Cited by 1,521Cancer-related Molecular PathwaysHeat shock proteins researchPI3K/AKT/mTOR signaling in cancer

The Ink4a tumor suppressor gene product, p19Arf, interacts with MDM2 and neutralizes MDM2’s inhibition of p53

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Pomerantz, Jason, Schreiber-Agus, Nicole, Liégeois, Nanette J, Silverman, Adam, Alland, Leila, Chin, Lynda, Potes, Jason, Chen, Ken +4 more·1998·Cell

Abstract

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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Crossref · 10.1016/s0092-8674(00)81400-2

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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
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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