The hypoxia-controlled FBXL14 ubiquitin ligase targets SNAIL1 for proteasome degradation
| Autor: | Félix Bonilla, Irene Gómez, Gabriela Valls, Josep Baulida, Rosa Viñas-Castells, Bàrbara Montserrat-Sentís, Víctor M. Díaz, Antonio García de Herreros, Manuel Beltran, José Miguel García |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Small interfering RNA
Proteasome Endopeptidase Complex Ubiquitin-Protein Ligases Blotting Western Down-Regulation Protein degradation Transfection Biochemistry F-box protein Cell Line Small hairpin RNA Glycogen Synthase Kinase 3 Mice Ubiquitin Cell Line Tumor Animals Immunoprecipitation Phosphorylation Molecular Biology Transcription factor Binding Sites Glycogen Synthase Kinase 3 beta biology F-Box Proteins Protein Synthesis Post-Translational Modification and Degradation Twist-Related Protein 1 Ubiquitination Nuclear Proteins Cell Biology Cell Hypoxia Cell biology Ubiquitin ligase Mutation biology.protein NIH 3T3 Cells RNA Interference Snail Family Transcription Factors Protein Binding Transcription Factors |
| Zdroj: | The Journal of biological chemistry. 285(6) |
| ISSN: | 1083-351X |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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