1. Howard Hughes Medical Institute, Room K536C Health Sciences Building, Campus Box 357750, Department of Pharmacology, and Center for Developmental Biology, University of Washington School of Medicine, Seattle, Washington 98195, USA
2. Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, Illinois 60208-3500, USA
3. These authors contributed equally to this work

Correspondence to: Randall T. Moon¹ Correspondence and requests for materials should be addressed to R.T.M. (e-mail: Email: rtmoon@u.washington.edu). GenBank accession numbers for Cby are: human, AL050345; mouse, AK003719; Xenopus, BJ093998; zebrafish, BI885798; Drosophila, AE003736.

Abstract

Inappropriate activation of downstream target genes by the oncoprotein -catenin is implicated in development of numerous human cancers^{1, 2}. -catenin and its fruitfly counterpart Armadillo act as a coactivator in the canonical Wnt/Wingless pathway by binding to Tcf/Lef transcription factors^{3, 4, 5, 6}. 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.