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p90RSK Inhibition Ameliorates TGF-β1 Signaling and Pulmonary Fibrosis by Inhibiting Smad3 Transcriptional Activity

Title
p90RSK Inhibition Ameliorates TGF-β1 Signaling and Pulmonary Fibrosis by Inhibiting Smad3 Transcriptional Activity
Authors
Kim S.Han J.-H.Lee H.Kim J.-R.Lim J.H.Woo C.-H.
Ewha Authors
임재향
SCOPUS Author ID
임재향scopus
Issue Date
2020
Journal Title
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology
ISSN
1421-9778JCR Link
Citation
Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology vol. 54, no. 2, pp. 195 - 210
Keywords
Pulmonary fibrosisp90RSKTGF-β1ECMEMT
Publisher
NLM (Medline)
Indexed
SCOPUS scopus
Document Type
Article
Abstract
BACKGROUND/AIMS: Idiopathic pulmonary fibrosis (IPF) is a specific form of progressive and chronic interstitial lung disease of unknown cause. IPF is characterized by excessive deposition of extracellular matrix (ECM) and destructive pathological remodeling due to epithelial-to-mesenchymal transition (EMT). Eventually, lung interstitium thickens and stiffens and breathing becomes difficult. It has been well established that the transforming growth factor-β1 (TGF-β1)/Smad signaling pathway plays a critical role in the pathogenesis of pulmonary fibrosis. TGF-β1-mediated activation of mitogen activated protein kinase (MAPK) family affects Smad signaling. p90RSK is a serine/threonine kinase and is activated by the extracellular signal-regulated kinase (ERK) signaling pathway. However, the roles played by p90RSK in TGF-β1 signaling and the pathogenesis of pulmonary fibrosis remain unknown. METHODS: We investigated whether p90RSK regulates the pathogenesis of pulmonary fibrosis using in vitro and in vivo systems and Western blotting, real-time quantitative PCR, transcriptional activity assays and immunofluorescence studies. RESULTS: Pharmacological inhibition of p90RSK by FMK or inhibition of p90RSK with adenoviral vector encoding a dominant negative form of p90RSK suppressed TGF-β1-induced ECM accumulation and EMT in lung epithelial cells and fibroblasts. Interestingly, FMK significantly inhibited TGF-β1-induced Smad3 nuclear translocation and smad binding element-dependent transcriptional activity, but not Smad3 phosphorylation. Furthermore, in a mouse model of bleomycin-induced lung fibrosis, FMK ameliorated pulmonary fibrosis. CONCLUSION: These findings indicate that p90RSK plays critical roles in pulmonary fibrosis, which suggests it be viewed as a novel therapeutic target for the treatment of lung fibrosis. © Copyright by the Author(s). Published by Cell Physiol Biochem Press.
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DOI
10.33594/000000214
Appears in Collections:
의과대학 > 의학과 > Journal papers
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