ArticleGenes & development2018
Wild-type and cancer-related p53 proteins are preferentially degraded by MDM2 as dimers rather than tetramers.
Article in Genes & development, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 33 citations in OpenAlex.
- Molecular Characteristics, Circularization Mechanism, and Potential Functions of circRNA-0172.Genes · 2025Article
- IMPDH inhibition induces DNA replication stress and ATR sensitivity in Merkel cell carcinoma.iScience · 2025Article
- Correlation of p53 oligomeric status and its subcellular localization in the presence of the AML-associated NPM mutant.PloS one · 2025Article
- Identify Non-mutational p53 Functional Deficiency in Human Cancers.Genomics, proteomics & bioinformatics · 2024Article
- The Ashkenazi-Centric G334R Variant ofMolecular and cellular biology · 2024Article
- NFE2L3 drives hepatocellular carcinoma cell proliferation by regulating the proteasome-dependent degradation of ISGylated p53.Cancer science · 2023Article
- How Do Cancer-Related Mutations Affect the Oligomerisation State of the p53 Tetramerisation Domain?Current issues in molecular biology · 2023Article
- Li-Fraumeni Syndrome-Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death.Cancer discovery · 2023Article
- The ubiquitin ligase TRIM21 regulates mutant p53 accumulation and gain of function in cancer.The Journal of clinical investigation · 2023Article
- p53 Frameshift Mutations Couple Loss-of-Function with Unique Neomorphic Activities.Molecular cancer research : MCR · 2021Article
- Article
- Targeting Triple Negative Breast Cancer with a Nucleus-Directed p53 Tetramerization Domain Peptide.Molecular pharmaceutics · 2021Article
- Circular RNA CDR1as disrupts the p53/MDM2 complex to inhibit Gliomagenesis.Molecular cancer · 2020Article
- p53 tetramerization: at the center of the dominant-negative effect of mutant p53.Genes & development · 2020Review
- The Status of p53 Oligomeric and Aggregation States in Cancer.Biomolecules · 2020Review
- Oncogenic Gain of Function in Glioblastoma Is Linked to Mutant p53 Amyloid Oligomers.iScience · 2020Article
- Regulation of the MDM2-p53 pathway by the ubiquitin ligase HERC2.Molecular oncology · 2020Article
- Stepwise multipolyubiquitination of p53 by the E6AP-E6 ubiquitin ligase complex.The Journal of biological chemistry · 2019Article
- Regulators of Oncogenic Mutant TP53 Gain of Function.Cancers · 2018Review
- Mouse Homolog of the HumanCancer research · 2018Article
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
The p53 tumor suppressor protein is the most well studied as a regulator of transcription in the nucleus, where it exists primarily as a tetramer. However, there are other oligomeric states of p53 that are relevant to its regulation and activities. In unstressed cells, p53 is normally held in check by MDM2 that targets p53 for transcriptional repression, proteasomal degradation, and cytoplasmic localization. Here we discovered a hydrophobic region within the MDM2 N-terminal domain that binds exclusively to the dimeric form of the p53 C-terminal domain in vitro. In cell-based assays, MDM2 exhibits superior binding to, hyperdegradation of, and increased nuclear exclusion of dimeric p53 when compared with tetrameric wild-type p53. Correspondingly, impairing the hydrophobicity of the newly identified N-terminal MDM2 region leads to p53 stabilization. Interestingly, we found that dimeric mutant p53 is partially unfolded and is a target for ubiquitin-independent degradation by the 20S proteasome. Finally, forcing certain tumor-derived mutant forms of p53 into dimer configuration results in hyperdegradation of mutant p53 and inhibition of p53-mediated cancer cell migration. Gaining insight into different oligomeric forms of p53 may provide novel approaches to cancer therapy.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.