The many faces of p53: something for everyone
Open accessAbstract
Forty years ago four research laboratories in London, Paris, New York/Bethesda, and Princeton uncovered the existence of the p53 protein (Deleo et al., 1979; Lane and Crawford, 1979; Linzer and Levine, 1979; Kress et al., 1979). Each laboratory came upon this protein for a different reason and with a different experimental approach that uncovered this unanticipated result. Together, the four papers permitted one to conclude the following: (i) in SV40-infected and transformed cells the SV40-encoded oncogene protein, the large T-antigen, formed a protein complex with a cellular-encoded protein of ~53000 daltons in size. (ii) This p53 protein was detected at high levels in a variety of transformed cells derived from viral, chemical, or inherited (teratocarcinomas) transformation events. (iii) Nontransformed cells expressed lower levels of the p53 protein. (iv) Animals bearing tumors produced antibodies directed against the p53 protein. A temperature-sensitive mutation in the SV40 large T-antigen gene (the oncogene of this virus) was employed to demonstrate that the p53–T-antigen complex was formed at the permissive temperature, where the cells are transformed, but not at the nonpermissive temperature, where the cells behave normally (Linzer and Levine, 1979; Linzer et al., 1979). At a later date p53 protein complexes with viral oncogene products were observed, including the adenovirus E1b-58kd protein (Sarnow et al., 1982) and the human papilloma virus E6 oncoprotein (Scheffner, et al. 1990; Werness et al., 1990; which is the cause of human cervical cancers and some head and neck cancers). In order to explore the functions of the p53 protein, several p53 cDNAs were isolated and cloned (Oren and Levine, 1983; Oren et al., 1983; Pennica et al., 1984). These clones were tested for oncogene activities and found to cooperate with the RAS oncogene in transforming embryonic cells (Eliyahu et al., 1984; Parada et al., 1984). Thus, it appeared that the p53 gene was an oncogene whose protein forms a complex with viral oncogene proteins, possibly mediating transformation. However, the cDNA clone isolated by Pennica failed to transform cells in culture and had a single amino acid change when compared with the Oren cDNA clone, which did transform cells. Was the amino acid difference between these clones significant? Was this difference a sequencing mistake? A polymorphism? Or a mutation? If it was a mutation, which clone was the wild-type and which was the mutant? To address these questions, Oren and Levine exchanged clones (and reproduced each other’s observations). By 1989 it became clear that mutations in the p53 cDNA clones resulted in cellular transformation, and wild-type p53 protein prevented transformation and functioned as a tumor suppressor (Eliyahu et al., 1989; Finlay et al., 1989). p53 mutations in both p53 alleles in colon cancers of humans resulted in the same conclusion; p53 functioned as a tumor suppressor gene that helped to prevent cancer (Baker et al., 1990a, b, Nigro et al., 1995). From 1979 to 1989 the p53 protein was alternatively referred to as a fetal antigen expressed in the teratocarcinoma stem cells, a tumor antigen that induced antibodies in animals and humans with tumors, an oncogene whose mutant forms could transform cells, and, finally, a tumor suppressor gene that prevented cancers. During this time the p53 protein was demonstrated to increase its concentration in response to DNA damage (Maltzman and Czyzyk, 1984). Over these first 10 years of research the p53 protein was shown to have many diverse faces and activities, functioning as an oncogene and a tumor suppressor gene while responding to DNA damage in a cell. The mutant forms of p53 add to the many faces of p53. There are multiple ways to inactivate p53 protein functions. There are mutations such as deletions, nonsense mutations, and frameshift mutations, which are all true loss-of-function mutations, but more commonly there are missense mutations localized in the p53 protein DNA-binding domain (Bouaoun et al., 2016). In addition, there are gene amplifications in the MDM-2 gene that overexpress this ubiquitin ligase, which is a negative regulator of the levels of the p53 protein. Thirdly, there are protein modifications that reduce or eliminate p53 transcriptional activity (Zhu et al., 2016; Levine, 2017). To date, >500 different missense mutations, located in the DNA-binding domain of the p53 protein, have been isolated and sequenced from human cancers. Missense mutations that produce high levels of mutant p53 proteins can function as dominant negative proteins, inactivating the wild-type p53 protein, in cells with normal levels of wild-type proteins. This is why mutant p53 cDNA clones transform normal cells in culture. A tetramer of the wild-type p53 protein functions as the transcription factor. Faulty or mutant monomeric proteins contributing to the tetrameric protein poison its activity and act in a dominant negative fashion. A s
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?
