An intact HDM2 RING-finger domain is required for nuclear exclusion of p53

Boyd, Scott D.; Tsai, Kenneth Y.; Jacks, Tyler

doi:10.1038/35023500

Cited by 334Cancer-related Molecular PathwaysUbiquitin and proteasome pathwaysHeat shock proteins research

An intact HDM2 RING-finger domain is required for nuclear exclusion of p53

Boyd, Scott D., Tsai, Kenneth Y., Jacks, Tyler·2000·Nature Cell Biology

DOI 10.1038/35023500

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Abstract

The p53 tumour-suppressor protein is negatively regulated by HDM2. Recent reports indicate that the leucine-rich nuclear-export sequence (NES) of HDM2 enables it to shuttle to the cytoplasm, and that this activity is required for degradation of p53. However, it is unclear whether HDM2 is involved in nuclear export of p53, partly because p53 has itself been shown to contain a functional NES within its tetramerization domain. Here we show that co-expression of HDM2 with green fluorescent protein (GFP)-tagged p53 causes redistribution of p53 from the nucleus to the cytoplasm of the cell. This activity is dependent on binding of p53 to HDM2, and requires an intact p53 NES, but is independent of the HDM2 NES. A mutant of the HDM2 RING-finger domain that is unable to ubiquitinate p53 does not cause relocalization of p53, indicating that ubiquitin ligation or other activities of this region of HDM2 may be necessary for its regulation of p53 localization.

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Efficient degradation of p53 requires its nuclear export.
“Several reports suggest that nuclear export of p53, mediated through the nuclear export signal (NES) of Mdm2 and/or through the NES of p53 itself, is required for its efficient degradation (Roth et al., 1998;Tao and Levine, 1999;Boyd et al., 2000;Geyer et al., 2000).”
From Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms (2001) · cites this paper as Boyd et al., 2000
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 Boyd 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 Boyd et al., 2000

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Authors: Boyd, S. D., Tsai, K. Y., & Jacks, T.
Affiliations: Massachusetts Institute of Technology (US)
Harvard–MIT Division of Health Sciences and Technology (US)
Howard Hughes Medical Institute (US)
Corresponding author: Jacks, Tyler
ORCID: Boyd, Scott D.
Tsai, Kenneth Y.
Jacks, Tyler
Venue: Nature Cell Biology
Publisher: Springer Science and Business Media LLC
Published: 2000-08-09
Volume: 2
Issue: 9
Pages: 563-568
ISSN: 1465-7392 (ISSN-L)
1476-4679
DOI: 10.1038/35023500
OpenAlex: W2135300227
Cited by: 334
References: 33
Citations by year: 2026: 2 · 2025: 4 · 2024: 1 · 2023: 10 · 2022: 7 · 2021: 7 · 2020: 7 · 2019: 5 · 2018: 3 · 2017: 7 · 2016: 11 · 2015: 8 · 2014: 7 · 2013: 10 · 2012: 8
FWCI: 14.39
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Nature Cell Biology (publishedVersion)
PubMed (publishedVersion)
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, RING domain, nuclear export, nuclear exclusion, nuclear export sequence, protein-protein interaction, ubiquitination, p53 degradation, subcellular localization, tumor suppressor regulation
MeSH terms: Animals, Cell Nucleus, Cytoplasm, Humans, Nuclear Proteins, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Tumor Cells, Cultured, Ubiquitins, Tumor Suppressor Protein p53, Mutagenesis, Zinc Fingers, 3T3 Cells, Protein Structure, Tertiary, Active Transport, Cell Nucleus, Mice, Proto-Oncogene Proteins c-mdm2

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An intact HDM2 RING-finger domain is required for nuclear exclusion of p53

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