miR-200b downregulates CFTR during hypoxia in human lung epithelial cells

Bartoszewska, Sylwia; Kamysz, Wojciech; Jakieła, Bogdan; Sanak, Marek; Króliczewski, Jarosław; Bebök, Zsuzsa; Bartoszewski, Rafał; Collawn, James F.

doi:10.1186/s11658-017-0054-0

Cited by 45 publications

(40 citation statements)

References 30 publications

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“…Additionally, miR-145 has been shown to mediate TGF-β inhibition of CFTR function and knockdown of miR-145 restored Phe508del function in human primary epithelial cells [66]. Likewise, miR-200b reduces CFTR during prolonged hypoxia, although inhibition of miR-200b also rescues CFTR mRNA levels in primary bronchial epithelial cells [67]. These studies lend further support to the strategy of manipulating microRNAs or their target genes to enhance CFTR expression or alleviate symptoms associated with CF.…”

Section: Non-coding Rna Profilingmentioning

confidence: 68%

Transcriptomic and Proteostasis Networks of CFTR and the Development of Small Molecule Modulators for the Treatment of Cystic Fibrosis Lung Disease

Strub

McCray

2020

Genes

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Cystic fibrosis (CF) is a lethal autosomal recessive disease caused by mutations in the CF transmembrane conductance regulator (CFTR) gene. The diversity of mutations and the multiple ways by which the protein is affected present challenges for therapeutic development. The observation that the Phe508del-CFTR mutant protein is temperature sensitive provided proof of principle that mutant CFTR could escape proteosomal degradation and retain partial function. Several specific protein interactors and quality control checkpoints encountered by CFTR during its proteostasis have been investigated for therapeutic purposes, but remain incompletely understood. Furthermore, pharmacological manipulation of many CFTR interactors has not been thoroughly investigated for the rescue of Phe508del-CFTR. However, high-throughput screening technologies helped identify several small molecule modulators that rescue CFTR from proteosomal degradation and restore partial function to the protein. Here, we discuss the current state of CFTR transcriptomic and biogenesis research and small molecule therapy development. We also review recent progress in CFTR proteostasis modulators and discuss how such treatments could complement current FDA-approved small molecules.

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Section: Non-coding Rna Profilingmentioning

confidence: 68%

Transcriptomic and Proteostasis Networks of CFTR and the Development of Small Molecule Modulators for the Treatment of Cystic Fibrosis Lung Disease

Strub

McCray

2020

Genes

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“…In this context, KLF5 maintains epithelial characteristics by transcriptionally activating miR-200 family member in epithelial cells [45]. Interestingly miR-200b was recently shown to down-regulate CFTR expression during hypoxia [46], suggesting an additional pathway for repression of CFTR by KLF5.…”

Section: Discussionmentioning

confidence: 99%

A transcription factor network represses CFTR gene expression in airway epithelial cells

Mutolo

Leir

Fossum

et al. 2018

Biochemical Journal

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Mutations in the cystic fibrosis transmembrane conductance regulator () gene cause the inherited disorder cystic fibrosis (CF). Lung disease is the major cause of CF morbidity, though expression levels are substantially lower in the airway epithelium than in pancreatic duct and intestinal epithelia, which also show compromised function in CF. Recently developed small molecule therapeutics for CF are highly successful for one specific mutation and have a positive impact on others. However, the low abundance of transcripts in the airway limits the opportunity for drugs to correct the defective substrate. Elucidation of the transcriptional mechanisms for the locus has largely focused on intragenic and intergenic tissue-specific enhancers and their activating -factors. Here, we investigate whether the low CFTR levels in the airway epithelium result from the recruitment of repressive proteins directly to the locus. Using an siRNA screen to deplete ∼1500 transcription factors (TFs) and associated regulatory proteins in Calu-3 lung epithelial cells, we identified nearly 40 factors that upon depletion elevated CFTR mRNA levels more than 2-fold. A subset of these TFs was validated in primary human bronchial epithelial cells. Among the strongest repressors of airway expression of were Krüppel-like factor 5 and Ets homologous factor, both of which have pivotal roles in the airway epithelium. Depletion of these factors, which are both recruited to an airway-selective -regulatory element at -35 kb from the promoter, improved CFTR production and function, thus defining novel therapeutic targets for enhancement of CFTR.

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“…We used TaqMan One-Step Real-Time PCR Master Mix Reagents (Thermo Fisher Scientific) as previously described (25,26) using the manufacturer's protocol (retrotranscription: 15 min, 48°C). The relative expressions were calculated using the 2 2DDCt method (27) with the TATA-binding protein (TBP) and 18S rRNA genes as reference genes for the mRNA.…”

Section: Measurement Of Mrna Quantitative Real-time Pcrmentioning

confidence: 99%

Primary endothelial cell–specific regulation of hypoxia‐inducible factor (HIF)‐1 and HIF‐2 and their target gene expression profiles during hypoxia

et al. 2019

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During hypoxia, a cellular adaptive response activates hypoxia‐inducible factors (HIFs; HIF‐1 and HIF‐2) that respond to low tissue‐oxygen levels and induce the expression of a number of genes that promote angiogenesis, energy metabolism, and cell survival. HIF‐1 and HIF‐2 regulate endothelial cell (EC) adaptation by activating genesignaling cascades that promote endothelial migration, growth, and differentiation. An HIF‐1 to HIF‐2 transition or switch governs this process from acute to prolonged hypoxia. In the present study, we evaluated the mechanisms governing the HIF switch in 10 different primary human ECs from different vascular beds during the early stages of hypoxia. The studies demonstrate that the switch from HIF‐1 to HIF‐2 constitutes a universal mechanism of cellular adaptation to hypoxic stress and that HIF1A and HIF2A mRNA stability differences contribute to HIF switch. Furthermore, using 4 genome‐wide mRNA expression arrays of HUVECs during normoxia and after 2, 8, and 16 h of hypoxia, we show using bioinformatics analyses that, although a number of genes appeared to be regulated exclusively by HIF‐1 or HIF‐2, the largest number of genes appeared to be regulated by both.—Bartoszewski, R., Moszynska, A., Serocki, M., Cabaj, A., Polten, A., Ochocka, R., Dell'Italia, L., Bartoszewska, S., Króliczewski, J., Dabrowski, M., Collawn, J. F. Primary endothelial cell–specific regulation of hypoxia‐inducible factor (HIF)‐1 and HIF‐2 and their target gene expression profiles during hypoxia. FASEB J. 33, 7929–7941 (2019). http://www.fasebj.org

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miR-200b downregulates CFTR during hypoxia in human lung epithelial cells

Cited by 45 publications

References 30 publications

Transcriptomic and Proteostasis Networks of CFTR and the Development of Small Molecule Modulators for the Treatment of Cystic Fibrosis Lung Disease

Transcriptomic and Proteostasis Networks of CFTR and the Development of Small Molecule Modulators for the Treatment of Cystic Fibrosis Lung Disease

A transcription factor network represses CFTR gene expression in airway epithelial cells

Primary endothelial cell–specific regulation of hypoxia‐inducible factor (HIF)‐1 and HIF‐2 and their target gene expression profiles during hypoxia

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