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TBL1–TBLR1 and β-catenin recruit each other to Wnt target-gene promoter for transcription activation and oncogenesis

Nature Cell Biology volume 10, pages 160–169 (2008)Cite this article

Abstract

Aberrant Wnt signalling promotes oncogenesis by increasing the nuclear accumulation of β-catenin to activate downstream target genes. However, the mechanism of β-catenin recruitment to the Wnt target-gene promoter, a critical step for removing the co-repressor complex, is largely unknown. Here, we report that transducin β-like protein 1 (TBL1) and its highly related family member TBLR1 were required for Wnt–β-catenin-mediated transcription. Wnt signalling induced the interaction between β-catenin and TBL1–TBLR1, as well as their binding to Wnt target genes. Importantly, the recruitment of TBL1–TBLR1 and β-catenin to Wnt target-gene promoters was mutually dependent on each other. Furthermore, the depletion of TBL1–TBLR1 significantly inhibited Wnt–β-catenin-induced gene expression and oncogenic growth in vitro and in vivo. Our results unravel two new components required for nuclear β-catenin function, and have important implications in developing new strategies for inhibiting Wnt–β-catenin-mediated tumorigenesis.

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Figure 1: Both TBL1 and TBLR1 are required for β-catenin–Tcf-mediated transcription.
Figure 2: Wnt signalling stimulates the interaction between β-catenin and TBL1–TBLR1.
Figure 3: TBL1–TBLR1 constitutively occupied on the Wnt target-gene promoter in colorectal cancer cell lines.
Figure 4: Both TBL1 and TBLR1 are required for the recruitment of β-catenin to the Wnt target-gene promoter.
Figure 5: TBL1–TBLR1 and β-catenin co-occupied the Wnt target-gene promoter.
Figure 6: TBL1 and TBLR1 play a critical role in β-catenin-mediated oncogenesis.
Figure 7: Schematic representation of a model for the role of TBL1–TBLR1 in the recruitment of β-catenin to the Wnt target-gene promoter.

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Acknowledgements

We thank K. Cadigan for suggestions and reagents, and D. Saims and J. Guan for reading the manuscript. This work was supported by National Institutes of Health (NIH) grants to C.Y.W.

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Authors and Affiliations

  1. Division of Oral Biology and Medicine, Laboratory of Molecular Signalling, UCLA School of Dentistry, Los Angeles, 90095, CA, USA

    Jiong Li & Cun-Yu Wang

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  1. Jiong Li
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Contributions

J.L. performed the experiments. J.L. and C.Y.W. designed the experiments, analysed the data and wrote the manuscript.

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Correspondence to Cun-Yu Wang.

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Supplementary Figures S1, S2, S3, S4, s5 and S6 (PDF 690 kb)

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Li, J., Wang, CY. TBL1–TBLR1 and β-catenin recruit each other to Wnt target-gene promoter for transcription activation and oncogenesis. Nat Cell Biol 10, 160–169 (2008). https://doi.org/10.1038/ncb1684

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