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Mutant p53 Sequestration of the MDM2 Acidic Domain Inhibits E3 Ligase Activity
- Source :
- Molecular and Cellular Biology. 39
- Publication Year :
- 2019
- Publisher :
- Informa UK Limited, 2019.
-
Abstract
- Missense p53 mutants often accumulate in tumors and drive progression through gain of function. MDM2 efficiently degrades wild-type p53 but fails to degrade mutant p53 in tumor cells. Previous studies revealed that mutant p53 inhibits MDM2 autoubiquitination, suggesting that the interaction inhibits MDM2 E3 activity. Recent work showed that MDM2 E3 activity is stimulated by intramolecular interaction between the RING and acidic domains. Here, we show that in the mutant p53-MDM2 complex, the mutant p53 core domain binds to the MDM2 acidic domain with significantly higher avidity than wild-type p53. The mutant p53-MDM2 complex is deficient in catalyzing ubiquitin release from the activated E2 conjugating enzyme. An MDM2 construct with extra copies of the acidic domain is resistant to inhibition by mutant p53 and efficiently promotes mutant p53 ubiquitination and degradation. The results suggest that mutant p53 interferes with the intramolecular autoactivation mechanism of MDM2, contributing to reduced ubiquitination and increased accumulation in tumor cells.
- Subjects :
- Ubiquitin-Protein Ligases
Mutant
Mutation, Missense
03 medical and health sciences
0302 clinical medicine
Ubiquitin
Cell Line, Tumor
Humans
Missense mutation
Avidity
neoplasms
Molecular Biology
030304 developmental biology
chemistry.chemical_classification
0303 health sciences
Binding Sites
biology
Ubiquitination
Nuclear Proteins
Proto-Oncogene Proteins c-mdm2
Cell Biology
Cell biology
Ubiquitin ligase
enzymes and coenzymes (carbohydrates)
Enzyme
chemistry
030220 oncology & carcinogenesis
Domain (ring theory)
biology.protein
Mdm2
Tumor Suppressor Protein p53
Research Article
Protein Binding
Subjects
Details
- ISSN :
- 10985549
- Volume :
- 39
- Database :
- OpenAIRE
- Journal :
- Molecular and Cellular Biology
- Accession number :
- edsair.doi.dedup.....4b58c2789481f0482e9ab392ae549906