Domain analysis of Ras-association domain family member 6 upon interaction with MDM2

FEBS Lett. 2017 Jan;591(2):260-272. doi: 10.1002/1873-3468.12551. Epub 2017 Jan 17.

Abstract

The tumor suppressor Ras-association domain family member 6 (RASSF6) has Ras-association domain (RA) and Salvador/RASSF/Hippo domain (SARAH). RASSF6 antagonizes MDM2, stabilizes p53, and induces apoptosis and cell cycle arrest. We previously demonstrated the interaction between RASSF6 and MDM2, but did not determine how both proteins interact with each other. We have shown here that N-terminal, RA, and SARAH domains of RASSF6 interact with MDM2 at distinct regions. RA binds to the RING-finger region of MDM2 and stabilizes p53. SARAH binds RA and blocks the interaction between RA and MDM2. RA overexpression induces p53-dependent apoptosis and senescence. In the presence of active KRas, the interaction between RA and MDM2 is recovered. In this way, RA and SARAH play an important role in Ras-mediated regulation of p53.

Keywords: MDM2; RASSF6; p53.

Publication types

  • Letter
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / radiation effects
  • Caspases / metabolism
  • Cell Line
  • Cellular Senescence / radiation effects
  • Humans
  • Monomeric GTP-Binding Proteins / chemistry*
  • Monomeric GTP-Binding Proteins / metabolism*
  • NF-kappa B / metabolism
  • Protein Binding / radiation effects
  • Protein Domains
  • Protein Stability / radiation effects
  • Proto-Oncogene Proteins c-mdm2 / chemistry
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Signal Transduction / radiation effects
  • Structure-Activity Relationship
  • Transcription, Genetic / radiation effects
  • Tumor Suppressor Protein p53 / metabolism
  • Ultraviolet Rays

Substances

  • NF-kappa B
  • Tumor Suppressor Protein p53
  • Proto-Oncogene Proteins c-mdm2
  • Caspases
  • Monomeric GTP-Binding Proteins