p53-mediated control of gene expression via mRNA translation during Endoplasmic Reticulum stress

Cell Cycle. 2015;14(21):3373-8. doi: 10.1080/15384101.2015.1090066.

Abstract

p53 is activated by different stress and damage pathways and regulates cell biological responses including cell cycle arrest, repair pathways, apoptosis and senescence. Following DNA damage, the levels of p53 increase and via binding to target gene promoters, p53 induces expression of multiple genes including p21(CDKN1A) and mdm2. The effects of p53 on gene expression during the DNA damage response are well mimicked by overexpressing p53 under normal conditions. However, stress to the Endoplasmic Reticulum (ER) and the consequent Unfolded Protein Response (UPR) leads to the induction of the p53/47 isoform that lacks the first 40 aa of p53 and to an active suppression of p21(CDKN1A) transcription and mRNA translation. We now show that during ER stress p53 also suppresses MDM2 protein levels via a similar mechanism. These observations not only raise questions about the physiological role of MDM2 during ER stress but it also reveals a new facet of p53 as a repressor toward 2 of its major target genes during the UPR. As suppression of p21(CDKN1A) and MDM2 protein synthesis is mediated via their coding sequences, it raises the possibility that p53 controls mRNA translation via a common mechanism that might play an important role in how p53 regulates gene expression during the UPR, as compared to the transcription-dependent gene regulation taking place during the DNA damage response.

Keywords: ER stress; MDM2; mRNA translation; p53; p53/47.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cyclin-Dependent Kinase Inhibitor p21 / biosynthesis
  • Cyclin-Dependent Kinase Inhibitor p21 / genetics*
  • Down-Regulation
  • Endoplasmic Reticulum Stress*
  • Gene Expression Regulation, Neoplastic*
  • Gene Knockdown Techniques
  • HCT116 Cells
  • Heat-Shock Proteins / metabolism
  • Humans
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Proto-Oncogene Proteins c-mdm2 / biosynthesis
  • Proto-Oncogene Proteins c-mdm2 / genetics*
  • RNA, Messenger / genetics*
  • RNA, Messenger / metabolism
  • Signal Transduction
  • Transfection
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism
  • Unfolded Protein Response

Substances

  • CDKN1A protein, human
  • Cyclin-Dependent Kinase Inhibitor p21
  • Heat-Shock Proteins
  • RNA, Messenger
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • molecular chaperone GRP78