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Identification of NPM and DDX5 as Therapeutic Targets in TSC

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Technical Report,30 Sep 2015,29 Sep 2017

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Washington University St. Louis United States

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TSC is a common inherited predisposition syndrome, affecting nearly 1 in 7,500 individuals. Individuals with TSC develop benign tumors in multiple organs, including the retina, skin, lung, kidney and brain. The identification of valid targets in TSC has been discouraging. In search of TSC targets, we recently identified NPM as a downstream effector of mTOR signaling in TSC cells, providing cells with an abundant supply of ribosomes necessary for supporting their increased growth rate. We now provide evidence that NPM forms a novel complex with DDX5 to drive TSC cell growth. Using the NCI diversity set and Maybridge chemical compound sets, we have now identified two compounds that potently inhibit split-luciferase activity in two TSC cells lines. Notably, these two compounds also inhibit the proliferation of TSCp53-null and UMB1949 TSC cells while not altering the growth rates of p53-null cells that maintain TSC function, suggesting that these compounds might specifically target NPM-DDX5 complex formation when it is enhanced in TSC cells. We have also shown that these two compounds inhibit the formation of endogenous NPM-DDX5 complexes in TSC cells.

Subject Categories:

  • Medicine and Medical Research
  • Genetic Engineering and Molecular Biology
  • Biochemistry

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