title: STAT3 integrates cooperative Ras and TGF-β signals that induce Snail expression.
abstract: The epithelial-mesenchymal transition (EMT) is a crucial morphological event that occurs during the progression of epithelial tumors. EMT can be induced by transforming growth factor β (TGF-β) in certain kinds of cancer cells through the induction of Snail, a key regulator of EMT. We have previously found that TGF-β remarkably induces Snail expression in cooperation with Ras signals; however, the underlying mechanism of this synergism has not yet been determined. Here, we demonstrate that signal transducer and activator of transcription 3 (STAT3) acts as a mediator that synergizes TGF-β and Ras signals. The overexpression of STAT3 enhanced Snail induction, whereas siRNA-mediated knockdown of STAT3 inhibited it. The STAT3-YF mutant, which has Tyr 705 substituted with Phe, did not enhance Snail induction. Several STAT3 mutants lacking transcriptional activity also failed to enhance it; however, the putative STAT3-binding elements in the Snail promoter regions were not required for STAT3-mediated Snail induction. Protein inhibitor of activated STAT3 (PIAS3) inhibited the enhanced Snail promoter activity induced by TGF-β and Ras. The interaction between PIAS3 and STAT3 was reduced by TGF-β in cells harboring oncogenic Ras, whereas TGF-β promoted the binding of PIAS3 to Smad3, a crucial mediator of TGF-β signaling. Therefore, these findings suggest that STAT3 enhances Snail induction when it is dissociated from PIAS3 by TGF-β in cooperation with Ras signals.
authors.affiliation: Department of Biochemistry, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Saitoh
authors.affiliation: Department of Biochemistry, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Endo
authors.affiliation: Department of Biochemistry, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan.|Research Training Program for Undergraduates, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Furuya
authors.affiliation: Department of Biochemistry, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan.|Research Training Program for Undergraduates, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Minami
authors.affiliation: Department of Biochemistry, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan.
authors.forename: A
authors.initials: A
authors.lastname: Fukasawa
authors.affiliation: Department of Molecular Medicine for Pathogenesis, Ehime University Graduate School of Medicine, Ehime, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Imamura
authors.affiliation: Department of Biochemistry, Interdisciplinary Graduate School of Medicine and Engineering, University of Yamanashi, Chuo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Miyazawa
mesh_terms: D002478:Cells, Cultured; D006367:HeLa Cells; D006801:Humans; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015398:Signal Transduction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: D050796:STAT3 Transcription Factor; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; D018631:ras Proteins