DNA Damage-Induced Phosphorylation of MdmX at Serine 367 Activates p53 by Targeting MdmX for Mdm2-Dependent Degradation
Open accessAbstract
Understanding how p53 activity is regulated is crucial in elucidating mechanisms of cellular defense against cancer. Genetic data indicate that Mdmx as well as Mdm2 plays a major role in maintaining p53 activity at low levels in nonstressed cells. However, biochemical mechanisms of how Mdmx regulates p53 activity are not well understood. Through identification of Mdmx-binding proteins, we found that 14-3-3 proteins are associated with Mdmx. Mdmx harbors a consensus sequence for binding of 14-3-3. Serine 367 (S367) is located within the putative binding sequence for 14-3-3, and its substitution with alanine (S367A) abolishes binding of Mdmx to 14-3-3. Transfection assays indicated that the S367A mutation, in cooperation with Mdm2, enhances the ability of Mdmx to repress the transcriptional activity of p53. The S367A mutant is more resistant to Mdm2-dependent ubiquitination and degradation than wild-type Mdmx, and Mdmx phosphorylated at S367 is preferentially degraded by Mdm2. Several types of DNA damage markedly enhance S367 phosphorylation, coinciding with increased binding of Mdmx to 14-3-3 and accelerated Mdmx degradation. Furthermore, promotion of growth of normal human fibroblasts after introduction of Mdmx is enhanced by the S367 mutation. We propose that Mdmx phosphorylation at S367 plays an important role in p53 activation after DNA damage by triggering Mdm2-dependent degradation of Mdmx.
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Phosphorylation of Mdm2 and Mdmx at serine residues close to the RING domain by ATM or ATM-dependent kinases leads to accelerated auto-degradation of both Mdm2 and Mdmx, with consequent p53 accumulation and activation.
“Additionally, phosphorylation of Mdm2 and Mdmx at serine residues close to the RING domain by ATM or ATM-dependent kinases leads to accelerated auto-degradation of both Mdm2 [54] and Mdmx [41,55–58], with consequent p53 accumulation and activation.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [57]
In contrast to DNA damage, 14-3-3 binding induced by Akt leads to Mdmx stabilization and p53 inactivation.
“However, in contrast to DNA damage, 14-3-3 binding induced by Akt leads to Mdmx stabilization and p53 inactivation.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [57]
Akt phosphorylates Mdmx at Ser367, and both DNA damage and Akt-induced Ser367 phosphorylation stimulate binding of Mdmx to 14-3-3 proteins.
“Interestingly, one of the damage kinase target residues (Ser367) of Mdmx is also phosphorylated by Akt [65]. Furthermore, DNA damage and Akt-induced Ser367 phosphorylation both stimulate binding of Mdmx to 14-3-3 proteins [57,64].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [57]
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References 58 · Cited by 129
- Authors
- Okamoto, K., Kashima, K., Pereg, Y., Ishida, M., Yamazaki, S., Nota, A., Teunisse, A., Migliorini, D., Kitabayashi, I., Marine, J.-C., Prives, C., Shiloh, Y., Jochemsen, A. G., & Taya, Y.
- Affiliations
- Japan Science and Technology Agency (JP)
- Tel Aviv University (IL)
- Leiden University Medical Center (NL)
- Columbia University (US)
- National Cancer Center Research Institute (JP)
- Vlaams Instituut voor Biotechnologie (BE)
- Corresponding author
- Okamoto, Koji
- ORCID
- Venue
- Molecular and Cellular Biology
- Publisher
- Informa UK Limited
- Published
- 2005-11-01
- Volume
- 25
- Issue
- 21
- Pages
- 9608-9620
- ISSN
- 0270-7306 (ISSN-L)
- 1098-5549
- PMC
- PMC1265801
- OpenAlex
- W2153478539
- Cited by
- 129
- References
- 58
- Citations by year
- 2026: 1 · 2025: 1 · 2024: 2 · 2023: 3 · 2022: 2 · 2021: 4 · 2020: 4 · 2019: 2 · 2018: 3 · 2017: 3 · 2016: 9 · 2015: 4 · 2014: 5 · 2013: 6 · 2012: 9
- FWCI
- 5.91
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Molecular and Cellular Biology (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Ghent University Academic Bibliography (Ghent University) (submittedVersion)
- Institutional Repositories DataBase (IRDB) (submittedVersion)
- Funders
- Tokyo Biochemical Research Foundation
- Ministry of Education, Culture, Sports, Science and Technology
- Princess Takamatsu Cancer Research Fund
- Centers for Disease Control and Prevention (NCI 87497)
- National Cancer Institute
- National Institute of Neurological Disorders and Stroke (R01NS031763, NS 31763)
- 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 › Heat shock proteins research
- Keywords
- MDMX, p53 activation, DNA damage, 14-3-3 proteins, MDM2, ubiquitination, protein degradation, tumor suppressor regulation
- MeSH terms
- Amino Acid Sequence, Animals, Cell Line, Chlorocebus aethiops, DNA Damage, Fibroblasts, Humans, Molecular Sequence Data, Mutation, Nuclear Proteins, Phosphorylation, Protein Binding, Proto-Oncogene Proteins, Serine, Tumor Suppressor Protein p53, Cell Cycle Proteins, Proteasome Endopeptidase Complex, 14-3-3 Proteins, Mice, Proto-Oncogene Proteins c-mdm2
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