The DOI matches its Crossref record; 164 of the 164 references it cites were found in a registry or an index; 2 of the 148 sources its claims cite were checked for support.
The TP53 tumor suppressor gene: From molecular biology to clinical investigations
Open accessAbstract
Extensively studied over the past four decades, the TP53 gene has emerged as a pivotal watchman in cellular defense and a key factor in cancer biology. TP53 is the most frequently mutated gene in human malignancies, 50% of which carry alterations to it. Initially, the functions of p53 were thought to be restricted to cell‐cycle arrest and apoptosis. With time, however, a growing number of functions have been discovered, illustrating p53's role as a master switch between any cellular stress and cellular or multicellular responses that contribute to its anti‐tumor activity. Indeed, the peculiar landscape of TP53 mutations and its high heterogeneity are linked both to the structure of the protein and its ubiquitous function in regulating cellular homeostasis. Mutations in p53 are associated with poor response to therapy and shorter survival in most cancer types, and the diagnosis of p53 mutations is currently used to improve case management in some types of leukemia and lymphoma. Although TP53 has been defined as a tumor suppressor gene, overexpressed mutated p53 variants found in human tumors are defined as dominant oncogenes with a potential gain of function, which makes the gene a very attractive target for developing new cancer treatments. Beyond its role in cancer, our review also highlights TP53's significance in non‐neoplastic conditions, such as bone marrow failure syndromes and certain developmental disorders, where chronic p53 activation plays a crucial role in cellular stress responses, demonstrating its broader biological importance.
Overview
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TL;DR
TP53 is the most frequently mutated gene in human cancer, with roughly 50% of malignancies carrying an alteration, and it acts as a context-dependent transcription factor whose loss or mutation promotes therapy resistance and poor survival. This review synthesizes p53 molecular biology, variant heterogeneity, clinical associations, germline syndromes, and therapeutic strategies, while noting that clinical translation remains limited and p53 is still considered largely undruggable.
Key findings
- TP53 alterations occur in an estimated 50% of human cancers; frequency is highly heterogeneous, from a few percent in thyroid cancer to about 30% in breast cancer and nearly 100% in high-grade serous ovarian cancer or small cell lung cancer.
- TP53 mutations are associated with poor response to therapy and shorter survival in most cancer types, with clinical applications established mainly in chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML); in mantle cell lymphoma, updated NCCN guidelines recommend TP53 sequencing before treatment.
- p53 regulates cell-cycle arrest, apoptosis, DNA repair, autophagy, senescence, immunity, and the p53-p21 DREAM pathway; mutant p53 may exert dominant-negative and proposed gain-of-function effects, but recent isogenic models challenge gain of function and emphasize loss of function and dominant-negative effects.
- Germline TP53 mutations cause Li-Fraumeni syndrome, and surveillance (Toronto protocol) has been shown to improve survival; the Brazilian founder variant p.R337H is found in 0.3% of the general southern and southeastern Brazilian population. Non-neoplastic phenotypes, including inherited bone marrow failure syndromes and developmental disorders, can arise from chronic p53 activation.
Methods
- Design: narrative review by two authors, covering p53 molecular biology, TP53 mutation heterogeneity, clinical associations, germline mutations, polymorphisms, non-neoplastic syndromes, and therapeutic targeting.
- Data/sample: no primary cohort or systematic search is described; the review cites a literature base including more than 120,000 articles, 13,000 reviews, 500 meta-analyses, sequencing of several hundred thousand tumors, and description of 250,000 mutations, plus TCGA (11,000 cases) and ICGC (25,000 cases) sequencing projects.
- Analysis: thematic synthesis of published mechanistic, structural, murine-model, genomic, and clinical studies, with selected figures summarizing mutation frequency, p53 domains, signaling, and therapeutic strategies.
Limitations
- The authors state the field is too broad to cover fully and refer readers to other reviews for TP53 isoforms, p63/p73, therapeutic strategies, and detailed p53 pathways; they also state that clinical applications of TP53 findings remain restricted to a few cancer types and that p53 is still considered undruggable.
- The authors state that the clinical relevance of the dominant-negative effect remains to be established, that gain-of-function findings have been challenged by more recent isogenic models, and that p53 gene-expression signatures are not currently pertinent for clinic use.
- Evident from the text: as a narrative review, it does not describe a systematic search strategy, inclusion criteria, or formal quality appraisal, so the selection and weighting of cited evidence are author-dependent.
