Trim24 targets endogenous p53 for degradation.
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.
Allton
Kendra
K
Department of Biochemistry and Molecular Biology, Program in Genes and Development, Graduate School of Biomedical Sciences and Center for Stem Cell and Developmental Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Jain
Abhinav K
AK
Herz
Hans-Martin
HM
Tsai
Wen-Wei
WW
Jung
Sung Yun
SY
Qin
Jun
J
Bergmann
Andreas
A
Johnson
Randy L
RL
Barton
Michelle Craig
MC
D000818:Animals; D017209:Apoptosis / Q000235:genetics; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D002850:Chromatography, Gel; D004330:Drosophila; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism*; D055879:Gene Knock-In Techniques; D006801:Humans; D015151:Immunoblotting; D013058:Mass Spectrometry; D051379:Mice; D009154:Mutation / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination / Q000235:genetics*
C502013:Bon protein, Drosophila; D029721:Drosophila Proteins; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases