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- Title
Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer.
- Authors
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; Lum, Lawrence
- Abstract
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.
- Publication
Nature chemical biology, 2009, Vol 5, Issue 2, p100
- ISSN
1552-4469
- Publication type
Journal Article
- DOI
10.1038/nchembio.137