Mutant p53 promotes tumorigenesis and wild-type p53 has broad-spectrum tumor inhibition.
“P53 can be categorized as mutant type or wild type, with mutant p53 promoting tumorigenesis and wild-type p53 having broad-spectrum tumor inhibition.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [207]
Approximately half of all human cancers have alterations in the p53 gene, resulting in loss of p53 function or decreased p53 expression.
“Studies have shown that approximately half of all human cancers, including serous ovarian cancer, lung squamous cell cancer, lung small cell cancer, triple-negative breast cancer, and squamous esophageal cancer, have alterations in the p53 gene, resulting in a loss of p53 function or decreased p53 expression.”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [207]
The p53 protein, a crucial tumor suppressor, plays a significant role in preventing cancer initiation and progression.
“The p53 protein, a crucial tumor suppressor, plays a significant role in preventing cancer initiation and progression.206–208”
From Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials (2023) · cites this paper as [207]
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
Vogelstein, B., Lane, D., & Levine, A. J. (2000) · Nature · doi:10.1038/35042675 · Cited by 6,607 · see citing works
Self-citationThe E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53
Scheffner, M., Werness, B. A., Huibregtse, J. M., Levine, A. J., & Howley, P. M. (1990) · Cell · doi:10.1016/0092-8674(90)90409-8 · Cited by 3,995 · see citing works
Self-citationDNA methylation-based biomarkers and the epigenetic clock theory of ageing
Horvath, S., & Raj, K. (2018) · Nature Reviews Genetics · doi:10.1038/s41576-018-0004-3 · Cited by 3,095 · see citing works
Mutations in the p53 gene occur in diverse human tumour types
Nigro, J. M., Baker, S. J., Preisinger, A. C., Jessup, J. M., Hosteller, R., Cleary, K. R., Signer, S. H., Davidson, N. E., Baylin, S., Devilee, P., et al. (1989) · Nature · doi:10.1038/342705a0 · Cited by 2,730 · see citing works
Association of Human Papillomavirus Types 16 and 18 E6 Proteins with p53
Werness, B. A., Levine, A. J., & Howley, P. M. (1990) · Science · doi:10.1126/science.2157286 · Cited by 2,562 · see citing works
Self-citationT antigen is bound to a host protein in SY40-transformed cells
Lane, D. P., & Crawford, L. V. (1979) · Nature · doi:10.1038/278261a0 · Cited by 2,443 · see citing works
The p53 proto-oncogene can act as a suppressor of transformation
Finlay, C. A., Hinds, P. W., & Levine, A. J. (1989) · Cell · doi:10.1016/0092-8674(89)90045-7 · Cited by 1,987 · see citing works
Self-citationKastenhuber, E. R., & Lowe, S. W. (2017) · Cell · doi:10.1016/j.cell.2017.08.028 · Cited by 1,906 · see citing works
Linzer, D. I. H., & Levine, A. J. (1979) · Cell · doi:10.1016/0092-8674(79)90293-9 · Cited by 1,814 · see citing works
Self-citationThe 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-citationSuppression of Human Colorectal Carcinoma Cell Growth by Wild-Type p53
Baker, S. J., Markowitz, S. D., Fearon, E. R., Willson, J. K. V., & Vogelstein, B. (1990) · Science · doi:10.1126/science.2144057 · Cited by 1,742 · see citing works
Petitjean, A., Mathe, E., Kato, S., Ishioka, C., Tavtigian, S. V., Hainaut, P., & Olivier, M. (2007) · Human Mutation · doi:10.1002/humu.20495 · Cited by 1,598 · cited 1× · see citing works
“Different missense mutants transcribe seven different p53responsive genes in a yeast cell assay at a wide variety of different efficiencies (Kato et al., 2003; Mathe et al., 2006; Petitjean et al., 2007).”
