Gain of function of a p53 hot spot mutation in a mouse model of Li-Fraumeni syndrome
Open accessAbstract
Individuals with Li-Fraumeni syndrome carry inherited mutations in the p53 tumor suppressor gene and are predisposed to tumor development. To examine the mechanistic nature of these p53 missense mutations, we generated mice harboring a G-to-A substitution at nucleotide 515 of p53 (p53+/515A) corresponding to the p53R175H hot spot mutation in human cancers. Although p53+/515A mice display a similar tumor spectrum and survival curve as p53+/- mice, tumors from p53+/515A mice metastasized with high frequency. Correspondingly, the embryonic fibroblasts from the p53515A/515A mutant mice displayed enhanced cell proliferation, DNA synthesis, and transformation potential. The disruption of p63 and p73 in p53-/- cells increased transformation capacity and reinitiated DNA synthesis to levels observed in p53515A/515A cells. Additionally, p63 and p73 were functionally inactivated in p53515A cells. These results provide in vivo validation for the gain-of-function properties of certain p53 missense mutations and suggest a mechanistic basis for these phenotypes.
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Mut-p53 protein is highly expressed in glioblastoma and possesses oncogenic functions beyond those acquired through wild type p53 loss.
“Importantly, mut-p53 protein is highly expressed in GBM and numerous studies have demonstrated that mut-p53 possesses oncogenic functions beyond those acquired through wt-p53 loss.”
From The p53 Pathway in Glioblastoma (2018) · cites this paper as [60]
The Generation of p53 515A Knockin Mice section reports that mutant-p53 mouse embryonic fibroblasts bypassed contact inhibition more than p53-null cells, supporting an oncogenic gain of function beyond wild-type p53 loss. It also reports high mutant-p53 protein levels in those fibroblasts, but the passages do not establish high expression in glioblastoma. Page numbers are unavailable in our copy. (LLM, conf=0.88)
Experimental — accuracy not yet measuredMice heterozygous for mutant p53 develop many metastatic tumors that are uncommon in mice lacking p53.
“Mutant p53-heterozygous mice develop many metastatic tumors that are rare in mice lacking p53 (Lang, et al., 2004; Olive, et al., 2004).”
From The Mdm network and its regulation of p53 activities: a rheostat of cancer risk (2014) · cites this paper as Lang, et al., 2004
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p53 controls cancer cell invasion by inducing the MDM2-mediated degradation of Slug
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Mutant p53 Drives Pancreatic Cancer Metastasis through Cell-Autonomous PDGF Receptor β Signaling
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“…with previous studies showing that (1) loss of p73 in a p53 null background might be functionally equivalent to the expression of mutant p53 (Lang et al., 2004); (2) aberrant transcriptional regulation by mutant p53 is mediated through the transcriptional activator NF-Y (Di Agostino et al.,…”
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Smoking, p53 Mutation, and Lung Cancer
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- Authors
- Lang, G. A., Iwakuma, T., Suh, Y.-A., Liu, G., Rao, V. A., Parant, J. M., Valentin-Vega, Y. A., Terzian, T., Caldwell, L. C., Strong, L. C., El-Naggar, A. K., & Lozano, G.
- Affiliations
- The University of Texas MD Anderson Cancer Center (US)
- Corresponding author
- Lozano, Guillermina
- ORCID
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 2004-12
- Volume
- 119
- Issue
- 6
- Pages
- 861-872
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W2034882416
- Cited by
- 1,069
- References
- 69
- Citations by year
- 2026: 16 · 2025: 40 · 2024: 48 · 2023: 49 · 2022: 34 · 2021: 53 · 2020: 48 · 2019: 53 · 2018: 60 · 2017: 61 · 2016: 73 · 2015: 50 · 2014: 81 · 2013: 42 · 2012: 53
- FWCI
- 19.34
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (P01CA34936, P01CA034936)
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- Li-Fraumeni syndrome, p53, gain-of-function mutations, p53 missense mutations, metastasis, cancer susceptibility, p63, p73, embryonic fibroblasts, cell transformation, DNA synthesis, mouse model
- MeSH terms
- Tumor Protein p73, Animals, Cell Transformation, Neoplastic, Cells, Cultured, DNA Replication, DNA-Binding Proteins, Fibroblasts, Mice, Transgenic, Mutation, Neoplasms, Nuclear Proteins, Phosphoproteins, Trans-Activators, Genes, Tumor Suppressor, Genes, p53, Li-Fraumeni Syndrome, Tumor Suppressor Proteins, Cell Proliferation, Mice, Rats
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