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David M. Virshup, M.D. Professor and Director of the Program in Cancer and Stem Cell Biology Duke-NUS Graduate Medical School Singapore [email protected] duke-nus.edu.sg http://www.duke-nus.edu.sg/web/research_faculty_david.htm Research Synopsis The Virshup laboratory is interested in specific post-translational modifications that control key regulatory pathways. Wnt signaling is a series of highly conserved pathways important in stem cell maintenance, cell proliferation, development and cancer. The Virshup laboratory studies Wnt signaling with a emphasis on the posttranslational modifications of proteins that regulate these pathways and and that control the fate of cells. Project 1. Molecular regulation of the Wnt/-catenin signaling pathway The Wnt/-catenin signaling pathway is critical in both cellular proliferation and organismal development. My laboratory is interested in the kinases and phosphatases that lie downstream of Wnt receptor activation. We have identified regulation of Casein Kinase I, and several serine-threonine phosphatases as key events regulated by, and regulating Wnt signaling. Diverse molecular, cellular and developmental approaches are used to analyze these enzymes. Project 2. Regulation of Wnt production The connection between Wnt/β-catenin or “canonical” Wnt signaling and cancer is well appreciated. Some cancers, such as colon cancer, have mutations in components of the signaling pathway (i.e. adenomatous polyposis coli protein, “APC”, axin, and β-catenin). In breast cancer and leukemias, cancer stem cell maintenance has been shown to depend on Wnt signaling. Both β-catenin dependent and independent signaling pathways are implicated in stem cell maintenance. In the more overtly Wnt dependent cancers, it is clear that intervention at multiple points in the Wnt signaling pathway(s) is required for effective treatment of a broad range of cancers. We are studying diverse aspects of Wnt production and, using a cell based screen for inhibitors of Wnt signaling have identified lead compound inhibitors throughout the entire pathway, with an emphasis on inhibitors of secretion from Wnt expressing cells. These lead compounds have low toxicity and significant efficacy on Wnt-stimulated signaling. A deeper understanding of Wnt production, including further development of small molecules, may lead to useful cancer chemotherapeutics. Project 3. Circadian Rhythms My lab has a longstanding interest in how our daily body clock, known as circadian rhythms, are regulated in cells. We have previously dissected how the protein kinase CKI controls rhythms by regulating the stability of the key circadian protein PER2. Now I would like to study the physiologic and pathologic events that regulate phosphorylation of PER2 and hence timing of the clock. Specific projects include, but are not limited to, identification of the specific phosphatase holoenzyme that controls PER2 stability, and analyzing the potential circadian regulation of the phosphatase in mammalian cells. These phosphatases can themselves be key circadian regulators. Additional projects related to circadian rhythms and cancer are possible as well. Methods used include measuring circadian rhythms in cultured cells and mice.