Chloroquine normalizes aberrant transforming growth factor beta activity in cystic fibrosis bronchial epithelial cells

2006 ◽  
Vol 41 (8) ◽  
pp. 771-778 ◽  
Author(s):  
Elizabeth A. Perkett ◽  
Wojciech Ornatowski ◽  
Jens F. Poschet ◽  
Vojo Deretic
Keyword(s):  
Cystic Fibrosis ◽  
Growth Factor ◽  
Epithelial Cells ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Bronchial Epithelial Cells ◽  
Beta Activity ◽  
Bronchial Epithelial ◽  
Growth Factor Beta

scholarly journals 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

2019 ◽  
Vol 20 (19) ◽  
pp. 4933 ◽  
Author(s):  
Nilay Mitash ◽  
Fangping Mu ◽  
Joshua E. Donovan ◽  
Michael M. Myerburg ◽  
Sarangarajan Ranganathan ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Growth Factor ◽  
Epithelial Cells ◽  
Transforming Growth Factor ◽  
Bronchial Epithelial Cells ◽  
Common Mutation ◽  
Human Bronchial Epithelial Cells ◽  
Bronchial Epithelial ◽  
Cftr Protein

<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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