Author/Authors :
Lepourcelet، نويسنده , , Maina and Chen، نويسنده , , Ying-Nan P. and France، نويسنده , , Dennis S. and Wang، نويسنده , , Huisheng and Crews، نويسنده , , Phillip and Petersen، نويسنده , , Frank and Bruseo، نويسنده , , Charles and Wood، نويسنده , , Alexander W. and Shivdasani، نويسنده , , Ramesh A.، نويسنده ,
Abstract :
Key molecular lesions in colorectal and other cancers cause β-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 β-catenin, we screened libraries of natural compounds in a high-throughput assay for immunoenzymatic detection of the protein-protein interaction. Selected compounds disrupt Tcf/β-catenin complexes in several independent in vitro assays and potently antagonize cellular effects of β-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/β-catenin complexes and define a general standard to establish mechanism-based activity of small molecule inhibitors of this pathogenic protein-protein interaction.
