Synergy between tumor suppressor APC and the beta-catenin-Tcf4 target Tcf1.
Mutations in APC or beta-catenin inappropriately activate the transcription factor Tcf4, thereby transforming intestinal epithelial cells. Here it is shown that one of the target genes of Tcf4 in epithelial cells is Tcf1. The most abundant Tcf1 isoforms lack a beta-catenin interaction domain. Tcf1(-/-) mice develop adenomas in the gut and mammary glands. Introduction of a mutant APC allele into these mice substantially increases the number of these adenomas. Tcf1 may act as a feedback repressor of beta-catenin-Tcf4 target genes and thus may cooperate with APC to suppress malignant transformation of epithelial cells.
Roose
J
J
Department of Immunology and Center for Biomedical Genetics, Department of Pathology, University Medical Center Utrecht, Post Office Box 85500, 3508 GA Utrecht, Netherlands.
Huls
G
G
van Beest
M
M
Moerer
P
P
van der Horn
K
K
Goldschmeding
R
R
Logtenberg
T
T
Clevers
H
H
D000236:Adenoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D025601:Adenomatous Polyposis Coli Protein; D000818:Animals; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D016147:Genes, Tumor Suppressor; D051538:Hepatocyte Nuclear Factor 1-alpha; D006801:Humans; D007414:Intestinal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051821:Lymphoid Enhancer-Binding Factor 1; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic; D051822:T Cell Transcription Factor 1; D051820:TCF Transcription Factors; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism*; D014162:Transfection; D014407:Tumor Cells, Cultured; D051176:beta Catenin
D025601:Adenomatous Polyposis Coli Protein; C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; D051538:Hepatocyte Nuclear Factor 1-alpha; C496488:Hnf1a protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D009363:Neoplasm Proteins; D051822:T Cell Transcription Factor 1; D051820:TCF Transcription Factors; C497576:TCF7 protein, human; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D051176:beta Catenin