The tumour suppressor RASSF1A promotes MDM2 self-ubiquitination by disrupting the MDM2-DAXX-HAUSP complex

EMBO J. 2008 Jul 9;27(13):1863-74. doi: 10.1038/emboj.2008.115. Epub 2008 Jun 19.


The tumour suppressor p53, which accumulates in response to DNA damage and induces cell-cycle arrest and apoptosis, has a key function in the maintenance of genome integrity. Under normal conditions, the antiproliferative effects of p53 are inhibited by MDM2, a ubiquitin ligase that promotes p53 ubiquitination and degradation. MDM2 is also self-ubiquitinated and degraded. Here, we show that the tumour suppressor RASSF1A regulates G(1)-S cell-cycle progression in a p53-dependent manner by promoting MDM2 self-ubiquitination and preventing p53 degradation. Importantly, RASSF1A associates with MDM2 and death-domain-associated protein (DAXX) in the nucleus, thereby disrupting the interactions between MDM2, DAXX, and the deubiquitinase, HAUSP, and enhancing the self-ubiquitin ligase activity of MDM2. Moreover, RASSF1A partially contributes to p53-dependent checkpoint activation at early time points in response to DNA damage. These findings reveal a new and important function for RASSF1A in regulating the p53-MDM2 pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / metabolism*
  • Animals
  • Cell Line, Tumor
  • Co-Repressor Proteins
  • Fibroblasts / metabolism
  • Humans
  • Mice
  • Molecular Chaperones
  • Nuclear Proteins / metabolism*
  • Proto-Oncogene Proteins c-mdm2 / metabolism*
  • Tumor Suppressor Proteins / metabolism*
  • Ubiquitin Thiolesterase / metabolism*
  • Ubiquitin-Specific Peptidase 7
  • Ubiquitination


  • Adaptor Proteins, Signal Transducing
  • Co-Repressor Proteins
  • DAXX protein, human
  • Molecular Chaperones
  • Nuclear Proteins
  • RASSF1 protein, human
  • Tumor Suppressor Proteins
  • MDM2 protein, human
  • Proto-Oncogene Proteins c-mdm2
  • USP7 protein, human
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Peptidase 7