Phosphorylation of MDMX Mediated by Akt Leads to Stabilization and Induces 14-3-3 Binding
Open accessAbstract
The critical tumor suppressor p53 is mutated or functionally inactivated in nearly all cancers. We have shown previously that the MDM2-MDMX complex functions as an integral unit in targeting p53 for degradation. Here we identify the small protein 14-3-3 as a binding partner of MDMX, which binds at the C terminus (Ser367) in a phosphorylation-dependent manner. Importantly, we demonstrate that the serine/threonine kinase Akt mediates phosphorylation of MDMX at Ser367. This phosphorylation leads to stabilization of MDMX and consequent stabilization of MDM2. Previous studies have shown that Akt phosphorylates and stabilizes MDM2. Our data suggest that stabilization of MDMX by Akt may be an alternative mechanism by which Akt up-regulates MDM2 protein levels and exerts its oncogenic effects on p53 in tumor cells.
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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 [64]
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 [64]
Phosphorylation of MDM2 at Ser166 and Ser186, and of MDMX at Ser367, leads to their stabilization and is associated with p53 inhibition.
“Phosphorylation of MDM2 at Ser166 and Ser186 (Ref. 32), and of MDMX at Ser367 (Ref. 33), leads to their stabilization, and is associated with p53 inhibition.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [33]
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References 48 · Cited by 79
Research works printed but not linked: 4
- Linares, L. K., Hengstermann, A., Ciechanover, A., Muller, S., and Schef- fner, M. (2003) Proc. Natl. Acad. Sci. U. S. A. 100, 12009 -12014
- You, H., Jang, Y., You-Ten, A. I., Okada, H., Liepa, J., Wakeham, A., Zaugg, K., and Mak, T. W. (2004) Proc. Natl. Acad. Sci. U. S. A. 101, 14057-14062
- Mayo, L. D., and Donner, D. B. (2001) Proc. Natl. Acad. Sci. U. S. A. 98, 11598 -11603
- Pereg, Y., Shkedy, D., de Graaf, P., Meulmeester, E., Edelson-Averbukh, M., Salek, M., Biton, S., Teunisse, A. F., Lehmann, W. D., Jochemsen, A. G., and Shiloh, Y. (2005) Proc. Natl. Acad. Sci. U. S. A. 102, 5056 -5061
- Authors
- Lopez-Pajares, V., Kim, M. M., & Yuan, Z.-M.
- Affiliations
- Harvard University (US)
- Corresponding author
- Yuan, Zhi-Min
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2008-05
- Volume
- 283
- Issue
- 20
- Pages
- 13707-13713
- ISSN
- 0021-9258 (ISSN-L)
- PMC
- PMC2376244
- OpenAlex
- W1971283175
- Cited by
- 79
- References
- 48
- Citations by year
- 2026: 1 · 2025: 2 · 2024: 4 · 2023: 1 · 2022: 1 · 2021: 4 · 2020: 4 · 2019: 4 · 2018: 5 · 2017: 3 · 2016: 6 · 2015: 6 · 2014: 7 · 2013: 4 · 2012: 3
- FWCI
- 4.22
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5t32es007155-24, T32ES07155)
- National Cancer Institute (R01 CA85679-02, R01CA085679)
- National Institute of Environmental Health Sciences (T32-ES07155)
- 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 › PI3K/AKT/mTOR signaling in cancer
- Keywords
- MDMX, Akt, phosphorylation, 14-3-3 proteins, MDM2, p53, protein stabilization, p53 degradation, tumor suppressor inactivation, oncogenic signaling
- MeSH terms
- Amino Acid Sequence, Cell Line, Gene Expression Regulation, Humans, Models, Biological, Molecular Sequence Data, Nuclear Proteins, Phosphorylation, Protein Binding, Proto-Oncogene Proteins, Tumor Suppressor Protein p53, Sequence Homology, Amino Acid, Protein Structure, Tertiary, Cell Cycle Proteins, Amino Acid Motifs, 14-3-3 Proteins, Proto-Oncogene Proteins c-akt
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