstract

Aberrant oncogene activation induces cellular senescence, an irreversible growth arrest that acts as a barrier against tumorigenesis. To identify microRNAs (miRNAs) involved in oncogene-induced senescence, we examined the expression of miRNAs in primary human TIG3 fibroblasts after constitutive activation of B-RAF. Among the regulated miRNAs, both miR-34a and miR-146a were strongly induced during senescence. Although members of the miR-34 family are known to be transcriptionally regulated by p53, we find that miR-34a is regulated independently of p53 during oncogene-induced senescence. Instead, upregulation of miR-34a is mediated by the ETS family transcription factor, ELK1. During senescence, miR-34a targets the important proto-oncogene MYC and our data suggest that miR-34a thereby coordinately controls a set of cell cycle regulators. Hence, in addition to its integration in the p53 pathway, we show that alternative cancer-related pathways regulate miR-34a, emphasising its significance as a tumour suppressor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Cycle / genetics
  • Cell Division / genetics
  • Cell Line, Transformed
  • Cellular Senescence / genetics*
  • Fibroblasts / cytology*
  • Fibroblasts / physiology*
  • Humans
  • MicroRNAs / genetics*
  • MicroRNAs / metabolism
  • Neoplasms / genetics
  • Neoplasms / pathology
  • Oncogenes / physiology
  • Proto-Oncogene Proteins B-raf / genetics
  • Proto-Oncogene Proteins B-raf / metabolism
  • Proto-Oncogene Proteins c-myc / genetics*
  • Proto-Oncogene Proteins c-myc / metabolism
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism
  • Up-Regulation / physiology
  • ets-Domain Protein Elk-1 / genetics
  • ets-Domain Protein Elk-1 / metabolism

Substances

  • ELK1 protein, human
  • MIRN146 microRNA, human
  • MIRN34 microRNA, human
  • MYC protein, human
  • MicroRNAs
  • Proto-Oncogene Proteins c-myc
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • ets-Domain Protein Elk-1
  • BRAF protein, human
  • Proto-Oncogene Proteins B-raf