The DOI matches its Crossref record; 63 of the 73 references it cites were found in a registry or an index.
DNA Damage-Induced Phosphorylation of p53 Alleviates Inhibition by MDM2
Open accessAbstract
DNA-damaging agents signal to p53 through as yet unidentified posttranscriptional mechanisms. Here we show that phosphorylation of human p53 at serine 15 occurs after DNA damage and that this leads to reduced interaction of p53 with its negative regulator, the oncoprotein MDM2, in vivo and in vitro. Furthermore, using purified DNA-dependent protein kinase (DNA-PK), we demonstrate that phosphorylation of p53 at serines 15 and 37 impairs the ability of MDM2 to inhibit p53-dependent transactivation. We present evidence that these effects are most likely due to a conformational change induced upon phosphorylation of p53. Our studies provide a plausible mechanism by which the induction of p53 can be modulated by DNA-PK (or other protein kinases with similar specificity) in response to DNA damage.
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In the citing paper
“Doxorubicin treatment of early passage tumor cell lines revealed that five of five early generation mTerc Ink4a / Arf -/ -tumors maintained intact p53 response evidenced by p53 Ser-18 phosphorylation (37, 38) and associated induction of p21 CIP1 .”
From Ink4a / Arf tumor suppressor does not modulate the degenerative conditions or tumor spectrum of the telomerase-deficient mouse (2007) · cites this paper as [37]
In the citing paper
“Induction of double strand breaks in DNA by ionizing radiation or genotoxic chemotherapy leads to the rapid stabilization of p53 through phosphorylation of its N terminus (Shieh et al. 1997; Siliciano et al. 1997”
From p53 Deficiency Rescues the Adverse Effects of Telomere Loss and Cooperates with Telomere Dysfunction to Accelerate Carcinogenesis (1999) · cites this paper as Shieh et al. 1997
In the citing paper
“ATM also activates Chk2, which in turn phosphorylates p53 on serine 20 and inhibits MDM2 binding (Shieh et al, 1997;Banin et al, 1998;Chehab et al, 2000;Shieh et al, 2000).”
From ATM and Chk2-dependent phosphorylation of MDMX contribute to p53 activation after DNA damage (2005) · cites this paper as Shieh et al, 1997
In the citing paper
“ATM also activates Chk2, which in turn phosphorylates p53 on S20, which is a part of the MDM2-binding site (Shieh et al, 1997(Shieh et al, , 2000;;Banin et al, 1998;Chehab et al, 2000).”
From ATM activates p53 by regulating MDM2 oligomerization and E3 processivity (2009) · cites this paper as Shieh et al, 1997
In the citing paper
“Several landmark studies showed that DNA double strand breaks induce phosphorylation of p53 S15 by DNA-PK and ATM (Mayo et al, 1997;Shieh et al, 1997;Banin et al, 1998;Prives and Hall, 1999).”
From ATM activates p53 by regulating MDM2 oligomerization and E3 processivity (2009) · cites this paper as Shieh et al, 1997
Citations
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
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
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
Kastan, M. B., Zhan, Q., El-Deiry, W. S., Carrier, F., Jacks, T., Walsh, W. V., Plunkett, B. S., Vogelstein, B., & Fornace, A. J. (1992) · Cell · doi:10.1016/0092-8674(92)90593-2 · Cited by 3,047
A Single Ataxia Telangiectasia Gene with a Product Similar to PI-3 Kinase
Savitsky, K., Bar-Shira, A., Gilad, S., Rotman, G., Ziv, Y., Vanagaite, L., Tagle, D. A., Smith, S., Uziel, T., Sfez, S., et al. (1995) · Science · doi:10.1126/science.7792600 · Cited by 2,785
p53: puzzle and paradigm.Preprint
Ko, L. J., & Prives, C. L. (1996) · Genes & Development · doi:10.1101/gad.10.9.1054 · Cited by 2,346
Self-citationStructure of the MDM2 Oncoprotein Bound to the p53 Tumor Suppressor Transactivation Domain
Kussie, P. H., Gorina, S., Marechal, V., Elenbaas, B., Moreau, J., Levine, A. J., & Pavletich, N. P. (1996) · Science · doi:10.1126/science.274.5289.948 · Cited by 2,206
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
Oncoprotein 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
The DNA-dependent protein kinase: Requirement for DNA ends and association with Ku antigen
Gottlieb, T. M., & Jackson, S. P. (1993) · Cell · doi:10.1016/0092-8674(93)90057-w · Cited by 1,233
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
