C-terminal modifications regulate MDM2 dissociation and nuclear export of p53
Abstract
p53 functions to prevent malignant progression, in part by inhibiting proliferation or inducing the death of potential tumour cells. One of the most important regulators of p53 is MDM2, a RING domain E3 ligase that ubiquitinates p53, leading to both proteasomal degradation and relocation of p53 from the nucleus to the cytoplasm. Previous studies have suggested that although polyubiquitination is required for degradation, monoubiquitination of p53 is sufficient for nuclear export. Using a p53-ubiquitin fusion protein we show that ubiquitination contributes to two steps before export: exposure of a carboxy-terminal nuclear export sequence (NES), and dissociation of MDM2. Monoubiquitination can directly promote further modifications of p53 with ubiquitin-like proteins and MDM2 promotes the interaction of the SUMO E3 ligase PIASy with p53, enhancing both sumoylation and nuclear export. Our results suggest that modifications such as sumoylation can regulate the strength of the p53-MDM2 interaction and participate in driving the export of p53.
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Mono-ubiquitination of p53 can facilitate export of p53 from the nucleus to the cytoplasm, thereby inhibiting its role as a transcription factor.
“Additionally, mono-ubiquitination of p53 can facilitate export of p53 from the nucleus to the cytoplasm, thereby inhibiting its role as a transcription factor [110,111].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [110]
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- Authors
- Carter, S., Bischof, O., Dejean, A., & Vousden, K. H.
- Affiliations
- Cancer Research UK Scotland Institute (GB)
- Inserm (FR)
- Corresponding author
- Vousden, Karen H.
- Venue
- Nature Cell Biology
- Published
- 2007-03-18
- Volume
- 9
- Issue
- 4
- Pages
- 428-435
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2021176126
- Cited by
- 225
- References
- 34
- Citations by year
- 2026: 6 · 2025: 5 · 2024: 2 · 2023: 6 · 2022: 10 · 2021: 6 · 2020: 7 · 2019: 6 · 2018: 10 · 2017: 13 · 2016: 6 · 2015: 11 · 2014: 13 · 2013: 16 · 2012: 15
- FWCI
- 13.28
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- HAL (submittedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- p53, MDM2, nuclear export, monoubiquitination, polyubiquitination, SUMOylation, PIASy, E3 ubiquitin ligase, p53-MDM2 interaction, nuclear export sequence, ubiquitination, tumor suppressor regulation
- MeSH terms
- Animals, Cell Nucleus, Cells, Cultured, Electrophoresis, Polyacrylamide Gel, Humans, Microscopy, Fluorescence, Models, Biological, Nuclear Proteins, Protein Binding, Recombinant Fusion Proteins, Blotting, Western, Tumor Suppressor Protein p53, Active Transport, Cell Nucleus, Ubiquitin, Ubiquitin-Protein Ligases, Cell Line, Tumor, Green Fluorescent Proteins, Mice, Proto-Oncogene Proteins c-mdm2
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