Abnormal MDMX degradation in tumor cells due to ARF deficiency
Open accessAbstract
MDMX is a heterodimeric partner of MDM2 and a critical regulator of p53. The MDMX level is generally elevated in tumors with wild-type p53 and contributes to p53 inactivation. MDMX degradation is controlled in part by MDM2-mediated ubiquitination. Here, we show that MDMX turnover is highly responsive to changes in MDM2 level in non-transformed cells, but not in tumor cells. We found that loss of alternate reading frame (ARF) expression, which occurs in most tumors with wild-type p53, significantly reduces MDMX sensitivity to MDM2. Restoration of ARF expression in tumor cells enables MDM2 to degrade MDMX in a dose-dependent manner. ARF binds to MDM2 and stimulates a second-site interaction between the central region of MDM2 and MDMX, and thus increases MDMX-MDM2 binding and MDMX ubiquitination. These results reveal an important abnormality in the p53-regulatory pathway as a consequence of ARF deficiency. Loss of ARF during tumor development not only prevents p53 stabilization by proliferative stress but also causes accumulation of MDMX that compromises p53 activity. This phenomenon may reduce the clinical efficacy of MDM2-specific inhibitors by preventing MDMX downregulation.
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Nutlin treatment raises Mdm2 protein levels in cells regardless of whether p53 is present.
“It has been reported that a consequence of Nutlin treatment is elevated Mdm2 protein levels, and this occurs in cells with or without p53 (6,8).”
From Pharmacologically increasing Mdm2 Inhibits DNA repair and cooperates with genotoxic agents to kill p53-inactivated ovarian cancer cells (2015) · cites this paper as [8]
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- Authors
- Li, X., Gilkes, D., Li, B., Cheng, Q., Pernazza, D., Lawrence, H., Lawrence, N., & Chen, J.
- Affiliations
- Moffitt Cancer Center (US)
- University of South Florida (US)
- Corresponding author
- Chen, J
- Venue
- Oncogene
- Published
- 2011-11-28
- Volume
- 31
- Issue
- 32
- Pages
- 3721-3732
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC3290737
- OpenAlex
- W2057923521
- Cited by
- 32
- References
- 56
- Citations by year
- 2025: 1 · 2024: 2 · 2023: 1 · 2021: 3 · 2020: 2 · 2019: 1 · 2018: 1 · 2017: 1 · 2016: 6 · 2015: 5 · 2014: 5 · 2013: 1 · 2012: 3
- FWCI
- 1.42
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA109636, CA 109636, CA 118210, P01CA118210, CA141244, R01CA141244)
- 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
- MDMX, MDM2, ARF, p53 regulation, protein degradation, ubiquitination, cancer cells, wild-type p53, MDM2 inhibitors, tumor suppressor loss
- MeSH terms
- Humans, Imidazoles, Indoles, Nuclear Proteins, Piperazines, Protein Binding, Protein Processing, Post-Translational, Proto-Oncogene Proteins, Spiro Compounds, Gene Expression, Tumor Suppressor Protein p53, Cell Cycle Proteins, Tumor Suppressor Protein p14ARF, Cell Line, Tumor, Proteasome Endopeptidase Complex, Immunoprecipitation, Proto-Oncogene Proteins c-mdm2, Protein Interaction Domains and Motifs, Ubiquitination, Protein Multimerization, Protein Stability, Cell Cycle Checkpoints, Proteolysis, Proteasome Inhibitors
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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