Nucleocytoplasmic shuttling of oncoprotein Hdm2 is required for Hdm2-mediated degradation of p53
Open accessAbstract
The Hdm2 oncoprotein inhibits p53 functions by two means: ( i ) it blocks p53’s transactivation activity and ( ii ) it targets p53 for degradation in a proteasome-dependent manner. Recent data indicate that Hdm2 shuttles between the nucleus and the cytoplasm and that the regulation of p53 levels by Hdm2 requires its nuclear export activity. Two different models are consistent with these observations. In the first, Hdm2 binds to p53 in the nucleus and shuttles p53 from the nucleus to the cytoplasm, and then it targets p53 to the cytoplasmic proteasome. Alternatively, Hdm2 and p53 could be exported separately from the nucleus and then associate in the cytoplasm, where Hdm2 promotes the degradation of p53. To distinguish between these two models, several Hdm2 mutants were employed. Hdm2NLS lacks the ability to enter the nucleus, whereas Hdm2NES is deficient in nuclear export. Hdm2NLS, Hdm2NES, or the combination of both mutants were unable to promote p53 degradation in the cotransfected 2KO cells (which were null for both the p53 and mdm2 genes), although wild-type Hdm2 efficiently reduced p53 levels under the same conditions. This observation is not a result of the differences in expression levels or stability between Hdm2 and these mutants. Moreover, coexpression of these mutants had no effect on wild-type Hdm-2-induced p53 destabilization. Thus, Hdm2 must shuttle p53 from the nucleus to the cytoplasm to target it for degradation in the cytoplasm.
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.
Integrity signals
Registry
Cites
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.
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?
Efficient degradation of p53 requires its nuclear export.
“Several reports suggest that nuclear export of p53, mediated through the nuclear export signal (NES) of Mdm2 and/or through the NES of p53 itself, is required for its efficient degradation (Roth et al., 1998;Tao and Levine, 1999;Boyd et al., 2000;Geyer et al., 2000).”
From Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms (2001) · cites this paper as Tao and Levine, 1999
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
WAF1, a potential mediator of p53 tumor suppression
El-Deiry, W. S., Tokino, T., Velculescu, V. E., Levy, D. B., Parsons, R., Trent, J. M., Lin, D., Mercer, W. E., Kinzler, K. W., & Vogelstein, B. (1993) · Cell · doi:10.1016/0092-8674(93)90500-p · Cited by 8,321 · see citing works
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 · see citing works
Self-citationThe p21 Cdk-interacting protein Cip1 is a potent inhibitor of G1 cyclin-dependent kinases.
Wade Harper, J. (1993) · Cell · doi:10.1016/0092-8674(93)90499-g · Cited by 5,651 · see citing works
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 · see citing works
Tumor suppressor p53 is a direct transcriptional activator of the human bax gene
Toshiyuki, M., & Reed, J. C. (1995) · Cell · doi:10.1016/0092-8674(95)90412-3 · Cited by 4,063 · see citing works
p21 is a universal inhibitor of cyclin kinases
Xiong, Y., Hannon, G., Zhang, H., Casso, D., Kobayashi, R., & Beach, D. (1993) · Nature · doi:10.1038/366701a0 · Cited by 3,691 · see citing works
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 · see citing works
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 · see citing works
Self-citationp53: puzzle and paradigm.Preprint
Ko, L. J., & Prives, C. L. (1996) · Genes & Development · doi:10.1101/gad.10.9.1054 · Cited by 2,338 · see citing works
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 · see citing works
Nuclear targeting sequences — a consensus?
Dingwall, C., & Laskey, R. A. (1991) · Trends in Biochemical Sciences · doi:10.1016/0968-0004(91)90184-w · Cited by 1,891 · see citing works
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 · see citing works
Self-citationA novel form of Epstein-Barr virus latency in normal B cells in vivo
Miyashita, E. M., Yang, B., Lam, K. M. C., Crawford, D., & Thorley‐Lawson, D. A. (1995) · Cell · doi:10.1016/0092-8674(95)90513-8 · Cited by 1,591 · see citing works
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 1,447 · see citing works
mdm2 expression is induced by wild type p53 activity.