BackgroundThe Control of the Metabolic Switch in Cancers by Oncogenes and Tumor Suppressor Genes
Levine, A. J., & Puzio-Kuter, A. M. (2010) · Science · doi:10.1126/science.1193494 · Cited by 1,243 · see citing works
Self-citationIdentification of unique neoantigen qualities in long-term survivors of pancreatic cancer
Initiative, A. P. C. G., Balachandran, V. P., Łuksza, M., Zhao, J. N., Makarov, V., Moral, J. A., Remark, R., Herbst, B., Askan, G., Bhanot, U., et al. (2017) · Nature · doi:10.1038/nature24462 · Cited by 1,191 · see citing works
Self-citationBaker, S. J., Preisinger, A. C., Jessup, J. M., Paraskeva, C., Markowitz, S. D., Willson, J. K. V., Hamilton, S. R., & Vogelstein, B. (1990) · PubMed · Cited by 1,065 · see citing works
Gain of function mutations in p53
Dittmer, D., Pati, S., Zambetti, G., Chu, S., Teresky, A. K., Moore, M., Finlay, C., & Levine, A. J. (1993) · Nature Genetics · doi:10.1038/ng0593-42 · Cited by 894 · 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 · Cited by 893 · see citing works
Kato, S., Han, S., Liu, W., Otsuka, K., Shibata, H., Kanamaru, R., & Ishioka, C. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1431692100 · Cited by 877 · see citing works
Sarnow, P., Ho, Y.-S., Williams, J., & Levine, A. J. (1982) · Cell · doi:10.1016/0092-8674(82)90356-7 · Cited by 836 · see citing works
Self-citationCooperation between gene encoding p53 tumour antigen and ras in cellular transformation
Parada, L. F., Land, H., Weinberg, R. A., Wolf, D., & Rotter, V. (1984) · Nature · doi:10.1038/312649a0 · Cited by 731 · see citing works
Bouaoun, L., Sonkin, D., Ardin, M., Hollstein, M., Byrnes, G., Zavadil, J., & Olivier, M. (2016) · Human Mutation · doi:10.1002/humu.23035 · Cited by 730 · see citing works
DeLeo, A. B., Jay, G. D., Appella, E., DuBois, G. C., Law, L. W., & Old, L. J. (1979) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.76.5.2420 · Cited by 721 · see citing works
Participation of p53 cellular tumour antigen in transformation of normal embryonic cells
Eliyahu, D., Raz, A., Gruß, P., Givol, D., & Oren, M. (1984) · Nature · doi:10.1038/312646a0 · Cited by 706 · see citing works
Wild-type p53 can inhibit oncogene-mediated focus formation.
Eliyahu, D., Michalovitz, D., Eliyahu, S., Pinhasi-Kimhi, O., & Oren, M. (1989) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.86.22.8763 · Cited by 681 · see citing works
Lin, J., Chen, J., Elenbaas, B., & Levine, A. J. (1994) · Genes & Development · doi:10.1101/gad.8.10.1235 · Cited by 652 · see citing works
Self-citationA neoantigen fitness model predicts tumor response to checkpoint blockade immunotherapy
Łuksza, M., Riaz, N., Makarov, V., Balachandran, V., Hellmann, M., Solovyov, A., Rizvi, N., Merghoub, T., Levine, A., Chan, T., et al. (2017) · Nature · doi:10.1038/nature24473 · Cited by 624 · see citing works
Self-citationTherapeutic targeting of p53: all mutants are equal, but some mutants are more equal than others
Sabapathy, K., & Lane, D. P. (2018) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2017.151 · Cited by 517 · see citing works
p53 regulates maternal reproduction through LIF
Hu, W., Feng, Z., Teresky, A. K., & Levine, A. J. (2007) · Nature · doi:10.1038/nature05993 · Cited by 446 · see citing works
Self-citationKress, M., May, E., Cassingena, R., & May, P. (1979) · Journal of Virology · doi:10.1128/jvi.31.2.472-483.1979 · Cited by 359 · see citing works
Mathé, E. A. (2006) · Nucleic Acids Research · doi:10.1093/nar/gkj518 · Cited by 340 · see citing works
The Origins and Evolution of the p53 Family of GenesPreprint
Белый, В. А., Ak, P., Markert, E. K., Wang, H., Hu, W., Puzio‐Kuter, A. M., & Levine, A. J. (2009) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a001198 · Cited by 293 · see citing works
Self-citationFeng, Z., Hu, W., Teresky, A. K., Hernando, E., Cordon-Cardo, C., & Levine, A. J. (2007) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0708043104 · Cited by 264 · see citing works
Self-citationThe p53 family: guardians of maternal reproduction
Levine, A. J., Tomasini, R., McKeon, F., Mak, T. W., & Melino, G. (2011) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm3086 · Cited by 252 · see citing works
Self-citation14-3-3σ Positively Regulates p53 and Suppresses Tumor Growth
Yang, H.-Y., Wen, Y.-Y., Chen, C.-H., Lozano, G., & Lee, M. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.20.7096-7107.2003 · Cited by 229 · 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.4.9.1689-1694.1984 · Cited by 226 · see citing works
The SV40 a gene product is required for the production of a 54,000 MW cellular tumor antigen
Linzer, D. I. H., Maltzman, W., & Levine, A. J. (1979) · Virology · doi:10.1016/0042-6822(79)90554-3 · Cited by 184 · see citing works
Self-citationMolecular cloning of a cDNA specific for the murine p53 cellular tumor antigen.
