Small-Molecule Reactivation of Mutant p53 to Wild-Type-like p53 through the p53-Hsp40 Regulatory Axis
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TP53 is the most frequently mutated gene in human cancer, and small-molecule reactivation of mutant p53 function represents an important anticancer strategy. A cell-based, high-throughput small-molecule screen identified chetomin (CTM) as a mutant p53 R175H reactivator. CTM enabled p53 to transactivate target genes, restored MDM2 negative regulation, and selectively inhibited the growth of cancer cells harboring mutant p53 R175H in vitro and in vivo. We found that CTM binds to Hsp40 and increases the binding capacity of Hsp40 to the p53 R175H mutant protein, causing a potential conformational change to a wild-type-like p53. Thus, CTM acts as a specific reactivator of the p53 R175H mutant form through Hsp40. These results provide new insights into the mechanism of reactivation of this specific p53 mutant.
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RITA was found to suppress growth of cancer cell lines carrying various p53 mutations and restored the transcriptional functions of several p53 mutant alleles including R175H, R213Q, Y234H, R248W, R273H and R280K that resulted in induction of apoptosis.
“In particular, RITA was found to suppress growth of cancer cell lines carrying various p53 mutations and restored the transcriptional functions of several p53 mutant alleles including R175H, R213Q, Y234H, R248W, R273H and R280K that resulted in induction of apoptosis [36, 48].”
From Ligand dependent restoration of human TLR3 signaling and death in p53 mutant cells (2016) · cites this paper as [48]
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- Authors
- Hiraki, M., Hwang, S.-Y., Cao, S., Ramadhar, T. R., Byun, S., Yoon, K. W., Lee, J. H., Chu, K., Gurkar, A. U., Kolev, V., Zhang, J., Namba, T., Murphy, M. E., Newman, D. J., Mandinova, A., Clardy, J., & Lee, S. W.
- Affiliations
- Harvard University (US)
- The Wistar Institute (US)
- Frederick National Laboratory for Cancer Research (US)
- Broad Institute (US)
- Corresponding author
- Lee, Jung Hyun
- Clardy, Jon
- Lee, Sam W.
- ORCID
- Venue
- Chemistry & Biology
- Publisher
- Elsevier BV
- Published
- 2015-09
- Volume
- 22
- Issue
- 9
- Pages
- 1206-1216
- ISSN
- 1074-5521 (ISSN-L)
- PMC
- PMC4670040
- OpenAlex
- W1763368382
- Cited by
- 81
- References
- 5
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 6 · 2023: 8 · 2022: 5 · 2021: 5 · 2020: 7 · 2019: 10 · 2018: 9 · 2017: 8 · 2016: 6 · 2015: 1
- FWCI
- 3.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Chemistry & Biology (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-nd)
- PMC
- Funders
- Harvard University
- National Institutes of Health (CA142805, CA80058)
- Japan Society for the Promotion of Science (26893181)
- National Cancer Institute (P01CA114046, CA 80058, R01CA142805, R01CA149477, R01CA139319, P01CA080058, P30CA010815, CA142805)
- National Institute of General Medical Sciences (GM 086258, GM108415, R01GM086258, F32GM108415)
- FAS Division of Science, Harvard University
- 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 › PI3K/AKT/mTOR signaling in cancer
- Keywords
- mutant p53 reactivation, TP53, p53 R175H, chetomin, Hsp40, high-throughput screening, tumor cell growth inhibition
- MeSH terms
- Animals, Antineoplastic Agents, Disulfides, Drug Screening Assays, Antitumor, Humans, Mice, Nude, Mutation, Tumor Suppressor Protein p53, Xenograft Model Antitumor Assays, Indole Alkaloids, HCT116 Cells, Cell Line, Tumor, HSP40 Heat-Shock Proteins, Mice, Small Molecule Libraries, High-Throughput Screening Assays
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