ICAT inhibits beta-catenin binding to Tcf/Lef-family transcription factors and the general coactivator p300 using independent structural modules.
In the canonical Wnt signaling pathway, beta-catenin activates target genes through its interactions with Tcf/Lef-family transcription factors and additional transcriptional coactivators. The crystal structure of ICAT, an inhibitor of beta-catenin-mediated transcription, bound to the armadillo repeat domain of beta-catenin, has been determined. ICAT contains an N-terminal helilical domain that binds ... to repeats 11 and 12 of beta-catenin, and an extended C-terminal region that binds to repeats 5-10 in a manner similar to that of Tcfs and other beta-catenin ligands. Full-length ICAT dissociates complexes of beta-catenin, Lef-1, and the transcriptional coactivator p300, whereas the helical domain alone selectively blocks binding to p300. The C-terminal armadillo repeats of beta-catenin may be an attractive target for compounds designed to disrupt aberrant beta-catenin-mediated transcription associated with various cancers.
Mesh Terms:
Amino Acid Sequence, Animals, Cell Cycle Proteins, Crystallography, X-Ray, Cytoskeletal Proteins, DNA-Binding Proteins, E1A-Associated p300 Protein, Genes, Reporter, Humans, Intracellular Signaling Peptides and Proteins, Lymphoid Enhancer-Binding Factor 1, Macromolecular Substances, Mice, Models, Molecular, Molecular Sequence Data, Muscle Proteins, Nuclear Proteins, Protein Binding, Protein Conformation, Protein Structure, Secondary, Protein Structure, Tertiary, Recombinant Fusion Proteins, Repressor Proteins, Sequence Alignment, Trans-Activators, Transcription Factors, Transcription, Genetic, beta Catenin
Amino Acid Sequence, Animals, Cell Cycle Proteins, Crystallography, X-Ray, Cytoskeletal Proteins, DNA-Binding Proteins, E1A-Associated p300 Protein, Genes, Reporter, Humans, Intracellular Signaling Peptides and Proteins, Lymphoid Enhancer-Binding Factor 1, Macromolecular Substances, Mice, Models, Molecular, Molecular Sequence Data, Muscle Proteins, Nuclear Proteins, Protein Binding, Protein Conformation, Protein Structure, Secondary, Protein Structure, Tertiary, Recombinant Fusion Proteins, Repressor Proteins, Sequence Alignment, Trans-Activators, Transcription Factors, Transcription, Genetic, beta Catenin
Mol. Cell
Date: Sep. 01, 2002
PubMed ID: 12408825
View in: Pubmed Google Scholar
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