Cited by 206Cancer-related Molecular PathwaysUbiquitin and proteasome pathwaysHeat shock proteins research

MDM2 promotes p21waf1/cip1 proteasomal turnover independently of ubiquitylation

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Jin, Yetao, Lee, Hunjoo, Zeng, Shelya X., Dai, Mu‐Shui, Lu, Hua·2003·The EMBO Journal

Abstract

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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Crossref · 10.1093/emboj/cdg600

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107 of 107 references verified0 citation errors · 0 not checkable

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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).”

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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
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
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

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