• Register
Forgot Password

If you have forgotten your password you can enter your email here and get a temporary password sent to your email.


Leaving Community

Are you sure you want to leave this community? Leaving the community will revoke any permissions you have been granted in this community.


MDM2 acts downstream of p53 as an E3 ligase to promote FOXO ubiquitination and degradation.

Members of the FOXO (forkhead O) class of transcription factors are tumor suppressors that also control aging and organismal life span. Mammalian FOXO degradation is proteasome-mediated, although the ubiquitin E3 ligase for FOXO factors remains to be defined. We show that MDM2 binds to FOXO1 and FOXO3A and promotes their ubiquitination and degradation, a process apparently dependent on FOXO phosphorylation at AKT sites and the E3 ligase activity of MDM2. Binding of MDM2 to FOXO occurs through the region of MDM2 that directs its cellular trafficking and the forkhead box of FOXO1. MDM2 promotes the ubiquitination of FOXO1 in a cell-free system, and its knockdown by small interfering RNA causes accumulation of endogenous FOXO3A protein in cells and enhances the expression of FOXO target genes. In cells stably expressing a temperature-sensitive p53 mutant, activation of p53 by shifting to permissive temperatures leads to MDM2 induction and degradation of endogenous FOXO3A. These data suggest that MDM2 acts as an ubiquitin E3 ligase, downstream of p53, to regulate the degradation of mammalian FOXO factors.

Pubmed ID: 19321440


  • Fu W
  • Ma Q
  • Chen L
  • Li P
  • Zhang M
  • Ramamoorthy S
  • Nawaz Z
  • Shimojima T
  • Wang H
  • Yang Y
  • Shen Z
  • Zhang Y
  • Zhang X
  • Nicosia SV
  • Zhang Y
  • Pledger JW
  • Chen J
  • Bai W


The Journal of biological chemistry

Publication Data

May 22, 2009

Associated Grants

  • Agency: NCI NIH HHS, Id: R01 CA093666
  • Agency: NCI NIH HHS, Id: R01 CA100302
  • Agency: NCI NIH HHS, Id: R01 CA127770

Mesh Terms

  • Animals
  • Apoptosis
  • Cell Line
  • Cell Nucleus
  • Cytoprotection
  • Forkhead Transcription Factors
  • Gene Expression Regulation
  • Humans
  • Mice
  • Phosphorylation
  • Protein Binding
  • Protein Processing, Post-Translational
  • Protein Transport
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-mdm2
  • Tumor Suppressor Protein p53
  • Ubiquitin-Protein Ligases
  • Ubiquitination