Click here to close
Hello! We notice that you are using Internet Explorer, which is not supported by Xenbase and may cause the site to display incorrectly.
We suggest using a current version of Chrome,
FireFox, or Safari.
Carcinogenesis
2010 Feb 01;312:159-66. doi: 10.1093/carcin/bgp213.
Show Gene links
Show Anatomy links
The intestine-specific transcription factor Cdx2 inhibits beta-catenin/TCF transcriptional activity by disrupting the beta-catenin-TCF protein complex.
Guo RJ
,
Funakoshi S
,
Lee HH
,
Kong J
,
Lynch JP
.
???displayArticle.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 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.
Aoki,
Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc+/Delta716 Cdx2+/- compound mutant mice.
2003, Pubmed
Aoki,
Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc+/Delta716 Cdx2+/- compound mutant mice.
2003,
Pubmed
Arcinas,
Molecular mechanisms of transcriptional control of bcl-2 and c-myc in follicular and transformed lymphoma.
2001,
Pubmed
Bonhomme,
The Cdx2 homeobox gene has a tumour suppressor function in the distal colon in addition to a homeotic role during gut development.
2003,
Pubmed
Boudreau,
Sucrase-isomaltase gene transcription requires the hepatocyte nuclear factor-1 (HNF-1) regulatory element and is regulated by the ratio of HNF-1 alpha to HNF-1 beta.
2001,
Pubmed
Boudreau,
Hepatocyte nuclear factor-1 alpha, GATA-4, and caudal related homeodomain protein Cdx2 interact functionally to modulate intestinal gene transcription. Implication for the developmental regulation of the sucrase-isomaltase gene.
2002,
Pubmed
Boulanger,
Cdk2-dependent phosphorylation of homeobox transcription factor CDX2 regulates its nuclear translocation and proteasome-mediated degradation in human intestinal epithelial cells.
2005,
Pubmed
Clevers,
Wnt/beta-catenin signaling in development and disease.
2006,
Pubmed
Crissey,
The homeodomain transcription factor Cdx1 does not behave as an oncogene in normal mouse intestine.
2008,
Pubmed
Dang,
CDX2 has tumorigenic potential in the human colon cancer cell lines LOVO and SW48.
2006,
Pubmed
Dang,
Expression of the gut-enriched Krüppel-like factor (Krüppel-like factor 4) gene in the human colon cancer cell line RKO is dependent on CDX2.
2001,
Pubmed
Ee,
Cdx-2 homeodomain protein expression in human and rat colorectal adenoma and carcinoma.
1995,
Pubmed
Ezaki,
The homeodomain transcription factors Cdx1 and Cdx2 induce E-cadherin adhesion activity by reducing beta- and p120-catenin tyrosine phosphorylation.
2007,
Pubmed
Funakoshi,
Repression of the desmocollin 2 gene expression in human colon cancer cells is relieved by the homeodomain transcription factors Cdx1 and Cdx2.
2008,
Pubmed
Galceran,
Rescue of a Wnt mutation by an activated form of LEF-1: regulation of maintenance but not initiation of Brachyury expression.
2001,
Pubmed
Gao,
Establishment of intestinal identity and epithelial-mesenchymal signaling by Cdx2.
2009,
Pubmed
Gottardi,
E-cadherin suppresses cellular transformation by inhibiting beta-catenin signaling in an adhesion-independent manner.
2001,
Pubmed
Gross,
Phosphorylation of the homeotic tumor suppressor Cdx2 mediates its ubiquitin-dependent proteasome degradation.
2005,
Pubmed
Guo,
Cdx1 inhibits human colon cancer cell proliferation by reducing beta-catenin/T-cell factor transcriptional activity.
2004,
Pubmed
,
Xenbase
Guo,
The role of Cdx proteins in intestinal development and cancer.
2004,
Pubmed
Hecht,
Regulation of sucrase and lactase in developing rats: role of nuclear factors that bind to two gene regulatory elements.
1997,
Pubmed
Hinoi,
CDX2 regulates liver intestine-cadherin expression in normal and malignant colon epithelium and intestinal metaplasia.
