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Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2
Open accessAbstract
The INK4a-ARF locus encodes two proteins, p16(INK4a) and p19(ARF), that restrain cell growth by affecting the functions of the retinoblastoma protein and p53, respectively. Disruption of this locus by deletions or point mutations is a common event in human cancer, perhaps second only to the loss of p53. Using insect cells infected with baculovirus vectors and NIH 3T3 fibroblasts infected with ARF retrovirus, we determined that mouse p19(ARF) can interact directly with p53, as well as with the p53 regulator mdm2. ARF can bind p53-DNA complexes, and it depends upon functional p53 to transcriptionally induce mdm2 and the cyclin-dependent kinase inhibitor p21(Cip1), and to arrest cell proliferation. Binding of p19(ARF) to p53 requires the ARF N-terminal domain (amino acids 1-62) that is necessary and sufficient to induce cell cycle arrest. Overexpression of p19(ARF) in wild type or ARF-null mouse embryo fibroblasts increases the half-life of p53 from 15 to approximately 75 min, correlating with an increased p53-dependent transcriptional response and growth arrest. Surprisingly, when overexpressed at supra-physiologic levels after introduction into ARF-null NIH 3T3 cells or mouse embryo fibroblasts, the p53 protein is handicapped in inducing this checkpoint response. In this setting, reintroduction of p19(ARF) restores p53's ability to induce p21(Cip1) and mdm2, implying that, in addition to stabilizing p53, ARF modulates p53-dependent function through an additional mechanism.
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“Under most conditions ARF functions as a tumor suppressor by binding and inhibiting Mdm2 activity [47–49].”
From Integration of DNA damage and repair with murine double-minute 2 (Mdm2) in tumorigenesis (2012) · cites this paper as [47]
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Metadata
- Authors
- Kamijo, T., Weber, J. D., Zambetti, G., Zindy, F., Roussel, M. F., & Sherr, C. J.
- Affiliations
- St. Jude Children's Research Hospital (US)
- Howard Hughes Medical Institute and Departments of Tumor Cell Biology and Biochemistry, St. Jude Children’s Research Hospital, 332 North Lauderdale, Memphis, TN 38105
- Corresponding author
- Sherr, Charles J.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1998-07-07
- Volume
- 95
- Issue
- 14
- Pages
- 8292-8297
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC20969
- OpenAlex
- W2141529421
- Cited by
- 899
- References
- 61
- Citations by year
- 2026: 5 · 2025: 5 · 2024: 2 · 2023: 10 · 2022: 11 · 2021: 15 · 2020: 10 · 2019: 10 · 2018: 12 · 2017: 14 · 2016: 26 · 2015: 21 · 2014: 33 · 2013: 28 · 2012: 34
- FWCI
- 31.09
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- St. Jude Children's Research Hospital (CA21765)
- American Lebanese Syrian Associated Charities (CA 21765)
- National Institutes of Health (CA21765))
- National Cancer Institute (R01CA063230, CA-71907, CA-63230, CA21765, P30CA021765, P01CA071907)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- p19ARF, p53, MDM2, INK4a/ARF locus, p16INK4a, protein-protein interaction, p53 stabilization, p21 Cip1, cell cycle arrest, p53-dependent transcription, tumor suppressor, p53 DNA binding, N-terminal domain
- MeSH terms
- Animals, Humans, Neoplasm Proteins, Nuclear Proteins, Proteins, Proto-Oncogene Proteins, Retroviridae, Transfection, Gene Expression Regulation, Neoplastic, Genes, Tumor Suppressor, Tumor Suppressor Protein p53, 3T3 Cells, Tumor Suppressor Protein p14ARF, Mice, Proto-Oncogene Proteins c-mdm2
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