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

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 Deb; Sumitra Deb

doi:10.1038/s41467-021-20928-8

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

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 Deb, Sumitra Deb

Oral Biology & Dx Sciences

Research output: Contribution to journal › Article › peer-review

11 Scopus citations

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.

Original language	English (US)
Article number	704
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-20928-8
State	Published - Dec 1 2021

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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10.1038/s41467-021-20928-8

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title = "The oncogenicity of tumor-derived mutant p53 is enhanced by the recruitment of PLK3",

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.",

author = "Vaughan, {Catherine A.} and Shilpa Singh and Subler, {Mark A.} and Windle, {Jolene J.} and Kazushi Inoue and Fry, {Elizabeth A.} and Raghavendra Pillappa and Grossman, {Steven R.} and Brad Windle and {Andrew Yeudall}, W. and Deb, {Swati Palit} and Sumitra Deb",

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doi = "10.1038/s41467-021-20928-8",

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AU - Singh, Shilpa

AU - Subler, Mark A.

AU - Windle, Jolene J.

AU - Inoue, Kazushi

AU - Fry, Elizabeth A.

AU - Pillappa, Raghavendra

AU - Grossman, Steven R.

AU - Windle, Brad

AU - Andrew Yeudall, W.

AU - Deb, Swati Palit

AU - Deb, Sumitra

PY - 2021/12/1

Y1 - 2021/12/1

N2 - 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.

AB - 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.

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

Abstract

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