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KLF4 Acts as a wt-CFTR Suppressor through an AKT-Mediated Pathway

Cystic Fibrosis (CF) is caused by >2000 mutations in the CF transmembrane conductance regulator (CFTR) gene, but one mutation—F508del—occurs in ~80% of patients worldwide. Besides its main function as an anion channel, the CFTR protein has been implicated in epithelial differentiation, tissue reg...

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Autores principales: Sousa, Luis, Pankonien, Ines, Clarke, Luka A, Silva, Iris, Kunzelmann, Karl, Amaral, Margarida D
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408019/
https://www.ncbi.nlm.nih.gov/pubmed/32630830
http://dx.doi.org/10.3390/cells9071607
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author Sousa, Luis
Pankonien, Ines
Clarke, Luka A
Silva, Iris
Kunzelmann, Karl
Amaral, Margarida D
author_facet Sousa, Luis
Pankonien, Ines
Clarke, Luka A
Silva, Iris
Kunzelmann, Karl
Amaral, Margarida D
author_sort Sousa, Luis
collection PubMed
description Cystic Fibrosis (CF) is caused by >2000 mutations in the CF transmembrane conductance regulator (CFTR) gene, but one mutation—F508del—occurs in ~80% of patients worldwide. Besides its main function as an anion channel, the CFTR protein has been implicated in epithelial differentiation, tissue regeneration, and, when dysfunctional, cancer. However, the mechanisms that regulate such relationships are not fully elucidated. Krüppel-like factors (KLFs) are a family of transcription factors (TFs) playing central roles in development, stem cell differentiation, and proliferation. Herein, we hypothesized that these TFs might have an impact on CFTR expression and function, being its missing link to differentiation. Our results indicate that KLF4 (but not KLF2 nor KLF5) is upregulated in CF vs. non-CF cells and that it negatively regulates wt-CFTR expression and function. Of note, F508del–CFTR expressing cells are insensitive to KLF4 modulation. Next, we investigated which KLF4-related pathways have an effect on CFTR. Our data also show that KLF4 modulates wt-CFTR (but not F508del–CFTR) via both the serine/threonine kinase AKT1 (AKT) and glycogen synthase kinase 3 beta (GSK3β) signaling. While AKT acts positively, GSK3β is a negative regulator of CFTR. This crosstalk between wt-CFTR and KLF4 via AKT/ GSK3β signaling, which is disrupted in CF, constitutes a novel mechanism linking CFTR to the epithelial differentiation.
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spelling pubmed-74080192020-08-12 KLF4 Acts as a wt-CFTR Suppressor through an AKT-Mediated Pathway Sousa, Luis Pankonien, Ines Clarke, Luka A Silva, Iris Kunzelmann, Karl Amaral, Margarida D Cells Article Cystic Fibrosis (CF) is caused by >2000 mutations in the CF transmembrane conductance regulator (CFTR) gene, but one mutation—F508del—occurs in ~80% of patients worldwide. Besides its main function as an anion channel, the CFTR protein has been implicated in epithelial differentiation, tissue regeneration, and, when dysfunctional, cancer. However, the mechanisms that regulate such relationships are not fully elucidated. Krüppel-like factors (KLFs) are a family of transcription factors (TFs) playing central roles in development, stem cell differentiation, and proliferation. Herein, we hypothesized that these TFs might have an impact on CFTR expression and function, being its missing link to differentiation. Our results indicate that KLF4 (but not KLF2 nor KLF5) is upregulated in CF vs. non-CF cells and that it negatively regulates wt-CFTR expression and function. Of note, F508del–CFTR expressing cells are insensitive to KLF4 modulation. Next, we investigated which KLF4-related pathways have an effect on CFTR. Our data also show that KLF4 modulates wt-CFTR (but not F508del–CFTR) via both the serine/threonine kinase AKT1 (AKT) and glycogen synthase kinase 3 beta (GSK3β) signaling. While AKT acts positively, GSK3β is a negative regulator of CFTR. This crosstalk between wt-CFTR and KLF4 via AKT/ GSK3β signaling, which is disrupted in CF, constitutes a novel mechanism linking CFTR to the epithelial differentiation. MDPI 2020-07-02 /pmc/articles/PMC7408019/ /pubmed/32630830 http://dx.doi.org/10.3390/cells9071607 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Sousa, Luis
Pankonien, Ines
Clarke, Luka A
Silva, Iris
Kunzelmann, Karl
Amaral, Margarida D
KLF4 Acts as a wt-CFTR Suppressor through an AKT-Mediated Pathway
title KLF4 Acts as a wt-CFTR Suppressor through an AKT-Mediated Pathway
title_full KLF4 Acts as a wt-CFTR Suppressor through an AKT-Mediated Pathway
title_fullStr KLF4 Acts as a wt-CFTR Suppressor through an AKT-Mediated Pathway
title_full_unstemmed KLF4 Acts as a wt-CFTR Suppressor through an AKT-Mediated Pathway
title_short KLF4 Acts as a wt-CFTR Suppressor through an AKT-Mediated Pathway
title_sort klf4 acts as a wt-cftr suppressor through an akt-mediated pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408019/
https://www.ncbi.nlm.nih.gov/pubmed/32630830
http://dx.doi.org/10.3390/cells9071607
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