2. Academic Validation
  3. The hypoxia-controlled FBXL14 ubiquitin ligase targets SNAIL1 for proteasome degradation

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

  • J Biol Chem. 2010 Feb 5;285(6):3794-3805. doi: 10.1074/jbc.M109.065995.
Rosa Viñas-Castells 1,  Manuel Beltran 1,  Gabriela Valls 1,  Irene Gómez 2,  José Miguel García 2,  Bàrbara Montserrat-Sentís 1,  Josep Baulida 1,  Félix Bonilla 2,  Antonio García de Herreros 3,  Víctor M Díaz 4
Affiliations

Affiliations

  • 1 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.
  • 2 the Servicio de Oncologia Médica, Hospital Universitario Puerta de Hierro, E-28222 Majadahonda, Spain, and.
  • 3 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.
  • 4 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.
PMID: 19955572 DOI: 10.1074/jbc.M109.065995
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.

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