2002,
Pubmed
Kahler,
Lymphoid enhancer factor-1 and beta-catenin inhibit Runx2-dependent transcriptional activation of the osteocalcin promoter.
2003,
Pubmed
Keller,
Cdx1 or Cdx2 expression activates E-cadherin-mediated cell-cell adhesion and compaction in human COLO 205 cells.
2004,
Pubmed
Korinek,
Constitutive transcriptional activation by a beta-catenin-Tcf complex in APC-/- colon carcinoma.
1997,
Pubmed
Korinek,
Depletion of epithelial stem-cell compartments in the small intestine of mice lacking Tcf-4.
1998,
Pubmed
Kuhnert,
Essential requirement for Wnt signaling in proliferation of adult small intestine and colon revealed by adenoviral expression of Dickkopf-1.
2004,
Pubmed
Lynch,
Cdx1 inhibits the proliferation of human colon cancer cells by reducing cyclin D1 gene expression.
2003,
Pubmed
Lynch,
The caudal-related homeodomain protein Cdx1 inhibits proliferation of intestinal epithelial cells by down-regulation of D-type cyclins.
2000,
Pubmed
Lynch,
The genetic pathogenesis of colorectal cancer.
2002,
Pubmed
Mallo,
Expression of the Cdx1 and Cdx2 homeotic genes leads to reduced malignancy in colon cancer-derived cells.
1998,
Pubmed
McLin,
Repression of Wnt/beta-catenin signaling in the anterior endoderm is essential for liver and pancreas development.
2007,
Pubmed
,
Xenbase
Okubo,
Hyperactive Wnt signaling changes the developmental potential of embryonic lung endoderm.
2004,
Pubmed
Orsulic,
E-cadherin binding prevents beta-catenin nuclear localization and beta-catenin/LEF-1-mediated transactivation.
1999,
Pubmed
Rawat,
Ectopic expression of the homeobox gene Cdx2 is the transforming event in a mouse model of t(12;13)(p13;q12) acute myeloid leukemia.
2004,
Pubmed
Rings,
Phosphorylation of the serine 60 residue within the Cdx2 activation domain mediates its transactivation capacity.
2001,
Pubmed
Saegusa,
A functional role of Cdx2 in beta-catenin signaling during transdifferentiation in endometrial carcinomas.
2007,
Pubmed
Sampson,
Negative regulation of the Wnt-beta-catenin pathway by the transcriptional repressor HBP1.
2001,
Pubmed
Schneikert,
The canonical Wnt signalling pathway and its APC partner in colon cancer development.
2007,
Pubmed
Silberg,
CDX1 protein expression in normal, metaplastic, and neoplastic human alimentary tract epithelium.
1997,
Pubmed
Soubeyran,
Cdx1 promotes differentiation in a rat intestinal epithelial cell line.
1999,
Pubmed
Stone,
Gut-enriched Krüppel-like factor regulates colonic cell growth through APC/beta-catenin pathway.
2002,
Pubmed
Suh,
A homeodomain protein related to caudal regulates intestine-specific gene transcription.
1994,
Pubmed
Suh,
An intestine-specific homeobox gene regulates proliferation and differentiation.
1996,
Pubmed
Suh,
DNA methylation down-regulates CDX1 gene expression in colorectal cancer cell lines.
2002,
Pubmed
Suzuki,
Epigenetic inactivation of SFRP genes allows constitutive WNT signaling in colorectal cancer.
2004,
Pubmed
Tago,
Inhibition of Wnt signaling by ICAT, a novel beta-catenin-interacting protein.
2000,
Pubmed
,
Xenbase
Van de Wetering,
Extensive alternative splicing and dual promoter usage generate Tcf-1 protein isoforms with differential transcription control properties.
1996,
Pubmed
Witek,
The putative tumor suppressor Cdx2 is overexpressed by human colorectal adenocarcinomas.
2005,
Pubmed
Wong,
Loss of CDX1 expression in colorectal carcinoma: promoter methylation, mutation, and loss of heterozygosity analyses of 37 cell lines.
2004,
Pubmed
Zorn,
Regulation of Wnt signaling by Sox proteins: XSox17 alpha/beta and XSox3 physically interact with beta-catenin.
1999,
Pubmed
,
Xenbase
