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Combined Point Mutation in a Single Allele of the TP53 Gene Potentiates the Oncogenic and Transcriptional Properties of TP53 in Lung Cancer
Open accessAbstract
Although multi-hit TP53 mutations correlate with rapid disease progression, treatment resistance, recurrence, and poor survival, their occurrence within an individual TP53 gene molecule (cbTP53) remains unexplored. Consequently, the impact of cbTP53 on protein conformation, transcriptional architecture, and oncogenicity is unknown. We show that cbTP53 with combined mutations (Y220C+R248Q+R282Q) does not drastically alter local stability or structural conformation, but significantly affects TP53 binding to DNA promoters comparing it to a single Y220C mutation. Functionally, cbTP53 promotes divergent cellular phenotypes, characterized by enhanced cell proliferation, increased formation of multicellular tumor spheroids (MCTS) and spheroids, altered responses to chemotherapeutic drugs (e.g., cisplatin, carboplatin) and p53 inhibitors (e.g., MB710, PK11007), and increased resistance to carboplatin-induced DNA damage. Furthermore, cbTP53 is linked to distinct immune cell profiles (e.g., CD4+ and CD8+ T cells, nature killer cells, dendritic cells), more circulating tumor cells, a higher rate of tumor engraftment, and an increased number of lung tumor nodules. Mechanistically, introduction of R248Q/R282Q mutations changes 42.7% of Y220C-regulated gene expression, and cbTP53 (vs Y220C) owns a distinctive transcriptomic signature with 1,004 up- and 1,747 down-regulated genes. cbTP53 shows the enhanced binding affinity in the promoters of inflammatory cytokines, leading to their increased production. This study establishes causative and mechanistic links of cbTP53 to lung aggressive cancer metastasis and disease progression, providing a novel perspective on the genetics of TP53 mutations in cancer.
Overview
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TL;DR
The paper engineers a combined TP53 mutation (Y220C+R248Q+R282Q, “cbTP53”) in a single allele and reports that it produces non-additive, epistatic effects on TP53 structure, DNA binding, transcription, drug response, and lung cancer aggressiveness. cbTP53 shifts cells toward enhanced anchorage-independent growth, chemoresistance, inflammatory cytokine production, immunosuppressive immune profiles, and greater metastatic burden in mice compared with the single Y220C mutant.
Key findings
- Structural analyses found overall TP53–DNA conformations were similar (RMSD 0.5–1 Å for all Cα atoms), but cbTP53 was predicted to cause local conformational shifts and altered DNA binding; ChIP showed cbTP53 had higher binding affinity at promoters of tested cytokines than Y220C.
- cbTP53 vs Y220C transcriptomes differed substantially: 1,004 upregulated and 1,747 downregulated genes, and introduction of R248Q/R282Q changed 42.7% of Y220C-regulated gene expression; TNFA signaling via NFκB was enriched in cbTP53 vs SC or Y220C but not Y220C vs SC.
- In vivo, cbTP53 cells produced more lung tumor burden: 5/9 mice vs 1/9 Y220C mice had heavier lungs with metastatic lesions and tumor nodules (P = 0.0221), and cbTP53-bearing mice had larger/heavier spleens (P < 0.001).
- cbTP53 cells showed altered drug sensitivity, with reported IC50 values for carboplatin of 10.096 (Y220C) vs 16.9258 (cbTP53) vs 8.0373 µM (scramble), and higher circulating tumor cells than Y220C (0.41% vs 0.07%).
Methods
- Structural comparison and mutagenesis modeling used ChimeraX with available TP53 crystal structures; mutations Y220C, R248Q, and R282Q were introduced into MigR1-TP53 by site-directed mutagenesis and expressed in LLC/2 cells via retrovirus with GFP sorting to >95% purity.
- In vitro assays included IncuCyte proliferation, CCK-8 drug sensitivity, multicellular tumor spheroid and Matrigel sphere formation, alkaline comet assay, cytokine arrays, qPCR, Western blotting, and ChIP-qPCR.
- RNA-seq was performed in triplicate on scramble, Y220C, and cbTP53 LLC/2 cells with differential expression, GO/KEGG, Venn, and GSEA analyses; in vivo work used intravenous injection of 2 × 10^4 LLC/2 cells into syngeneic C57BL/6 mice, with blood flow cytometry and tissue analysis.
Limitations
- The paper states that structural conclusions rely on computer modeling rather than crystal structures of TP53 carrying these combined mutations, and that R248 mutations may make such crystals difficult; thermal stability and methodological specificity may also limit structural clarity.
- The paper states that cytokine arrays have limited sensitivity, ChIP conclusions come from a limited set of upregulated cytokines and need EMSA or ChIP-seq validation, and overexpression of human TP53 mutants in murine LLC/2 cells with wild-type endogenous p53 may introduce hetero-tetramer interference; human or p53-null validation is needed.
