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

Autor:	Padmanabhan A; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA. achuth.padmanabhan@bcm.edu.; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA. achuth.padmanabhan@bcm.edu.; Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX, 77030, USA. achuth.padmanabhan@bcm.edu., Candelaria N; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.; Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX, 77030, USA., Wong KK; Department of Gynecologic Oncology and Reproductive Medicine - Research, Division of Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA., Nikolai BC; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.; Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX, 77030, USA., Lonard DM; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.; Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX, 77030, USA., O'Malley BW; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.; Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX, 77030, USA., Richards JS; Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, 77030, USA.; Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, 77030, USA.; Center for Reproductive Medicine, Baylor College of Medicine, Houston, TX, 77030, USA.
Jazyk:	angličtina
Zdroj:	Nature communications [Nat Commun] 2018 Mar 28; Vol. 9 (1), pp. 1270. Date of Electronic Publication: 2018 Mar 28.
DOI:	10.1038/s41467-018-03599-w
Abstrakt:	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.
Databáze:	MEDLINE
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