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

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Abstract

Inappropriate activation of downstream target genes by the oncoprotein β-catenin is implicated in development of numerous human cancers1,2. β-catenin and its fruitfly counterpart Armadillo act as a coactivator in the canonical Wnt/Wingless pathway by binding to Tcf/Lef transcription factors3,4,5,6. 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 β-catenin. In mammalian cultured cells we demonstrate that Chibby inhibits β-catenin-mediated transcriptional activation by competing with Lef-1 to bind to β-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.

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Figure 1: RNAi of cby in Drosophila embryos causes ectopic activation of the wg pathway.
Figure 2: Cby encodes a nuclear protein.
Figure 3: Physical interaction between Cby and β-catenin.
Figure 4: Cby antagonizes β-catenin signalling.
Figure 5: Genetic relationship between cby and genes in the wg pathway.

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Acknowledgements

We thank R. Holmgren, R. Pestell, M. Waterman and DSHB for reagents; M. Peifer, J. Treisman and Bloomington Stock Center for fly stocks; R. Holmgren, F.-Q. Li and members of the Carthew and Moon laboratories for critically reading the manuscript. This work was supported by postdoctoral fellowships from the Japan Science and Technology Corporation and Uehara Memorial Foundation (to K.-I.T.), the Pew Charitable Trust (to R.W.C.), and by an NIH grant (to R.T.M.). R.T.M. is an Investigator of the Howard Hughes Medical Institute.

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  1. Ken-Ichi Takemaru, Shinji Yamaguchi, Young Sik Lee and Richard W. Carthew: These authors contributed equally to this work

Authors and Affiliations

  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

    Ken-Ichi Takemaru, Yang Zhang & Randall T. Moon

  2. Department of Biochemistry, Molecular Biology, and Cell Biology, Northwestern University, Evanston, Illinois, 60208-3500, USA

    Shinji Yamaguchi, Young Sik Lee & Richard W. Carthew

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  1. Ken-Ichi Takemaru
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  2. Shinji Yamaguchi
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  3. Young Sik Lee
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  4. Yang Zhang
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  5. Richard W. Carthew
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  6. Randall T. Moon
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Correspondence to Randall T. Moon.

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The authors declare that they have no competing financial interests.

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Takemaru, KI., Yamaguchi, S., Lee, Y. et al. Chibby, a nuclear β-catenin-associated antagonist of the Wnt/Wingless pathway. Nature 422, 905–909 (2003). https://doi.org/10.1038/nature01570

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