- The paper states that clinical relevance is uncertain because multiple mutations within a single TP53 allele have not yet been reported in patients, and that the precise boundaries between dominant-negative and gain-of-function effects remain to be mapped; the text also notes subtle drug-response differences between Y220C and cbTP53.
- Evident from the text: no blinding or randomization was used, sample size was not predetermined by power analysis, and some conclusions rest on small in vivo groups (n = 9 mice per group for tumor burden).
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Claims the paper makes
0 Valid · 0 Not valid · 36 Not checked · 136 Own results and interpretations
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“As shown in Fig. 3F-3I, cbTP53 cells have higher potential of cancer engraftment, in which 5 out of 9 (vs 1 out of 9 in Y220C) mice have heavier lungs with metastatic lesions and tumor nodules (P = 0.0221), consistent with the higher potential of forming more spheroids and aggregates.”
§ Combined Point Mutation in a Single Allele of the TP53 Gene Potentiates the Oncogenic and Transcriptional Properties of TP53 in Lung Cancer > Results > Y220C and cbTP53 display divergent capacity to promote lung cancer growth in vitro and disease progression in mice
plainstates an association- Asserted: passes — The authors put it forward as true.
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- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Remarkably, the third mutation in cbTP53 partially rescued this deficit to yield an intermediate phenotype.”
§ Combined Point Mutation in a Single Allele of the TP53 Gene Potentiates the Oncogenic and Transcriptional Properties of TP53 in Lung Cancer > Results > Y220C and cbTP53 display divergent capacity to promote lung cancer growth in vitro and disease progression in mice
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In Matrigel Dome assays, cbTP53 generated a significantly higher total number of clonal spheroids compared to Y220C, the R248Q/R282Q control, and both intermediate double mutants.”
§ Combined Point Mutation in a Single Allele of the TP53 Gene Potentiates the Oncogenic and Transcriptional Properties of TP53 in Lung Cancer > Results > Y220C and cbTP53 display divergent capacity to promote lung cancer growth in vitro and disease progression in mice
plainstates a cause- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
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A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In the spleen, Y220C displays distinct boundaries between a prominent, peripheral white pulp and a larger, lightly stained red pulp.”
§ Combined Point Mutation in a Single Allele of the TP53 Gene Potentiates the Oncogenic and Transcriptional Properties of TP53 in Lung Cancer > Results > Y220C and cbTP53 display divergent capacity to promote lung cancer growth in vitro and disease progression in mice
plain- Asserted: passes — The authors put it forward as true.
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In the paper
“The R282Q mutation affects the packing of the Loop-Sheet-Helix motif, which binds the major groove of DNA 18.”
§ Combined Point Mutation in a Single Allele of the TP53 Gene Potentiates the Oncogenic and Transcriptional Properties of TP53 in Lung Cancer > Results > Combined mutation cbTP53 does not apparently change the conformation of TP53, but affects the protein-DNA interactions
What the sources say
- Not checked yetcites [18] Joerger AC Ang HC Fersht AR Structural basis for understanding oncogenic p53 mutations and designing rescue drugs Proc Natl Acad Sci U S A 2006 103 15056 61 PMC1635156 17015838
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Self-check
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 major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Combined Point Mutation in a Single Allele of the TP53 Gene Potentiates the Oncogenic and Transcriptional Properties of TP53 in Lung Cancer > Abstract
“enhanced cell proliferation, increased formation of multicellular tumor spheroids (MCTS) and spheroids”
§ Combined Point Mutation in a Single Allele of the TP53 Gene Potentiates the Oncogenic and Transcriptional Properties of TP53 in Lung Cancer > Results > Y220C and cbTP53 display divergent capacity to promote lung cancer growth in vitro and disease progression in mice
“cbTP53 cells generated a significantly higher volume of unanchored aggregates but fewer compact MCTSs compared to Y220C and Scramble controls”
Rated major: it would touch a result — a value a result rests on, reported and recomputed p-values on opposite sides of the significance level, two passages that conflict with no sign which is right, or a cited work retracted before this paper was published.
In the paper
§ Combined Point Mutation in a Single Allele of the TP53 Gene Potentiates the Oncogenic and Transcriptional Properties of TP53 in Lung Cancer > Materials and Methods > Establishment of metastatic lung cancer mouse model
“C57BL/6 mice (6-8 weeks old, female) were purchased from the Jackson Laboratory.”
