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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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Cites
p53, the cellular gatekeeper for growth and division
Levine, A. J. (1997) · Cell · doi:10.1016/s0092-8674(00)81871-1 · Cited by 7,693
Recombinant Genomes Which Express Chloramphenicol Acetyltransferase in Mammalian Cells
Gorman, C., Moffat, L. F., & Howard, B. H. (1982) · Molecular and Cellular Biology · doi:10.1128/mcb.2.9.1044 · Cited by 7,674
High-Efficiency Transformation of Mammalian Cells by Plasmid DNA
Chen, C., & Okayama, H. (1987) · Molecular and Cellular Biology · doi:10.1128/mcb.7.8.2745 · Cited by 5,327
Mdm2 promotes the rapid degradation of p53
Haupt, Y., Maya, R., Kazaz, A., & Oren, M. (1997) · Nature · doi:10.1038/387296a0 · Cited by 4,506
A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/CDK4.
Serrano, M., Hannon, G. J., & Beach, D. (1993) · Nature · doi:10.1038/366704a0 · Cited by 3,650
Regulation of p53 stability by Mdm2
Kubbutat, M. H. G., Jones, S. N., & Vousden, K. H. (1997) · Nature · doi:10.1038/387299a0 · Cited by 3,312
Momand, J., Zambetti, G. P., Olson, D. C., George, D., & Levine, A. J. (1992) · Cell · doi:10.1016/0092-8674(92)90644-r · Cited by 3,113
Self-citationTodaro, G. J., & Green, H. (1963) · The Journal of Cell Biology · doi:10.1083/jcb.17.2.299 · Cited by 2,747
Activation of p53 Sequence-Specific DNA Binding by Acetylation of the p53 C-Terminal Domain
Gu, W., & Roeder, R. G. (1997) · Cell · doi:10.1016/s0092-8674(00)80521-8 · Cited by 2,559
DNA damage-induced phosphorylation of p53 alleviates inhibition by MDM2
Shieh, S.-Y., Ikeda, M., Taya, Y., & Prives, C. (1997) · Cell · doi:10.1016/s0092-8674(00)80416-x · Cited by 2,100
Oncoprotein MDM2 is a ubiquitin ligase E3 for tumor suppressor p53
Honda, R., Tanaka, H., & Yasuda, H. (1997) · FEBS Letters · doi:10.1016/s0014-5793(97)01480-4 · Cited by 1,951
The p53-mdm-2 autoregulatory feedback loop.
Wu, X., Bayle, J. H., Olson, D., & Levine, A. J. (1993) · Genes & Development · doi:10.1101/gad.7.7a.1126 · Cited by 1,801
Zhang, Y., Xiong, Y., & Yarbrough, W. G. (1998) · Cell · doi:10.1016/s0092-8674(00)81401-4 · Cited by 1,626
Role of the INK4a Locus in Tumor Suppression and Cell Mortality
Serrano, M., Lee, H.-W., Chin, L., Cordon-Cardo, C., Beach, D., & DePinho, R. A. (1996) · Cell · doi:10.1016/s0092-8674(00)81079-x · Cited by 1,585
Tumor Suppression at the Mouse INK4a Locus Mediated by the Alternative Reading Frame Product p19
Kamijo, T., Zindy, F., Roussel, M. F., Quelle, D. E., Downing, J. R., Ashmun, R. A., Grosveld, G., & Sherr, C. J. (1997) · Cell · doi:10.1016/s0092-8674(00)80452-3 · Cited by 1,566
Self-citationPomerantz, J., Schreiber-Agus, N., Liégeois, N. J., Silverman, A., Alland, L., Chin, L., Potes, J., Chen, K., Orlow, I., Lee, H.-W., et al. (1998) · Cell · doi:10.1016/s0092-8674(00)81400-2 · Cited by 1,521
Ouelle, D. E., Zindy, F., Ashmun, R. A., & Sherr, C. J. (1995) · Cell · doi:10.1016/0092-8674(95)90214-7 · Cited by 1,485
Self-citationOncoprotein MDM2 conceals the activation domain of tumour suppressor p53
Oliner, J. D., Pietenpol, J. A., Thiagalingam, S., Gyuris, J., Kinzler, K. W., & Vogelstein, B. (1993) · Nature · doi:10.1038/362857a0 · Cited by 1,474
Rescue of early embryonic lethality in mdm2-deficient mice by deletion of p53
de Oca Luna, R. M., Wagner, D. S., & Lozano, G. (1995) · Nature · doi:10.1038/378203a0 · Cited by 1,420
Rescue of embryonic lethality in Mdm2-deficient mice by absence of p53
Jones, S. N., Roe, A. E., Donehower, L. A., & Bradley, A. (1995) · Nature · doi:10.1038/378206a0 · Cited by 1,280
(1993) · Genes & Development · doi:10.1101/gad.7.3.331 · Cited by 1,264
Self-citationFunctional interactions of the retinoblastoma protein with mammalian D-type cyclins
Ewen, M. E., Sluss, H. K., Sherr, C. J., Matsushime, H., Kato, J.-Y., & Livingston, D. M. (1993) · Cell · doi:10.1016/0092-8674(93)90136-e · Cited by 1,010
Self-citationOncogenic Forms of p53 Inhibit p53-Regulated Gene Expression
Kern, S. E., Pietenpol, J., Thiagalingam, S., Seymour, A., Kinzler, K. W., & Vogelstein, B. (1992) · Science · doi:10.1126/science.1589764 · Cited by 940
Regulation of the specific DNA binding function of p53
Hupp, T. R., Meek, D. W., Midgley, C., & Lane, D. P. (1992) · Cell · doi:10.1016/0092-8674(92)90562-q · Cited by 916
Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16
Lukas, J., Parry, D., Aagaard, L., Mann, D. J., Bartkova, J., Strauss, M., Peters, G., & Bartek, J. (1995) · Nature · doi:10.1038/375503a0 · Cited by 899
Database of p53 gene somatic mutations in human tumors and cell lines.