Blunt, T., Finnie, N., Taccioli, G. E., Smith, G. C. M., Demengeot, J., Gottlieb, T. M., Mizuta, R., Varghese, A. J., Alt, F. W., Jeggo, P. A., et al. (1995) · Cell · doi:10.1016/0092-8674(95)90360-7 · Cited by 865
Nelson, W. G., & Kastan, M. B. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.3.1815 · Cited by 855
Karin, M., & Hunter, T. R. (1995) · Current Biology · doi:10.1016/s0960-9822(95)00151-5 · Cited by 747
Hartley, K. O., Gell, D. A., Smith, G. C. M., Zhang, H., Divecha, N., Connelly, M. A., Admon, A., Lees‐Miller, S. P., Anderson, C. W., & Jackson, S. P. (1995) · Cell · doi:10.1016/0092-8674(95)90482-4 · Cited by 745
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
Binding and modulation of p53 by p300/CBP coactivators
Lill, N. L., Grossman, S. R., Ginsberg, D., DeCaprio, J. A., & Livingston, D. M. (1997) · Nature · doi:10.1038/42981 · Cited by 693
Recruitment of p300/CBP in p53-Dependent Signal Pathways
Avantaggiati, M. L., Ogryzko, V. V., Gardner, K., Giordano, A., Levine, A. S., & Kelly, K. (1997) · Cell · doi:10.1016/s0092-8674(00)80304-9 · Cited by 668
Requirement for Ku80 in growth and immunoglobulin V(D)J recombination
Nussenzweig, A., Chen, C., Soares, V. D. C., Sanchez, M., Sokol, K. A., Nussenzweig, M. C., & Li, G. C. (1996) · Nature · doi:10.1038/382551a0 · Cited by 662
Lin, J., Chen, J., Elenbaas, B., & Levine, A. J. (1994) · Genes & Development · doi:10.1101/gad.8.10.1235 · Cited by 652
In vivo ubiquitination and proteasome-mediated degradation of p53(1).
Maki, C. G., Huibregtse, J. M., & Howley, P. M. (1996) · PubMed · Cited by 645
DNA-Dependent Kinase (p350) as a Candidate Gene for the Murine SCID Defect
Kirchgessner, C. U., Patil, C. K., Evans, J., Cuomo, C. A., Fried, L. M., Carter, T., Oettinger, M. A., & Brown, J. M. (1995) · Science · doi:10.1126/science.7855601 · Cited by 609
Synergistic activation of transcription by CBP and p53
Gu, W., Shi, X.-L., & Roeder, R. G. (1997) · Nature · doi:10.1038/42972 · Cited by 599
Kitagawa, M., Higashi, H., Jung, H. K., Suzuki‐Takahashi, I., Ikeda, M., Tamai, K., Kato, J., Segawa, K., Yoshida, E., Nishimura, S., et al. (1996) · The EMBO Journal · doi:10.1002/j.1460-2075.1996.tb01097.x · Cited by 596
Self-citationWild-type p53 activates transcription in vitro
Farmer, G., Bargonetti, J., Zhu, H., Friedman, P., Prywes, R., & Prives, C. (1992) · Nature · doi:10.1038/358083a0 · Cited by 579
Self-citationAbsence of p350 Subunit of DNA-Activated Protein Kinase from a Radiosensitive Human Cell Line
Lees‐Miller, S. P., Godbout, R., Chan, D. W., Weinfeld, M., Day, R. S., Barron, G. M., & Allalunis‐Turner, J. (1995) · Science · doi:10.1126/science.7855602 · Cited by 529
PIK-Related Kinases: DNA Repair, Recombination, and Cell Cycle Checkpoints
Keith, C. T., & Schreiber, S. L. (1995) · Science · doi:10.1126/science.270.5233.50 · Cited by 521
Wortmannin as a unique probe for an intracellular signalling protein, phosphoinositide 3-kinase
Ui, M., Okada, T., Hazeki, K., & Hazeki, O. (1995) · Trends in Biochemical Sciences · doi:10.1016/s0968-0004(00)89056-8 · Cited by 520
Lees‐Miller, S. P., Sakaguchi, K., Ullrich, S. J., Appella, E., & Anderson, C. W. (1992) · Molecular and Cellular Biology · doi:10.1128/mcb.12.11.5041-5049.1992 · Cited by 487
p53 in growth control and neoplasia
Gottlieb, T. M., & Oren, M. (1996) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/0304-419x(95)00019-c · Cited by 483
p53 Transcriptional Activation Mediated by Coactivators TAF II 40 and TAF II 60
Thut, C. J., Chen, J.-L., Klemm, R. D., & Tjian, R. (1995) · Science · doi:10.1126/science.7809597 · Cited by 439
Zhu, C., Bogue, M. A., Lim, D., Hasty, P., & Roth, D. B. (1996) · Cell · doi:10.1016/s0092-8674(00)80111-7 · Cited by 433
Lees‐Miller, S. P., Chen, Y. R., & Anderson, C. W. (1990) · Molecular and Cellular Biology · doi:10.1128/mcb.10.12.6472 · Cited by 421
Finnie, N., Gottlieb, T. M., Blunt, T., Jeggo, P. A., & Jackson, S. P. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.1.320 · Cited by 337
Increased and altered DNA binding of human p53 by S and G2/M but not Gl cyclin-dependent kinases
Wang, Y., & Prives, C. (1995) · Nature · doi:10.1038/376088a0 · Cited by 336
Self-citationJuven‐Gershon, T., Barak, Y., Zauberman, A., George, D. L., & Oren, M. (1993) · PubMed · Cited by 332
Human TAFII31 protein is a transcriptional coactivator of the p53 protein.
