What do we need to know and understand about p53 to improve its clinical value?
Open accessAbstract
Few proteins are more studied than the p53 tumour suppressor, but what have we learned from these studies and what do we really know about p53 that can benefit clinical practice? The DNA sequence encoding p53 is frequently mutated in cancers but the functional outcomes of single mutations, in respect to loss or gain of different activities, especially in relation to immune evasion, are not clear. This illustrates p53's complexity which even after 40 years keeps providing surprises, but also explains why it has not yet lived up to its potential to benefit cancer treatment. We have reassessed a few key experiments that shaped the p53 field and we take a closer look at the interpretations of these experiments: what they have taught us, the resulting dogmas, and their potential clinical importance. One outcome is a more dynamic view of p53 in terms of its activity, its regulation, and downstream effectors, which will benefit the clinical application of p53 for diagnosis, prognosis, and therapy. Mutations and regulatory factors can have different effects on p53 activity depending on context, important but neglected aspects when interpreting p53 and its pathways in cancers. Even though p53 is undoubtedly unique as a multifunctional hub in different cellular pathways, the concept of a factor taking up different functions within a regulatory pathway during different conditions is not. In this sense, p53 continues to lead the way for a better understanding of the cellular and molecular mechanisms underlying cancer development in vivo. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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Activation of p53 in some cases may have the opposite effect.
“indicating that activation of p53 in some cases may have the opposite effect, which was consistent with results from other studies [94–96].”
From Targeting p53–MDM2 interaction by small-molecule inhibitors: learning from MDM2 inhibitors in clinical trials (2022) · cites this paper as [94]
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Jung, C., Kim, J., Park, J. K., Hwang, S., Moon, S., Kim, W., & Um, H. (2013) · Cancer Letters · doi:10.1016/j.canlet.2013.02.035 · Cited by 38 · see citing works
Splicing Up Mdm2 for Cancer Proteome Diversity
Okoro, D. R., Rosso, M., & Bargonetti, J. (2012) · Genes & Cancer · doi:10.1177/1947601912455323 · Cited by 36 · see citing works
Of mice, men and immunity: a case for evolutionary systems biology
Ernst, P. B., & Carvunis, A. (2018) · Nature Immunology · doi:10.1038/s41590-018-0084-4 · Cited by 35 · see citing works
Li, R., Zatloukalová, P., Müller, P., Gil-Mir, M., Kote, S., Wilkinson, S., Kemp, A. J., Hernychová, L., Wang, Y., Ball, K. L., et al. (2020) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-020-00233-w · Cited by 34 · see citing works
Self-citationp53mRNA and p53 Protein Structures Have Evolved Independently to Interact with MDM2
Karakostis, K., Ponnuswamy, A., Fusée, L. T. S., Bailly, X., Laguerre, L., Worrall, E. G., Vojtesek, B., Nylander, K., & Fåhræus, R. (2016) · Molecular Biology and Evolution · doi:10.1093/molbev/msw012 · Cited by 33 · see citing works
Self-citationMolecular Genetic Analysis of p53 Intratumoral Heterogeneity in Human Astrocytic Brain Tumors
Ren, Z.-P., Olofsson, T., Qu, M., Hesselager, G., Soussi, T., Kalimo, H., Smits, A., & Nistér, M. (2007) · Journal of Neuropathology & Experimental Neurology · doi:10.1097/nen.0b013e318156bc05 · Cited by 32 · see citing works
A Major Functional Difference between the Mouse and Human ARF Tumor Suppressor Proteins
Wadhwa, R., Sugihara, T., Hasan, M. K., Taira, K., Reddel, R. R., & Kaul, S. C. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m203222200 · Cited by 31 · see citing works
MDM2’s dual mRNA binding domains co-ordinate its oncogenic and tumour suppressor activities
Gnanasundram, S. V., Malbert-Colas, L., Chen, S., Fusée, L. T. S., Daskalogianni, C., Müller, P., Salomao, N., & Fåhræus, R. (2020) · Nucleic Acids Research · doi:10.1093/nar/gkaa431 · Cited by 27 · see citing works
Self-citationp53-mediated control of gene expression via mRNA translation during Endoplasmic Reticulum stress
López, I., Tournillon, A.-S., Nylander, K., & Fåhræus, R. (2015) · Cell Cycle · doi:10.1080/15384101.2015.1090066 · Cited by 25 · see citing works
Soussi, T. (2011) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2011.07.003 · Cited by 20 · see citing works
Shaping the regulation of the p53 mRNA tumour suppressor: the co-evolution of genetic signatures
Karakostis, K., & Fåhræus, R. (2019) · BMC Cancer · doi:10.1186/s12885-019-6118-y · Cited by 20 · see citing works
Self-citationMDM2 regulates RB levels during genotoxic stress
Hernández‐Monge, J., Martínez‐Sánchez, M., Rousset-Roman, A. B., Medina‐Medina, I., & Olivares‐Illana, V. (2020) · EMBO Reports · doi:10.15252/embr.202050615 · Cited by 20 · see citing works
MDM2 Overexpression with Alteration of the p53 Protein and Gene Status in Oral Carcinogenesis
Li, X., Murai, M., Koyama, T., Li, X., Wang, D., & Hashimoto, K. (2000) · Japanese Journal of Cancer Research · doi:10.1111/j.1349-7006.2000.tb00972.x · Cited by 10 · see citing works
Flagged first, then by citations
1 of the 99 references couldn’t be matched to a known paper.
