International journal of molecular sciences, 2019-10, Vol.20 (19), p.4933
2019
Volltextzugriff (PDF)
Details
- Autor(en) / Beteiligte
- Titel
- Transforming Growth Factor-β1 Selectively Recruits microRNAs to the RNA-Induced Silencing Complex and Degrades CFTR mRNA under Permissive Conditions in Human Bronchial Epithelial Cells
- Ist Teil von
- International journal of molecular sciences, 2019-10, Vol.20 (19), p.4933
- Ort / Verlag
- Switzerland: MDPI AG
- Erscheinungsjahr
- 2019
- Quelle
- Free E-Journal (出版社公開部分のみ）
- Beschreibungen/Notizen
- Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene lead to cystic fibrosis (CF). The most common mutation F508del inhibits folding and processing of CFTR protein. FDA-approved correctors rescue the biosynthetic processing of F508del-CFTR protein, while potentiators improve the rescued CFTR channel function. Transforming growth factor (TGF-β1), overexpressed in many CF patients, blocks corrector/potentiator rescue by inhibiting CFTR mRNA in vitro. Increased TGF-β1 signaling and acquired CFTR dysfunction are present in other lung diseases. To study the mechanism of TGF-β1 repression of CFTR, we used molecular, biochemical, and functional approaches in primary human bronchial epithelial cells from over 50 donors. TGF-β1 destabilized CFTR mRNA in cells from lungs with chronic disease, including CF, and impaired F508del-CFTR rescue by new-generation correctors. TGF-β1 increased the active pool of selected micro(mi)RNAs validated as CFTR inhibitors, recruiting them to the RNA-induced silencing complex (RISC). Expression of F508del-CFTR globally modulated TGF-β1-induced changes in the miRNA landscape, creating a permissive environment required for degradation of F508del-CFTR mRNA. In conclusion, TGF-β1 may impede the full benefit of corrector/potentiator therapy in CF patients. Studying miRNA recruitment to RISC under disease-specific conditions may help to better characterize the miRNAs utilized by TGF-β1 to destabilize CFTR mRNA.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 1422-0067, 1661-6596eISSN: 1422-0067DOI: 10.3390/ijms20194933Titel-ID: cdi_doaj_primary_oai_doaj_org_article_35946712e77b4b8280d658a8b22e0fcf
- Format
- –
- Schlagworte
- Bronchi - cytology, Bronchi - metabolism, Cells, Cultured, cftr, Chronic obstructive pulmonary disease, Conductance, Cystic fibrosis, Cystic fibrosis transmembrane conductance regulator, Cystic Fibrosis Transmembrane Conductance Regulator - genetics, Cystic Fibrosis Transmembrane Conductance Regulator - metabolism, Endoplasmic reticulum, Environmental degradation, Epithelial cells, Epithelium, FDA approval, Gene expression, Gene Silencing, Growth factors, Homeostasis, Humans, Kinases, Lung diseases, microrna, MicroRNAs, MicroRNAs - genetics, MicroRNAs - metabolism, miRNA, mRNA, Mutation, primary human bronchial epithelial cells, Protein folding, Proteins, Recruitment, Respiratory Mucosa - drug effects, Respiratory Mucosa - metabolism, RNA Stability, RNA-induced silencing complex, RNA-mediated interference, tgf-β1, Transforming Growth Factor beta - pharmacology, Transforming growth factor-b1