Abstract
We found that one-third of human sebaceous tumors examined had double-nucleotide substitutions in the same LEF1 allele, irrespective of DNA mismatch repair status. The mutations impaired both LEF1 binding to beta-catenin and transcriptional activation, and are the first tumor-associated mutations that inactivate Wnt signaling. Mutant LEF1 not only inhibited expression of beta-catenin target genes but also stimulated expression of sebocyte markers, suggesting that it may determine the differentiated characteristics of sebaceous tumors.
Publication types
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Comparative Study
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenoma / pathology
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Alleles
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Amino Acid Sequence
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Amino Acid Substitution*
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Base Sequence
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Cell Line
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Conserved Sequence
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DNA / analysis
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DNA / genetics
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Gene Expression Regulation, Neoplastic
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Genes, Reporter
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Genetic Markers
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Humans
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Luciferases / analysis
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Luciferases / metabolism
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Lymphoid Enhancer-Binding Factor 1 / analysis
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Lymphoid Enhancer-Binding Factor 1 / genetics*
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Lymphoid Enhancer-Binding Factor 1 / metabolism
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Molecular Sequence Data
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Sebaceous Gland Neoplasms / genetics*
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Sebaceous Gland Neoplasms / metabolism
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Sebaceous Gland Neoplasms / pathology
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Sequence Analysis, DNA
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Sequence Homology, Amino Acid
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Signal Transduction
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Transcription, Genetic
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Transcriptional Activation*
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Wnt Proteins / metabolism
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beta Catenin / analysis
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beta Catenin / genetics
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beta Catenin / metabolism*
Substances
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Genetic Markers
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Lymphoid Enhancer-Binding Factor 1
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Wnt Proteins
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beta Catenin
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DNA
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Luciferases