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USP15-dependent lysosomal pathway controls p53-R175H turnover in ovarian cancer cells

Author

Listed:
  • Achuth Padmanabhan

    (Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

  • Nicholes Candelaria

    (Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

  • Kwong-Kwok Wong

    (The University of Texas MD Anderson Cancer Center)

  • Bryan C. Nikolai

    (Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

  • David M. Lonard

    (Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

  • Bert W. O’Malley

    (Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

  • JoAnne S. Richards

    (Baylor College of Medicine
    Baylor College of Medicine
    Baylor College of Medicine)

Abstract

Gain-of-function p53 mutants such as p53-R175H form stable aggregates that accumulate in cells and play important roles in cancer progression. Selective degradation of gain-of-function p53 mutants has emerged as a highly attractive therapeutic strategy to target cancer cells harboring specific p53 mutations. We identified a small molecule called MCB-613 to cause rapid ubiquitination, nuclear export, and degradation of p53-R175H through a lysosome-mediated pathway, leading to catastrophic cancer cell death. In contrast to its effect on the p53-R175H mutant, MCB-613 causes slight stabilization of p53-WT and has weaker effects on other p53 gain-of-function mutants. Using state-of-the-art genetic and chemical approaches, we identified the deubiquitinase USP15 as the mediator of MCB-613’s effect on p53-R175H, and established USP15 as a selective upstream regulator of p53-R175H in ovarian cancer cells. These results confirm that distinct pathways regulate the turnover of p53-WT and the different p53 mutants and open new opportunities to selectively target them.

Suggested Citation

  • Achuth Padmanabhan & Nicholes Candelaria & Kwong-Kwok Wong & Bryan C. Nikolai & David M. Lonard & Bert W. O’Malley & JoAnne S. Richards, 2018. "USP15-dependent lysosomal pathway controls p53-R175H turnover in ovarian cancer cells," Nature Communications, Nature, vol. 9(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03599-w
    DOI: 10.1038/s41467-018-03599-w
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    Cited by:

    1. Zhenlei Zhang & Yufan Wu & Jinrong Fu & Xiujie Yu & Yang Su & Shikai Jia & Huili Cheng & Yan Shen & Xianghui He & Kai Ren & Xiangqian Zheng & Haixia Guan & Feng Rao & Li Zhao, 2024. "Proteostatic reactivation of the developmental transcription factor TBX3 drives BRAF/MAPK-mediated tumorigenesis," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

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