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RSS FeedsIJMS, Vol. 20, Pages 4933: Transforming Growth Factor-?1 Selectively Recruits microRNAs to the RNA-Induced Silencing Complex and Degrades CFTR mRNA under Permissive Conditions in Human Bronchial Epithelial Cells (International Journal of Molecular Sciences)

 
 

5 october 2019 18:03:21

 
IJMS, Vol. 20, Pages 4933: Transforming Growth Factor-?1 Selectively Recruits microRNAs to the RNA-Induced Silencing Complex and Degrades CFTR mRNA under Permissive Conditions in Human Bronchial Epithelial Cells (International Journal of Molecular Sciences)
 




<p>Mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (<italic>CFTR</italic>) 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-&#x3B2;1), overexpressed in many CF patients, blocks corrector/potentiator rescue by inhibiting CFTR mRNA in vitro. Increased TGF-&#x3B2;1 signaling and acquired CFTR dysfunction are present in other lung diseases. To study the mechanism of TGF-&#x3B2;1 repression of CFTR, we used molecular, biochemical, and functional approaches in primary human bronchial epithelial cells from over 50 donors. TGF-&#x3B2;1 destabilized CFTR mRNA in cells from lungs with chronic disease, including CF, and impaired F508del-CFTR rescue by new-generation correctors. TGF-&#x3B2;1 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-&#x3B2;1-induced changes in the miRNA landscape, creating a permissive environment required for degradation of F508del-CFTR mRNA. In conclusion, TGF-&#x3B2;1 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-&#x3B2;1 to destabilize CFTR mRNA.


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279 viewsCategory: Biochemistry, Biophysics, Molecular Biology
 
IJMS, Vol. 20, Pages 4937: A2A Receptor Homodimer-Disrupting Sequence Efficiently Delivered by a Protease-Resistant, Cyclic CPP Vector (International Journal of Molecular Sciences)
IJMS, Vol. 20, Pages 4935: Possible Phenotypic Consequences of Structural Differences in Idic(15) in a Small Cohort of Patients (International Journal of Molecular Sciences)
 
 
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