ArticleCell death and differentiation2013
Two hot spot mutant p53 mouse models display differential gain of function in tumorigenesis.
Article in Cell death and differentiation, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 183 papers, 1 of them a synthesis that pooled it.
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Who cites it
183 citing papers in PubMed, 1 synthesis or guideline pooled it.
- Pooled it
- Clonal Evolutionary Analysis during HER2 Blockade in HER2-Positive Inflammatory Breast Cancer: A Phase II Open-Label Clinical Trial of Afatinib +/- Vinorelbine.PLoS medicine · 2016Trial
- Impact of p53 Target Genes on Drug Resistance in TP53-Mutated B-Cell Precursor Acute Lymphoblastic Leukemia.Cancer medicine · 2026Article
- Impact of differentTranslational lung cancer research · 2026Article
- Mutant p53Molecular oncology · 2026Article
- Oncogenic p53 induces mitotic errors in lung cancer cells by recopying DNA replication forks conferring targetable proliferation advantage.Cell death and differentiation · 2026Article
- mTORC1 suppression by Trp53 mutation drives resistance to immune checkpoint blockade.Cell death & disease · 2026Article
- Targeting mutant p53 in cancer: from mechanistic insights to therapeutic strategies.Cellular & molecular biology letters · 2026Review
- Distinct functional heterogeneity of TP53 R175 mutations in platinum-resistant ovarian cancer: unveiling molecular mechanisms and therapeutic targets.Cell death & disease · 2025Article
- Review
- Mutant p53 regulates cancer cell invasion in complex three-dimensional environments through mevalonate pathway-dependent Rho/ROCK signaling.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Enhancement of colorectal cancer therapy through interruption of the HSF1-HSP90 axis by p53 activation or cell cycle inhibition.Cell death and differentiation · 2025Article
- Targeting macrophage migration inhibitory factor as a potential therapeutic strategy in colorectal cancer.Oncogenesis · 2025Article
- Humanized mouse models in MDS.Cell death & disease · 2025Review
- Article
- Mutant p53 Gain of Function: Why Many See It, Why Some Do Not.Cancer discovery · 2025Article
- Oncogenic and teratogenic effects ofeLife · 2025Article
- Subclonal TP53 and KRAS variants combined with poor treatment response identify ultrahigh-risk pediatric patients with T-ALL.Blood advances · 2025Article
- Therapy enhancing chromosome instability may be advantageous forNAR cancer · 2025Article
- Lipogenic enzyme FASN promotes mutant p53 accumulation and gain-of-function through palmitoylation.Nature communications · 2025Article
123 more citing papers are in PubMed but not listed here.
Corrections and comments
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6 authors.
Funding
Abstract
Mutant p53 proteins not only lose their tumor-suppressor function but some acquire oncogenic gain of function (GOF). The published mutp53 knock-in (KI) alleles (R172H, R270H, R248W) manifest GOF by broader tumor spectrum and more metastasis compared with the p53-null allele, but do not shorten survival. However, whether GOF also occurs with other mutations and whether they are all biologically equal is unknown. To answer this, we created novel humanized mutp53 KI mice harboring the hot spot alleles R248Q and G245S. Intriguingly, their impact was very different. Compared with p53-null mice, R248Q/- mice had accelerated onset of all tumor types and shorter survival, thus unprecedented strong GOF. In contrast, G245S/- mice were similar to null mice in tumor latency and survival. This was associated with a twofold higher T-lymphoma proliferation in R248Q/- mice compared with G245S/- and null mice. Moreover, R248Q/- hematopoietic and mesenchymal stem cells were expanded relative to G245S/- and null mice, the first indication that GOF also acts by perturbing pretumorous progenitor pools. Importantly, these models closely mirror Li-Fraumeni patients who show higher tumor numbers, accelerated onset and shorter tumor-free survival by 10.5 years when harboring codon R248Q mutations as compared with Li-Fraumeni patients with codon G245S mutations or p53 deletions/loss. Conversely, both KI alleles caused a modest broadening of tumor spectrum with enhanced Akt signaling compared with null mice. These models are the first in vivo proof for differential oncogenic strength among p53 GOF alleles, with genotype-phenotype correlations borne out in humans.
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