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Lum, Lawrence; Chen, Baozhi; Dodge, Michael E; Tang, Wei; Lu, Jianming; Ma, Zhiqiang; Fan, Chih-Wei; Wei, Shuguang; Hao, Wayne; Kilgore, Jessica; Williams, Noelle S; Roth, Michael G; Amatruda, James F; Chen, Chuo
Nature chemical biology, 02/2009, Letnik: 5, Številka: 2Journal Article
The pervasive influence of secreted Wnt signaling proteins in tissue homeostasis and tumorigenesis has galvanized efforts to identify small molecules that target Wnt-mediated cellular responses. By screening a diverse synthetic chemical library, we have discovered two new classes of small molecules that disrupt Wnt pathway responses; whereas one class inhibits the activity of Porcupine, a membrane-bound acyltransferase that is essential to the production of Wnt proteins, the other abrogates destruction of Axin proteins, which are suppressors of Wnt/beta-catenin pathway activity. With these small molecules, we establish a chemical genetic approach for studying Wnt pathway responses and stem cell function in adult tissue. We achieve transient, reversible suppression of Wnt/beta-catenin pathway response in vivo, and we establish a mechanism-based approach to target cancerous cell growth. The signal transduction mechanisms shown here to be chemically tractable additionally contribute to Wnt-independent signal transduction pathways and thus could be broadly exploited for chemical genetics and therapeutic goals.
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