Ubiquitin-dependent mechanisms of tissue-specific cell cycle control

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This proposal describes an integrated approach to identify modules of tissue-specific cell cycle control. Despite clear evidence for tissue-specificity in proliferation and the outstanding importance of tissue-specific cell cycle regulation for development and disease, the underlying mechanisms have not been uncovered. The identification and characterization of tissue-specific modules in proliferative networks will not only provide deep insight into development of multicellular organisms and tumorigenesis, but also lay the groundwork for the discovery of tissue-specific chemotherapeutics. Because of the crucial role of ubiquitination in cell cycle control, the tissue-specific expression of ubiquitination enzymes, the frequent misregulation of ubiquitination in cancer, and the enzymatic nature of ubiquitination, we will focus the dissection of tissue- specific cell cycle regulation on members of the ubiquitination machinery. Using synthetic lethality siRNA screens in different cell lines, we will identify ubiquitination enzymes required for tissue-specific cell cycle control. By isolating substrates of these enzymes unique to a certain tissue, we will delineate pathways underlying cell cycle regulation in this tissue. Finally, by developing and miniaturizing quantifiable ubiquitination assays, we will isolate small-molecule inhibitors that allow further dissection of proliferative networks and may serve as lead structures for novel tissue-specific chemotherapeutics. We are convinced that this integrated approach using genetic discovery, biochemical dissection, and inhibitor identification based on chemical biology will provide deep insights into cell cycle and developmental regulation and lay the groundwork for novel, innovative chemotherapeutics with improved tissue-specificity.