title: The hypoxia-controlled FBXL14 ubiquitin ligase targets SNAIL1 for proteasome degradation.
abstract: The transcription factor SNAIL1 is a master regulator of epithelial to mesenchymal transition. SNAIL1 is a very unstable protein, and its levels are regulated by the E3 ubiquitin ligase beta-TrCP1 that interacts with SNAIL1 upon its phosphorylation by GSK-3beta. Here we show that SNAIL1 polyubiquitylation and degradation may occur in conditions precluding SNAIL1 phosphorylation by GSK-3beta, suggesting that additional E3 ligases participate in the control of SNAIL1 protein stability. In particular, we demonstrate that the F-box E3 ubiquitin ligase FBXl14 interacts with SNAIL1 and promotes its ubiquitylation and proteasome degradation independently of phosphorylation by GSK-3beta. In vivo, inhibition of FBXl14 using short hairpin RNA stabilizes both ectopically expressed and endogenous SNAIL1. Moreover, the expression of FBXl14 is potently down-regulated during hypoxia, a condition that increases the levels of SNAIL1 protein but not SNAIL1 mRNA. FBXL14 mRNA is decreased in tumors with a high expression of two proteins up-regulated in hypoxia, carbonic anhydrase 9 and TWIST1. In addition, Twist1 small interfering RNA prevents hypoxia-induced Fbxl14 down-regulation and SNAIL1 stabilization in NMuMG cells. Altogether, these results demonstrate the existence of an alternative mechanism controlling SNAIL1 protein levels relevant for the induction of SNAIL1 during hypoxia.
authors: From the Programa de Recerca en Càncer, Institut Municipal d'Investigació Mèdica, Hospital del Mar, Parc de Recerca Biomèdica de Barcelona, Doctor Aiguader 88, E-08003 Barcelona, Spain.
authors: Rosa
authors: R
authors: Viñas-Castells
authors: From the Programa de Recerca en Càncer, Institut Municipal d'Investigació Mèdica, Hospital del Mar, Parc de Recerca Biomèdica de Barcelona, Doctor Aiguader 88, E-08003 Barcelona, Spain.
authors: Manuel
authors: M
authors: Beltran
authors: From the Programa de Recerca en Càncer, Institut Municipal d'Investigació Mèdica, Hospital del Mar, Parc de Recerca Biomèdica de Barcelona, Doctor Aiguader 88, E-08003 Barcelona, Spain.
authors: Gabriela
authors: G
authors: Valls
authors: the Servicio de Oncologia Médica, Hospital Universitario Puerta de Hierro, E-28222 Majadahonda, Spain, and.
authors: Irene
authors: I
authors: Gómez
authors: the Servicio de Oncologia Médica, Hospital Universitario Puerta de Hierro, E-28222 Majadahonda, Spain, and.
authors: José Miguel
authors: JM
authors: García
authors: From the Programa de Recerca en Càncer, Institut Municipal d'Investigació Mèdica, Hospital del Mar, Parc de Recerca Biomèdica de Barcelona, Doctor Aiguader 88, E-08003 Barcelona, Spain.
authors: Bàrbara
authors: B
authors: Montserrat-Sentís
authors: From the Programa de Recerca en Càncer, Institut Municipal d'Investigació Mèdica, Hospital del Mar, Parc de Recerca Biomèdica de Barcelona, Doctor Aiguader 88, E-08003 Barcelona, Spain.
authors: Josep
authors: J
authors: Baulida
authors: the Servicio de Oncologia Médica, Hospital Universitario Puerta de Hierro, E-28222 Majadahonda, Spain, and.
authors: Félix
authors: F
authors: Bonilla
authors: From the Programa de Recerca en Càncer, Institut Municipal d'Investigació Mèdica, Hospital del Mar, Parc de Recerca Biomèdica de Barcelona, Doctor Aiguader 88, E-08003 Barcelona, Spain; the Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, E-08003 Barcelona, Spain. Electronic address: agarcia@imim.es.
authors: Antonio García
authors: AG
authors: de Herreros
authors: From the Programa de Recerca en Càncer, Institut Municipal d'Investigació Mèdica, Hospital del Mar, Parc de Recerca Biomèdica de Barcelona, Doctor Aiguader 88, E-08003 Barcelona, Spain; the Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, E-08003 Barcelona, Spain. Electronic address: vdiaz@imim.es.
authors: Víctor M
authors: VM
authors: Díaz
mesh_terms: D000818:Animals; D001665:Binding Sites; D015153:Blotting, Western; D015687:Cell Hypoxia; D002460:Cell Line; D045744:Cell Line, Tumor; D015536:Down-Regulation; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D047468:Immunoprecipitation; D051379:Mice; D009154:Mutation; D041681:NIH 3T3 Cells; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D034622:RNA Interference; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D044783:F-Box Proteins; C547521:FBXL14 protein, human; D009687:Nuclear Proteins; C000604407:SNAI1 protein, human; C000604429:Snai1 protein, mouse; D000071250:Snail Family Transcription Factors; C103173:TWIST1 protein, human; D014157:Transcription Factors; D051879:Twist-Related Protein 1; C067250:Twist1 protein, mouse; D044767:Ubiquitin-Protein Ligases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D038362:Glycogen Synthase Kinase 3; D046988:Proteasome Endopeptidase Complex