Lu, H., & Levine, A. J. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.11.5154 · Cited by 301
A DNA-Activated Protein Kinase from HeLa Cell Nuclei
Carter, T., Vancurova, I., Sun, I. Y., Lou, W., & DeLeon, S. (1990) · Molecular and Cellular Biology · doi:10.1128/mcb.10.12.6460 · Cited by 288
Peterson, S., Kurimasa, A., Oshimura, M., Dynan, W. S., Bradbury, E. M., & Chen, D. J. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.8.3171 · Cited by 284
V(D)J recombination activates a p53-dependent DNA damage checkpoint in scid lymphocyte precursors.Preprint
Guidos, C. J., Williams, C. J., Grandal, I., Knowles, G. C., Huang, M. T. F., & Danska, J. S. (1996) · Genes & Development · doi:10.1101/gad.10.16.2038 · Cited by 276
The p53-dependent G1 cell cycle checkpoint pathway and ataxia-telangiectasia.
Canman, C. E., Wolff, A. C., Chen, C.-Y., Fornace, A. J., & Kastan, M. B. (1994) · PubMed · Cited by 246
Picksley, S. M., Vojtĕsek, B., Sparks, A., & Lane, D. P. (1994) · PubMed · Cited by 238
Takenaka, I. M., Morin, F., Seizinger, B. R., & Kley, N. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.10.5405 · Cited by 198
Identification of novel mdm2 binding peptides by phage display.
Böttger, V., Böttger, A., Howard, S. F., Picksley, S. M., Chêne, P., Garcı́a-Echeverrı́a, C., Hochkeppel, H. K., & Lane, D. P. (1996) · PubMed · Cited by 182
Biochemical and Genetic Defects in the DNA-Dependent Protein Kinase in Murine scid Lymphocytes
Danska, J. S., Holland, D. P., Mariathasan, S., Williams, K. M., & Guidos, C. J. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.10.5507 · Cited by 181
Proteolysis by Calpains: a Possible Contribution to Degradation of p53
Pariât, M., Carillo, S., Molinari, M., Salvat, C., Debüssche, L., Bracco, L. P., Milner, J., & Piechaczyk, M. (1997) · Molecular and Cellular Biology · doi:10.1128/mcb.17.5.2806 · Cited by 163
Fiscella, M., Sj, U., Zambrano, N., Shields, M. T., Lin, D., Lees‐Miller, S. P., Anderson, C. W., Mercer, W. E., & Appella, E. (1993) · PubMed · Cited by 139
Post-translational modification of p53.