Hollstein, M. C., Rice, K., Greenblatt, M. S., Soussi, T., Fuchs, R., Sørlie, T., Hovig, E. J., Smith‐Sørensen, B., Montesano, R., & Harris, C. C. (1994) · Europe PMC (PubMed Central) · Cited by 858
DNA damage induces phosphorylation of the amino terminus of p53
Siliciano, J. D., Canman, C. E., Taya, Y., Sakaguchi, K., Appella, E., & Kastan, M. B. (1997) · Genes & Development · doi:10.1101/gad.11.24.3471 · Cited by 818
Abnormal Centrosome Amplification in the Absence of p53
Fukasawa, K., Choi, T., Kuriyama, R., Rulong, S., & Woude, G. F. V. (1996) · Science · doi:10.1126/science.271.5256.1744 · Cited by 794
Genetic alterations of cyclins, cyclin-dependent kinases, and Cdk inhibitors in human cancer
(1996) · Advances in cancer research · doi:10.1016/s0065-230x(08)60352-8 · Cited by 752
Mapping of the p53 and mdm-2 Interaction Domains
Chen, J., Maréchal, V., & Levine, A. J. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.7.4107 · Cited by 700
Lin, J., Chen, J., Elenbaas, B., & Levine, A. J. (1994) · Genes & Development · doi:10.1101/gad.8.10.1235 · Cited by 652
Paulovich, A. G., Toczyski, D. P., & Hartwell, L. H. (1997) · Cell · doi:10.1016/s0092-8674(00)81870-x · Cited by 625
Roth, J., Dobbelstein, M., Freedman, D. A., Shenk, T., & Levine, A. J. (1998) · The EMBO Journal · doi:10.1093/emboj/17.2.554 · Cited by 610
Zindy, F., Quelle, D. E., Roussel, M. F., & Sherr, C. J. (1997) · Oncogene · doi:10.1038/sj.onc.1201178 · Cited by 574
Self-citationTumour-derived p16 alleles encoding proteins defective in cell-cycle inhibition
Koh, J., Enders, G. H., David Dynlacht, B., & Harlow, E. (1995) · Nature · doi:10.1038/375506a0 · Cited by 516
Characterization of the p53-Dependent Postmitotic Checkpoint following Spindle Disruption
Lanni, J. S., & Jacks, T. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.2.1055 · Cited by 493
Identification of redox/repair protein Ref-1 as a potent activator of p53.Preprint
Jayaraman, L., Murthy, K. G. K., Zhu, C., Curran, T., Xanthoudakis, S., & Prives, C. L. (1997) · Genes & Development · doi:10.1101/gad.11.5.558 · Cited by 485
Harvey, D. M., & Levine, A. J. (1991) · Genes & Development · doi:10.1101/gad.5.12b.2375 · Cited by 453
Small peptides activate the latent sequence-specific DNA binding function of p53
Hupp, T. R., Sparks, A., & Lane, D. P. (1995) · Cell · doi:10.1016/0092-8674(95)90165-5 · Cited by 439
Growth suppression by p16ink4 requires functional retinoblastoma protein
Medema, R. H., Herrera, R. E., Lam, F., & Weinberg, R. A. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.14.6289 · Cited by 433
Hinds, P. W., Finlay, C. A., Quartin, R. S., Baker, S. J., Fearon, E. R., Vogelstein, B., & Levine, A. J. (1990) · PubMed · Cited by 408
Complex structure and regulation of the P16 (MTS1) locus.
