Lymphoid enhancer factor 1 makes cells resistant to transforming growth factor beta-induced repression of c-myc.
The activation of lymphoid enhancer factor (LEF)/T-cell factor (TCF)-mediated transcription by sustained expression of beta-catenin and the loss of transforming growth factor beta (TGF-beta) 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. beta-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-beta dissociated beta-catenin and repressed the transcriptional activity of the c-myc promoter. However, TGF-beta could not dissociate beta-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-beta.
Sasaki
Toru
T
Department of Biochemistry, The Cancer Institute of the Japanese Foundation for Cancer Research, Tokyo 170-8455, Japan.
Suzuki
Hiroyuki
H
Yagi
Ken
K
Furuhashi
Masao
M
Yao
Ryoji
R
Susa
Shinji
S
Noda
Tetsuo
T
Arai
Yoichi
Y
Miyazono
Kohei
K
Kato
Mitsuyasu
M
D016475:3T3 Cells; D000818:Animals; D019556:COS Cells; D002522:Chlorocebus aethiops; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D016259:Genes, myc / Q000235:genetics*; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1; D051379:Mice; D011401:Promoter Regions, Genetic; D015398:Signal Transduction; D051900:Smad3 Protein; D051820:TCF Transcription Factors; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015533:Transcriptional Activation / Q000187:drug effects / Q000502:physiology; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D015854:Up-Regulation; 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; C497790:SMAD3 protein, human; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051820:TCF Transcription Factors; C544894:TCF7L2 protein, human; C544895:Tcf7l2 protein, mouse; D015534:Trans-Activators; D058118:Transcription Factor 7-Like 2 Protein; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D051176:beta Catenin