| Literature DB >> 33514736 |
Catherine A Vaughan1, Shilpa Singh1, Mark A Subler2, Jolene J Windle2, Kazushi Inoue3, Elizabeth A Fry3, Raghavendra Pillappa4, Steven R Grossman5,6, Brad Windle1,5, W Andrew Yeudall7,8, Swati Palit Deb5,9, Sumitra Deb10,11.
Abstract
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.Entities:
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Year: 2021 PMID： 33514736 PMCID： PMC7846773 DOI： 10.1038/s41467-021-20928-8
Source DB: PubMed Journal: Nat Commun ISSN： 2041-1723 Impact factor: 14.919