Cited by
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Zhu, H., Gao, H., Ji, Y., Zhou, Q., Du, Z., Tian, L., Jiang, Y., Yao, K., & Zhou, Z. (2022) · Journal of Hematology & Oncology · doi:10.1186/s13045-022-01314-3 · Cited by 223 · see citing works
Hároníková, L., Bonczek, O., Zatloukalová, P., Kokas, F. Z., Kucerikova, M., Coates, P. J., Fåhræus, R., & Vojtěšek, B. (2021) · Cellular & Molecular Biology Letters · doi:10.1186/s11658-021-00293-6 · Cited by 71 · see citing works
Karagiannakos, A., Adamaki, M., Tsintarakis, A., Vojtěšek, B., Fåhræus, R., Zoumpourlis, V. C., & Karakostis, K. (2022) · Cancers · doi:10.3390/cancers14030664 · Cited by 55 · see citing works
Self-citationRamos‐García, P., González‐Moles, M. Á., & Warnakulasuriya, S. (2022) · Oral Oncology · doi:10.1016/j.oraloncology.2022.105734 · Cited by 48 · see citing works
Impact of TP53 mutations in Triple Negative Breast Cancer
Mitri, Z. I., Abuhadra, N. K., Goodyear, S. M., Hobbs, E. A., Kaempf, A. J., Thompson, A. M., & Moulder, S. L. (2022) · npj Precision Oncology · doi:10.1038/s41698-022-00303-6 · Cited by 43 · see citing works
The Elephant Evolved p53 Isoforms that Escape MDM2-Mediated Repression and Cancer
Padariya, M., Jooste, M.-L., Hupp, T., Fåhraeus, R., Vojtesek, B., Vollrath, F., Kalathiya, U., & Karakostis, K. (2022) · Molecular Biology and Evolution · doi:10.1093/molbev/msac149 · Cited by 33 · see citing works
Self-citationWang, Z., He, Z., Xuan, Q., Zhang, Y., Xu, J., Lin, J., Li, H., Chen, W., & Jiang, T. (2022) · Frontiers in Physiology · doi:10.3389/fphys.2022.934901 · Cited by 30 · see citing works
Clinical and Immunological Effects of p53-Targeting Vaccines
Zhou, S., Fan, C., Zeng, Z., Young, K. H., & Li, Y. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.762796 · Cited by 28 · see citing works
Potential role of Marine Bioactive Compounds in cancer signaling pathways: A review
Manoharan, S., & Perumal, E. (2022) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2022.175330 · Cited by 26 · see citing works
Recent Advances in Pathology: the 2021 Annual Review Issue of The Journal of Pathology
Herrington, C. S., Poulsom, R., Koeppen, H., & Coates, P. J. (2021) · The Journal of Pathology · doi:10.1002/path.5687 · Cited by 25 · see citing works
Dratwa, M., Wysoczańska, B., Brankiewicz, W., Stachowicz-Suhs, M., Wietrzyk, J., Matkowski, R., Ekiert, M., Szelachowska, J., Maciejczyk, A., Szajewski, M., et al. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23095164 · Cited by 16 · see citing works
Encoding and Decoding of p53 Dynamics in Cellular Response to Stresses
Wang, P., Wang, H., Gao, X., Zhu, H.-X., Zhang, X., Liu, F., & Wang, W. (2023) · Cells · doi:10.3390/cells12030490 · Cited by 12 · see citing works
Kang, Z., & Yang, J. (2022) · Journal of Investigative Medicine · doi:10.1136/jim-2022-002379 · Cited by 6 · see citing works
Ranjbar-Niavol, F., Rezaei, N., Zhao, Y., Mirzaei, H., Hassan, M., & Vosough, M. (2024) · Frontiers in Oncology · doi:10.3389/fonc.2024.1377761 · Cited by 5 · see citing works
Tracing the expansion of p53 retrogenes in elephant species: A foundation for functional insightsPreprint
Karakostis, K., Campoy, E., Puig, M., Fåhræus, R., Vollrath, F. W., & Cáceres, M. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.25.707932
Self-citation
- Authors
- Salomao, N., Karakostis, K., Hupp, T., Vollrath, F., Vojtesek, B., & Fahraeus, R.
- Affiliations
- Inserm (FR)
- University of Gdańsk (PL)
- University of Oxford (GB)
- RECAMO, Masaryk Memorial Cancer Institute Brno Czech Republic
- Inserm UMRS1131, Institut de Génétique Moléculaire, Université Paris 7, Hôpital St Louis Paris France
- Corresponding author
- Salomao, Norman
- Karakostis, Konstantinos
- Hupp, Ted
- Vollrath, Friz
- Venue
- The Journal of Pathology
- Publisher
- Wiley
- Published
- 2021-05-06
- Volume
- 254
- Issue
- 4
- Pages
- 443-453
- ISSN
- 0022-3417 (ISSN-L)
- 1096-9896
- OpenAlex
- W3141926258
- Cited by
- 15
- References
- 99
- Citations by year
- 2026: 1 · 2024: 1 · 2023: 1 · 2022: 9 · 2021: 3
- FWCI
- 0.42
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- The Journal of Pathology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- European Regional Development Fund (CZ.02.1.01/0.0/0.0/16_019/0000868)
- 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 › PI3K/AKT/mTOR signaling in cancer
- Keywords
- p53, tumour suppressor, TP53 mutation, p53 regulation, immune evasion, cancer therapy, cancer diagnosis and prognosis
- MeSH terms
- Animals, Humans, Neoplasms, 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.
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