The intestine-specific transcription factor Cdx2 inhibits β-catenin/TCF transcriptional activity by disrupting the β-catenin–TCF protein complex

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Abstract
Cdx2 is an intestine-specific transcription factor known to regulate proliferation and differentiation. We have reported previously that Cdx2 limits the proliferation of human colon cancer cells by inhibiting the transcriptional activity of the β-catenin–T-cell factor (TCF) bipartite complex. Herein we further elucidate this mechanism. Studies with a classic Cdx2 target gene and a canonical Wnt/β-catenin/TCF reporter suggest that Cdx2 regulates these promoters by distinctly different processes. Specifically, inhibition of β-catenin/TCF activity by Cdx2 does not require Cdx2 transcriptional activity. Instead, Cdx2 binds β-catenin and disrupts its interaction with the DNA-binding TCF factors, thereby silencing β-catenin/TCF target gene expression. Using Cdx2 mutants, we map the Cdx2 domains required for the inhibition of β-catenin/TCF activity. We identify a subdomain in the N-terminus that is highly conserved and when mutated significantly reduces Cdx2 inhibition of β-catenin/TCF transcriptional activity. Mutation of this subdomain also abrogates Cdx2’s anti-proliferative effects in colon cancer cells. In summary, we conclude that Cdx2 binds β-catenin and disrupts the β-catenin–TCF complex. Considering the pivotal role of β-catenin/TCF activity in driving proliferation of normal intestinal epithelial and colon cancer cells, our findings suggest a novel mechanism for Cdx2-mediated regulation of Wnt/β-catenin signaling and cell proliferation.

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