Abstract
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.
Publication types
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Research Support, U.S. Gov't, Non-P.H.S.
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Adaptor Proteins, Signal Transducing
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Amino Acid Sequence
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Animals
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Cell Cycle Proteins*
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Crystallography, X-Ray
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Cytoskeletal Proteins / chemistry
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Cytoskeletal Proteins / genetics
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Cytoskeletal Proteins / metabolism*
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DNA-Binding Proteins / metabolism*
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E1A-Associated p300 Protein
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Genes, Reporter
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Humans
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Intracellular Signaling Peptides and Proteins
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Lymphoid Enhancer-Binding Factor 1
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Macromolecular Substances
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Mice
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Models, Molecular
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Molecular Sequence Data
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Muscle Proteins / chemistry
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Muscle Proteins / genetics
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Muscle Proteins / metabolism*
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Nuclear Proteins / metabolism*
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Protein Binding
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Protein Conformation
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Protein Structure, Secondary
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Protein Structure, Tertiary
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Recombinant Fusion Proteins / genetics
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Recombinant Fusion Proteins / metabolism
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Repressor Proteins*
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Sequence Alignment
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Trans-Activators / metabolism*
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Transcription Factors / metabolism*
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Transcription, Genetic
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beta Catenin
Substances
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Adaptor Proteins, Signal Transducing
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CTNNB1 protein, human
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CTNNB1 protein, mouse
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CTNNBIP1 protein, human
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Cell Cycle Proteins
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Ctnnbip1 protein, mouse
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Cytoskeletal Proteins
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DNA-Binding Proteins
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Intracellular Signaling Peptides and Proteins
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LEF1 protein, human
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Lef1 protein, mouse
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Lymphoid Enhancer-Binding Factor 1
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Macromolecular Substances
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Muscle Proteins
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Nuclear Proteins
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Recombinant Fusion Proteins
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Repressor Proteins
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Trans-Activators
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Transcription Factors
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beta Catenin
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E1A-Associated p300 Protein
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Ep300 protein, mouse