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Trim24 targets endogenous p53 for degradation
Open accessAbstract
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.
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“TRIM24 can bind an acetylated peptide of the tumour suppressor p53, leading to ubiquitylation and degradation of the target 130 .”
From Targeted protein degradation: expanding the toolbox (2019) · cites this paper as [130]
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Metadata
- Authors
- Allton, K., Jain, A. K., Herz, H.-M., Tsai, W.-W., Jung, S. Y., Qin, J., Bergmann, A., Johnson, R. L., & Barton, M. C.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- The University of Texas Health Science Center at Houston (US)
- Baylor College of Medicine (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2009-07-14
- Volume
- 106
- Issue
- 28
- Pages
- 11612-11616
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2710642
- OpenAlex
- W2037942882
- Cited by
- 292
- References
- 40
- Citations by year
- 2026: 7 · 2025: 24 · 2024: 8 · 2023: 25 · 2022: 15 · 2021: 20 · 2020: 23 · 2019: 12 · 2018: 17 · 2017: 23 · 2016: 15 · 2015: 13 · 2014: 16 · 2013: 11 · 2012: 28
- FWCI
- 10.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of General Medical Sciences (GM081627, P01GM081627, GM068016, R01GM068016)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Keywords
- TRIM24, p53, protein degradation, ubiquitination, tumor suppressor regulation, Drosophila, embryonic stem cells, tandem affinity purification, tumor suppression, breast cancer, apoptosis
- MeSH terms
- Animals, Chromatography, Gel, Drosophila, Humans, Mutation, Mass Spectrometry, Immunoblotting, Tumor Suppressor Protein p53, Apoptosis, Drosophila Proteins, Ubiquitin-Protein Ligases, Cell Line, Tumor, Chromatin Immunoprecipitation, Mice, Ubiquitination, Gene Knock-In Techniques
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