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.
Takeda
Hikaru
H
Cancer Research UK London Research Institute, 44 Lincoln's Inn Fields, London WC2A 3PX, UK.
Lyle
Stephen
S
Lazar
Alexander J F
AJ
Zouboulis
Christos C
CC
Smyth
Ian
I
Watt
Fiona M
FM
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