Oren, M., & Levine, A. J. (1983) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.80.1.56 · Cited by 130 · see citing works
Self-citationOren, M., Reich, N. C., & Levine, A. J. (1982) · Molecular and Cellular Biology · doi:10.1128/mcb.2.4.443 · Cited by 110 · see citing works
Self-citationThe amino acid sequence of murine p53 determined from a c-DNA clone
Pennica, D., Goeddel, D. V., Hayflick, J. S., Reich, N. C., Anderson, C. W., & Levine, A. J. (1984) · Virology · doi:10.1016/0042-6822(84)90316-7 · Cited by 98 · see citing works
Self-citationRegulation of female reproduction by p53 and its family members
Feng, Z., Zhang, C., Kang, H., et al. (2011) · The FASEB Journal · doi:10.1096/fj.10-180166 · Cited by 86 · see citing works
Multiple Roles of p53-Related Pathways in Somatic Cell Reprogramming and Stem Cell Differentiation
Yi, L., Lu, C.-W., Hu, W., Sun, Y., & Levine, A. J. (2012) · Cancer Research · doi:10.1158/0008-5472.can-12-1451 · Cited by 85 · see citing works
Self-citationYang, H., Wen, Y.-Y., Zhao, R., Lin, Y., Fournier, K. F., Yang, H.-Y., Qiu, Y., Diaz, J. I., Laronga, C., & Lee, M. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3620 · Cited by 84 · see citing works
Targeting Therapies for the p53 Protein in Cancer Treatments
Levine, A. J. (2019) · Annual Review of Cancer Biology · doi:10.1146/annurev-cancerbio-030518-055455 · Cited by 84 · see citing works
Self-citationDistinguishing the immunostimulatory properties of noncoding RNAs expressed in cancer cells
Tanne, A., Muniz, L. R., Puzio-Kuter, A., Leonova, K. I., Gudkov, A. V., Ting, D. T., Monasson, R., Cocco, S., Levine, A. J., Bhardwaj, N., et al. (2015) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1517584112 · Cited by 74 · see citing works
Self-citationP53 and the defenses against genome instability caused by transposons and repetitive elements
Levine, A. J., Ting, D. T., & Greenbaum, B. D. (2016) · BioEssays · doi:10.1002/bies.201600031 · Cited by 72 · see citing works
Self-citationNon-oncogenic roles of TAp73: from multiciliogenesis to metabolism
Nemajerová, A., Amelio, I., Gebel, J., Dötsch, V., Melino, G., & Moll, U. M. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2017.178 · Cited by 70 · see citing works
One billion years of p53/p63/p73 evolution
Белый, В. А., & Levine, A. J. (2009) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0910634106 · Cited by 58 · see citing works
Self-citationAnalysis of recombinant DNA clones specific for the murine p53 cellular tumor antigen.
