The oncogenicity of tumor-derived mutant p53 is enhanced by the recruitment of PLK3
| Autor: | Shilpa Singh, Brad Windle, Sumitra Deb, Elizabeth A. Fry, Jolene J. Windle, W. Andrew Yeudall, Kazushi Inoue, Swati Palit Deb, Catherine A. Vaughan, Steven R. Grossman, Mark A. Subler, Raghavendra Pillappa |
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| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
Transcriptional Activation Lung Neoplasms Carcinogenesis Science Mutant General Physics and Astronomy Mice Transgenic Oncogenicity Protein Serine-Threonine Kinases medicine.disease_cause General Biochemistry Genetics and Molecular Biology Article PLK3 Serine 03 medical and health sciences Transactivation Gene Knockout Techniques Mice 0302 clinical medicine Protein Domains Cell Line Tumor Spheroids Cellular medicine Animals Humans Gene Knock-In Techniques Phosphorylation Tumour-suppressor proteins Lung Mutation Multidisciplinary Chemistry Tumor Suppressor Proteins General Chemistry Cell biology Disease Models Animal 030104 developmental biology Mechanisms of disease 030220 oncology & carcinogenesis Gain of Function Mutation Female Lung cancer Tumor Suppressor Protein p53 |
| Zdroj: | Nature Communications Nature Communications, Vol 12, Iss 1, Pp 1-19 (2021) |
| ISSN: | 2041-1723 |
| Popis: | p53 mutations with single amino acid changes in cancer often lead to dominant oncogenic changes. Here, we have developed a mouse model of gain-of-function (GOF) p53-driven lung cancer utilizing conditionally active LSL p53-R172H and LSL K-Ras-G12D knock-in alleles that can be activated by Cre in lung club cells. Mutation of the p53 transactivation domain (TAD) (p53-L25Q/W26S/R172H) eliminating significant transactivation activity resulted in loss of tumorigenicity, demonstrating that transactivation mediated by or dependent on TAD is required for oncogenicity by GOF p53. GOF p53 TAD mutations significantly reduce phosphorylation of nearby p53 serine 20 (S20), which is a target for PLK3 phosphorylation. Knocking out PLK3 attenuated S20 phosphorylation along with transactivation and oncogenicity by GOF p53, indicating that GOF p53 exploits PLK3 to trigger its transactivation capability and exert oncogenic functions. Our data show a mechanistic involvement of PLK3 in mutant p53 pathway of oncogenesis. The mechanisms of how gain-of-function (GOF) mutant p53 drives carcinogenesis are unclear. Here, the authors show that a GOF mutant p53 requires its transactivation capability to induce mouse lung tumors and this is dependent on PLK3 phosphorylation of GOF mutant p53. |
| Databáze: | OpenAIRE |
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