Cited by 122Cancer-related Molecular Pathways14-3-3 protein interactionsDNA Repair Mechanisms

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Regulation of MDMX nuclear import and degradation by Chk2 and 14-3-3

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LeBron, Cynthia, Chen, Lihong, Gilkes, Daniele M, Chen, Jiandong·2006·The EMBO Journal

DOI 10.1038/sj.emboj.7601032PMC PMC1422166

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Abstract

The MDM2 homolog MDMX is an important regulator of p53 during mouse embryonic development. DNA damage promotes MDMX phosphorylation, nuclear translocation, and degradation by MDM2. Here we show that MDMX copurifies with 14-3-3, and DNA damage stimulates MDMX binding to 14-3-3. Chk2-mediated phosphorylation of MDMX on S367 is important for stimulating 14-3-3 binding, MDMX nuclear import by a cryptic nuclear import signal, and degradation by MDM2. Mutation of MDMX S367 inhibits ubiquitination and degradation by MDM2, and prevents MDMX nuclear import. Expression of 14-3-3 stimulates the degradation of phosphorylated MDMX. Chk2 and 14-3-3 cooperatively stimulate MDMX ubiquitination and overcome the inhibition of p53 by MDMX. These results suggest that MDMX-14-3-3 interaction plays a role in p53 response to DNA damage by regulating MDMX localization and stability.

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Authors: LeBron, C., Chen, L., Gilkes, D. M., & Chen, J.
Affiliations: Moffitt Cancer Center (US)
Corresponding author: Chen, Jiandong
ORCID: Chen, Lihong
Gilkes, Daniele M
Chen, Jiandong
Venue: The EMBO Journal
Publisher: Springer Science and Business Media LLC
Published: 2006-03-02
Volume: 25
Issue: 6
Pages: 1196-1206
ISSN: 0261-4189 (ISSN-L)
1460-2075
DOI: 10.1038/sj.emboj.7601032
PMC: PMC1422166
OpenAlex: W2068624303
Cited by: 122
References: 255
Citations by year: 2025: 2 · 2024: 3 · 2022: 1 · 2021: 6 · 2020: 4 · 2019: 5 · 2018: 2 · 2017: 3 · 2016: 8 · 2015: 2 · 2014: 7 · 2013: 11 · 2012: 9
FWCI: 6.78
Type: journal article
Language: en
Open access: green
europepmc.org
Licence: www.springernature.com/gp/researchers/text-and-data-mining (tdm)
www.springernature.com/gp/researchers/text-and-data-mining (vor)
Locations: The EMBO Journal (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Digital Commons - University of South Florida (University of South Florida) (submittedVersion)
Funders: American Cancer Society
National Institutes of Health
Topics: Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › 14-3-3 protein interactions
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
Keywords: MDMX, Chk2, MDM2, p53, DNA damage response, nuclear import, protein degradation, ubiquitination, phosphorylation, nuclear import signal, protein stability, mouse embryo development
MeSH terms: Animals, Breast Neoplasms, DNA Damage, Gene Expression Regulation, HeLa Cells, Humans, Nuclear Proteins, Phosphorylation, Protein Binding, Proto-Oncogene Proteins, Osteosarcoma, Tumor Suppressor Protein p53, Mice, Knockout, Cell Cycle Proteins, Active Transport, Cell Nucleus, Ubiquitin, Immunoprecipitation, 14-3-3 Proteins, Cyclin-Dependent Kinase 2, Mice

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Regulation of MDMX nuclear import and degradation by Chk2 and 14-3-3

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