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


ABSTRACT: 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 (GSK3?) signaling. While AKT acts positively, GSK3? is a negative regulator of CFTR. This crosstalk between wt-CFTR and KLF4 via AKT/ GSK3? signaling, which is disrupted in CF, constitutes a novel mechanism linking CFTR to the epithelial differentiation.

SUBMITTER: Sousa L 

PROVIDER: S-EPMC7408019 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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

Sousa Luis L   Pankonien Ines I   Clarke Luka A LA   Silva Iris I   Kunzelmann Karl K   Amaral Margarida D MD  

Cells 20200702 7


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) play  ...[more]

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