ArticleCancer discovery2023
Li-Fraumeni Syndrome-Associated Dimer-Forming Mutant p53 Promotes Transactivation-Independent Mitochondrial Cell Death.
Article in Cancer discovery, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 19 citations in OpenAlex.
- TP53 Loss Elevates NF-κB-IFN-β-MHC-Ia Signaling to Promote NK Cell Resistance in Osteosarcoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Variation at the R181 Residue of p53 Confers Loss of p53 DNA Binding Cooperativity with the Retention of Mitochondria-Associated Apoptosis.Molecular cancer research : MCR · 2026Article
- An Isogenic Yeast Model Reveals the Influence of Native Promoter G‑Quadruplex Forming Sequences on P53 and NF-κB Transactivation.ACS bio & med chem Au · 2026Article
- The p53 Isoforms as Potential Biomarkers in Different Cancer Entities.International journal of molecular sciences · 2026Review
- Alternative splicing in cancer drug resistance: Mechanisms and therapeutic prospects (Review).Oncology reports · 2026Review
- Targeting mitochondrial homeostasis as a cancer treatment strategy: current status and future prospects.Molecular cancer · 2026Review
- Mice carrying nonsense mutant p53 develop frequent multicentric or metastatic tumors.Cell death & disease · 2025Article
- Targeted citrullination enables p53 binding to non-canonical sites.Molecular cell · 2025Article
- High-throughput evaluation of genetic variants with prime editing sensor libraries.Nature biotechnology · 2025Article
- In-frame germline TP53 variant impairs p53 oligomerization and predisposes to cancer.Scientific reports · 2025Article
- Lipogenic enzyme FASN promotes mutant p53 accumulation and gain-of-function through palmitoylation.Nature communications · 2025Article
- Decoding cancer etiology with cellular reprogramming.Current opinion in genetics & development · 2025Review
- Correlation of p53 oligomeric status and its subcellular localization in the presence of the AML-associated NPM mutant.PloS one · 2025Article
- Decoding the molecular symphony: interactions between the mNAR cancer · 2024Review
- Understanding the complexity of p53 in a new era of tumor suppression.Cancer cell · 2024Review
- Cancer metabolic reprogramming and precision medicine-current perspective.Frontiers in pharmacology · 2024Review
- The Ashkenazi-Centric G334R Variant ofMolecular and cellular biology · 2024Article
- Elucidating the chain of command: our current understanding of critical target genes for p53-mediated tumor suppression.Critical reviews in biochemistry and molecular biologyReview
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Authors and funding
16 authors at 8 institutions in 2 countries.
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Abstract
Cancer-relevant mutations in the oligomerization domain (OD) of the p53 tumor suppressor protein, unlike those in the DNA binding domain, have not been well elucidated. Here, we characterized the germline OD mutant p53(A347D), which occurs in cancer-prone Li-Fraumeni syndrome (LFS) patients. Unlike wild-type p53, mutant p53(A347D) cannot form tetramers and exists as a hyperstable dimeric protein. Further, p53(A347D) cannot bind or transactivate the majority of canonical p53 target genes. Isogenic cell lines harboring either p53(A347D) or no p53 yield comparable tumorigenic properties, yet p53(A347D) displays remarkable neomorphic activities. Cells bearing p53(A347D) possess a distinct transcriptional profile and undergo metabolic reprogramming. Further, p53(A347D) induces striking mitochondrial network aberration and associates with mitochondria to drive apoptotic cell death upon topoisomerase II inhibition in the absence of transcription. Thus, dimer-forming p53 demonstrates both loss-of-function (LOF) and gain-of-function (GOF) properties compared with the wild-type form of the protein. SIGNIFICANCE: A mutant p53 (A347D), which can only form dimers, is associated with increased cancer susceptibility in LFS individuals. We found that this mutant wields a double-edged sword, driving tumorigenesis through LOF while gaining enhanced apoptogenic activity as a new GOF, thereby yielding a potential vulnerability to select therapeutic approaches. See related commentary by Stieg et al., p. 1046. See related article by Gencel-Augusto et al., p. 1230. This article is highlighted in the In This Issue feature, p. 1027.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.