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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2009-01-04

AUTHORS

Baozhi Chen, Michael E. Dodge, Wei Tang, Jianming Lu, Zhiqiang Ma, Chih-Wei Fan, Shuguang Wei, Wayne Hao, Jessica Kilgore, Noelle S. Williams, Michael G. Roth, James F. Amatruda, Chuo Chen, Lawrence Lum

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. More... »

PAGES

100-107

References to SciGraph publications

Journal

TITLE

Nature Chemical Biology

ISSUE

2

VOLUME

5

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nchembio.137

    DOI

    http://dx.doi.org/10.1038/nchembio.137

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1002662847

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/19125156


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    18 schema:description 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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