Cancer-derived p53 mutants suppress p53-target gene expression--potential mechanism for gain of function of mutant p53
Open accessAbstract
Tumour-derived p53 mutants are thought to have acquired 'gain-of-function' properties that contribute to oncogenicity. We have tested the hypothesis that p53 mutants suppress p53-target gene expression, leading to enhanced cellular growth. Silencing of mutant p53 expression in several human cell lines was found to lead to the upregulation of wild-type p53-target genes such as p21, gadd45, PERP and PTEN. The expression of these genes was also suppressed in H1299-based isogenic cell lines expressing various hot-spot p53 mutants, and silencing of mutant p53, but not TAp73, abrogated the suppression. Consistently, these hot-spot p53 mutants were able to suppress a variety of p53-target gene promoters. Analysis using the proto-type p21 promoter construct indicated that the p53-binding sites are dispensable for mutant p53-mediated suppression. However, treatment with the histone deacetylase inhibitor trichostatin-A resulted in relief of mutant p53-mediated suppression, suggesting that mutant p53 may induce hypo-acetylation of target gene promoters leading to the suppressive effects. Finally, we show that stable down-regulation of mutant p53 expression resulted in reduced cellular colony growth in human cancer cells, which was found to be due to the induction of apoptosis. Together, the results demonstrate another mechanism through which p53 mutants could promote cellular growth.
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GOF mut-p53 has been shown to abnormally regulate a multitude of genes that play critical roles in glioblastoma pathogenesis, including CD95/Fas/Apo1, PARP, PTEN, and more.
“Furthermore, GOF mut-p53 has been shown to abnormally regulate a multitude of genes that play critical roles in GBM pathogenesis, but have not been analyzed in the context of GBM. This includes CD95/Fas/Apo1, PARP, PTEN, and more [63,94,95,96,97,98].”
From The p53 Pathway in Glioblastoma (2018) · cites this paper as [98]
The Results (page unavailable) show that silencing mutant p53 increased PTEN and PERP expression in HUH-7 hepatoma cells, supporting regulation of those genes outside GBM. The Introduction and Discussion cite an earlier report of CD95/Fas/Apo-1 repression. The paper does not establish regulation of PARP (which is distinct from PERP) or these genes’ roles in GBM pathogenesis; its Methods identify non-GBM cell lines. (LLM, conf=0.88)
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- Authors
- Vikhanskaya, F., Lee, M. K., Mazzoletti, M., Broggini, M., & Sabapathy, K.
- Affiliations
- National Cancer Centre Singapore (SG)
- National University of Singapore (SG)
- Corresponding author
- Sabapathy, K.
- Venue
- Nucleic Acids Research
- Publisher
- Oxford University Press (OUP)
- Published
- 2007-03-01
- Volume
- 35
- Issue
- 6
- Pages
- 2093-2104
- ISSN
- 0305-1048 (ISSN-L)
- 1362-4962
- PMC
- PMC1874625
- OpenAlex
- W2111523470
- Cited by
- 145
- References
- 38
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 8 · 2023: 6 · 2022: 6 · 2021: 4 · 2020: 8 · 2019: 6 · 2018: 9 · 2017: 9 · 2016: 12 · 2015: 10 · 2014: 12 · 2013: 11 · 2012: 4
- FWCI
- 3.21
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- cc-by-nc
- Locations
- Nucleic Acids Research (publishedVersion, cc-by-nc)
- PubMed Central (publishedVersion, cc-by-nc)
- PubMed (publishedVersion)
- National University of Singapore (submittedVersion)
- Funders
- Medical Research Council
- National Medical Research Council
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Cell death mechanisms and regulation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Keywords
- mutant p53, gain-of-function, p21, GADD45, PERP, PTEN, p53 binding sites, histone deacetylation, trichostatin A, apoptosis, cell growth, TAp73
- MeSH terms
- Binding Sites, Enzyme Inhibitors, Humans, Hydroxamic Acids, Mutation, Neoplasms, Promoter Regions, Genetic, Down-Regulation, Gene Expression Regulation, Neoplastic, Genes, p53, Tumor Suppressor Protein p53, Apoptosis, RNA Interference, Cell Line, Tumor, Cyclin-Dependent Kinase Inhibitor p21, Histone Deacetylase Inhibitors
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