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Biochem Biophys Res Commun. 1999 Mar 24;256(3):584-90.

Identification of Tcf4 residues involved in high-affinity beta-catenin binding.

Author information

1
Department of Cancer Research, Merck Research Laboratories, Sumneytown Pike, West Point, Pennsylvania, 19486, USA. chuck_omer@merck.com

Abstract

The N-termini of members of the T-cell factor (Tcf) and lymphocyte-enhancement factor (Lef) protein families bind to beta-catenin, forming bipartite transcription factors which regulate expression of genes involved in organismal development and the growth of normal and malignant colon epithelium. Elevated levels of Tcf4:beta-catenin are found in colon tumor cells with mutations in the adenomatous polyposis coli (APC) gene. The elevated levels of Tcf4:beta-catenin result in increased transcription of genes, including c-myc, important for the growth of these tumor cells. Here we analyze the interaction between beta-catenin and Tcf4 and show that the N-terminal 53 amino acids of Tcf4 bind with high affinity to beta-catenin. We show that this high-affinity interaction involves multiple contact points including Tcf4 Asp-16, which is essential for beta-catenin binding. In addition to Tcf/Lef family members, beta-catenin binds to APC and cadherins. We found that the binding of beta-catenin to Tcf4, APC, or E-cadherin was mutually exclusive. These results are discussed with regard to how beta-catenin interacts with its binding partners and to the potential for identifying specific, small molecule inhibitors of these interactions.

PMID:
10080941
DOI:
10.1006/bbrc.1999.0379
[Indexed for MEDLINE]

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