title: IKK(α) controls canonical TGF(ß)-SMAD signaling to regulate genes expressing SNAIL and SLUG during EMT in panc1 cells.
abstract: The epithelial to mesenchymal transition (EMT) is a crucial step in tumor progression, and the TGFβ-SMAD signaling pathway is an inductor of EMT in many tumor types. One hallmark of EMT is downregulation of the adherens junction protein E-cadherin, a process mediated by transcription factors such as the zinc fingers SNAIL and SLUG. Here, we report that the catalytic IκB kinase (IKK) subunit IKKα is necessary for the silencing of E-cadherin in a Panc1 cell model of TGFβ-SMAD-mediated EMT, independently of NFκB. IKKα regulates canonical TGFβ-SMAD signaling by interacting with SMAD3 and controlling SMAD complex formation on DNA. Furthermore, we demonstrate that the TGFβ-IKKα-SMAD signaling pathway induces transcription of the genes encoding SNAIL and SLUG. In addition, we demonstrate that IKKα also modulates canonical TGFβ-SMAD signaling in human MDA-MB231 breast cancer cells, arguing for a more general impact of IKKα on the control of TGFβ-SMAD signaling. Taken together, these findings indicate that IKKα contributes to the tumor-promoting function of the TGFβ-SMAD signaling pathway in particular cancers.
authors.affiliation: II. Medizinische Klinik, Technische Universität München, Ismaninger Strasse 22, 81675 München, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Brandl
authors.forename: Barbara
authors.initials: B
authors.lastname: Seidler
authors.forename: Ferdinand
authors.initials: F
authors.lastname: Haller
authors.forename: Jerzy
authors.initials: J
authors.lastname: Adamski
authors.forename: Roland M
authors.initials: RM
authors.lastname: Schmid
authors.forename: Dieter
authors.initials: D
authors.lastname: Saur
authors.forename: Günter
authors.initials: G
authors.lastname: Schneider
mesh_terms: D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006801:Humans; D051550:I-kappa B Kinase / Q000378:metabolism*; D008954:Models, Biological; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D051785:Smad Proteins / Q000378:metabolism*; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
chemical_list: D015820:Cadherins; C000604407:SNAI1 protein, human; D051785:Smad Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D016212:Transforming Growth Factor beta; C496559:CHUK protein, human; D051550:I-kappa B Kinase