Trim24 targets endogenous p53 for degradation

Proc Natl Acad Sci U S A. 2009 Jul 14;106(28):11612-6. doi: 10.1073/pnas.0813177106. Epub 2009 Jun 25.


Numerous studies focus on the tumor suppressor p53 as a protector of genomic stability, mediator of cell cycle arrest and apoptosis, and target of mutation in 50% of all human cancers. The vast majority of information on p53, its protein-interaction partners and regulation, comes from studies of tumor-derived, cultured cells where p53 and its regulatory controls may be mutated or dysfunctional. To address regulation of endogenous p53 in normal cells, we created a mouse and stem cell model by knock-in (KI) of a tandem-affinity-purification (TAP) epitope at the endogenous Trp-53 locus. Mass spectrometry of TAP-purified p53-complexes from embryonic stem cells revealed Tripartite-motif protein 24 (Trim24), a previously unknown partner of p53. Mutation of TRIM24 homolog, bonus, in Drosophila led to apoptosis, which could be rescued by p53-depletion. These in vivo analyses establish TRIM24/bonus as a pathway that negatively regulates p53 in Drosophila. The Trim24-p53 link is evolutionarily conserved, as TRIM24 depletion in human breast cancer cells caused p53-dependent, spontaneous apoptosis. We found that Trim24 ubiquitylates and negatively regulates p53 levels, suggesting Trim24 as a therapeutic target to restore tumor suppression by p53.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Apoptosis / genetics
  • Cell Line, Tumor
  • Chromatin Immunoprecipitation
  • Chromatography, Gel
  • Drosophila
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism*
  • Gene Knock-In Techniques
  • Humans
  • Immunoblotting
  • Mass Spectrometry
  • Mice
  • Mutation / genetics
  • Tumor Suppressor Protein p53 / genetics
  • Tumor Suppressor Protein p53 / metabolism*
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination / genetics*


  • Bon protein, Drosophila
  • Drosophila Proteins
  • Tumor Suppressor Protein p53
  • Ubiquitin-Protein Ligases