Barak, Y., Juven, T., Haffner, R., & Oren, M. (1993) · The EMBO Journal · doi:10.1002/j.1460-2075.1993.tb05678.x · Cited by 1,290 · see citing works
UV Irradiation Stimulates Levels of p53 Cellular Tumor Antigen in Nontransformed Mouse Cells
Maltzman, W., & Czyzyk, L. (1984) · Molecular and Cellular Biology · doi:10.1128/mcb.4.9.1689 · Cited by 893 · see citing works
Fakharzadeh, S. S., Trusko, S. P., & George, D. L. (1991) · The EMBO Journal · doi:10.1002/j.1460-2075.1991.tb07676.x · Cited by 704 · see citing works
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 689 · see citing works
Self-citationRoth, 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 · see citing works
Self-citationNuclear Export Is Required for Degradation of Endogenous p53 by MDM2 and Human Papillomavirus E6
Freedman, D. A., & Levine, A. J. (1998) · Molecular and Cellular Biology · doi:10.1128/mcb.18.12.7288 · Cited by 513 · see citing works
Self-citationmdm-2 Inhibits the G1 Arrest and Apoptosis Functions of the p53 Tumor Suppressor Protein
Chen, J., Wu, X., Lin, J., & Levine, A. J. (1996) · Molecular and Cellular Biology · doi:10.1128/mcb.16.5.2445 · Cited by 350 · see citing works
Self-citationBarak, Y., Gottlieb, E., Juven-Gershon, T., & Oren, M. (1994) · Genes & Development · doi:10.1101/gad.8.15.1739 · Cited by 328 · see citing works
The mdm-2 oncogene can overcome wild-type p53 suppression of transformed cell growth.
Finlay, C. A. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.1.301 · Cited by 311 · see citing works
Mdm2: keeping p53 under control
Piette, J. G., Neel, H., & Maréchal, V. (1997) · Oncogene · doi:10.1038/sj.onc.1201432 · Cited by 268 · see citing works
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.13.7.4107-4114.1993 · Cited by 247 · see citing works
Self-citationUV Irradiation Stimulates Levels of p53 Cellular Tumor Antigen in Nontransformed Mouse Cells
Maltzman, W., & Czyzyk, L. (1984) · Molecular and Cellular Biology · doi:10.1128/mcb.4.9.1689-1694.1984 · Cited by 226 · see citing works
Regulation of Transcription Functions of the p53 Tumor Suppressor by the mdm-2 Oncogene
Chen, J., Lin, J., & Levine, A. J. (1995) · Molecular Medicine · doi:10.1007/bf03401562 · Cited by 214 · see citing works
Self-citationModulation of Cell Death in Yeast by the Bcl-2 Family of Proteins
Tao, W., Kurschner, C., & Morgan, J. I. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.24.15547 · Cited by 109 · see citing works
Self-citationA Genetic Approach to Mapping the p53 Binding Site in the MDM2 Protein
Freedman, D. A., Epstein, C. B., Roth, J. C., & Levine, A. J. (1997) · Molecular Medicine · doi:10.1007/bf03401678 · Cited by 91 · see citing works
Self-citationThe mdm-2 Oncogene Can Overcome Wild-Type p53 Suppression of Transformed Cell Growth
Finlay, C. A. (1993) · Molecular and Cellular Biology · doi:10.1128/mcb.13.1.301-306.1993 · Cited by 83 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Dingwall, C. & Laskey, R. A. (1991) Trends Biochem. Sci. 16, 478-481. 3080 Medical Sciences: Tao and Levine Proc. Natl. Acad. Sci. USA 96 (1999)
Cited by
Sorted by citations
Mayo, L. D., & Donner, D. B. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.181181198 · Cited by 1,230 · see citing works
Mdm2 Is a RING Finger-dependent Ubiquitin Protein Ligase for Itself and p53
Fang, S., Jensen, J. P., Ludwig, R. L., Vousden, K. H., & Weissman, A. M. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.12.8945 · Cited by 1,044 · see citing works
Regulation of p53 in response to DNA damage
Lakin, N. D., & Jackson, S. P. (1999) · Oncogene · doi:10.1038/sj.onc.1203015 · Cited by 987 · see citing works
Inhibiting the p53–MDM2 interaction: an important target for cancer therapy
Chène, P. (2003) · Nature Reviews Cancer · doi:10.1038/nrc991 · Cited by 765 · see citing works
ATM-dependent phosphorylation of Mdm2 on serine 395: role in p53 activation by DNA damage
Maya, R., Balass, M., Kim, S.-T., Shkedy, D., Leal, J.-F. M., Shifman, O., Moas, M., Buschmann, T., Ronai, Z., Shiloh, Y., et al. (2001) · Genes & Development · doi:10.1101/gad.886901 · Cited by 716 · see citing works
“export of p53 into the cytoplasm is essential for its effective Mdm2-mediated degradation (Roth et al. 1998; Lain et al. 1999; Tao and Levine 1999a, b).”
