TY - JOUR
T1 - Discovery of Novel Small Molecule Activators of beta-Catenin Signaling
AU - Verkaar, Folkert
AU - van der Stelt, Mario
AU - Blankesteijn, W. Matthijs
AU - van der Doelen, Antoon A.
AU - Zaman, Guido J. R.
PY - 2011/4/29
Y1 - 2011/4/29
N2 - Wnt/beta-catenin signaling plays a major role in embryonic development and adult stem cell maintenance. Reduced activation of the Wnt/beta-catenin pathway underlies neurodegenerative disorders and aberrations in bone formation. Screening of a small molecule compound library with a beta-galactosidase fragment complementation assay measuring beta-catenin nuclear entry revealed bona fide activators of beta-catenin signaling. The compounds stabilized cytoplasmic beta-catenin and activated beta-catenin-dependent reporter gene activity. Although the mechanism through which the compounds activate beta-catenin signaling has yet to be determined, several key regulators of Wnt/beta-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 beta-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/beta-catenin signaling machinery can be exploited to identify cell type-specific activators of Wnt/beta-catenin signaling.
AB - Wnt/beta-catenin signaling plays a major role in embryonic development and adult stem cell maintenance. Reduced activation of the Wnt/beta-catenin pathway underlies neurodegenerative disorders and aberrations in bone formation. Screening of a small molecule compound library with a beta-galactosidase fragment complementation assay measuring beta-catenin nuclear entry revealed bona fide activators of beta-catenin signaling. The compounds stabilized cytoplasmic beta-catenin and activated beta-catenin-dependent reporter gene activity. Although the mechanism through which the compounds activate beta-catenin signaling has yet to be determined, several key regulators of Wnt/beta-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 beta-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/beta-catenin signaling machinery can be exploited to identify cell type-specific activators of Wnt/beta-catenin signaling.
U2 - 10.1371/journal.pone.0019185
DO - 10.1371/journal.pone.0019185
M3 - Article
C2 - 21559429
SN - 1932-6203
VL - 6
SP - 7
JO - PLOS ONE
JF - PLOS ONE
IS - 4
ER -