MDM2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation
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The CDK inhibitor p21waf1/cip1 is degraded by a ubiquitin-independent proteolytic pathway. Here, we show that MDM2 mediates this degradation process. Overexpression of wild-type or ring finger-deleted, but not nuclear localization signal (NLS)-deleted, MDM2 decreased p21waf1/cip1 levels without ubiquitylating this protein and affecting its mRNA level in p53(-/-) cells. This decrease was reversed by the proteasome inhibitors MG132 and lactacystin, by p19(arf), and by small interfering RNA (siRNA) against MDM2. p21waf1/cip1 bound to MDM2 in vitro and in cells. The p21waf1/cip1-binding-defective mutant of MDM2 was unable to degrade p21waf1/cip1. MDM2 shortened the half-life of both exogenous and endogenous p21waf1/cip1 by 50% and led to the degradation of its lysine-free mutant. Consequently, MDM2 suppressed p21waf1/cip1-induced cell growth arrest of human p53(-/-) and p53(-/-)/Rb(-/-)cells. These results demonstrate that MDM2 directly inhibits p21waf1/cip1 function by reducing p21waf1/cip1 stability in a ubiquitin-independent fashion.
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Mdm2 expression can lead to degradation of p21, and loss of p21 results in endoreduplication and polyploid cells.
“Moreover, Mdm2 expression can lead to the degradation of the p53 transcriptional target gene and cell cycle inhibitor p21, and loss of p21 results in endoreduplication and polyploid cells (Jin et al., 2003, Stewart et al., 1999).”
From Aging mice have increased chromosome instability that is exacerbated by elevated Mdm2 expression (2011) · cites this paper as Jin et al., 2003
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MDM2 Promotes Proteasome-Dependent Ubiquitin-Independent Degradation of Retinoblastoma Protein
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Multiple degradation pathways regulate versatile CIP/KIP CDK inhibitors
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Regulation of p53-MDMX interaction by casein kinase 1 alpha
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IFN Regulatory Factor 8 Regulates MDM2 in Germinal Center B Cells
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Aging mice have increased chromosome instability that is exacerbated by elevated Mdm2 expression
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Protecting the genome from mdm2 and mdmx
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- Authors
- Jin, Y., Lee, H., Zeng, S. X., Dai, M., & Lu, H.
- Affiliations
- Oregon Health & Science University (US)
- Corresponding author
- Lu, Hua
- Venue
- The EMBO Journal
- Published
- 2003-12-01
- Volume
- 22
- Issue
- 23
- Pages
- 6365-6377
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC291841
- OpenAlex
- W1996675458
- Cited by
- 206
- References
- 107
- Citations by year
- 2026: 4 · 2025: 4 · 2024: 4 · 2023: 5 · 2022: 1 · 2021: 6 · 2020: 6 · 2019: 8 · 2018: 2 · 2017: 5 · 2016: 6 · 2015: 3 · 2014: 12 · 2013: 7 · 2012: 14
- FWCI
- 4.49
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (R01CA093614, CA79721, CA095441, CA 93614, R01CA079721, R01CA095441)
- 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, p21, ubiquitin-independent degradation, protein stability, cyclin-dependent kinase inhibitors, p19ARF, RING domain, protein-protein interaction
- MeSH terms
- Adenocarcinoma, Animals, Cell Division, Cell Line, Cells, Cultured, Cysteine Endopeptidases, Enzyme Inhibitors, Gene Expression Regulation, Humans, Kinetics, Male, Multienzyme Complexes, Nuclear Proteins, Proto-Oncogene Proteins, Recombinant Proteins, Testicular Neoplasms, Transfection, Tumor Cells, Cultured, Tumor Suppressor Protein p53, Cyclins, Mice, Knockout, Ubiquitin, RNA, Small Interfering, Proteasome Endopeptidase Complex, Cyclin-Dependent Kinase Inhibitor p21, Mice, Proto-Oncogene Proteins c-mdm2
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.
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