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Figures
![Fig. 1 TP53 mutation in human cancer: (a) worldwide cancer burden (new cases and number of deaths, Globocan 2022) and average TP53 mutation frequency in the 14 most frequent cancers. * In cervical cancer, loss of TP53 function occurs by interaction with the E6 protein of oncogenic human papilloma viruses. (b) Schema showing the domain structure of the p53 protein, including the transactivation domains (TAD 1 and 2), the proline‐rich domain (PRD), the DNA‐binding domain (DBD), the tetramerization domain (TET), and the negative regulatory domain (NEG‐REG). The aligned graphs indicate the relative frequency of mutations across different domains of p53. The DNA‐binding domain is the most frequent location for p53 mutations, according to the UMD_TP53 database. High‐penetrant p53 variants can be either structural or contact variants, depending on the function of the residue. In contrast, residue association with p53 multimerization shows a lower penetrance with only a partial activity loss. (c) X‐ray structure of p53 DBD showing locations of the most frequent mutations. DNA contact variants at positions 280, 248, or 273 are localized in the vicinity of the DNA molecules, whereas structural variants (175 or 220) are buried inside the molecule (taken from [8]).](/paper-figures/8cc6b85b69d5477f8e20bd84aa454198/the-tp53-tumor-suppressor-gene-from-molecular-biology-to-clinical-investigations-figure-1.jpg)
Verification
Claims the paper makes
2 Valid · 8 Not valid · 88 Not checked · 54 Own results and interpretations
Every source the paper cites for this claim was checked and supports it.
In the paper
“It was later shown to have a broader effect unrelated to p53 by inducing oxidative stress within tumor cells, therefore enhancing its cytotoxic effects [116].”
§ The TP53 tumor suppressor gene: From molecular biology to clinical investigations > Introduction > TP53: a promising target for therapy?
What the sources say
- Supportedcites [116] Peng X, Zhang M‐Q‐Z, Conserva F, Hosny G, Selivanova G, Bykov VJN, et al. APR‐246/PRIMA‐1MET inhibits thioredoxin reductase 1 and converts the enzyme to a dedicated NADPH oxidase. Cell Death Dis. 2013; 4: e881. 24157875 PMC3920950 source
The Abstract of our copy states that APR-246 (eprenetapopt), via its conversion product MQ, inhibits thioredoxin reductase 1 and leaves it functional as a pro-oxidant NADPH oxidase, so that 'APR-246 can directly affect cellular redox status via targeting of TrxR1' and provides 'an explanation for the previously observed effects of APR-246 on tumor cells lacking mutant p53'. The Discussion makes the p53-independence and cytotoxic link explicit: direct targeting of TrxR1 '(converting the enzyme to a NADPH oxidase) contributed to its p53-independent cytotoxicity', and Results show APR-246-induced ROS in tumor cells with TrxR1 contributing significantly to that ROS. The only caveat is that the paper ranks TrxR1 as a less important target than mutant p53, but it does state the broader p53-unrelated oxidative-stress mechanism the claim attributes to it. (LLM, conf=0.88)
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Supported
The cited sources support only part of this claim — read each source’s verdict below.
In the paper
“Surprisingly, in these AML patients, TP53 mutations have also been found in non‐tumoral hematological cells several years before the development of the malignancies. These mutations likely result from CH [158].”
§ The TP53 tumor suppressor gene: From molecular biology to clinical investigations > Introduction > TP53 and non‐neoplastic syndromes
What the sources say
- Partly supportedcites [158] Machado HE, Øbro NF, Williams N, Tan S, Boukerrou AZ, Davies M, et al. Convergent somatic evolution commences in utero in a germline ribosomopathy. Nat Commun. 2023; 14: 5092. 37608017 PMC10444798 sourceExperimental — accuracy not yet measured
Our copy does support TP53-mutated clones in NON-tumoural haematopoietic cells of individuals with SDS, arising long before any malignancy: the Abstract/Results report mutually exclusive TP53 (and other target-gene) mutations in ~30% of 323 single-colony genomes, and 'Timing haematopoietic clonal expansions in individuals with SDS' dates 14 driver-mutated expansions (incl. TP53) as commencing 'from early in utero up to age 12', with the Discussion calling these 'monoallelic TP53 clonal expansions ... each potentially serving as a substrate for clonal evolution to aggressive disease' — i.e. clonal haematopoiesis antecedent to cancer. But the claim's specific element — detection in AML patients 'several years before the development of the malignancies' — is not in our copy: transformation was documented in a single individual (SDS8) to MDS, not AML, whose phylogeny was reconstructed from blood '<1 month post diagnosis of MDS', and the Discussion explicitly states the study is limited by 'the lack of longitudinal sampling'. The pre-dating is inferred from mutational-clock modelling (age of transformation 23.5 years, 95% CI 19.2–24.9, vs MDS diagnosis at 25), not from cells sampled years before malignancy. (LLM, conf=0.75)
hedgedstates a possible cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
- Partly supported
In the paper
“However, their high degeneracy is linked with varying affinities of p53 and, consequently, different levels in transcriptional response.”