Meek, D. W. (1994) · PubMed · Cited by 139
DNA-dependent protein kinase is activated by nicks and larger single-stranded gaps
Morozov, V. E., Falzon, M., Anderson, C. W., & Kuff, E. L. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)89444-9 · Cited by 135
Regulation of the Cryptic Sequence-specific DNA-binding Function of p53 by Protein KinasesPreprint
Hupp, T. R., & Lane, D. P. (1994) · Cold Spring Harbor Symposia on Quantitative Biology · doi:10.1101/sqb.1994.059.01.024 · Cited by 109
A DNA-Activated Protein Kinase from HeLa Cell Nuclei
Carter, T., Vancurova, I., Sun, I., et al. (1990) · Molecular and Cellular Biology · doi:10.1128/mcb.10.12.6460-6471.1990 · Cited by 109
p53 phosphorylation: Biochemical and functional consequences
Milczarek, G. J., Martinez, J. D., & Bowden, G. T. (1996) · Life Sciences · doi:10.1016/s0024-3205(96)00479-1 · Cited by 101
Fried, L. M., Koumenis, C., Peterson, S., Green, S., van Zijl, P., Allalunis‐Turner, J., Chen, D. J., Fishel, R. A., Giaccia, A. J., Brown, J. M., et al. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.24.13825 · Cited by 94
Nature of G1/S cell cycle checkpoint defect in ataxia-telangiectasia.
Khanna, K. K., Beamish, H., Yan, J., Hobson, K., Williams, R. T., Dunn, I. S., & Lavin, M. F. (1995) · PubMed · Cited by 90
Rathmell, W. K., Kaufmann, W. K., Hurt, J. C., Byrd, L. L., & Chu, G. (1997) · PubMed · Cited by 82
Phosphorylation sites in the amino-terminal region of mouse p53.
Wang, Y., & Eckhart, W. (1992) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.89.10.4231 · Cited by 72
Hawley, R. S., & Friend, S. H. (1996) · Genes & Development · doi:10.1101/gad.10.19.2383 · Cited by 68
Huang, L., Clarkin, K., & Wahl, G. M. (1996) · PubMed · Cited by 58
p53 induction, cell cycle checkpoints, and apoptosis in DNAPK- deficient scid mice
Gurley, K. E., & Kemp, C. J. (1996) · Carcinogenesis · doi:10.1093/carcin/17.12.2537 · Cited by 48
Research works printed but not linked: 3
- Hawley, 1996, Stange bedfellows in even stranger places, Genes Dev., 10, 1383
- Meek, 1994, Posttranslational modification of p53, Semin. Cancer Biol., 5, 203
- Nelson, 1994, DNA strand breaks, Mol. Cell. Biol., 14, 1815
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Siddik, Z. H. (2003) · Oncogene · doi:10.1038/sj.onc.1206933 · Cited by 3,335
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Luo, J., Nikolaev, A. Y., Imai, S.-I., Chen, D., Su, F., Shiloh, A., Guarente, L., & Gu, W. (2001) · Cell · doi:10.1016/s0092-8674(01)00524-4 · Cited by 2,081
Activation of the ATM Kinase by Ionizing Radiation and Phosphorylation of p53
Canman, C. E., Lim, D.-S., Cimprich, K. A., Taya, Y., Tamai, K., Sakaguchi, K., Appella, E., Kastan, M. B., & Siliciano, J. D. (1998) · Science · doi:10.1126/science.281.5383.1677 · Cited by 2,042
Self-citationATM, ATR, and DNA-PK: The Trinity at the Heart of the DNA Damage Response
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Kastenhuber, E. R., & Lowe, S. W. (2017) · Cell · doi:10.1016/j.cell.2017.08.028 · Cited by 1,906
Metadata
- Authors
- Shieh, S.-Y., Ikeda, M., Taya, Y., & Prives, C.
- Affiliations
- Columbia University (US)
- Medical & Biological Laboratories (Japan) (JP)
- National Cancer Center Research Institute (JP)
- Corresponding author
- Prives, Carol
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 1997-10
- Volume
- 91
- Issue
- 3
- Pages
- 325-334
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W1978518304
- Cited by
- 2,100
- References
- 73
- Citations by year
- 2026: 15 · 2025: 25 · 2024: 40 · 2023: 53 · 2022: 72 · 2021: 53 · 2020: 49 · 2019: 45 · 2018: 47 · 2017: 72 · 2016: 50 · 2015: 55 · 2014: 74 · 2013: 86 · 2012: 84
- FWCI
- 45.42
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Cell (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA 58316)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- p53, MDM2, DNA damage response, DNA-dependent protein kinase, p53-MDM2 interaction, protein conformational change
- MeSH terms
- Binding Sites, DNA Damage, DNA-Binding Proteins, Humans, Nuclear Proteins, Phosphorylation, Proto-Oncogene Proteins, Serine, Tumor Cells, Cultured, Transcriptional Activation, Down-Regulation, Tumor Suppressor Protein p53, Protein Serine-Threonine Kinases, Protein Structure, Tertiary, Proto-Oncogene Proteins c-mdm2, DNA-Activated Protein Kinase
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