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Updated: Jun 16, 2025
Purification of Ubiquitinated p53 Proteins from Mammalian Cells
Published on: March 21, 2022
USP38 functions as an oncoprotein by downregulating the p53 pathway through deubiquitination and stabilization of
Shanyu Zhao1,2, Xiaoli Liu1,3, Rongkui Luo4
1Department of Pathology, School of Basic Medical Sciences, Shanghai Fifth People's Hospital, Fudan University, Shanghai, China.
Abstract:
Dysregulation of the MDM2-p53 pathway is a commonly observed phenomenon in cancer, where overexpression or amplification of MDM2 leads to increased degradation of p53. This results in reduced levels of p53, leading to the loss of its tumor-suppressive functions. The study focused on investigating the role of Ubiquitin-specific protease 38 (USP38) in cancer and its interaction with the MDM2-p53 axis. We revealed that USP38 positively correlates with MDM2 and negatively correlates with p53 expression. Mechanistically, USP38 directly binds to MDM2, functioning as a deubiquitinating enzyme (DUB) to stabilize MDM2 and suppress p53 expression. Knockout of USP38 hindered cancer cell proliferation, migration, and invasion, and enhanced apoptosis. Moreover, USP38 deficiency increased sensitivity to chemotherapy drugs and promoted ferroptosis in gastric and breast cancer cell lines. Importantly, these effects were found to be dependent on p53, as the downregulation of p53 reversed the phenotypic changes induced by USP38 knockout. These findings shed light on the oncogenic role of USP38 by modulating the MDM2-p53 axis, providing valuable insights into the molecular mechanisms of USP38 in cancer and potential therapeutic strategies for gastric and breast cancer.
Insights
Ubiquitin-specific protease 38 (USP38) stabilizes MDM2, suppressing tumor suppressor p53 in cancer. USP38 knockout inhibits cancer growth and enhances treatment sensitivity, offering new therapeutic avenues.
Area of Science:
- Oncology
- Molecular Biology
- Biochemistry
Background:
- Dysregulation of the MDM2-p53 pathway is a hallmark of many cancers.
- MDM2 overexpression promotes p53 degradation, compromising tumor suppression.
Purpose of the Study:
- To investigate the role of Ubiquitin-specific protease 38 (USP38) in cancer.
- To elucidate USP38's interaction with the MDM2-p53 axis.
Main Methods:
- Correlation analysis of USP38, MDM2, and p53 expression.
- Biochemical assays to determine USP38's deubiquitinating activity on MDM2.
- USP38 knockout experiments in gastric and breast cancer cell lines.
- Assessment of cancer cell phenotypes, drug sensitivity, and ferroptosis.
Main Results:
- USP38 positively correlates with MDM2 and negatively with p53.
- USP38 deubiquitinates and stabilizes MDM2, leading to p53 suppression.
- USP38 knockout inhibits cancer cell proliferation, migration, invasion, and enhances apoptosis.
- USP38 deficiency increases chemotherapy sensitivity and promotes ferroptosis, dependent on p53.
Conclusions:
- USP38 acts as an oncogene by modulating the MDM2-p53 pathway.
- USP38 is a potential therapeutic target for gastric and breast cancers.
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