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Updated: Apr 16, 2026
Yeast As a Chassis for Developing Functional Assays to Study Human P53
Published on: August 4, 2019
TRIM25 has a dual function in the p53/Mdm2 circuit
P Zhang1,2, S Elabd1, S Hammer3
1Institute of Toxicology and Genetics, Karlsruhe Institute of Technology, Karlsruhe, Germany.
Abstract:
P53 is an important tumor suppressor that, upon activation, induces growth arrest and cell death. Control of p53 is thus of prime importance for proliferating cells, but also for cancer therapy, where p53 activity contributes to the eradication of tumors. Mdm2 functionally inhibits p53 and targets the tumor suppressor protein for degradation. In a genetic screen, we identified TRIM25 as a novel regulator of p53 and Mdm2. TRIM25 increased p53 and Mdm2 abundance by inhibiting their ubiquitination and degradation in 26 S proteasomes. TRIM25 co-precipitated with p53 and Mdm2 and interfered with the association of p300 and Mdm2, a critical step for p53 polyubiquitination. Despite the increase in p53 levels, p53 activity was inhibited in the presence of TRIM25. Downregulation of TRIM25 resulted in an increased acetylation of p53 and p53-dependent cell death in HCT116 cells. Upon genotoxic insults, TRIM25 dampened the p53-dependent DNA damage response. The downregulation of TRIM25 furthermore resulted in massive apoptosis during early embryogenesis of medaka, which was rescued by the concomitant downregulation of p53, demonstrating the functional relevance of the regulation of p53 by TRIM25 in an organismal context.
Insights
TRIM25 is a novel regulator of the tumor suppressor p53 and its inhibitor Mdm2. TRIM25 increases p53 and Mdm2 levels but inhibits p53 activity, impacting cell death and DNA damage response.
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- The p53 protein is a critical tumor suppressor that halts cell growth and induces cell death.
- Mdm2 protein inhibits p53, targeting it for degradation, which is crucial for controlling p53 levels.
Purpose of the Study:
- To identify novel regulators of p53 and Mdm2.
- To elucidate the mechanism by which TRIM25 affects p53 and Mdm2.
Main Methods:
- Genetic screening to identify TRIM25 as a regulator.
- Co-precipitation assays to study protein interactions.
- Analysis of ubiquitination and degradation pathways.
- Cell death assays in HCT116 cells.
- Embryogenesis studies in medaka.
Main Results:
- TRIM25 was identified as a novel regulator of p53 and Mdm2.
- TRIM25 increases p53 and Mdm2 protein levels by inhibiting their ubiquitination and proteasomal degradation.
- TRIM25 interferes with p300 and Mdm2 association, a key step for p53 polyubiquitination.
- TRIM25 inhibits p53 activity, leading to reduced p53-dependent cell death and DNA damage response.
- TRIM25 downregulation causes apoptosis during medaka embryogenesis, which is rescued by p53 downregulation.
Conclusions:
- TRIM25 is a novel negative regulator of p53 tumor suppressor activity.
- TRIM25 plays a significant role in controlling cell death and DNA damage response pathways.
- TRIM25's regulation of p53 is functionally relevant in an organismal context, impacting embryonic development.
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