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Proprotein convertase inhibition promotes ciliated cell differentiation - a potential mechanism for the inhibition of Notch1 signalling by decanoyl-RVKR-chloromethylketone

Authors
 Sang‐Nam Lee  ;  In‐Suk Choi  ;  Hyun Jun Kim  ;  Eun Jin Yang  ;  Hyun Jin Min  ;  Joo‐Heon Yoon 
Citation
 Journal of Tissue Engineering and Regenerative Medicine, Vol.11(9) : 2667-2680, 2017 
Journal Title
 Journal of Tissue Engineering and Regenerative Medicine 
ISSN
 1932-6254 
Issue Date
2017
MeSH
Amino Acid Chloromethyl Ketones/pharmacology* ; Cell Differentiation/drug effects* ; Cilia/metabolism ; Epithelial Cells/cytology ; Epithelial Cells/metabolism* ; Furin/metabolism ; Humans ; Nasal Mucosa/cytology ; Nasal Mucosa/metabolism* ; Proprotein Convertases/antagonists & inhibitors* ; Proprotein Convertases/metabolism ; Protein Synthesis Inhibitors/pharmacology* ; Receptor, Notch1/metabolism*
Keywords
airway remodelling ; basal progenitor cells ; ciliated cell differentiation ; cultured human nasal epithelial cells ; notch1 ; proprotein convertases
Abstract
Chronic repetitive rounds of injury and repair in the airway lead to airway remodelling, including ciliated cell loss and mucous cell hyperplasia. Airway remodelling is mediated by many growth and differentiation factors including Notch1, which are proteolytically processed by proprotein convertases (PCs). The present study evaluated a novel approach for controlling basal cell-type determination based on the inhibition of PCs. It was found that decanoyl-RVKR-chloromethylketone (CMK), a PC inhibitor, promotes ciliated cell differentiation and has no effect on the ciliary beat frequency in air-liquid interface (ALI) cultures of human nasal epithelial cells (HNECs). Comparative microarray analysis revealed that CMK considerably increases ciliogenesis-related gene expression. Use of cell-permeable and cell-impermeable PC inhibitors suggests that intracellular PCs regulate basal cell-type determination in ALI culture. Furthermore, CMK effect on ciliated cell differentiation was reversed by a Notch inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT). CMK inhibited the processing of Notch1, a key regulator of basal cell differentiation toward secretory cell lineages in the airway epithelium, and down-regulated the expression of Notch1 target genes together with furin, a PC. Specific lentiviral shRNA-mediated knockdown of furin resulted in reduced Notch1 processing and increased numbers of ciliated cells in HNECs. Moreover, CMK inhibited Notch1 processing and promoted regeneration and ciliogenesis of the mouse nasal respiratory epithelium after ZnSO4 injury. These observations suggest that PC inhibition promotes airway ciliated cell differentiation, possibly through suppression of furin-mediated Notch1 processing.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/160846
DOI
10.1002/term.2240
Appears in Collections:
1. Journal Papers (연구논문) > 1. College of Medicine (의과대학) > Dept. of Otorhinolaryngology (이비인후과학교실)
1. Journal Papers (연구논문) > 5. Research Institutes (연구소) > Research Center for Human Natural Defense System (생체방어연구센터)
Yonsei Authors
윤주헌(Yoon, Joo Heon)
이상남(Lee, Sang Nam)
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Full Text
https://onlinelibrary.wiley.com/doi/abs/10.1002/term.2240
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