TGF-beta induces novel Lef-1 splice variants through a Smad-independent signaling pathway.
The lymphoid enhancer-binding factor (Lef-1) transcription factor is best known for the ability to transduce Wnt signals during development and to mediate excessive Wnt signaling in certain types of cancer. We recently identified and characterized a novel Wnt-like effect of transforming growth factor-beta (TGF-beta) on beta-catenin, the binding partner of Lef-1. Therefore, we sought to determine the effect of TGF-beta on expression of the Lef/T-cell-specific transcription factor (TCF) components of the Wnt pathway. We found that TGF-beta markedly induced Lef-1 mRNA expression in cell lines originating from fetal lung (Mv1Lu) and newborn skin (Balb/MK), tissues that normally express Lef-1 during development. Lef-1 induction was temporally related to but independent of TGF-beta-induced G1 cell cycle arrest. Furthermore, the induction of Lef-1 was independent of both new protein synthesis and Smad-mediated signaling. Using TGF-beta-treated Mv1Lu cells, we identified multiple splice forms of Lef-1, including novel variants that lack both exons 2 and 3. We conclude that the induction of Lef-1 has permissive effects on the well-characterized TGF-beta signal that inhibits c-myc expression and induces a G1 arrest.
Cordray
Pauline
P
University of Utah, Huntsman Cancer Institute, Salt Lake City, Utah, USA.
Satterwhite
Daniel J
DJ
D017398:Alternative Splicing / Q000187:drug effects / Q000235:genetics; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051821:Lymphoid Enhancer-Binding Factor 1; D051379:Mice; D008907:Mink / Q000502:physiology*; D008969:Molecular Sequence Data; D020033:Protein Isoforms / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D004268:DNA-Binding Proteins; C497573:LEF1 protein, human; C497574:Lef1 protein, mouse; C497575:Lef1 protein, rat; D051821:Lymphoid Enhancer-Binding Factor 1; D020033:Protein Isoforms; D051785:Smad Proteins; D015534:Trans-Activators; D014157:Transcription Factors; D016212:Transforming Growth Factor beta