{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,12]],"date-time":"2025-10-12T03:01:00Z","timestamp":1760238060583,"version":"build-2065373602"},"reference-count":55,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2020,7,2]],"date-time":"2020-07-02T00:00:00Z","timestamp":1593648000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001871","name":"Funda\u00e7\u00e3o para a Ci\u00eancia e a Tecnologia","doi-asserted-by":"publisher","award":["PTDC\/BIM-MEC\/2131\/2014","SFRH\/BD\/106087\/2015","UIDB\/04046\/2020","UIDP\/04046\/2020"],"award-info":[{"award-number":["PTDC\/BIM-MEC\/2131\/2014","SFRH\/BD\/106087\/2015","UIDB\/04046\/2020","UIDP\/04046\/2020"]}],"id":[{"id":"10.13039\/501100001871","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000292","name":"Cystic Fibrosis Trust","doi-asserted-by":"publisher","award":["SRC 013"],"award-info":[{"award-number":["SRC 013"]}],"id":[{"id":"10.13039\/501100000292","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100012623","name":"Federation of European Biochemical Societies","doi-asserted-by":"publisher","award":["Short term fellowship"],"award-info":[{"award-number":["Short term fellowship"]}],"id":[{"id":"10.13039\/100012623","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Cystic Fibrosis (CF) is caused by &gt;2000 mutations in the CF transmembrane conductance regulator (CFTR) gene, but one mutation\u2014F508del\u2014occurs 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. Kr\u00fcppel-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\u2013CFTR 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\u2013CFTR) via both the serine\/threonine kinase AKT1 (AKT) and glycogen synthase kinase 3 beta (GSK3\u03b2) signaling. While AKT acts positively, GSK3\u03b2 is a negative regulator of CFTR. This crosstalk between wt-CFTR and KLF4 via AKT\/ GSK3\u03b2 signaling, which is disrupted in CF, constitutes a novel mechanism linking CFTR to the epithelial differentiation.<\/jats:p>","DOI":"10.3390\/cells9071607","type":"journal-article","created":{"date-parts":[[2020,7,6]],"date-time":"2020-07-06T09:49:11Z","timestamp":1594028951000},"page":"1607","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["KLF4 Acts as a wt-CFTR Suppressor through an AKT-Mediated Pathway"],"prefix":"10.3390","volume":"9","author":[{"given":"Luis","family":"Sousa","sequence":"first","affiliation":[{"name":"BioISI \u2013 Biosystems &amp; Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal"}]},{"given":"Ines","family":"Pankonien","sequence":"additional","affiliation":[{"name":"BioISI \u2013 Biosystems &amp; Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal"}]},{"given":"Luka A","family":"Clarke","sequence":"additional","affiliation":[{"name":"BioISI \u2013 Biosystems &amp; Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8062-5558","authenticated-orcid":false,"given":"Iris","family":"Silva","sequence":"additional","affiliation":[{"name":"BioISI \u2013 Biosystems &amp; Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6222-4593","authenticated-orcid":false,"given":"Karl","family":"Kunzelmann","sequence":"additional","affiliation":[{"name":"Department of Physiology, University of Regensburg, 93053 Regensburg, Germany"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0828-8630","authenticated-orcid":false,"given":"Margarida D","family":"Amaral","sequence":"additional","affiliation":[{"name":"BioISI \u2013 Biosystems &amp; Integrative Sciences Institute, Faculty of Sciences, University of Lisbon, 1749-016 Lisbon, Portugal"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,2]]},"reference":[{"unstructured":"Zolin, A., Orenti, A., Naehrlich, L., and van Rens, J. 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