Chibby, a nuclear b-catenin-associated antagonist of the Wnt/Wingless pathway.

Inappropriate activation of downstream target genes by the oncoprotein ?-catenin is implicated in development of numerous human cancers. ?-catenin and its fruitfly counterpart Armadillo act as a coactivator in the canonical Wnt/Wingless pathway by binding to Tcf/Lef transcription factors. Here we report a conserved nuclear protein, named Chibby, which was identified in a screen for proteins that directly interact with the C-terminal region of ?-catenin. In mammalian cultured cells we demonstrate that Chibby inhibits ?-catenin-mediated transcriptional activation by competing with Lef-1 to bind to ?-catenin. Inhibition of Drosophila Chibby by RNA interference results in segment polarity defects that mimick a wingless gain-of-function phenotype, and overexpression of the wingless target genes engrailed and Ultrabithorax. In addition, epistasis experiments indicate that chibby acts downstream of wingless and upstream of armadillo. [ABSTRACT FROM AUTHOR]