Beta-catenin-sensitive isoforms of lymphoid enhancer factor-1 are selectively expressed in colon cancer.
Constitutive activation of the Wnt signaling pathway is a root cause of many colon cancers. Activation of this pathway is caused by genetic mutations that stabilize the beta-catenin protein, allowing it to accumulate in the nucleus and form complexes with any member of the lymphoid enhancer factor (LEF1) and T-cell factor (TCF1, TCF3, TCF4) family of transcription factors (referred to collectively as LEF/TCFs) to activate transcription of target genes. Target genes such as MYC, CCND1, MMP7 and TCF7 (refs. 5-9) are normally expressed in colon tissue, so it has been proposed that abnormal expression levels or patterns imposed by beta-catenin/TCF complexes have a role in tumor progression. We report here that LEF1 is a new type of target gene ectopically activated in colon cancer. The pattern of this ectopic expression is unusual because it derives from selective activation of a promoter for a full-length LEF1 isoform that binds beta-catenin, but not a second, intronic promoter that drives expression of a dominant-negative isoform. beta-catenin/TCF complexes can activate the promoter for full-length LEF1, indicating that in cancer high levels of these complexes misregulate transcription to favor a positive feedback loop for Wnt signaling by inducing selective expression of full-length, beta-catenin-sensitive forms of LEF/TCFs.
Hovanes
K
K
Microbiology and Molecular Genetics Department, University of California, Irvine, Irvine, California, USA.
Li
T W
TW
Munguia
J E
JE
Truong
T
T
Milovanovic
T
T
Lawrence Marsh
J
J
Holcombe
R F
RF
Waterman
M L
ML
D003110:Colonic Neoplasms / Q000235:genetics*; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007438:Introns; D051821:Lymphoid Enhancer-Binding Factor 1; D008969:Molecular Sequence Data; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D015398:Signal Transduction; D051822:T Cell Transcription Factor 1; D015534:Trans-Activators; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin
C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C497573:LEF1 protein, human; D051821:Lymphoid Enhancer-Binding Factor 1; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D011518:Proto-Oncogene Proteins; D051822:T Cell Transcription Factor 1; C497576:TCF7 protein, human; D015534:Trans-Activators; D014157:Transcription Factors; D051153:Wnt Proteins; D029961:Zebrafish Proteins; D051176:beta Catenin