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

Author

Listed:
  • Catherine A. Vaughan

    (Virginia Commonwealth University)

  • Shilpa Singh

    (Virginia Commonwealth University)

  • Mark A. Subler

    (Virginia Commonwealth University)

  • Jolene J. Windle

    (Virginia Commonwealth University)

  • Kazushi Inoue

    (Wake Forest School of Medicine)

  • Elizabeth A. Fry

    (Wake Forest School of Medicine)

  • Raghavendra Pillappa

    (Virginia Commonwealth University)

  • Steven R. Grossman

    (Virginia Commonwealth University
    Virginia Commonwealth University)

  • Brad Windle

    (Virginia Commonwealth University
    Virginia Commonwealth University)

  • W. Andrew Yeudall

    (Augusta University
    Augusta University)

  • Swati Palit Deb

    (Virginia Commonwealth University
    Virginia Commonwealth University)

  • Sumitra Deb

    (Virginia Commonwealth University
    Virginia Commonwealth University)

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.

Suggested Citation

  • Catherine A. Vaughan & Shilpa Singh & Mark A. Subler & Jolene J. Windle & Kazushi Inoue & Elizabeth A. Fry & Raghavendra Pillappa & Steven R. Grossman & Brad Windle & W. Andrew Yeudall & Swati Palit D, 2021. "The oncogenicity of tumor-derived mutant p53 is enhanced by the recruitment of PLK3," Nature Communications, Nature, vol. 12(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-20928-8
    DOI: 10.1038/s41467-021-20928-8
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