Stabilization of the MDM2 Oncoprotein by Interaction with the Structurally Related MDMX Protein
Open accessAbstract
The MDM2 oncoprotein has transforming potential that can be activated by overexpression, and it represents a critical regulator of the p53 tumor suppressor protein. To identify other factors with a potential role in influencing the expression and/or function of MDM2, we utilized a yeast two-hybrid screening protocol. Here we report that MDM2 physically interacts with a structurally related protein termed MDMX. The results obtained in these studies provide evidence that C-terminal RING finger domains, contained within both of these proteins, play an important role in mediating the association between MDM2 and MDMX. The interaction of these proteins interferes with MDM2 degradation, leading to an increase in the steady-state levels of MDM2. MDMX also inhibits MDM2-mediated p53 degradation, with subsequent accumulation of p53. Taken together, these data indicate that MDMX has the potential to regulate the expression and function of the MDM2 oncoprotein.
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The Mdmx mutant lacking the RING domain (MxΔRING) is unable to heterodimerize with Mdm2.
“we generated a deletion mutant of Mdmx (1–345 amino acids) that lacked its RING domain (MxΔRING), and thus, was unable to heterodimerize with Mdm2.26,27”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [27]
Through their RING domains, Mdmx binds Mdm2 and enhances Mdm2's ability to regulate p53.
“Additionally, it has been shown that through their RING domains, Mdmx binds Mdm2 and enhances the ability of Mdm2 to regulate p53.23,24,26–28”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [27]
The RING domain of Mdmx is required for binding to Mdm2 through its RING domain.
“The RING domain of Mdmx is required to bind to Mdm2 through its RING domain.26,27”
From Mdmx promotes genomic instability independent of p53 and Mdm2 (2015) · cites this paper as [27]
Mdmx does not target p53 for degradation but instead stabilizes p53 and Mdm2.
“However, Mdmx does not target p53 for degradation but even prevents Mdm2-mediated degradation of p53 and also stabilizes Mdm2 (Sharp et al., 1999;Jackson and Berberich, 2000;Stad et al., 2000).”
From Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms (2001) · cites this paper as Sharp et al., 1999
The RING finger of Mdmx is needed for stabilization of p53.
“Since the RING finger of Mdmx is needed for stabilization of p53”
From Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms (2001) · cites this paper as Sharp et al., 1999
Mdmx and Mdm2 interact via their RING finger domains.
“Mdmx and Mdm2 interact via their RING finger domains (Sharp et al., 1999;Stad et al., 2000)”
From Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms (2001) · cites this paper as Sharp et al., 1999
Mdmx-Mdm2 heterodimers form preferentially over their respective homodimers.
“Mdmx-Mdm2 heterodimers are preferentially formed over their respective homodimers (Sharp et al., 1999)”
From Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms (2001) · cites this paper as Sharp et al., 1999
MDMX and MDM2 form heterodimers through their C-terminal RING domains, and the MDM2 RING domain alone is sufficient to degrade MDMX.
“MDMX and MDM2 form heterodimers through the C-terminal RING domains and the MDM2 RING domain alone is sufficient to degrade MDMX (Sharp et al, 1999;Tanimura et al, 1999;Pan and Chen, 2003).”
From ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage (2005) · cites this paper as Sharp et al, 1999
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Mdmx enhances p53 ubiquitination by altering the substrate preference of the Mdm2 ubiquitin ligase
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Mdmx promotes genomic instability independent of p53 and Mdm2
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c-Abl Phosphorylates Hdmx and Regulates Its Interaction with p53
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Cytoplasmic tethering is involved in synergistic inhibition of p53 by Mdmx and Mdm2
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- Authors
- Sharp, D. A., Kratowicz, S. A., Sank, M. J., & George, D. L.
- Affiliations
- University of Pennsylvania (US)
- Corresponding author
- George, Donna L.
- ORCID
- George, Donna L.
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 1999-12
- Volume
- 274
- Issue
- 53
- Pages
- 38189-38196
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2023950025
- Cited by
- 286
- References
- 50
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 7 · 2023: 7 · 2022: 10 · 2021: 10 · 2020: 8 · 2019: 2 · 2018: 9 · 2017: 6 · 2016: 14 · 2015: 11 · 2014: 18 · 2013: 7 · 2012: 16
- FWCI
- 5.74
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ca066741-05)
- National Cancer Institute (CA66741)
- 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, MDMX, p53, protein-protein interaction, RING domain, protein stabilization, p53 degradation, tumor suppressor regulation, oncoprotein, protein degradation
- MeSH terms
- Base Sequence, Humans, Nuclear Proteins, Protein Binding, Protein Conformation, Proto-Oncogene Proteins, Tumor Cells, Cultured, Tumor Suppressor Protein p53, DNA Primers, Two-Hybrid System Techniques, Proto-Oncogene Proteins c-mdm2
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