Related Experiment Video
Updated: Jun 26, 2025
10:55
Purification of Ubiquitinated p53 Proteins from Mammalian Cells
Published on: March 21, 2022
2.1K
P53 upregulation by USP7-engaging molecular glues
Zhaoyang Li1, Ziying Wang1, Chao Zhong1
1The State Key Laboratory of Medical Neurobiology and MOE Frontiers Center for Brain Science, Huashan Hospital, the Institutes of Brain Science, School of Life Sciences, Fudan University, Shanghai 200438, China.
Science Bulletin
|May 11, 2024
Summary
Researchers identified molecular glues that stabilize the P53 protein by targeting USP7, a deubiquitinase. Bromocriptine, an FDA-approved drug, showed significant effects, inhibiting cancer cell proliferation and tumor growth.
Area of Science:
- Chemical Biology
- Drug Discovery
- Proteostasis
Background:
- Molecular glues are small molecules that induce protein degradation or stabilization by forming ternary complexes.
- Identifying molecular glues, especially those upregulating target proteins like P53, is challenging.
- P53 protein levels are regulated by E3 ligases and deubiquitinases (DUBs); stabilizing P53 may involve enhancing its interaction with DUBs.
Purpose of the Study:
- To identify novel molecular glues that upregulate P53 protein levels.
- To investigate the mechanism by which molecular glues stabilize P53.
- To evaluate the anti-cancer effects of identified P53-stabilizing molecular glues.
Main Methods:
- Utilized small-molecule microarray technology for unbiased screening.
- Identified compounds that tether P53 to the deubiquitinase USP7.
- Verified the mechanism of action and evaluated anti-cancer efficacy in vitro and in vivo.
Main Results:
- Discovered three potential molecular glues that increase P53 levels by engaging USP7.
- Bromocriptine (BC), an FDA-approved drug, demonstrated robust P53 stabilization via USP7.
- BC inhibited cancer cell proliferation and suppressed tumor growth in a xenograft model.
Conclusions:
- Established a screening platform for identifying P53-upregulating molecular glues.
- Bromocriptine acts as a molecular glue to stabilize P53 through USP7, offering therapeutic potential.
- The developed strategy can be applied to discover other molecular glues for drug discovery and chemical biology.
Related Concept Videos
02:23Abnormal Proliferation
4.5K
Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the...
4.5K
02:04Covalently Linked Protein Regulators
6.8K
Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
These groups modify specific amino acids in a protein....
6.8K
02:37DNA Damage can Stall the Cell Cycle
9.1K
In response to DNA damage, cells can pause the cell cycle to assess and repair the breaks. However, the cell must check the DNA at certain critical stages during the cell cycle. If the cell cycle pauses before DNA replication, the cells will contain twice the amount of DNA. On the other hand, if cells arrest after DNA replication but before mitosis, they will contain four times the normal amount of DNA. With a host of specialized proteins at their disposal,cells must use the right protein at...
9.1K
01:23Negative Regulator Molecules
35.3K
Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
35.3K
01:19Interactions Between Signaling Pathways
6.3K
Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
6.3K