§ Combined Point Mutation in a Single Allele of the TP53 Gene Potentiates the Oncogenic and Transcriptional Properties of TP53 in Lung Cancer > Materials and Methods > Establishment of metastatic lung cancer mouse model
“2 × 104 LLC/2 cells expressing Y220C or cbTP53 were injected intravenously via the tail vein into syngeneic C57BL/6 mice (male, 4-6 weeks)”
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
§ Combined Point Mutation in a Single Allele of the TP53 Gene Potentiates the Oncogenic and Transcriptional Properties of TP53 in Lung Cancer > Results > Lung cancer cells carrying cbTP53 or Y220C mutations have dissimilar sensitivity to chemotherapeutic drugs and TP53 inhibitors
“cbTP53 (Y220C+R248Q+R282R)”
§ Combined Point Mutation in a Single Allele of the TP53 Gene Potentiates the Oncogenic and Transcriptional Properties of TP53 in Lung Cancer > Results > Y220C and cbTP53 display divergent capacity to promote lung cancer growth in vitro and disease progression in mice
“the compound triple-mutant configuration (Y220C/ R248Q/R282Q, termed cbTP53)”
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
§ Combined Point Mutation in a Single Allele of the TP53 Gene Potentiates the Oncogenic and Transcriptional Properties of TP53 in Lung Cancer > Materials and Methods > RNA sequencing and data processing
“The six GO categories”
§ Combined Point Mutation in a Single Allele of the TP53 Gene Potentiates the Oncogenic and Transcriptional Properties of TP53 in Lung Cancer > Materials and Methods > RNA sequencing and data processing
“(biological processes, environmental information processing, cellular components, genetic information processing, human disease, metabolism, and organismal system)”
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
§ Combined Point Mutation in a Single Allele of the TP53 Gene Potentiates the Oncogenic and Transcriptional Properties of TP53 in Lung Cancer > Results > Circulating cbTP53 and Y220C lung cancer cells stimulate distinct immunological responses
“In Y220C vs cbTP53, 83.27 vs 91.41% (live CD45+ cells), 66.02% vs 71.93% (myeloid cells; CD3e+/CD11b+), 44.33% vs 59.17% (B cells; CD3e+/B220+), 30.97% vs 25.77% (T cells; CD3e+/B220+), 5.9% vs 3.83% (NK cells; CD3e+/NK1.1+), 45.34% vs 40.15% (CD8+ T; CD4-/CD8+), 47.72% vs 53.12% (CD4+ T; CD4+/CD8-), 73.51% vs 64.5% (Treg; CD25+/CD127-), 29.73 vs 34.97% (Monocyte; CCR2+/LyC6+) as well as 0.07% vs 0.41% (circulating tumor cells, CTCs; CD45-/PD-L1+).”
§ Combined Point Mutation in a Single Allele of the TP53 Gene Potentiates the Oncogenic and Transcriptional Properties of TP53 in Lung Cancer > Results > Circulating cbTP53 and Y220C lung cancer cells stimulate distinct immunological responses
“mice bearing cbTP53 cells have a much higher number of CTCs than Y220C cells (0.07% vs 0.41%)”
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Metadata
- Authors
- Bian, S., Bian, H., Koyama, H., Kompaniiets, D., Tse, W., Shah, M. V., Al-Kali, A., Miron, A., Liu, B., & Liu, S.
- Affiliations
- MetroHealth (US)
- University of Minnesota (US)
- Mayo Clinic (US)
- Corresponding author
- Liu, Shujun
- ORCID
- Kompaniiets, Dmytro
- Venue
- International Journal of Biological Sciences
- Publisher
- Ivyspring International Publisher
- Published
- 2026-09-10
- Volume
- 22
- Issue
- 15
- Pages
- 8139-8157
- ISSN
- 1449-2288 (ISSN-L)
- PMC
- PMC13685541
- OpenAlex
- W7214639723
- Semantic Scholar
- cb2c2659f6deec9b91225257cd2e4887ef0fd107
- Cited by
- 0
- References
- 46
- FWCI
- 0.00
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by
- Locations
- International Journal of Biological Sciences (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Funders
- Case Western Reserve University
- National Cancer Institute (R01CA248019, R01CA266256)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- TP53, lung cancer, tumor spheroids, chemoresistance, carboplatin resistance, p53 inhibitors, tumor immune cell infiltration, circulating tumor cells, metastasis, inflammatory cytokines, gene expression signatures
- MeSH terms
- Alleles, Animals, Humans, Lung Neoplasms, Gene Expression Regulation, Neoplastic, Tumor Suppressor Protein p53, Point Mutation, Cell Line, Tumor, Cell Proliferation, Mice
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.
A language model drew the claims from the paper on 2026-11-13, under version 3 of the claim definition (model deepseek-v4.1-flash, prompt extract-v3).
A second model labelled each claim on 2026-11-13 (model jev-1.13-20260917, definition revision gold-guideline-v0.2).
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.
