Mdm2 facilitates the association of p53 with the proteasome
Open accessAbstract
The ubiquitin ligase Mdm2 targets the p53 tumor suppressor protein for proteasomal degradation. Mutating phosphorylation sites in the central domain of Mdm2 prevents p53 degradation, although it is still ubiquitylated, indicating that Mdm2 has a post-ubiquitylation function for p53 degradation. We show that Mdm2 associates with several subunits of the 19S proteasome regulatory particle in a ubiquitylation-independent manner. Mdm2 furthermore promotes the formation of a ternary complex of itself, p53, and the proteasome. Replacing phosphorylation sites within the central domain with alanines reduced the formation of the ternary complex. The C-terminus of Mdm2 was sufficient for interaction with the proteasome despite an additional proteasome binding site in the Mdm2 N-terminus. In addition to binding to the proteasome, the C-terminus of Mdm2 bound to the central domain, possibly competing with, and therefore blocking, Mdm2/proteasome interaction. We propose that Mdm2 facilitates, or at least enhances, the association of p53 with the proteasome and that phosphorylation of the central domain of Mdm2 regulates this process.
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Mdm2 functions as an E3 ubiquitin ligase that conjugates ubiquitin to proteins including p53, signaling their destruction by the 26S proteasome to keep cellular p53 levels low.
“Mdm2 typically functions as an E3 ubiquitin ligase and conjugates ubiquitin to several proteins including, the tumor suppressor p53. This ultimately signals for destruction by the 26S proteasome to keep cellular p53 levels low [1,2].”
From Integration of DNA damage and repair with murine double-minute 2 (Mdm2) in tumorigenesis (2012) · cites this paper as [2]
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 · see citing works
Momand, 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 · see citing works
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 · see citing works
Protein degradation and protection against misfolded or damaged proteins.
Goldberg, A. L. (2003) · Nature · doi:10.1038/nature02263 · Cited by 2,088 · see citing works
A 26 S protease subunit that binds ubiquitin conjugates.
Deveraux, Q. L., Ustrell, V., Pickart, C. M., & Rechsteiner, M. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)37244-7 · Cited by 763 · see citing works
A proteasomal ATPase subunit recognizes the polyubiquitin degradation signal
Lam, Y. A., Lawson, T. G., Velayutham, M., Zweier, J. L., & Pickart, C. M. (2002) · Nature · doi:10.1038/416763a · Cited by 446 · see citing works
p300/MDM2 complexes participate in MDM2-mediated p53 degradation
Grossman, S. R., Perez, M., Kung, A. L., Joseph, M., Mansur, C., Xiao, Z.-X., Kumar, S., Howley, P. M., & Livingston, D. M. (1998) · Molecular Cell · doi:10.1016/s1097-2765(00)80140-9 · Cited by 414 · see citing works
Self-citationHonda, R., & Yasuda, H. (2000) · Oncogene · doi:10.1038/sj.onc.1203464 · Cited by 376 · see citing works
Ubiquitination of p53 and p21 Is Differentially Affected by Ionizing and UV Radiation
Maki, C. G., & Howley, P. M. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.1.355 · Cited by 305 · see citing works
MDM2 Promotes Proteasome-Dependent Ubiquitin-Independent Degradation of Retinoblastoma Protein
Sdek, P., Ying, H., Chang, D. L. F., Qiu, W., Zheng, H., Touitou, R., Allday, M. J., & Jim Xiao, Z.-X. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.10.017 · Cited by 288 · see citing works
Förster, A., Masters, E. I., Whitby, F. G., Robinson, H. H., & Hill, C. P. (2005) · Molecular Cell · doi:10.1016/j.molcel.2005.04.016 · Cited by 236 · see citing works
Ubiquitination and Degradation of Mutant p53
Lukashchuk, N., & Vousden, K. H. (2007) · Molecular and Cellular Biology · doi:10.1128/mcb.00050-07 · Cited by 223 · see citing works
Ubiquitin-independent proteolytic functions of the proteasome
Orłowski, M., & Wilk, S. (2003) · Archives of Biochemistry and Biophysics · doi:10.1016/s0003-9861(03)00197-8 · Cited by 213 · see citing works
Substrate access and processing by the 20S proteasome core particle
Groll, M., & Huber, R. (2003) · The International Journal of Biochemistry & Cell Biology · doi:10.1016/s1357-2725(02)00390-4 · Cited by 199 · see citing works
p53 stabilization in response to DNA damage requires Akt/PKB and DNA-PK
Boehme, K. A., Kulikov, R., & Blattner, C. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0703423105 · Cited by 151 · see citing works
