Journal
CANCER CELL
Volume 5, Issue 1, Pages 91-102Publisher
CELL PRESS
DOI: 10.1016/S1535-6108(03)00334-9
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Funding
- NATIONAL CANCER INSTITUTE [U19CA052955, U01CA052955] Funding Source: NIH RePORTER
- NCI NIH HHS [CA52955] Funding Source: Medline
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Key molecular lesions in colorectal and other cancers cause beta-catenin-dependent transactivation of T cell factor (Tcf)dependent genes. Disruption of this signal represents an opportunity for rational cancer therapy. To identify compounds that inhibit association between Tcf4 and beta-catenin, we screened libraries of natural compounds in a high-throughput assay for immunoenzymatic detection of the protein-protein interaction. Selected compounds disrupt Tcf/beta-catenin complexes in several independent in vitro assays and potently antagonize cellular effects of beta-catenin-dependent activities, including reporter gene activation, c-myc or cyclin D1 expression, cell proliferation, and duplication of the Xenopus embryonic dorsal axis. These compounds thus meet predicted criteria for disrupting Tcf/beta-catenin complexes and define a general standard to establish mechanism-based activity of small molecule inhibitors of this pathogenic protein-protein interaction.
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