Modulation of transcriptional regulation by LEF-1 in response to Wnt-1 signaling and association with beta-catenin.
Wnt signaling is thought to be mediated via interactions between beta-catenin and members of the LEF-1/TCF family of transcription factors. Here we study the mechanism of transcriptional regulation by LEF-1 in response to a Wnt-1 signal under conditions of endogenous beta-catenin in NIH 3T3 cells, and we examine whether association with beta-catenin is obligatory for the function of LEF-1. We find that Wnt-1 signaling confers transcriptional activation potential upon LEF-1 by association with beta-catenin in the nucleus. By mutagenesis, we identified specific residues in LEF-1 important for interaction with beta-catenin, and we delineated two transcriptional activation domains in beta-catenin whose function is augmented in specific association with LEF-1. Finally, we show that a Wnt-1 signal and beta-catenin association are not required for the architectural function of LEF-1 in the regulation of the T-cell receptor alpha enhancer, which involves association of LEF-1 with a different cofactor, ALY. Thus, LEF-1 can assume diverse regulatory functions by association with different proteins.
Howard Hughes Medical Institute, Departments of Microbiology and Biochemistry, University of California, San Francisco, California 94143-0414, USA.
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Hsu
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Galceran
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Grosschedl
D016475:3T3 Cells; D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D019556:COS Cells; D002467:Cell Nucleus / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1; D051379:Mice; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D015534:Trans-Activators; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D051153:Wnt Proteins; D051155:Wnt1 Protein; D029961:Zebrafish Proteins; D051176:beta Catenin
C495270:CTNNB1 protein, human; C495267:CTNNB1 protein, mouse; D003598:Cytoskeletal Proteins; D004268:DNA-Binding Proteins; C497573:LEF1 protein, human; C497574:Lef1 protein, mouse; D051821:Lymphoid Enhancer-Binding Factor 1; D011518:Proto-Oncogene Proteins; D015534:Trans-Activators; D014157:Transcription Factors; C495247:WNT1 protein, human; D051153:Wnt Proteins; D051155:Wnt1 Protein; C495246:Wnt1 protein, mouse; D029961:Zebrafish Proteins; D051176:beta Catenin