2026-04-14T03:39:47Zhttps://recercat.cat/oai/request

oai:recercat.cat:10230/233462025-12-20T16:51:47Zcom_2072_6col_2072_452952

00925njm 22002777a 4500 dc Viñas Castells, Rosa, 1985- author Frías Hernández, Àlex, 1985- author Robles Lanuza, Estefanía author Zhang, Kun author Longmore, Gregory D author García de Herreros, Antonio author Díaz, Víctor M. author 2015-04-07T09:36:26Z 2015-04-07T09:36:26Z 2014 The zinc finger transcription factor Snail1 regulates epithelial to mesenchymal transition, repressing epithelial markers and activating mesenchymal genes. Snail1 is an extremely labile protein degraded by the cytoplasmic ubiquitin-ligases β-TrCP1/FBXW1 and Ppa/FBXL14. Using a short hairpin RNA screening, we have identified FBXL5 as a novel Snail1 ubiquitin ligase. FBXL5 is located in the nucleus where it interacts with Snail1 promoting its polyubiquitination and affecting Snail1 protein stability and function by impairing DNA binding. Snail1 downregulation by FBXL5 is prevented by Lats2, a protein kinase that phosphorylates Snail1 precluding its nuclear export but not its polyubiquitination. Actually, although polyubiquitination by FBXL5 takes place in the nucleus, Snail1 is degraded in the cytosol. Finally, FBXL5 is highly sensitive to stress conditions and is downregulated by iron depletion and γ-irradiation, explaining Snail1 stabilization in these conditions. These results characterize a novel nuclear ubiquitin ligase controlling Snail1 protein stability and provide the molecular basis for understanding how radiotherapy upregulates the epithelial to mesenchymal transition-inducer Snail1. Fundación Científica de la Asociación Española contra el Cáncer, the Ministerio de Ciencia y Tecnología [SAF2010-16089] and Fundació La Marató de TV3 (to A.G.H.); The authors also acknowledge support from ISCIII/FEDER [RD06/0020/0040] and Generalitat de Catalunya [2009SGR867]; a predoctoral fellowship from ISCIII (to R.V.-C.). Funding for open access charge: Ministerio de Ciencia y Tecnología [SAF2010-16089]. Nuclis cel·lulars Proteïnes Metabolisme -- Regulació Nuclear ubiquitination by FBXL5 modulates Snail1 DNA binding and stability