Mdm2 Is a RING Finger-dependent Ubiquitin Protein Ligase for Itself and p53
Open accessAbstract
Mdm2 has been shown to regulate p53 stability by targeting the p53 protein for proteasomal degradation. We now report that Mdm2 is a ubiquitin protein ligase (E3) for p53 and that its activity is dependent on its RING finger. Furthermore, we show that Mdm2 mediates its own ubiquitination in a RING finger-dependent manner, which requires no eukaryotic proteins other than ubiquitin-activating enzyme (E1) and an ubiquitin-conjugating enzyme (E2). It is apparent, therefore, that Mdm2 manifests an intrinsic capacity to mediate ubiquitination. Mutation of putative zinc coordination residues abrogated this activity, as did chelation of divalent cations. After cation chelation, the full activity could be restored by addition of zinc. We further demonstrate that the degradation of p53 and Mdm2 in cells requires additional potential zinc-coordinating residues beyond those required for the intrinsic activity of Mdm2 in vitro. Replacement of the Mdm2 RING with that of another protein (Praja1) reconstituted ubiquitination and proteasomal degradation of Mdm2. However, this RING was ineffective in ubiquitination and proteasomal targeting of p53, suggesting that there may be specificity at the level of the RING in the recognition of heterologous substrates.
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In previously authenticated RING domain-containing E3s, wild-type in vitro ubiquitin ligase activity and inhibition by mutation of cognate Cys/His residues have been seen.
“The in vitro ubiquitin ligase activity of wild-type protein and the inhibitory effect of mutation of residues cognate with Cys-101 and His-103 has been seen with previously authenticated RING domain-containing E3s (9, 18)”
From RNF170 Protein, an Endoplasmic Reticulum Membrane Ubiquitin Ligase, Mediates Inositol 1,4,5-Trisphosphate Receptor Ubiquitination and Degradation (2011) · cites this paper as [18]
RNF170 is an E3 ubiquitin ligase.
“shows that RNF170 is an E3.”
From RNF170 Protein, an Endoplasmic Reticulum Membrane Ubiquitin Ligase, Mediates Inositol 1,4,5-Trisphosphate Receptor Ubiquitination and Degradation (2011) · cites this paper as [18]
The paper states that Mdm2 is an E3 ligase (opening section; Discussion), but those passages do not address RNF170. Searches for “RNF170” and “RNF 170 E3 ubiquitin ligase” found no passage about that protein in our copy. (LLM, conf=0.76)
Experimental — accuracy not yet measuredMdm2 is a RING-type E3 ubiquitin ligase that ubiquitylates itself and p53, leading to their proteasomal degradation.
“Mdm2 is a RING-type E3 ubiquitin ligase (Honda et al., 1997;Fang et al., 2000;Honda and Yasuda, 2000), which directs the ubiquitylation of itself and p53.”
From Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms (2001) · cites this paper as Fang et al., 2000
Swapping Mdm2's RING finger with Praja 1's RING finger did not affect Mdm2 ubiquitylation but prevented p53 ubiquitylation.
“This switch did not affect Mdm2 ubiquitylation but prevented the ubiquitylation of p53 (Fang et al., 2000).”
From Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms (2001) · cites this paper as Fang et al., 2000
Mdm2 undergoes auto-degradation and targets Mdmx for degradation, which is critical for optimal p53 activation after stress.
“However, in addition to degrading p53, Mdm2 also undergoes auto-degradation [12,13] and targets Mdmx for degradation [14–16], which is critical for optimal p53 activation after stress.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [13]
MDM2 ubiquitylates p53 and leads to its proteasomal degradation, keeping p53 levels and activity low in unstressed cells.
“On binding, MDM2 ubiquitylates p53 and leads to its proteasomal degradation; this keeps p53 levels and activity low in unstressed cells.”
From MDM2, MDMX and p53 in oncogenesis and cancer therapy (2013) · cites this paper as [15]
Transfected GFP-Mdm2 is a labile protein target for degradation, and PKB phosphorylation is required for protecting Mdm2 from proteasome-dependent destruction, increasing Mdm2 stability.
“These data suggested that transfected GFP-Mdm2 is a labile protein that is a target for degradation (20,21) and, furthermore, that PKB phosphorylation is required for protecting Mdm2 from proteasome-dependent destruction, thus increasing Mdm2 stability.”
From Stabilization of Mdm2 via Decreased Ubiquitination Is Mediated by Protein Kinase B/Akt-dependent Phosphorylation (2004) · cites this paper as [21]
Mdm2 harbors self- and p53-specific E3 ubiquitin ligase activity within its C-terminal RING finger domain, which mediates p53 ubiquitination and rapid degradation by the 26 S proteasome.
“Mdm2 harbors a self-and p53specific E3 ubiquitin ligase activity within its evolutionarily conserved C-terminal RING finger domain, which mediates p53 ubiquitination and rapid degradation by the 26 S proteasome (20,21).”
