Cytokine-induced apoptosis in beta-cells is a large contributor to the development of type 1 diabetes. A screen for small-molecule suppressors of cytokine-induced apoptosis yielded a compound from the diversity-oriented synthesis (DOS) library, BRD0476. BRD0476 targets the deubiquitinase Usp9x, an enzyme not typically associated with beta-cell apoptosis, to inhibit Jak/Stat signaling.
Here we examined the mechanism of action of BRD0476. To do so, we performed ELISAs and Western blots to study the compound’s effects on total Jak2 and phosphorylated Jak2 levels in rat INS-1E cells.
We observed a decrease in phosphorylated Jak2 levels with addition of BRD0476 but no decrease in total Jak2 levels. These findings could be attributed to ubiquitin’s steric interference with phosphorylation of Jak2. Our results may suggest a new interaction between protein phosphorylation and ubiquitination and present an alternative method of suppressing the Jak2/Stat1 pathway for many different applications.
PROJECT: Identification and characterization of a small molecule suppressor of β-Cell apoptosis in type 1 diabetes
Mentors: Amedeo Vetere and Bridget Wagner, Chemical Biology Program
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