Oren, M., Bienz, B., Givol, D., et al. (1983) · The EMBO Journal · doi:10.1002/j.1460-2075.1983.tb01637.x · Cited by 56 · see citing works
Conservation and Divergence of p53 Oscillation Dynamics across Species
Stewart-Ornstein, J., Cheng, H. W., & Lahav, G. (2017) · Cell Systems · doi:10.1016/j.cels.2017.09.012 · Cited by 54 · see citing works
Lysine methylation represses p53 activity in teratocarcinoma cancer cells
Zhu, J., Dou, Z., Sammons, M. A., Levine, A. J., & Berger, S. L. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1610387113 · Cited by 44 · see citing works
Self-citationReviewing the future of the P53 field
Levine, A. J. (2017) · Cell Death and Differentiation · doi:10.1038/cdd.2017.181 · Cited by 38 · see citing works
Self-citationSelected drugs that inhibit DNA methylation can preferentially kill p53 deficient cells
Yi, L., Sun, Y., & Levine, A. J. (2014) · Oncotarget · doi:10.18632/oncotarget.2441 · Cited by 37 · see citing works
Self-citationOren, M., Reich, N. C., & Levine, A. J. (1982) · Molecular and Cellular Biology · doi:10.1128/mcb.2.4.443-449.1982 · Cited by 36 · see citing works
Self-citationThe Mdm2 and p53 genes are conserved in the Arachnids
Lane, D. P., Cheok, C. F., Brown, C. J., et al. (2010) · Cell Cycle · doi:10.4161/cc.9.4.10616 · Cited by 28 · see citing works
Characterizing Cancer Drug Response and Biological Correlates: A Geometric Network Approach
Pouryahya, M., Oh, J. H., Mathews, J. C., Deasy, J. O., & Tannenbaum, A. (2018) · Scientific Reports · doi:10.1038/s41598-018-24679-3 · Cited by 23 · see citing works
The regulation of human reproduction by p53 and its pathway
Hu, W., Feng, Z., & Levine, A. J. (2009) · Cell Cycle · doi:10.4161/cc.8.22.9938 · Cited by 16 · see citing works
Self-citationLevine, A. J. (2017) · Oncotarget · doi:10.18632/oncotarget.14805 · Cited by 16 · see citing works
Self-citationGraph Curvature and the Robustness of Cancer NetworksPreprint
Tannenbaum, A., Sander, C., Zhu, L., et al. (2015) · arXiv (Cornell University) · doi:10.48550/arxiv.1502.04512 · Cited by 13 · see citing works
Levine, A. J. (2015) · Aging · doi:10.18632/aging.100776 · Cited by 4 · see citing works
Self-citation
Flagged first, then by citations
Research works printed but not linked: 1
- Raj N., and Attardi L.D. (2016). The transactivation domains of the p53 protein In: Lozano G., and Levine A.J. (eds). The p53 Protein: From Cell Regulation to Cancer. New York: Cold Spring Harbor Laboratory Press, 51– 68.
Cited by
Sorted by citations
Bernard, E., Nannya, Y., Hasserjian, R. P., Devlin, S. M., Tuechler, H., Medina-Martinez, J. S., Yoshizato, T., Shiozawa, Y., Saiki, R., Malcovati, L., et al. (2020) · Nature Medicine · doi:10.1038/s41591-020-1008-z · Cited by 648 · see citing works
Recent advances in targeting the “undruggable” proteins: from drug discovery to clinical trials
Xie, X., Yu, T., Li, X., Zhang, N., Foster, L. J., Peng, C., Huang, W., & He, G. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01589-z · Cited by 396 · see citing works
P53 and The Immune Response: 40 Years of Exploration—A Plan for the Future
Levine, A. J. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21020541 · Cited by 97 · see citing works
Self-citation
- Authors
- Levine, A. J.
- Affiliations
- Institute for Advanced Study (US)
- Corresponding author
- Levine, Arnold J
- ORCID
- Levine, Arnold J
- Venue
- Journal of Molecular Cell Biology
- Publisher
- Oxford University Press (OUP)
- Published
- 2019-07
- Volume
- 11
- Issue
- 7
- Pages
- 524-530
- ISSN
- 1674-2788 (ISSN-L)
- 1759-4685
- PMC
- PMC6736316
- OpenAlex
- W2929402967
- Cited by
- 163
- References
- 59
- Citations by year
- 2026: 9 · 2025: 19 · 2024: 20 · 2023: 41 · 2022: 25 · 2021: 23 · 2020: 23 · 2019: 2 · 2018: 1
- FWCI
- 1.74
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Journal of Molecular Cell Biology (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- National Cancer Institute (5PO1CA087497-17)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- p53, tumor suppressor, SV40 large T antigen, E6 oncoprotein, TP53 mutation, p53 function
- MeSH terms
- Humans, Tumor Suppressor Protein p53
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
