Cited by 899Cancer-related Molecular PathwaysHeat shock proteins researchChromatin Remodeling and Cancer

Functional and physical interactions of the ARF tumor suppressor with p53 and Mdm2

Open access
Kamijo, Takehiko, Weber, Jason D., Zambetti, Gerard, Zindy, Frederique, Roussel, Martine F., Sherr, Charles J.·1998·Proceedings of the National Academy of Sciences

Abstract

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.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1073/pnas.95.14.8292

Cites

65 of 65 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 4

  1. [13]Medema, R. H., Herrera, R. E., Lam, F. & Weinberg, R. A. (1995) Proc. Natl. Acad. Sci. USA 92, 6289-6293.
  2. [34]Quelle, D. E., Cheng, M., Ashmun, R. A. & Sherr, C. J. (1997) Proc. Natl. Acad. Sci. USA 94, 3436-3440.
  3. [46]Chernov, M. V., Ramana, C. V., Adler, V. V. & Stark, G. R. (1998) Proc. Natl. Acad. Sci. USA 95, 2284-2289.
  4. [49]Kapoor, M. & Lozano, G. (1998) Proc. Natl. Acad. Sci. USA 95, 2834-2837.

Cited by

Sorted by citations

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
Published
1998-07-07
Volume
95
Issue
14
Pages
8292-8297
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
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
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

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review