Self-citationHypophosphorylation of Mdm2 Augments p53 Stability
Blattner, C., Hay, T., Meek, D. W., & Lane, D. P. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.17.6170-6182.2002 · Cited by 144 · see citing works
Self-citationGlycogen synthase kinase 3-dependent phosphorylation of Mdm2 regulates p53 abundance
Kulikov, R., Boehme, K. A., & Blattner, C. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.16.7170-7180.2005 · Cited by 132 · see citing works
Self-citationRegulation of p53 - insights into a complex process
Boehme, K. A., & Blattner, C. (2009) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.3109/10409230903401507 · Cited by 106 · see citing works
Self-citationThe contribution of the acidic domain of MDM2 to p53 and MDM2 stability
Argentini, M., Barboule, N., & Wasylyk, B. (2001) · Oncogene · doi:10.1038/sj.onc.1204241 · Cited by 90 · see citing works
Binding of p53 to the Central Domain of Mdm2 Is Regulated by Phosphorylation
Kulikov, R., Winter, M., & Blattner, C. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m513311200 · Cited by 79 · see citing works
Self-citationCorn, P. G., McDonald, E. R., Herman, J. G., & El‐Deiry, W. S. (2003) · Nature Genetics · doi:10.1038/ng1254 · Cited by 78 · see citing works
A post-ubiquitination role for MDM2 and hHR23A in the p53 degradation pathway
Brignone, C., Bradley, K., Kisselev, A. F., & Grossman, S. R. (2004) · Oncogene · doi:10.1038/sj.onc.1207540 · Cited by 73 · see citing works
Self-citationThe COP9 signalosome: an alternative lid for the 26S proteasome?
Li, L. (2003) · Trends in Cell Biology · doi:10.1016/j.tcb.2003.08.002 · Cited by 69 · see citing works
Nucleotide Binding by the MDM2 RING Domain Facilitates Arf-Independent MDM2 Nucleolar Localization
Poyurovsky, M. V., Jacq, X., Ma, C., Karni-Schmidt, O., Parker, P. J., Chalfie, M., Manley, J. L., & Prives, C. L. (2003) · Molecular Cell · doi:10.1016/s1097-2765(03)00400-3 · Cited by 58 · see citing works
Parkin interacts with the proteasome subunit α4
Dächsel, J. C., Lücking, C. B., Deeg, S., Schultz, E., Lalowski, M. M., Casademunt, E., Corti, O., Hampe, C., Patenge, N., Vaupel, K., et al. (2005) · FEBS Letters · doi:10.1016/j.febslet.2005.06.003 · Cited by 52 · see citing works
Lee, S., Choi, D., Rhim, H., & Kang, S. (2005) · Biochemical Journal · doi:10.1042/bj20041982 · Cited by 23 · see citing works
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Pederson, T. (2011) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a000638 · Cited by 455 · see citing works
The role of ubiquitin modification in the regulation of p53
Hock, A. K., & Vousden, K. H. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2013.05.022 · Cited by 168 · see citing works
The roles of MDM2 and MDMX phosphorylation in stress signaling to p53
Chen, J. (2012) · Genes & Cancer · doi:10.1177/1947601912454733 · Cited by 33 · see citing works
Integration of DNA damage and repair with murine double-minute 2 (Mdm2) in tumorigenesis
Lehman, J., & Mayo, L. (2012) · International Journal of Molecular Sciences · doi:10.3390/ijms131216373 · Cited by 9 · see citing works
- Authors
- Kulikov, R., Letienne, J., Kaur, M., Grossman, S. R., Arts, J., & Blattner, C.
- Affiliations
- Karlsruhe Institute of Technology (DE)
- University of Massachusetts Chan Medical School (US)
- Oncology Discovery Research and Early Development, Johnson and Johnson Pharmaceutical Research and Development, 2340 Beerse, Belgium
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-05-17
- Volume
- 107
- Issue
- 22
- Pages
- 10038-10043
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2890462
- OpenAlex
- W2148541632
- Cited by
- 94
- References
- 26
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 6 · 2023: 7 · 2022: 4 · 2021: 4 · 2020: 5 · 2019: 2 · 2018: 4 · 2017: 2 · 2016: 2 · 2015: 6 · 2014: 6 · 2013: 7 · 2012: 17
- FWCI
- 6.16
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (R01CA107532)
- 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, p53, proteasome, 19S regulatory particle, ubiquitin ligase, p53 degradation, ternary complex, protein-protein interaction, phosphorylation
- MeSH terms
- Amino Acid Sequence, Binding Sites, Cell Line, Humans, Molecular Sequence Data, Phosphorylation, Recombinant Proteins, Tumor Suppressor Protein p53, Mutagenesis, Site-Directed, Protein Structure, Tertiary, Amino Acid Motifs, Multiprotein Complexes, Proteasome Endopeptidase Complex, Proto-Oncogene Proteins c-mdm2, Ubiquitination
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