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Updated: Feb 16, 2026

In Vitro Analysis of E3 Ubiquitin Ligase Function
Published on: May 14, 2021
Regulation of the Mdm2-p53 pathway by the ubiquitin E3 ligase MARCH7
Kailiang Zhao1, Yang Yang1, Guang Zhang1
1CAS Key Laboratory of Innate Immunity and Chronic Disease, School of Life Sciences and Medical Center, University of Science & Technology of China, Hefei, Anhui, China.
Abstract:
The tumor suppressor p53 plays a prominent role in the protection against cancer. The activity of p53 is mainly controlled by the ubiquitin E3 ligase Mdm2, which targets p53 for proteasomal degradation. However, the regulation of Mdm2 remains not well understood. Here, we show that MARCH7, a RING domain-containing ubiquitin E3 ligase, physically interacts with Mdm2 and is essential for maintaining the stability of Mdm2. MARCH7 catalyzes Lys63-linked polyubiquitination of Mdm2, which impedes Mdm2 autoubiquitination and degradation, thereby leading to the stabilization of Mdm2. MARCH7 also promotes Mdm2-dependent polyubiquitination and degradation of p53. Furthermore, MARCH7 is able to regulate cell proliferation, DNA damage-induced apoptosis, and tumorigenesis via a p53-dependent mechanism. These findings uncover a novel mechanism for the regulation of Mdm2 and reveal MARCH7 as an important regulator of the Mdm2-p53 pathway.
Insights
The E3 ligase MARCH7 stabilizes Mdm2 by preventing its degradation. This stabilization enhances Mdm2
Area of Science:
- Molecular Biology
- Cancer Biology
- Biochemistry
Background:
- The tumor suppressor p53 is crucial for cancer prevention.
- Mdm2, a ubiquitin E3 ligase, regulates p53 stability and activity.
- The regulatory mechanisms of Mdm2 are not fully understood.
Purpose of the Study:
- To investigate the role of MARCH7 in regulating Mdm2.
- To elucidate the mechanism by which MARCH7 affects the Mdm2-p53 pathway.
Main Methods:
- Co-immunoprecipitation to assess protein interactions.
- Ubiquitination assays to determine polyubiquitination patterns.
- Western blotting to evaluate protein stability.
- Cell proliferation and apoptosis assays.
Main Results:
- MARCH7 physically interacts with Mdm2.
- MARCH7 catalyzes Lys63-linked polyubiquitination of Mdm2, stabilizing it.
- MARCH7 promotes Mdm2-dependent degradation of p53.
- MARCH7 influences cell proliferation, apoptosis, and tumorigenesis via p53.
Conclusions:
- MARCH7 is a novel regulator of Mdm2 stability.
- MARCH7 plays a significant role in the Mdm2-p53 pathway.
- MARCH7 impacts cancer-related cellular processes through p53 regulation.
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