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The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2’s inhibition of p53
Open accessAbstract
The INK4a gene encodes two distinct growth inhibitors--the cyclin-dependent kinase inhibitor p16Ink4a, which is a component of the Rb pathway, and the tumor suppressor p19Arf, which has been functionally linked to p53. Here we show that p19Arf potently suppresses oncogenic transformation in primary cells and that this function is abrogated when p53 is neutralized by viral oncoproteins and dominant-negative mutants but not by the p53 antagonist MDM2. This finding, coupled with the observations that p19Arf and MDM2 physically interact and that p19Rrf blocks MDM2-induced p53 degradation and transactivational silencing, suggests that p19Arf functions mechanistically to prevent MDM2's neutralization of p53. Together, our findings ascribe INK4a's potent tumor suppressor activity to the cooperative actions of its two protein products and their relation to the two central growth control pathways, Rb and p53.
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“p19 Arf has been shown to inhibit Mdm2-mediated degradation of p53 (19-21) and is clearly required for activation of p53 in response to aberrant cell cycle entry (19) and oncogene activation (22-24).”
From Ink4a / Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse (2007) · cites this paper as [19]
In the citing paper
“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 [48]
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Metadata
- Authors
- Pomerantz, J., Schreiber-Agus, N., Liégeois, N. J., Silverman, A., Alland, L., Chin, L., Potes, J., Chen, K., Orlow, I., Lee, H.-W., Cordon-Cardo, C., & DePinho, R. A.
- Affiliations
- Albert Einstein College of Medicine (US)
- Memorial Sloan Kettering Cancer Center (US)
- Corresponding author
- DePinho, Ronald A
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 1998-03
- Volume
- 92
- Issue
- 6
- Pages
- 713-723
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2039463309
- Cited by
- 1,521
- References
- 72
- Citations by year
- 2026: 4 · 2025: 10 · 2024: 6 · 2023: 23 · 2022: 19 · 2021: 23 · 2020: 19 · 2019: 16 · 2018: 12 · 2017: 24 · 2016: 27 · 2015: 32 · 2014: 44 · 2013: 44 · 2012: 47
- FWCI
- 64.86
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA 47179, CA 47538, CADK97650, P01CA047179)
- 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 › PI3K/AKT/mTOR signaling in cancer
- Keywords
- p19ARF, INK4A, MDM2, p53, tumor suppression, protein-protein interaction, p53 degradation, p53 transactivation, oncogenic transformation, Rb pathway, viral oncoproteins, dominant-negative mutant
- MeSH terms
- Animals, Biotin, Cell Line, Deoxyuracil Nucleotides, Lens, Crystalline, Neoplasm Proteins, Nuclear Proteins, Osteoblasts, Proteins, Proto-Oncogene Proteins, Staining and Labeling, Transformation, Genetic, Tumor Suppressor Protein p53, Retinoblastoma Protein, Apoptosis, Genes, p16, Tumor Suppressor Protein p14ARF, Mice, Proto-Oncogene Proteins c-mdm2, DNA Fragmentation
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