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Differential Gain-of-Function Activity of Three p53 Hotspot Mutants In Vivo
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Abstract
The majority of TP53 missense mutations identified in cancer patients are in the DNA-binding domain and are characterized as either structural or contact mutations. These missense mutations exhibit inhibitory effects on wild-type p53 activity. More importantly, these mutations also demonstrate gain-of-function (GOF) activities characterized by increased metastasis, poor prognosis, and drug resistance. To better understand the activities by which TP53 mutations, identified in Li–Fraumeni syndrome, contribute to tumorigenesis, we generated mice harboring a novel germline Trp53R245W allele (contact mutation) and compared them with existing models with Trp53R172H (structural mutation) and Trp53R270H (contact mutation) alleles. Thymocytes from heterozygous mice showed that all three hotspot mutations exhibited similar inhibitory effects on wild-type p53 transcription in vivo, and tumors from these mice had similar levels of loss of heterozygosity. However, the overall survival of Trp53R245W/+ and Trp53R270H/+ mice, but not Trp53R172H/+ mice, was significantly shorter than that of Trp53+/− mice, providing strong evidence for p53-mutant–specific GOF contributions to tumor development. Furthermore, Trp53R245W/+ and Trp53R270H/+ mice had more osteosarcoma metastases than Trp53R172H/+ mice, suggesting that these two contact mutants have stronger GOF in driving osteosarcoma metastasis. Transcriptomic analyses using RNA sequencing data from Trp53R172H/+, Trp53R245W/+, and Trp53R270H/+ primary osteosarcomas in comparison with Trp53+/– indicated that GOF of the three mutants was mediated by distinct pathways. Thus, both the inhibitory effect of mutant over wild-type p53 and GOF activities of mutant p53 contributed to tumorigenesis in vivo. Targeting p53 mutant–specific pathways may be important for therapeutic outcomes in osteosarcoma. Significance: p53 hotspot mutants inhibit wild-type p53 similarly but differ in their GOF activities, with stronger tumor-promoting activity in contact mutants and distinct protein partners of each mutant driving tumorigenesis and metastasis.
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“The activity of the p53 mutant GOF has been reported to be associated with cellular physiopathology and poor clinical outcomes in cancer patients236–246 (Fig. 5).”
From Targeting p53 pathways: mechanisms, structures, and advances in therapy (2023) · cites this paper as [237]
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Cited by
Targeting p53 pathways: mechanisms, structures, and advances in therapy
Wang, H., Guo, M., Wei, H., & Chen, Y. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01347-1 · Cited by 1,016
Wong, T. N., & Link, D. C. (2024) · Hematology · doi:10.1182/hematology.2024000556 · Cited by 11
Metadata
- Authors
- Xiong, S., Chachad, D., Zhang, Y., Gencel-Augusto, J., Sirito, M., Pant, V., Yang, P., Sun, C., Chau, G., Qi, Y., Su, X., Whitley, E. M., El-Naggar, A. K., & Lozano, G.
- Affiliations
- 1Department of Genetics, The University of Texas MD Anderson Cancer Center, UT Health Graduate School of Biomedical Sciences, Houston, Texas.
- 3Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Texas Southern University, Houston, Texas.
- 4Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- 5Department of Veterinary Medicine and Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- 6Department of Pathology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
- ORCID
- Venue
- Cancer Research
- Published
- 2022-03-23
- Volume
- 82
- Issue
- 10
- Pages
- 1926-1936
- ISSN
- 0008-5472
- 1538-7445
- Cited by
- 44
- References
- 9
- Language
- en
- Funders
- NCI NIH (P30CA016672)
- Cancer Prevention and Research Institute of Texas (RP170231)
- NIH (CA82577)
- Anderson institutional research grant (2015-00051082-Y1)
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- Xiong, S., Chachad, D., Zhang, Y., Gencel-Augusto, J., Sirito, M., Pant, V., Yang, P., Sun, C., Chau, G., Qi, Y., Su, X., Whitley, E. M., El-Naggar, A. K., & Lozano, G. (2022). Differential Gain-of-Function Activity of Three p53 Hotspot Mutants In Vivo. Cancer Research. https://doi.org/10.1158/0008-5472.can-21-3376
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