ArticleCell death & disease2017
p53 loss-of-heterozygosity is a necessary prerequisite for mutant p53 stabilization and gain-of-function in vivo.
Article in Cell death & disease, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 70 papers.
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Who cites it
70 citing papers in PubMed, 104 citations in OpenAlex.
- The guardian of the genome meets immunotherapy: p53-based strategies.Frontiers in immunology · 2026Review
- Case Report: Rare pheochromocytoma in a patient with Li-Fraumeni syndrome: a 3-event, 4-hit model of pathogenesis.Frontiers in oncology · 2026Article
- p53 prophylactic therapy for cancer prevention.Cell death and differentiation · 2025Article
- The search for a TNBC vaccine: the guardian vaccine.Cancer biology & therapy · 2025Review
- Article
- Mutant p53 Gain of Function: Why Many See It, Why Some Do Not.Cancer discovery · 2025Article
- FGFR2 Abrogation Intercepts Pancreatic Ductal Adenocarcinoma Development.Cancer research · 2025Article
- PTEN loss drives p53 LOH and immune evasion in a novel urothelial organoid model harboring p53 missense mutations.Oncogene · 2025Article
- Missense Mutant p53 Transactivates Wnt/β-Catenin Signaling in Neighboring p53-Destabilized Cells through the COX-2/PGE2 Pathway.Cancer research communications · 2025Article
- Clinical Relevance ofCancers · 2024Article
- Mutant p53 reactivation restricts the protumorigenic consequences of wild type p53 loss of heterozygosity in Li-Fraumeni syndrome patient-derived fibroblasts.Cell death and differentiation · 2024Article
- Gain-of-Function p53 Mutation Acts as a Genetic Switch for TGFβ Signaling-Induced Epithelial-to-Mesenchymal Transition in Intestinal Tumors.Cancer research · 2024Article
- Proteasome inhibition paradoxically degrades gain-of-function mutant p53 R273H in NSCLC and could have therapeutic implications.Frontiers in oncology · 2024Article
- Quality Control of an Isogenic H/N/KRAS-Less Mouse Embryonic Fibroblast Cell Line Panel.Methods in molecular biology (Clifton, N.J.) · 2024Article
- p53R245W Mutation Fuels Cancer Initiation and Metastases in NASH-driven Liver Tumorigenesis.Cancer research communications · 2023Article
- Association ofmedRxiv : the preprint server for health sciences · 2023Article
- Multidimensional quantitative phenotypic and molecular analysis reveals neomorphic behaviors of p53 missense mutants.NPJ breast cancer · 2023Article
- Genetic and nongenetic mechanisms for colorectal cancer evolution.Cancer science · 2023Review
- Triple-negative breast tumors are dependent on mutant p53 for growth and survival.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Dimeric p53 Mutant Elicits Unique Tumor-Suppressive Activities through an Altered Metabolic Program.Cancer discovery · 2023Article
10 more citing papers are in PubMed but not listed here.
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Authors and funding
6 authors at 2 institutions in 2 countries.
Funding
Abstract
Missense mutations in TP53 comprise >75% of all p53 alterations in cancer, resulting in highly stabilized mutant p53 proteins that not only lose their tumor-suppressor activity, but often acquire oncogenic gain-of-functions (GOFs). GOF manifests itself in accelerated tumor onset, increased metastasis, increased drug resistance and shortened survival in patients and mice. A known prerequisite for GOF is mutant p53 protein stabilization, which itself is linked to aberrant protein conformation. However, additional determinants for mutant p53 stabilization likely exist. Here we show that in initially heterozygous mouse tumors carrying the hotspot GOF allele R248Q (p53Q/+), another necessary prerequisite for mutant p53 stabilization and GOF in vivo is loss of the remaining wild-type p53 allele, termed loss-of-heterozygosity (LOH). Thus, in mouse tumors with high frequency of p53 LOH (osteosarcomas and fibrosarcomas), we find that mutant p53 protein is stabilized (16/17 cases, 94%) and tumor onset is significantly accelerated compared with p53+/- tumors (GOF). In contrast, in mouse tumors with low frequency of p53 LOH (MMTV-Neu breast carcinomas), mutant p53 protein is not stabilized (16/20 cases, 80%) and GOF is not observed. Of note, human genomic databases (TCGA, METABRIC etc.) show a high degree of p53 LOH in all examined tumor types that carry missense p53 mutations, including sarcomas and breast carcinomas (with and without HER2 amplification). These data - while cautioning that not all genetic mouse models faithfully represent the human situation - demonstrate for the first time that p53 LOH is a critical prerequisite for missense mutant p53 stabilization and GOF in vivo.
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