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Updated: Mar 15, 2026
Purification of Ubiquitinated p53 Proteins from Mammalian Cells
Published on: March 21, 2022
Ubiquitination of MEIS1 by MDM2 serves as a switch for p53 stabilization and DNA damage response activation
Jiaxin Liu1,2, Yanxia Duan1, Qing Xiao3
1Department of Pathology, Xiangya Hospital, XiangYa School of Basic Medical Sciences, Central South University, Changsha, China.
Abstract:
Targeting MDM2 by disrupting its interaction with p53 or inhibiting its E3 ligase activity is a promising strategy to restore p53 functionality. However, achieving anticancer efficacy while minimizing dose-limiting toxicities remains a significant challenge. Moreover, MDM2 also ubiquitinates various non-p53 targets, complicating its therapeutic targeting. In this study, we demonstrate that MDM2 directly facilitates K48-linked polyubiquitination of MEIS1 at K178, leading to its proteasomal degradation. Notably, MEIS1 forms a non-competitive ternary complex with MDM2 and p53, effectively promoting ubiquitin transfer to itself and preventing p53 ubiquitination. The MEIS1 K178R mutant, which is deficient in ubiquitination, fails to suppress MDM2-mediated p53 ubiquitination, demonstrating a mechanistic link between MEIS1 self-ubiquitination and p53 stabilization. Furthermore, MDM2-mediated MEIS1 ubiquitination is a prerequisite for p53 activation in the DNA damage response. Importantly, a MEIS1-derived peptide, which mimics the MDM2-mediating ubiquitination motif, enhances both MEIS1 and p53 stability, suppresses cell proliferation and tumor growth. Collectively, our findings identify MEIS1 as a molecular decoy that competes for ubiquitin transfer to protect p53 and highlight that MEIS1 ubiquitination could be a novel therapeutic target for reactivating p53-dependent tumor suppression.
Insights
MDM2 targets MEIS1 for degradation, but MEIS1 acts as a decoy, protecting p53. Targeting MEIS1 ubiquitination may restore p53 tumor suppression.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Targeting MDM2 is a promising cancer therapy strategy to restore p53 function.
- Challenges include dose-limiting toxicities and MDM2's non-p53 targets.
- Understanding MDM2's complex interactions is crucial for effective therapeutic development.
Purpose of the Study:
- To investigate the role of MEIS1 in MDM2-mediated p53 regulation.
- To explore MEIS1 as a potential therapeutic target for cancer treatment.
- To elucidate the mechanism by which MEIS1 influences p53 stability and ubiquitination.
Main Methods:
- Investigated MDM2-mediated ubiquitination of MEIS1 using biochemical assays.
- Utilized a MEIS1 K178R mutant to assess the role of MEIS1 ubiquitination.
- Developed a MEIS1-derived peptide to mimic ubiquitination motifs.
- Assessed effects on cell proliferation and tumor growth in vivo.
Main Results:
- MDM2 directly ubiquitinates MEIS1 at K178, leading to its degradation.
- MEIS1 forms a ternary complex with MDM2 and p53, acting as a decoy for ubiquitination.
- MEIS1 ubiquitination is essential for p53 stabilization and activation during DNA damage response.
- A MEIS1-derived peptide stabilized MEIS1 and p53, inhibiting tumor growth.
Conclusions:
- MEIS1 acts as a molecular decoy, protecting p53 from MDM2-mediated ubiquitination.
- MEIS1 ubiquitination is a critical prerequisite for p53 activation in DNA damage response.
- Targeting MEIS1 ubiquitination represents a novel therapeutic strategy for reactivating p53-dependent tumor suppression.
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