The oncogenicity of tumor-derived mutant p53 is enhanced by the recruitment of PLK3.

Autor: Vaughan CA; Philips Institute, Virginia Commonwealth University, Richmond, VA, 23298, USA., Singh S; Philips Institute, Virginia Commonwealth University, Richmond, VA, 23298, USA., Subler MA; Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, 23298, USA., Windle JJ; Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, 23298, USA., Inoue K; Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, 27101, USA., Fry EA; Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC, 27101, USA., Pillappa R; Department of Pathology, Virginia Commonwealth University, Richmond, VA, 23298, USA., Grossman SR; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA.; Department of Internal Medicine, Division of Hematology, Oncology and Palliative Care, Virginia Commonwealth University, Richmond, VA, 23298, USA., Windle B; Philips Institute, Virginia Commonwealth University, Richmond, VA, 23298, USA.; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA., Andrew Yeudall W; Department of Oral Biology & Diagnostic Sciences, Augusta University, Augusta, GA, 30912, USA.; Georgia Cancer Center, Augusta University, Augusta, GA, 30912, USA., Deb SP; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA.; Department of Biochemistry & Molecular Biology, Virginia Commonwealth University, Richmond, VA, 23298, USA., Deb S; Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, 23298, USA. sumitra.deb@vcuhealth.org.; Department of Biochemistry & Molecular Biology, Virginia Commonwealth University, Richmond, VA, 23298, USA. sumitra.deb@vcuhealth.org.
Jazyk: angličtina
Zdroj: Nature communications [Nat Commun] 2021 Jan 29; Vol. 12 (1), pp. 704. Date of Electronic Publication: 2021 Jan 29.
DOI: 10.1038/s41467-021-20928-8
Abstrakt: 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.
Databáze: MEDLINE