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Small molecule-mediated disruption of Wnt-dependent signaling in tissue regeneration and cancer

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 novel classes of small molecule...

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Detalles Bibliográficos
Autores principales: 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
Formato: Texto
Lenguaje:English
Publicado: 2009
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2628455/
https://www.ncbi.nlm.nih.gov/pubmed/19125156
http://dx.doi.org/10.1038/nchembio.137
Descripción
Sumario: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 novel classes of small molecules that disrupt Wnt pathway responses - whereas one class inhibits the activity of Porcupine (Porcn), a membrane-bound acyltransferase that is essential to the production of Wnt proteins, the other abrogates destruction of Axin proteins, suppressors of Wnt/β-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/β-catenin pathway response in vivo, and 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.