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Reactivation of mutant p53: molecular mechanisms and therapeutic potential
Abstract
The p53 tumor suppressor gene is the most frequently mutated gene in cancer. Most p53 mutations are missense point mutations that cluster in the DNA-binding core domain. This results in distortion of core domain folding and disruption of DNA binding and transcriptional transactivation of p53 target genes. Structural studies have demonstrated that mutant p53 core domain unfolding is not irreversible. Mutant p53 is expressed at high levels in many tumors. Therefore, mutant p53 is a promising target for novel cancer therapy. Mutant p53 reactivation will restore p53-dependent apoptosis, resulting in efficient removal of tumor cells. A number of strategies for targeting mutant p53 have been designed, including peptides and small molecules that restore the active conformation and DNA binding to mutant p53 and induce p53-dependent suppression of tumor cell growth in vitro and in vivo. This opens possibilities for the clinical application of mutant p53 reactivation in the treatment of cancer.
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“since many of the deleterious side effects of genotoxic chemotherapies could actually result from chemoresistance arising from p53 mutations [50].”
From Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells (2016) · cites this paper as [50]
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Principles of Protein−Protein Interactions: What are the Preferred Ways For Proteins To Interact?
Keskin, O., Gursoy, A., Ma, B., & Nussinov, R. (2008) · Chemical Reviews · doi:10.1021/cr040409x · Cited by 697
Metadata
- Authors
- Selivanova, G., & Wiman, K. G.
- Affiliations
- Karolinska Institutet (SE)
- Corresponding author
- Wiman, K G
- Venue
- Oncogene
- Published
- 2007-04-02
- Volume
- 26
- Issue
- 15
- Pages
- 2243-2254
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- OpenAlex
- W2025977492
- Cited by
- 186
- References
- 105
- Citations by year
- 2026: 1 · 2025: 4 · 2024: 3 · 2023: 7 · 2022: 6 · 2021: 9 · 2020: 8 · 2019: 6 · 2018: 9 · 2017: 7 · 2016: 16 · 2015: 11 · 2014: 9 · 2013: 11 · 2012: 7
- FWCI
- 1.98
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cancerfonden
- Karolinska Institutet
- Cancerföreningen i Stockholm
- Topics
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Heat shock proteins research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
- Keywords
- mutant p53, p53 reactivation, p53 tumor suppressor, missense mutations, protein unfolding, p53-dependent apoptosis, transcriptional activation, cancer therapy
- MeSH terms
- Humans, Mutation, Neoplasms, Protein Conformation, Tumor Suppressor Protein p53
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