Journal
NATURE COMMUNICATIONS
Volume 9, Issue -, Pages -Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/s41467-018-03599-w
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Funding
- NIH [NIH-CA-181808, DK56338, CA125123]
- CPRIT [RP150578]
- Dan L. Duncan Comprehensive Cancer Center
- John S. Dunn Gulf Coast Consortium for Chemical Genomics
- Integrated Microscopy Core at BCM
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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.
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