Stone, S., Jiang, P., Dayananth, P., Tavtigian, S. V., Katcher, H. L., Parry, D., Peters, G., & Kamb, A. (1995) · PubMed · Cited by 383
Mao, L., Merlo, A. U., Bedi, G. C., Shapiro, G. I., Edwards, C. D., Rollins, B. J., & Sidransky, D. (1995) · PubMed · Cited by 329
Zambetti, G. P., Bargonetti, J., Walker, K. K., Prives, C. L., & Levine, A. J. (1992) · Genes & Development · doi:10.1101/gad.6.7.1143 · Cited by 311
Self-citationA Role for Endothelial NO Synthase in LTP Revealed by Adenovirus-Mediated Inhibition and Rescue
Kantor, D. B., Lanzrein, M., Stary, S. J., Sandoval, G. M., Smith, W. B., Sullivan, B. M., Davidson, N., & Schuman, E. M. (1996) · Science · doi:10.1126/science.274.5293.1744 · Cited by 304
The candidate tumour suppressor p33ING1cooperates with p53 in cell growth control
Garkavtsev, I., Grigorian, I. A., Ossovskaya, V., Chernov, M. V., Chumakov, P. M., & Gudkov, A. V. (1998) · Nature · doi:10.1038/34675 · Cited by 291
Cell-cycle control and its watchman
Jacks, T., & Weinberg, R. A. (1996) · Nature · doi:10.1038/381643a0 · Cited by 274
Lukáš, J., Müller, H., Bártková, J., Spitkovsky, D., Kjerulff, A. A., Jansen‐Dürr, P., Strauss, M., & Bártek, J. (1994) · The Journal of Cell Biology · doi:10.1083/jcb.125.3.625 · Cited by 269
Quelle, D. E., Cheng, M. M., Ashmun, R. A., & Sherr, C. J. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.2.669 · Cited by 217
Self-citationGutierres, S., Sabar, M., Lelandais‐Brière, C., Chétrit, P., Diolez, P., Degand, H., Boutry, M., VEDEL, F., de Kouchkovsky, Y., & Paepe, R. D. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.7.3436 · Cited by 215
Wang, E. H., Friedman, P. N., & Prives, C. L. (1989) · Cell · doi:10.1016/0092-8674(89)90913-6 · Cited by 215
Functional activation of p53 via phosphorylation following DNA damage by UV but not γ radiation
Kapoor, M., & Lozano, G. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.6.2834 · Cited by 209
Nuclear localization is essential for the activity of p53 protein.
Shaulsky, G., Goldfinger, N., Tosky, M. S., Levine, A. J., & Rotter, V. (1991) · PubMed · Cited by 192
Cannon, J. V., & Lane, D. P. (1991) · Nature · doi:10.1038/349802a0 · Cited by 169
Tan, T., Wallis, J., & Levine, A. J. (1986) · Journal of Virology · doi:10.1128/jvi.59.3.574-583.1986 · Cited by 159
Zauberman, A., Barak, Y., Ragimov, N., Levy, N., & Oren, M. (1993) · The EMBO Journal · doi:10.1002/j.1460-2075.1993.tb05941.x · Cited by 151
A new type of p16INK4/MTS1 gene transcript expressed in B-cell malignancies.
Duro, D., Bernard, O., Della-Valle, V., Berger, R., & Larsen, C. (1995) · PubMed · Cited by 130
Mutation of Phosphoserine 389 Affects p53 Function in Vivo
Hao, M., Lowy, A. M., Kapoor, M., Deffie, A. M., Liu, G., & Lozano, G. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.46.29380 · Cited by 102
Regulation of Mutant p53 Temperature-sensitive DNA Binding
Friedlander, P. A., Legros, Y., Soussi, T., & Prives, C. L. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.41.25468 · Cited by 94
Stabilization and activation of p53 are regulated independently by different phosphorylation events
Chernov, M. V., Ramana, C. V., Adler, V., & Stark, G. R. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.5.2284 · Cited by 78
The p53 activation and apoptosis induced by DNA damage are reversibly inhibited by salicylate
Chernov, M. V., & Stark, G. R. (1997) · Oncogene · doi:10.1038/sj.onc.1201104 · Cited by 46
Research works printed but not linked: 10
- M Hollstein, K Rice, M S Greenblatt, T Soussi, R Fuchs, T Sorlie, E Hovig, B Smith-Sorensen, R Montesano, C C Harris Nucleic Acids Res 22, 3551–3555 (1994).
- D Duro, O Bernard, V Della Valle, R Berger, C-J Larsen Oncogene 11, 21–29 (1995).
- L Mao, A Merlo, G Bedi, G I Shapiro, C D Edwards, B J Rollins, D Sidransky Cancer Res 55, 2995–2997 (1995).
- S Stone, P Jiang, P Dayananth, S V Tavtigian, H Katcher, D Parry, G Peters, A Kamb Cancer Res 55, 2988–2994 (1995).
- 10.1128/mcb.13.7.4107-4114.1993 · DOI
- P W Hinds, C A Finlay, R S Quartin, S J Baker, E R Fearon, B Vogelstein, A J Levine Cell Growth Diff 1, 571–580 (1990).
- 10.1128/mcb.7.8.2745-2752.1987 · DOI
- 10.1126/science.256.5058.827 · DOI
- 10.1128/mcb.2.9.1044-1051.1982 · DOI
- G Shaulsky, N Goldfinger, M S Tosky, A J Levine, V Rotter Oncogene 6, 2055–2065 (1991).
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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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