p53 mRNA and p53 Protein Structures Have Evolved Independently to Interact with MDM2

Mol Biol Evol. 2016 May;33(5):1280-92. doi: 10.1093/molbev/msw012. Epub 2016 Jan 27.

Abstract

The p53 tumor suppressor and its key regulator MDM2 play essential roles in development, ageing, cancer, and cellular stress responses in mammals. Following DNA damage, MDM2 interacts with p53 mRNA in an ATM kinase-dependent fashion and stimulates p53 synthesis, whereas under normal conditions, MDM2 targets the p53 protein for degradation. The peptide- and RNA motifs that interact with MDM2 are encoded by the same conserved BOX-I sequence, but how these interactions have evolved is unknown. Here, we show that a temperature-sensitive structure in the invertebrate Ciona intestinalis (Ci) p53 mRNA controls its interaction with MDM2. We also show that a nonconserved flanking region of Ci-BOX-I domain prevents the p53-MDM2 protein-protein interaction. These results indicate that the temperature-regulated p53 mRNA-MDM2 interaction evolved to become kinase regulated in the mammalian DNA damage response. The data also suggest that the negative regulation of p53 by MDM2 via protein-protein interaction evolved in vertebrates following changes in the BOX-I flanking sequence.

Keywords: Ciona intestinalis; MDM2; RNA structures; invertebrate.; p53; protein–RNA interactions.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Base Sequence
  • Cell Line, Tumor
  • Ciona intestinalis
  • DNA Damage
  • DNA Primers
  • Protein Binding
  • Protein Structure, Tertiary
  • Proto-Oncogene Proteins c-mdm2 / genetics*
  • Proto-Oncogene Proteins c-mdm2 / metabolism
  • RNA Recognition Motif Proteins / genetics
  • RNA Recognition Motif Proteins / metabolism
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Structure-Activity Relationship
  • Tumor Suppressor Protein p53 / genetics*
  • Tumor Suppressor Protein p53 / metabolism*

Substances

  • DNA Primers
  • RNA Recognition Motif Proteins
  • RNA, Messenger
  • Tumor Suppressor Protein p53
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2