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Updated: Jun 25, 2026
Purification of Ubiquitinated p53 Proteins from Mammalian Cells
Published on: March 21, 2022
Parthenolide promotes the ubiquitination of MDM2 and activates p53 cellular functions
Y N Vashisht Gopal1, Ekkawit Chanchorn, Michael W Van Dyke
1Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Unit 079, 1515 Holcombe Boulevard, Houston, TX 77030-4009, USA.
Abstract:
MDM2 belongs to a class of ring-finger domain-containing ubiquitin ligases that mediate the proteasomal degradation of numerous proteins, including themselves. Arguably, the most important substrate of MDM2 is p53, which controls cell cycle progression and apoptosis. MDM2 and p53 are parts of a feedback regulatory loop whose perturbations are often present in cancer and are targets for anticancer drug development. We found that the natural product, small-molecule anti-inflammatory agent parthenolide (PN), which is actively being investigated as a potential therapeutic for many human cancers, induces ubiquitination of MDM2 in treated cells, resulting in the activation of p53 and other MDM2-regulated tumor-suppressor proteins. Using cells with functional gene deletions and small interfering RNA knockdown studies, we found that these effects required the DNA damage transducer ataxia telangiectasia mutated. The effects of PN on tumor suppressor activation were comparable with that of nutlin-3a, a recently developed small molecule that was designed to interfere with the interaction between MDM2 and p53 but does not promote MDM2 ubiquitination. Our study illustrates an alternative approach for controlling MDM2 and p53 activities and identifies an additional critically important cancer pathway affected by PN.
Insights
Parthenolide (PN) activates tumor suppressors like p53 by inducing MDM2 ubiquitination, a novel cancer therapy target. This process, dependent on ATM, offers an alternative to MDM2-p53 interaction inhibitors.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- MDM2 is a ubiquitin ligase targeting proteins, notably p53, crucial for cell cycle and apoptosis.
- The MDM2-p53 regulatory loop is frequently dysregulated in cancer, presenting a target for drug development.
- Parthenolide (PN), a natural product, is explored for its anti-cancer potential.
Purpose of the Study:
- To investigate the mechanism by which parthenolide (PN) affects MDM2 and p53.
- To explore PN as a potential therapeutic agent targeting the MDM2-p53 pathway in cancer.
Main Methods:
- Cellular studies involving gene deletions and small interfering RNA (siRNA) knockdown.
- Analysis of protein ubiquitination and activation of tumor suppressor proteins.
- Comparison of PN effects with nutlin-3a, an MDM2-p53 interaction inhibitor.
Main Results:
- Parthenolide (PN) induces MDM2 ubiquitination in treated cells.
- PN treatment leads to the activation of p53 and other MDM2-regulated tumor suppressors.
- These effects are dependent on the DNA damage transducer ataxia telangiectasia mutated (ATM).
- PN's impact on tumor suppressor activation is comparable to nutlin-3a.
Conclusions:
- Parthenolide (PN) represents an alternative strategy for modulating MDM2 and p53 activity.
- PN's mechanism involves MDM2 ubiquitination, distinct from nutlin-3a's approach.
- The study identifies a critical cancer pathway influenced by PN, highlighting its therapeutic potential.
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