Endoplasmic reticulum stress sensitizes cells to DNA damage-induced apoptosis through p53-dependent suppression of p21(CDKN1A)

Nat Commun. 2014 Oct 8;5:5067. doi: 10.1038/ncomms6067.

Abstract

Endoplasmic reticulum (ER) stress occurs in poorly perfused tissues and activates the p53 isoform p53/47 to promote G2 arrest via 14-3-3σ. This contrasts with the p21(CDKN1A)-dependent G1 arrest caused by p53 following DNA damage. It is not known how cells respond to conditions when both pathways are activated. Here we show that p53/47 prevents p53-induced p21 transcription during ER stress and that both isoforms repress p21 mRNA translation. This prevents p21 from promoting COP1-mediated 14-3-3σ degradation and leads to G2 arrest. DNA damage does not result in p53-dependent induction of p21 during ER stress and instead results in an increase in p53-induced apoptosis. This illustrates how p53 isoforms target an intrinsic balance between the G1 and G2 checkpoints for cell cycle coordination and demonstrates an ER stress-dependent p53 pathway that suppresses p21 and lowers the apoptotic threshold to genotoxic drugs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 14-3-3 Proteins / metabolism
  • Apoptosis / genetics*
  • Biomarkers, Tumor / metabolism
  • Cell Cycle Checkpoints*
  • Cell Line, Tumor
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics*
  • Cyclin-Dependent Kinase Inhibitor p21 / metabolism
  • DNA Damage / genetics*
  • Endoplasmic Reticulum Stress*
  • Exoribonucleases / metabolism
  • G2 Phase Cell Cycle Checkpoints
  • HCT116 Cells
  • Humans
  • MCF-7 Cells
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • Ubiquitin-Protein Ligases / metabolism

Substances

  • 14-3-3 Proteins
  • Biomarkers, Tumor
  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • COP1 protein, human
  • Ubiquitin-Protein Ligases
  • Exoribonucleases
  • SFN protein, human