The hypoxia-controlled FBXL14 ubiquitin ligase targets SNAIL1 for proteasome degradation

Rosa Viñas-Castells, Manuel Beltran, Gabriela Valls, Irene Gómez, José Miguel García, Bàrbara Montserrat-Sentís, Josep Baulida, Félix Bonilla, Antonio García De Herreros, Víctor M. Díaz

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    111 Citations (Scopus)

    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 β-TrCP1 that interacts with SNAIL1 upon its phosphorylation by GSK-3β. Here we show that SNAIL1 polyubiquitylation and degradation may occur in conditions precluding SNAIL1 phosphorylation by GSK-3β, 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-3β. 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. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
    Original languageEnglish
    Pages (from-to)3794-3805
    JournalJournal of Biological Chemistry
    Volume285
    Issue number6
    DOIs
    Publication statusPublished - 5 Feb 2010

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