Trim24 targets endogenous p53 for degradation

Kendra Allton, Abhinav K. Jain, Hans Martin Herz, Wen Wei Tsai, Yun Jung Sung, Jun Qin, Andreas Bergmann, Randy L. Johnson, Michelle Craig Barton

Research output: Contribution to journalArticlepeer-review

167 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)11612-11616
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number28
DOIs
StatePublished - Jul 14 2009
Externally publishedYes

Keywords

  • Apoptosis
  • Bonus
  • TAP
  • Ubiquitylation

ASJC Scopus subject areas

  • General

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