Discovery of novel small molecule activators of ?-catenin signaling.

ABSTRACT: Wnt/?-catenin signaling plays a major role in embryonic development and adult stem cell maintenance. Reduced activation of the Wnt/?-catenin pathway underlies neurodegenerative disorders and aberrations in bone formation. Screening of a small molecule compound library with a ?-galactosidase fragment complementation assay measuring ?-catenin nuclear entry revealed bona fide activators of ?-catenin signaling. The compounds stabilized cytoplasmic ?-catenin and activated ?-catenin-dependent reporter gene activity. Although the mechanism through which the compounds activate ?-catenin signaling has yet to be determined, several key regulators of Wnt/?-catenin signaling, including glycogen synthase kinase 3 and Frizzled receptors, were excluded as the molecular target. The compounds displayed remarkable selectivity, as they only induced ?-catenin signaling in a human osteosarcoma U2OS cell line and not in a variety of other cell lines examined. Our data indicate that differences in cellular Wnt/?-catenin signaling machinery can be exploited to identify cell type-specific activators of Wnt/?-catenin signaling.

SUBMITTER: Verkaar F 

PROVIDER: S-EPMC3084789 | biostudies-literature | 2011 Apr

REPOSITORIES: biostudies-literature