title: Discovery of novel small molecule activators of β-catenin signaling.
abstract: Wnt/β-catenin signaling plays a major role in embryonic development and adult stem cell maintenance. Reduced activation of the Wnt/β-catenin pathway underlies neurodegenerative disorders and aberrations in bone formation. Screening of a small molecule compound library with a β-galactosidase fragment complementation assay measuring β-catenin nuclear entry revealed bona fide activators of β-catenin signaling. The compounds stabilized cytoplasmic β-catenin and activated β-catenin-dependent reporter gene activity. Although the mechanism through which the compounds activate β-catenin signaling has yet to be determined, several key regulators of Wnt/β-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 β-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/β-catenin signaling machinery can be exploited to identify cell type-specific activators of Wnt/β-catenin signaling.
authors.affiliation: Department of Molecular Pharmacology, Merck Research Laboratories, Oss, The Netherlands.
authors.forename: Folkert
authors.initials: F
authors.lastname: Verkaar
authors.forename: Mario
authors.initials: M
authors.lastname: van der Stelt
authors.forename: W Matthijs
authors.initials: WM
authors.lastname: Blankesteijn
authors.forename: Antoon A
authors.initials: AA
authors.lastname: van der Doelen
authors.forename: Guido J R
authors.initials: GJ
authors.lastname: Zaman
mesh_terms: D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D045744:Cell Line, Tumor; D006224:Cricetinae; D003412:Cricetulus; D003593:Cytoplasm / Q000378:metabolism; D015195:Drug Design; D038341:Glycogen Synthase Kinases / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D008954:Models, Biological; D011485:Protein Binding; D015398:Signal Transduction; D051176:beta Catenin / Q000378:metabolism*; D001616:beta-Galactosidase / Q000378:metabolism
chemical_list: D051176:beta Catenin; D038341:Glycogen Synthase Kinases; D001616:beta-Galactosidase