From Stabilization of Mdm2 via Decreased Ubiquitination Is Mediated by Protein Kinase B/Akt-dependent Phosphorylation (2004) · cites this paper as [21]
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Mono- Versus Polyubiquitination: Differential Control of p53 Fate by Mdm2
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ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage
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“Within Mdm2, the RING finger domain is of particular importance for this E3 activity, in vitro as well as in vivo (Kubbutat et al. 1997; Honda and Yasuda 1999; Fang et al. 2000).”
BackgroundThe complexity of p53 stabilization and activation
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Mutational processes shape the landscape of TP53 mutations in human cancer
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ATM and ATR: networking cellular responses to DNA damage
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Signaling to p53: ribosomal proteins find their way
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Mdm2-Mediated NEDD8 Conjugation of p53 Inhibits Its Transcriptional Activity
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Comparative genomics and evolution of proteins involved in RNA metabolism
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Coping with stress: multiple ways to activate p53
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Self-citationThe p53 orchestra: Mdm2 and Mdmx set the tone
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Concordant Regulation of Translation and mRNA Abundance for Hundreds of Targets of a Human microRNA
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Accelerated MDM2 auto‐degradation induced by DNA‐damage kinases is required for p53 activation
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HdmX stimulates Hdm2-mediated ubiquitination and degradation of p53
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Mdm2-mediated ubiquitylation: p53 and beyond
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An intact HDM2 RING-finger domain is required for nuclear exclusion of p53
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Two-phase dynamics of p53 in the DNA damage response
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Monoubiquitylation promotes mitochondrial p53 translocation
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MDM2 Promotes Proteasome-Dependent Ubiquitin-Independent Degradation of Retinoblastoma Protein
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The deubiquitinating enzyme USP2a regulates the p53 pathway by targeting Mdm2
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MDM2 promotes ubiquitination and degradation of MDMX
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Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms
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Cyclin G Recruits PP2A to Dephosphorylate Mdm2
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MDM2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation
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The RING domain of Mdm2 mediates histone ubiquitylation and transcriptional repression
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Phosphorylation of HDM2 by Akt
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An essential function of the extreme C-terminus of MDM2 can be provided by MDMX
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Self-citationTargeting Mdm2 and Mdmx in cancer therapy: better living through medicinal chemistry?
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Different effects of p14ARF on the levels of ubiquitinated p53 and Mdm2 in vivo
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DNA damage-induced MDMX degradation is mediated by MDM2
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Regulation of p53 by the Ubiquitin-conjugating Enzymes UbcH5B/C in Vivo
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Synergistic roles of Mdm2 and Mdm4 for p53 inhibition in central nervous system development
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Hdmx protein stability is regulated by the ubiquitin ligase activity of Mdm2
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Regulation of p53: a collaboration between Mdm2 and MdmX
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Solution structure of the Hdm2 C2H2C4 RING, a domain critical for ubiquitination of p53
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Regulation of MDMX nuclear import and degradation by Chk2 and 14-3-3
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Regulation of apoptosis by the ubiquitin and proteasome pathway
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USP7 Is a Master Regulator of Genome Stability
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“While Mdm2 is also targeted for proteasomal degradation due its auto-polyubiquitination (Fang et al., 2000), USP7 is able to stabilize Mdm2 by rapidly removing these ubiquitin chains (Cummins et al.”
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Discovery of Mdm2-MdmX E3 Ligase Inhibitors Using a Cell-Based Ubiquitination Assay
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MdmX is a substrate for the deubiquitinating enzyme USP2a
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An Alternative Splice Form of Mdm2 Induces p53-independent Cell Growth and Tumorigenesis
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P14ARF promotes accumulation of SUMO-1 conjugated (H)Mdm2
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Reconstitution of Mdm2-dependent post-translational modifications of p53 in yeast
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- Authors
- Fang, S., Jensen, J. P., Ludwig, R. L., Vousden, K. H., & Weissman, A. M.
- Affiliations
- National Institutes of Health (US)
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2000-03
- Volume
- 275
- Issue
- 12
- Pages
- 8945-8951
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2073936529
- Cited by
- 1,044
- References
- 76
- Citations by year
- 2026: 11 · 2025: 15 · 2024: 21 · 2023: 28 · 2022: 30 · 2021: 22 · 2020: 36 · 2019: 30 · 2018: 21 · 2017: 21 · 2016: 33 · 2015: 27 · 2014: 39 · 2013: 42 · 2012: 51
- FWCI
- 22.98
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Health and Human Services
- National Cancer Institute
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ubiquitin and proteasome pathways
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Keywords
- MDM2, p53, ring finger, E3 ubiquitin ligase, ubiquitination, proteasomal degradation, self-ubiquitination, zinc coordination, substrate specificity, p53 stabilization
- MeSH terms
- Alkylation, Amino Acid Sequence, Chelating Agents, Cysteine Endopeptidases, Ligases, Models, Molecular, Molecular Sequence Data, Multienzyme Complexes, Mutation, Nuclear Proteins, Protein Processing, Post-Translational, Proto-Oncogene Proteins, Recombinant Proteins, Ubiquitins, Zinc, Tumor Suppressor Protein p53, Zinc Fingers, Consensus Sequence, Ubiquitin-Activating Enzymes, Ubiquitin-Protein Ligases, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-mdm2
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