Cited by 1,626Cancer-related Molecular PathwaysPI3K/AKT/mTOR signaling in cancerHeat shock proteins research

ARF promotes MDM2 degradation and stabilizes p53: ARF-INK4a locus deletion impairs both the Rb and p53 tumor suppression pathways

Open access
Zhang, Yanping, Xiong, Yue, Yarbrough, Wendell G·1998·Cell

Abstract

The INK4a-ARF locus encodes two unrelated proteins that both function in tumor suppression. p16INK4 binds to and inhibits the activity of CDK4 and CDK6, and ARF arrests the cell cycle in a p53-dependent manner. We show here that ARF binds to MDM2 and promotes the rapid degradation of MDM2. This interaction is mediated by the exon 1beta-encoded N-terminal domain of ARF and a C-terminal region of MDM2. ARF-promoted MDM2 degradation is associated with MDM2 modification and concurrent p53 stabilization and accumulation. The functional consequence of ARF-regulated p53 levels via MDM2 proteolysis is evidenced by the ability of ectopically expressed ARF to restore a p53-imposed G1 cell cycle arrest that is otherwise abrogated by MDM2. Thus, deletion of the ARF-INK4a locus simultaneously impairs both the INK4a-cyclin D/CDK4-RB and the ARF-MDM2-p53 pathways.

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Crossref · 10.1016/s0092-8674(00)81401-4

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Authors
Zhang, Y., Xiong, Y., & Yarbrough, W. G.
Affiliations
University of North Carolina at Chapel Hill (US)
Corresponding author
Xiong, Yue
Venue
Cell
Publisher
Elsevier BV
Published
1998-03
Volume
92
Issue
6
Pages
725-734
ISSN
0092-8674 (ISSN-L)
OpenAlex
W1983751803
Cited by
1,626
References
47
Citations by year
2026: 7 · 2025: 10 · 2024: 16 · 2023: 27 · 2022: 25 · 2021: 32 · 2020: 39 · 2019: 22 · 2018: 31 · 2017: 39 · 2016: 42 · 2015: 44 · 2014: 57 · 2013: 57 · 2012: 71
FWCI
57.06
Type
journal article
Language
en
Open access
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • UNC Libraries
Funders
  • National Institutes of Health (5k08ca072968-04)
  • National Cancer Institute (R01CA065572, R01CA65572, KO8-CA72968)
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
Keywords
ARF, MDM2, p53 stabilization, INK4a/ARF locus, p16INK4a, tumor suppression, MDM2 degradation, protein-protein interaction, G1 cell cycle arrest, cyclin D
MeSH terms
Cell Division, Exons, HeLa Cells, Humans, Nuclear Proteins, Protein Binding, Proteins, Proto-Oncogene Proteins, Tumor Suppressor Protein p53, Retinoblastoma Protein, Mutagenesis, Gene Deletion, Genes, p16, Tumor Suppressor Protein p14ARF, Proto-Oncogene Proteins c-mdm2

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