BackgroundInfluentialSherr, C. J., & Weber, J. D. (2000) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(99)00038-6 · Cited by 654 · see citing works
MDM2 — master regulator of the p53 tumor suppressor protein
Momand, J., Wu, H.-H., & Dasgupta, G. (2000) · Gene · doi:10.1016/s0378-1119(99)00487-4 · Cited by 641 · see citing works
Akt Enhances Mdm2-mediated Ubiquitination and Degradation of p53
Ogawara, Y., Kishishita, S., Obata, T., Isazawa, Y., Suzuki, T., Tanaka, K., Masuyama, N., & Gotoh, Y. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m109745200 · Cited by 617 · see citing works
Rapid ATM-dependent phosphorylation of MDM2 precedes p53 accumulation in response to DNA damage
Khosravi, R., Maya, R., Gottlieb, T., Oren, M., Shiloh, Y., & Shkedy, D. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.26.14973 · Cited by 461 · see citing works
A p53 Amino-Terminal Nuclear Export Signal Inhibited by DNA Damage-Induced Phosphorylation
Zhang, Y., & Xiong, Y. (2001) · Science · doi:10.1126/science.1058637 · Cited by 378 · see citing works
Nitric oxide-induced cellular stress and p53 activation in chronic inflammation
Hofseth, L. J., Saito, S., Hussain, S. P., Espey, M. G., Miranda, K. M., Araki, Y., Jhappan, C., Higashimoto, Y., He, P., Linke, S. P., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0237083100 · Cited by 355 · see citing works
PTEN Protects p53 from Mdm2 and Sensitizes Cancer Cells to Chemotherapy
Mayo, L. D., Dixon, J. E., Durden, D. L., Tonks, N. K., & Donner, D. B. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m108302200 · Cited by 351 · see citing works
An intact HDM2 RING-finger domain is required for nuclear exclusion of p53
Boyd, S. D., Tsai, K. Y., & Jacks, T. (2000) · Nature Cell Biology · doi:10.1038/35023500 · Cited by 334 · see citing works
Migliorini, D., Denchi, E. L., Danovi, D., Jochemsen, A., Capillo, M., Gobbi, A., Helin, K., Pelicci, P. G., & Marine, J.-C. (2002) · Molecular and Cellular Biology · doi:10.1128/mcb.22.15.5527-5538.2002 · Cited by 313 · see citing works
Danovi, D., Meulmeester, E., Pasini, D., Migliorini, D., Capra, M., Frenk, R., de Graaf, P., Francoz, S., Gasparini, P., Gobbi, A., et al. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.13.5835-5843.2004 · Cited by 310 · see citing works
Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms
Stad, R., Little, N. A., Xirodimas, D. P., Frenk, R., van der Eb, A. J., Lane, D. P., Saville, M. K., & Jochemsen, A. G. (2001) · The EMBO Reports · doi:10.1093/embo-reports/kve227 · Cited by 234 · see citing works
MdmX Protects p53 from Mdm2-Mediated Degradation
Jackson, M. W., & Berberich, S. J. (2000) · Molecular and Cellular Biology · doi:10.1128/mcb.20.3.1001-1007.2000 · Cited by 211 · see citing works
Overholtzer, M., Rao, P. H., Favis, R., Lu, X.-Y., Elowitz, M. B., Barany, F., Ladanyi, M., Gorlick, R., & Levine, A. J. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1934852100 · Cited by 193 · see citing works
Self-citationp53 accumulates but is functionally impaired when DNA synthesis is blocked
Gottifredi, V., Shieh, S.-Y., Taya, Y., & Prives, C. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.98.3.1036 · Cited by 147 · see citing works
