The MDM2 RING-finger domain is required to promote p53 nuclear export
Abstract
MDM2 can bind to p53 and promote its ubiquitination and subsequent degradation by the proteasome. Current models propose that nuclear export of p53 is required for MDM2-mediated degradation, although the function of MDM2 in p53 nuclear export has not been clarified. Here we show that MDM2 can promote the nuclear export of p53 in transiently transfected cells. This activity requires the nuclear-export signal (NES) of p53, but not the NES of MDM2. A mutation within the MDM2 RING-finger domain that inhibits p53 ubiquitination also inhibits the ability of MDM2 to promote p53 nuclear export. Finally, inhibition of nuclear export stabilizes wild-type p53 and leads to accumulation of ubiquitinated p53 in the nucleus. Our results indicate that MDM2-mediated ubiquitination, or other activities associated with the RING-finger domain, can stimulate the export of p53 to the cytoplasm through the activity of the p53 NES.
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Co-expression of Mdm2 with p53 in Saos-2 or U2OS cells enhances nuclear export of p53, which is required for efficient degradation.
“Two recent reports suggest that co-expression of Mdm2 with p53 in Saos-2 or U2OS cells results in enhanced nuclear export of p53, required for its efficient degradation (Boyd et al., 2000;Geyer et al., 2000).”
From Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms (2001) · cites this paper as Geyer et al., 2000
Mdm2-mediated ubiquitination of p53 induces p53 nuclear export and degradation.
“Mdm2-mediated ubiquitination of p53 induces p53 nuclear export and degradation”
From USP10 Regulates p53 Localization and Stability by Deubiquitinating p53 (2010) · cites this paper as Geyer et al., 2000
p53 degradation can also occur in the nucleus.
“p53 degradation could also occur in the nucleus”
From USP10 Regulates p53 Localization and Stability by Deubiquitinating p53 (2010) · cites this paper as Geyer et al., 2000
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- Authors
- Geyer, R. K., Yu, Z. K., & Maki, C. G.
- Affiliations
- Harvard University (US)
- Corresponding author
- Maki, Carl G.
- ORCID
- Maki, Carl G.
- Venue
- Nature Cell Biology
- Published
- 2000-08-09
- Volume
- 2
- Issue
- 9
- Pages
- 569-573
- ISSN
- 1465-7392 (ISSN-L)
- 1476-4679
- OpenAlex
- W2116998164
- Cited by
- 361
- References
- 26
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 3 · 2023: 8 · 2022: 7 · 2021: 5 · 2020: 4 · 2019: 7 · 2018: 9 · 2017: 10 · 2016: 9 · 2015: 5 · 2014: 11 · 2013: 11 · 2012: 8
- FWCI
- 15.66
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature Cell Biology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancer Research Institute
- National Cancer Institute (R01CA080918)
- 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
- MDM2, p53, RING domain, nuclear export, nuclear export signal, p53 ubiquitination, proteasomal degradation, p53 stabilization, protein-protein interaction
- MeSH terms
- Cell Nucleus, Humans, Nuclear Proteins, Proto-Oncogene Proteins, Tumor Cells, Cultured, Ubiquitins, Tumor Suppressor Protein p53, Zinc Fingers, Protein Structure, Tertiary, Active Transport, Cell Nucleus, Proto-Oncogene Proteins c-mdm2
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