§ The TP53 tumor suppressor gene: From molecular biology to clinical investigations > Introduction > The p53 protein: structure and function
What the sources say
- Not checked yetcites [38] Fischer M, Sammons MA. Determinants of p53 DNA binding, gene regulation, and cell fate decisions. Cell Death Differ. 2024; 31: 836– 843. 38951700 PMC11239874 source
plainstates an association- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A statement the paper makes itself — it cites no source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In several cancer types (prostate and leukemia), the frequency of TP53 mutations at diagnosis can be low, but it may increase upon disease progression or during therapy.”
§ The TP53 tumor suppressor gene: From molecular biology to clinical investigations > Introduction
hedgedstates a possible cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
A statement the paper makes itself — it cites no source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“When the cell experiences stress (such as DNA damage, hypoxia, or oncogene activation), various pathways impair the interaction between MDM2 and p53, resulting in p53 accumulation.”
§ The TP53 tumor suppressor gene: From molecular biology to clinical investigations > Introduction > The p53 protein: structure and function
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
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Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ The TP53 tumor suppressor gene: From molecular biology to clinical investigations > Introduction > TP53 pathways
“cell cycle progression requires hypophosphorylation of RB to prevent binding to E2F transcription factors and form a repressive complex that block the expression of genes required for DNA replication and S‐phase entry.”
§ The TP53 tumor suppressor gene: From molecular biology to clinical investigations > Introduction > TP53 pathways
“Expression of p21 prevents RB phosphorylation, leaving RB complexed with E2F factors and histone deacetylases (HDAC) to maintain a repressive chromatin state and block S‐phase gene expression.”
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ The TP53 tumor suppressor gene: From molecular biology to clinical investigations > Introduction > TP53 mutation in cancer
“Lack of p21 induction also impairs the DREAM pathway (right part of the Fig.), leaving multiple genes repressed by the DREAM complex, as shown in Fig. 3.”
§ The TP53 tumor suppressor gene: From molecular biology to clinical investigations > Introduction > TP53 pathways
“Upon p21 expression in response to p53, hypophosphorylated Rb will not be released from this repressive complex, thus ensuring that cells do not progress through the cell cycle, whereas damaged (Fig. 3b). In tumors with p53 loss, dysregulation of the p21‐DREAM pathway will lead to uncontrolled proliferation and survival of damaged cells.”
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Metadata
- Authors
- Baliakas, P., & Soussi, T.
- Affiliations
- Uppsala University (SE)
- Corresponding author
- Soussi, Thierry
- Venue
- Journal of Internal Medicine
- Publisher
- Wiley
- Published
- 2025-06-16
- Volume
- 298
- Issue
- 2
- Pages
- 78-96
- ISSN
- 0954-6820 (ISSN-L)
- 1365-2796
- PMC
- PMC12239063
- OpenAlex
- W4411388612
- Semantic Scholar
- f422279b37d3fc7b3177be1ae5e2e34940dcc8f7
- Cited by
- 50
- References
- 164
- Citations by year
- 2026: 37 · 2025: 13
- FWCI
- 4.99
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Internal Medicine (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- Diva portal (Dalarna University Library) (submittedVersion, other-oa)
- Funders
- Institut National de la Santé et de la Recherche Médicale
- Conseil Régional, Île-de-France
- 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
- TP53, p53, tumor suppressor, TP53 mutation, gain-of-function p53, cell cycle arrest, apoptosis, cellular stress response, treatment resistance, leukemia, lymphoma, bone marrow failure syndromes, developmental disorders, cancer therapy targets
- MeSH terms
- Humans, Mutation, Neoplasms, Genes, Tumor Suppressor, Genes, p53, 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.
The claim verdicts this report counts are experimental: their accuracy is not yet measured.
A language model drew the claims from the paper on 2026-11-15, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-15 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
Cited sources are checked with a language model’s help (qwen3.8-omni-flash).
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 ›
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Data sources
Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
