Human sebaceous tumors harbor inactivating mutations in LEF1.
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.
Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Hikaru
H
Takeda
Stephen
S
Lyle
Alexander J F
AJ
Lazar
Christos C
CC
Zouboulis
Ian
I
Smyth
Fiona M
FM
Watt
D000236:Adenoma / Q000473:pathology; D000483:Alleles; D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D002460:Cell Line; D017124:Conserved Sequence; D004247:DNA / Q000032:analysis / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D017930:Genes, Reporter; D005819:Genetic Markers; D006801:Humans; D008156:Luciferases / Q000032:analysis / Q000378:metabolism; D051821:Lymphoid Enhancer-Binding Factor 1 / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D008969:Molecular Sequence Data; D012626:Sebaceous Gland Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D017422:Sequence Analysis, DNA; D017386:Sequence Homology, Amino Acid; D015398:Signal Transduction; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000032:analysis / Q000235:genetics / Q000378:metabolism*
D005819:Genetic Markers; D051821:Lymphoid Enhancer-Binding Factor 1; D051153:Wnt Proteins; D051176:beta Catenin; D004247:DNA; D008156:Luciferases