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Association of p19ARF with Mdm2 inhibits ubiquitin ligase activity of Mdm2 for tumor suppressor p53
Open accessAbstract
We have demonstrated previously that the oncoprotein Mdm2 has a ubiquitin ligase activity for the tumor suppressor p53 protein. In the present study, we characterize this ubiquitin ligase activity of Mdm2. We first demonstrate the ubiquitination of several p53 point mutants and deletion mutants by Mdm2. The point mutants, which cannot bind to Mdm2, are not ubiquitinated by Mdm2. The ubiquitination of the C-terminal deletion mutants, which contain so-called Mdm2-binding sites, is markedly decreased, compared with that of wild-type p53. The binding of Mdm2 to p53 is essential for ubiquitination, but p53's tertiary structure and/or C-terminal region may also be important for this reaction. DNA-dependent protein kinase is known to phosphorylate p53 on Mdm2-binding sites, where DNA damage induces phosphorylation, and p53 phosphorylated by this kinase is not a good substrate for Mdm2. This suggests that DNA damage-induced phosphorylation stabilizes p53 by inhibiting its ubiquitination by Mdm2. We further investigated whether the tumor suppressor p19(ARF) affects the ubiquitin ligase activity of Mdm2 for p53. The activity of p19(ARF)-bound Mdm2 was found to be lower than that of free Mdm2, suggesting that p19(ARF) promotes the stabilization of p53 by inactivating Mdm2.
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In the citing paper
“the tumor suppressor genes that stabilize p53 (Trp53) via inactivation of Mdm2 in response to a variety of oncogenic stresses (Honda and Yasuda, 1999;Brummelkamp et al., 2002;Lingbeek et al., 2002;Kim and Sharpless, 2006).”
From Tbx3 controls the fate of hepatic progenitor cells in liver development by suppressing p19ARF expression (2008) · cites this paper as Honda and Yasuda, 1999
Experimental — accuracy not yet measuredThe check wasn’t confident either way, so it gives no verdict — never disputed.
In the citing paper
“Tbx3 is known as a transcriptional repressor for p19 ARF (Cdkn2a -Mouse Genome Informatics) and p14 ARF (the human ortholog of p19 ARF )”
From Tbx3 controls the fate of hepatic progenitor cells in liver development by suppressing p19ARF expression (2008) · cites this paper as Honda and Yasuda, 1999
Experimental — accuracy not yet measuredIn the citing paper
“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 [20]
In the citing paper
“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 [20]
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Metadata
- Authors
- Honda, R., & Yasuda, H.
- Affiliations
- Tokyo University of Pharmacy and Life Sciences (JP)
- Corresponding author
- Yasuda, Hideyo
- Venue
- The EMBO Journal
- Published
- 1999-01-04
- Volume
- 18
- Issue
- 1
- Pages
- 22-27
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC1171098
- OpenAlex
- W2028210102
- Cited by
- 724
- References
- 43
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 3 · 2023: 12 · 2022: 12 · 2021: 3 · 2020: 10 · 2019: 4 · 2018: 11 · 2017: 5 · 2016: 14 · 2015: 19 · 2014: 20 · 2013: 24 · 2012: 20
- FWCI
- 33.88
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The EMBO Journal (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Molecular Biology Organization
- Institute of Genetics
- 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
- p19ARF, MDM2, p53, ubiquitin ligase activity, p53 ubiquitination, p53 stabilization, DNA-dependent protein kinase, p53 phosphorylation, DNA damage response, tumor suppressor proteins, protein-protein interaction
- MeSH terms
- Animals, Cell Line, Cloning, Molecular, DNA-Binding Proteins, HeLa Cells, Humans, Ligases, Mutation, Nuclear Proteins, Phosphorylation, Proteins, Proto-Oncogene Proteins, Recombinant Fusion Proteins, Ubiquitins, Tumor Suppressor Protein p53, Protein Serine-Threonine Kinases, Spodoptera, Tumor Suppressor Protein p14ARF, Ubiquitin-Protein Ligases, Proto-Oncogene Proteins c-mdm2, DNA-Activated Protein Kinase, In Vitro Techniques
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