Targeting the Ubiquitin-Proteasome System for Cancer

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Our laboratory is interested in understanding the molecular mechanisms of deubiquitinating enzymes during the cell cycle progression. The ubiquitin–proteasome system (UPS) maintains protein homeostasis through the selective degradation of proteins. The ubiquitin-proteasome system (UPS) has been implicated in many kinds of disease such as cancer. Deubiquitinating enzymes (DUBs) are proteases that cleave a single ubiquitin or polyubiquitin chains from target proteins. DUBs can affect protein-protein interactions and the localization or activity of a protein, thereby involve in many cellular process.
Our goal is to identify DUBs required for cell division and survival and to provide tools for interfering with their activity during disease. To achieve these goals, we isolate DUBs controlling proliferation and survival using high-throughput siRNA screening technology and then utilize an established biochemical discovery platform to identify the substrates of these DUBs, allowing for a detailed understanding of the biology underlying DUB-action. Finally, we will integrate our findings into a biochemical model of DUB-activity, allowing us to design and execute small molecule screens for DUB-inhibitors. Together, our approach will provide novel therapeutic strategies to modulate pathological cell cycle progression with an emphasis on cancer.