Stad, R., Ramos, Y. F. M., Little, N., Grivell, S., Attema, J., van der Eb, A. J., & Jochemsen, A. G. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m003496200 · Cited by 145 · see citing works
Discovery of a Small Molecule MDM2 Inhibitor (AMG 232) for Treating Cancer
Rew, Y., & Sun, D. (2014) · Journal of Medicinal Chemistry · doi:10.1021/jm500627s · Cited by 125 · see citing works
Regulation of MDMX nuclear import and degradation by Chk2 and 14-3-3
LeBron, C., Chen, L., Gilkes, D. M., & Chen, J. (2006) · The EMBO Journal · doi:10.1038/sj.emboj.7601032 · Cited by 122 · see citing works
Caspase-2 deficiency promotes aberrant DNA-damage response and genetic instability
Dorstyn, L., Puccini, J., Wilson, C. H., Shalini, S., Nicola, M., Moore, S., & Kumar, S. (2012) · Cell Death & Differentiation · doi:10.1038/cdd.2012.36 · Cited by 104 · see citing works
MDM2 and MDMX can interact differently with ARF and members of the p53 family
Wang, X., Arooz, T., Siu, W. Y., Chiu, C. H. S., Lau, A., Yamashita, K., & Poon, R. Y. C. (2001) · FEBS Letters · doi:10.1016/s0014-5793(01)02124-x · Cited by 94 · see citing works
Functional role of Mdm2 phosphorylation by ATR in attenuation of p53 nuclear export
Shinozaki, T., Nota, A., Taya, Y., & Okamoto, K. (2003) · Oncogene · doi:10.1038/sj.onc.1207176 · Cited by 93 · see citing works
Joseph, T. W., Zaika, A., & Moll, U. M. (2003) · The FASEB Journal · doi:10.1096/fj.02-0931com · Cited by 50 · see citing works
Zhu, N., Gu, L., Li, F., & Zhou, M. (2008) · Molecular Cancer Therapeutics · doi:10.1158/1535-7163.mct-08-0179 · Cited by 42 · see citing works
Jackson, M. W., Patt, L. E., LaRusch, G. A., Donner, D. B., Stark, G. R., & Mayo, L. D. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m511617200 · Cited by 29 · see citing works
Ubiquitination of human AP-endonuclease 1 (APE1) enhanced by T233E substitution and by CDK5
Busso, C. S., Wedgeworth, C. M., & Izumi, T. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr401 · Cited by 24 · see citing works
- Authors
- Tao, W., & Levine, A. J.
- Affiliations
- Princeton University (US)
- Corresponding author
- Levine, Arnold J.
- ORCID
- Levine, Arnold J.
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1999-03-16
- Volume
- 96
- Issue
- 6
- Pages
- 3077-3080
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC15897
- OpenAlex
- W2166213130
- Cited by
- 355
- References
- 30
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 4 · 2023: 4 · 2022: 1 · 2021: 4 · 2020: 7 · 2019: 7 · 2018: 5 · 2017: 5 · 2016: 10 · 2015: 8 · 2014: 8 · 2013: 12 · 2012: 8
- FWCI
- 15.98
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P01CA041086)
- 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 › Ubiquitin and proteasome pathways
- Keywords
- MDM2, p53, nucleocytoplasmic shuttling, p53 degradation, proteasomal degradation, nuclear export, nuclear localization signal, nuclear export signal, p53 stabilization, oncoprotein
- MeSH terms
- Amino Acid Sequence, Animals, Cell Line, Cell Nucleus, Cytoplasm, Molecular Sequence Data, Neoplasm Proteins, Nuclear Proteins, Proto-Oncogene Proteins, Transfection, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, 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
