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Published on: August 25, 2021
Therapeutic targeting of TP53 nonsense mutations in cancer
Charlotte Strandgren1, Klas G Wiman1
1Karolinska Institutet, Departement of Oncology-Pathology, Stockholm, Sweden.
Abstract:
Mutations in the TP53 tumor suppressor gene occur with high prevalence in a wide range of human tumors. A significant fraction of these mutations (around 10%) are nonsense mutations, creating a premature termination codon (PTC) that leads to the expression of truncated inactive p53 protein. Induction of translational readthrough across a PTC in nonsense mutant TP53 allows the production of full-length protein and potentially restoration of normal p53 function. Aminoglycoside antibiotics and a number of novel compounds have been shown to induce full-length p53 in tumor cells carrying various TP53 nonsense mutations. Full-length p53 protein generated by translational readthrough retains the capacity to transactivate p53 target genes and trigger tumor cell death. These findings raise hopes for efficient therapy of TP53 nonsense mutant tumors in the future.
Insights
Nonsense mutations in the TP53 tumor suppressor gene can be targeted for cancer therapy. Inducing translational readthrough can restore full-length p53 protein, potentially leading to tumor cell death.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- TP53 tumor suppressor gene mutations are common in human cancers.
- Approximately 10% of TP53 mutations are nonsense mutations, leading to truncated, inactive p53 protein.
Purpose of the Study:
- To investigate the potential of inducing translational readthrough to restore functional p53 protein in tumors with TP53 nonsense mutations.
- To evaluate the therapeutic implications of restoring p53 function through readthrough induction.
Main Methods:
- Utilized aminoglycoside antibiotics and novel compounds to induce translational readthrough.
- Assessed the production of full-length p53 protein in tumor cells with TP53 nonsense mutations.
- Evaluated the functional capacity of readthrough-induced p53 to transactivate target genes and induce tumor cell death.
Main Results:
- Successful induction of full-length p53 protein was achieved in tumor cells with various TP53 nonsense mutations.
- The generated full-length p53 protein retained its ability to transactivate p53 target genes.
- Readthrough-induced p53 triggered tumor cell death, indicating restored tumor suppressor function.
Conclusions:
- Translational readthrough is a viable strategy to counteract the effects of TP53 nonsense mutations.
- This approach holds promise for the development of novel therapies for a significant subset of human cancers harboring TP53 nonsense mutations.
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