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Lymphoid Enhancer Factor 1 Makes Cells Resistant to Transforming Growth Factor ß-induced Repression of c-myc¹

Departments of Biochemistry [T. S., H. S., K. Y., M. F., K. M., M. K.] and Cell Biology [R. Y., S. S., T. N.], The Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo 170-8455, Japan; Department of Molecular Pathology, Graduate School of Medicine, University of Tokyo, Tokyo 113-0033, Japan [H. S., K. M.]; Institute of Basic Medical Sciences, University of Tsukuba, Ibaraki 305-8575, Japan [M. K.]; and Department of Urology, Graduate School of Medicine, Tohoku University, Sendai 980-8574, Japan [Y. A.]

The activation of lymphoid enhancer factor (LEF)/T-cell factor (TCF)-mediated transcription by sustained expression of ß-catenin and the loss of transforming growth factor ß (TGF-ß) signaling are essential steps in carcinogenesis, particularly for cancers of the colon, breast, and liver. The oncogene c-myc is a common target of both of these signaling pathways and a key regulator of cell cycle progression. Here we have identified a novel LEF/TCF-responsive element in the promoter of the human c-myc gene. ß-Catenin activated the transcriptional activity of the c-myc promoter by binding to this element in various cell lines. When TCF-4 was bound to this element, TGF-ß dissociated ß-catenin and repressed the transcriptional activity of the c-myc promoter. However, TGF-ß could not dissociate ß-catenin and could not repress c-myc transcription when LEF-1 was bound to the element instead of TCF-4. These findings suggest that enhanced expression of LEF-1, which occurs frequently in colon cancer, may make cells refractory to the down-regulation of c-myc and the subsequent growth arrest induced by TGF-ß.

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