FBXO11 promotes the Neddylation of p53 and inhibits its transcriptional activity

J Biol Chem. 2007 Jan 19;282(3):1797-804. doi: 10.1074/jbc.M609001200. Epub 2006 Nov 9.

Abstract

The p53 tumor suppressor is regulated by post-translational modification, including ubiquitination, phosphorylation and acetylation. It has previously been shown that the ubiquitin ligase Mdm2 also promotes the conjugation of Nedd8, a ubiquitin-like protein, to p53, inhibiting its transcriptional activity. We report the identification of FBXO11, a member of the F-box protein family and a component of the Skp1.Cullin1.F-box (SCF) complex, as a new p53-interacting protein. We show that FBXO11 promotes the neddylation of p53 both in vitro and in vivo. In addition to the C-terminal lysine residues, FBXO11 can also promote Nedd8 conjugation to Lys-320 and Lys-321, and neddylation of p53 leads to suppression of p53 function. This is consistent with recent studies showing that a lysine to arginine mutation at Lys-320 significantly enhances p53 function, although Lys-320 was originally identified as an acetylation site involving PCAF-mediated activation of p53. Our study provides an example of an F-box protein acting as an adaptor protein that can mediate the neddylation of a non-cullin substrate.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Apoptosis
  • Arginine / chemistry
  • Cell Cycle Proteins / chemistry
  • Cell Cycle Proteins / metabolism
  • Cullin Proteins / chemistry
  • F-Box Proteins / metabolism*
  • HeLa Cells
  • Histone Acetyltransferases / metabolism
  • Humans
  • Lysine / chemistry
  • NEDD8 Protein
  • Protein Binding
  • Protein Structure, Tertiary
  • Protein-Arginine N-Methyltransferases / metabolism*
  • SKP Cullin F-Box Protein Ligases / chemistry
  • Transcription Factors / metabolism
  • Transcription, Genetic*
  • Tumor Suppressor Protein p53 / physiology*
  • Ubiquitin / chemistry
  • Ubiquitins / metabolism*
  • p300-CBP Transcription Factors

Substances

  • Cell Cycle Proteins
  • Cullin 1
  • Cullin Proteins
  • F-Box Proteins
  • NEDD8 Protein
  • NEDD8 protein, human
  • TP53 protein, human
  • Transcription Factors
  • Tumor Suppressor Protein p53
  • Ubiquitin
  • Ubiquitins
  • Arginine
  • FBXO11 protein, human
  • Protein-Arginine N-Methyltransferases
  • Histone Acetyltransferases
  • p300-CBP Transcription Factors
  • p300-CBP-associated factor
  • SKP Cullin F-Box Protein Ligases
  • Lysine