USP15-dependent lysosomal pathway controls p53-R175H turnover in ovarian cancer cells.
Achuth PadmanabhanNicholes CandelariaKwong-Kwok WongBryan C NikolaiDavid M LonardBert W O'MalleyJoAnne S RichardsPublished in: Nature communications (2018)
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.
Keyphrases
- small molecule
- cell death
- papillary thyroid
- wild type
- cell cycle arrest
- squamous cell
- induced apoptosis
- bone mineral density
- magnetic resonance
- minimally invasive
- genome wide
- squamous cell carcinoma
- dna methylation
- transcription factor
- signaling pathway
- magnetic resonance imaging
- computed tomography
- quantum dots
- protein protein
- endoplasmic reticulum stress