The DOI matches its Crossref record; 46 of the 46 references it cites were found in a registry or an index.
The Mdm2 RING domain C-terminus is required for supramolecular assembly and ubiquitin ligase activity
Open accessAbstract
Mdm2, a key negative regulator of the p53 tumor suppressor, is a RING-type E3 ubiquitin ligase. The Mdm2 RING domain can be biochemically fractionated into two discrete species, one of which exists as higher order oligomers that are visible by electron microscopy, whereas the other is a monomer. Both fractions are ATP binding and E3 ligase activity competent, although the oligomeric fraction exhibits lower dependence on the E2 component of ubiquitin polymerization reactions. The extreme C-terminal five amino acids of Mdm2 are essential for E3 ligase activity in vivo and in vitro, as well as for oligomeric assembly of the protein. A single residue (phenylalanine 490) in that sequence is critical for both properties. Interestingly, the C-terminus of the Mdm2 homologue, MdmX (itself inert as an E3 ligase), can fully substitute for the equivalent segment of Mdm2 and restore its E3 activity. We further show that the Mdm2 C-terminus is involved in intramolecular interactions and can set up a platform for direct protein-protein interactions with the E2.
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In the citing paper
“Work from both the Vousden and Prives laboratories indicatesthat oligomeric Mdm2is a more effectivep53 ubiquitin ligase than is monomeric Mdm2 [27,28].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [28]
In the citing paper
“Intriguingly, their data show that aromatic residues (Y489 and F490) outside the RING domain at the extreme C-terminus are also critical for Mdm2 ligase activity.”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [28]
In the citing paper
“Aromatic residues are conserved in the Mdmx C-terminal tail, and can also act in trans to reactivate E3 ligase function in Mdm2 C-terminal mutants [27,28].”
From The p53 orchestra: Mdm2 and Mdmx set the tone (2010) · cites this paper as [28]
In the citing paper
“Oligomerization of MDM2 RING domain increases its E3 ligase activity in vitro (Poyurovsky et al, 2007).”
From ATM activates p53 by regulating MDM2 oligomerization and E3 processivity (2009) · cites this paper as Poyurovsky et al, 2007
In the citing paper
“Formation of high-order oligomers is a common feature of RING domains (Kentsis et al, 2002;Poyurovsky et al, 2007).”
From ATM activates p53 by regulating MDM2 oligomerization and E3 processivity (2009) · cites this paper as Poyurovsky et al, 2007
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Citations
Cites
In Vivo Activation of the p53 Pathway by Small-Molecule Antagonists of MDM2
Vassilev, L. T., Vu, B. T., Graves, B., Carvajal, D., Podlaski, F., Filipovic, Z., Kong, N., Kammlott, U., Lukacs, C., Klein, C., et al. (2004) · Science · doi:10.1126/science.1092472 · Cited by 4,661
Mdm2 promotes the rapid degradation of p53
Haupt, Y., Maya, R., Kazaz, A., & Oren, M. (1997) · Nature · doi:10.1038/387296a0 · Cited by 4,506
Regulation of p53 stability by Mdm2
Kubbutat, M. H. G., Jones, S. N., & Vousden, K. H. (1997) · Nature · doi:10.1038/387299a0 · Cited by 3,312 · cited 1×
“…Harris and Levine, 2005; Poyurovsky and Prives, 2006), Mdm2 controls p53 through two distinct mechanisms, by directly binding and masking the N-terminal transactivation domain of p53 (Momand et al, 1992) and by promoting proteasomal degradation of p53 (Haupt et al, 1997; Kubbutat et al, 1997).”
BackgroundMomand, J., Zambetti, G. P., Olson, D. C., George, D., & Levine, A. J. (1992) · Cell · doi:10.1016/0092-8674(92)90644-r · Cited by 3,113
Enzyme structure and mechanism
Fersht, A. (1977) · Medical Entomology and Zoology · Cited by 2,875
Structure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain
Kussie, P. H., Gorina, S., Marechal, V., Elenbaas, B., Moreau, J., Levine, A. J., & Pavletich, N. P. (1996) · Science · doi:10.1126/science.274.5289.948 · Cited by 2,206
Self-citationThe p53 pathway: positive and negative feedback loops
Harris, S. L., & Levine, A. J. (2005) · Oncogene · doi:10.1038/sj.onc.1208615 · Cited by 1,967
Structure of the Cul1–Rbx1–Skp1–F boxSkp2 SCF ubiquitin ligase complex
Zheng, N., Schulman, B. A., Song, L., Miller, J. J., Jeffrey, P. D., Wang, P., Chu, C., Koepp, D. M., Elledge, S. J., Pagano, M., et al. (2002) · Nature · doi:10.1038/416703a · Cited by 1,507
Self-citationMdm2 Is a RING Finger-dependent Ubiquitin Protein Ligase for Itself and p53
Fang, S., Jensen, J. P., Ludwig, R. L., Vousden, K. H., & Weissman, A. M. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.12.8945 · Cited by 1,044
Melnick, A. M., & Licht, J. D. (1999) · Blood · doi:10.1182/blood.v93.10.3167.410k44_3167_3215 · Cited by 1,029
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Items 201–203 of 203
BindingDB Entry 50043548: 5-Deazaflavin derivatives as inhibitors of p53 ubiquitination by HDM2.
BindingDB (2014) · UC San Diego · doi:10.7270/q2ks6t01
Modulation of apoptosis and signalling in cancer cells after treatment with epigenetic modulators
Palani, R. N., & Devi, C. P. A. (2012) · Common Library Network (Der Gemeinsame Bibliotheksverbund)
Metadata
- Authors
- Poyurovsky, M. V., Priest, C., Kentsis, A., Borden, K. L., Pan, Z., Pavletich, N., & Prives, C.
- Affiliations
- Columbia University (US)
- New York University (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- Prives, Carol
- ORCID
- Venue
- The EMBO Journal
- Published
- 2006-12-14
- Volume
- 26
- Issue
- 1
- Pages
- 90-101
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1782380
- OpenAlex
- W2123242499
- Cited by
- 203
- References
- 46
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 12 · 2022: 3 · 2021: 11 · 2020: 14 · 2019: 6 · 2018: 6 · 2017: 9 · 2016: 10 · 2015: 7 · 2014: 9 · 2013: 10 · 2012: 18
- FWCI
- 7.80
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (CA58316, CA87497)
- National Cancer Institute (R37CA058316, CA-87497, P01CA087497, R01CA058316, CA 58316)
- 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 › TGF-β signaling in diseases
- Keywords
- MDM2, RING domain, E3 ubiquitin ligase, protein oligomerization, supramolecular self-assembly, C-terminal domain, p53 regulation, MDMX, E2 ubiquitin-conjugating enzyme, intramolecular interactions, protein-protein interaction, ubiquitination
- MeSH terms
- Adenosine Triphosphate, Escherichia coli, Humans, Microscopy, Electron, Models, Biological, Nuclear Proteins, Phenylalanine, Protein Binding, Protein Conformation, Tumor Suppressor Protein p53, Protein Structure, Tertiary, Ubiquitin, Ubiquitin-Protein Ligases, Cell Line, Tumor, Proto-Oncogene Proteins c-mdm2
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