The intestine-specific transcription factor Cdx2 inhibits beta-catenin/TCF transcriptional activity by disrupting the beta-catenin-TCF protein complex.
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 beta-catenin-T-cell factor (TCF) bipartite complex. Herein we further elucidate this mechanism. Studies with a classic Cdx2 target gene and a canonical Wnt/beta-catenin/TCF reporter suggest that Cdx2 regulates these promoters by distinctly different processes. Specifically, inhibition of beta-catenin/TCF activity by Cdx2 does not require Cdx2 transcriptional activity. Instead, Cdx2 binds beta-catenin and disrupts its interaction with the DNA-binding TCF factors, thereby silencing beta-catenin/TCF target gene expression. Using Cdx2 mutants, we map the Cdx2 domains required for the inhibition of beta-catenin/TCF activity. We identify a subdomain in the N-terminus that is highly conserved and when mutated significantly reduces Cdx2 inhibition of beta-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 beta-catenin and disrupts the beta-catenin-TCF complex. Considering the pivotal role of beta-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/beta-catenin signaling and cell proliferation.
Guo
Rong-Jun
RJ
Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Funakoshi
Shinsuke
S
Lee
Hannah H
HH
Kong
Jianping
J
Lynch
John P
JP
D000595:Amino Acid Sequence; D000818:Animals; D000071616:CDX2 Transcription Factor; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D015151:Immunoblotting; D047468:Immunoprecipitation; D007413:Intestinal Mucosa / Q000378:metabolism*; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D011401:Promoter Regions, Genetic; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D051820:TCF Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism; D014982:Xenopus laevis / Q000254:growth & development / Q000378:metabolism; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D018398:Homeodomain Proteins; D051820:TCF Transcription Factors; D051153:Wnt Proteins; D051176:beta Catenin