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Nuclear ubiquitination by FBXL5 modulates Snail1 DNA binding and stability
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 scre...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2014
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3902928/ https://www.ncbi.nlm.nih.gov/pubmed/24157836 http://dx.doi.org/10.1093/nar/gkt935 |
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author | Viñas-Castells, Rosa Frías, Álex Robles-Lanuza, Estefanía Zhang, Kun Longmore, Gregory D. García de Herreros, Antonio Díaz, Víctor M. |
author_facet | Viñas-Castells, Rosa Frías, Álex Robles-Lanuza, Estefanía Zhang, Kun Longmore, Gregory D. García de Herreros, Antonio Díaz, Víctor M. |
author_sort | Viñas-Castells, Rosa |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-3902928 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2014 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-39029282014-01-27 Nuclear ubiquitination by FBXL5 modulates Snail1 DNA binding and stability Viñas-Castells, Rosa Frías, Álex Robles-Lanuza, Estefanía Zhang, Kun Longmore, Gregory D. García de Herreros, Antonio Díaz, Víctor M. Nucleic Acids Res Molecular Biology 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. Oxford University Press 2014-01 2013-10-23 /pmc/articles/PMC3902928/ /pubmed/24157836 http://dx.doi.org/10.1093/nar/gkt935 Text en © The Author(s) 2013. Published by Oxford University Press. http://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Molecular Biology Viñas-Castells, Rosa Frías, Álex Robles-Lanuza, Estefanía Zhang, Kun Longmore, Gregory D. García de Herreros, Antonio Díaz, Víctor M. Nuclear ubiquitination by FBXL5 modulates Snail1 DNA binding and stability |
title | Nuclear ubiquitination by FBXL5 modulates Snail1 DNA binding and stability |
title_full | Nuclear ubiquitination by FBXL5 modulates Snail1 DNA binding and stability |
title_fullStr | Nuclear ubiquitination by FBXL5 modulates Snail1 DNA binding and stability |
title_full_unstemmed | Nuclear ubiquitination by FBXL5 modulates Snail1 DNA binding and stability |
title_short | Nuclear ubiquitination by FBXL5 modulates Snail1 DNA binding and stability |
title_sort | nuclear ubiquitination by fbxl5 modulates snail1 dna binding and stability |
topic | Molecular Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3902928/ https://www.ncbi.nlm.nih.gov/pubmed/24157836 http://dx.doi.org/10.1093/nar/gkt935 |
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