Ascochlorin suppresses TGF-beta 1-induced PAI-1 expression through the inhibition of phospho-EGFR in rat kidney fibroblast cells

Title
Ascochlorin suppresses TGF-beta 1-induced PAI-1 expression through the inhibition of phospho-EGFR in rat kidney fibroblast cells
Author(s)
장현욱조현지[조현지]강정한[강정한]정지학[정지학]정윤정[정윤정]박관규[박관규]박윤엽[박윤엽]문영숙[문영숙]김홍태[김홍태]정일경[정일경]김철호[김철호]장영채[장영채]
Keywords
PLASMINOGEN-ACTIVATOR; GENE-EXPRESSION; TGF-BETA; IN-VITRO; RECEPTOR TRANSACTIVATION; SIGNALING PATHWAY; UP-REGULATION; TYPE-1 GENE; ASCOFURANONE; KINASE
Issue Date
201204
Publisher
SPRINGER
Citation
MOLECULAR BIOLOGY REPORTS, v.39, no.4, pp.4597 - 4603
Abstract
Fibrosis is induced by the excessive and abnormal deposition of extracellular matrix (ECM) with various growth factors in tissues. Transforming growth factor-beta 1 (TGF-beta 1), the growth factor involved in fibrosis, modulates ECM synthesis and accumulation. TGF-beta 1 enhances the production of stimulators of ECM synthesis such as plasminogen activator inhibitor type 1 (PAI-1). As such, PAI-1 expression directly influences the proteolysis, invasion, and accumulation of ECM. It was shown in this study that ascochlorin, a prenylpenl antiobiotic, prevents the expression of profibrotic factors, such as PAI-1 and collagen type I, and that the TGF-beta 1-induced PAI-1 promoter activity is inhibited by ascochlorin. Ascochlorin abolishes the phosphorylation of the EGFR-MEK-ERK signaling pathway to regulate the TGF-beta 1-induced expression of PAI-1 without the inhibition of T beta RII phosphorylation. Furthermore, the MEK inhibitor and EGFR siRNA block PAI-1 expression, and the Raf-1, MEK, and ERK signaling pathways for the regulation of PAI-1 expression. Ascochlorin suppresses the matrix metalloproteinases (MMPs) activity to activate the heparin-binding EGF-like growth factor (HB-EGF), to induce the phosphorylation of EGFR, and the MMPs inhibitor suppresses EGFR phosphorylation and the PAI-1 mRNA levels. These results suggest that ascochlorin prevents the expression of PAI-1 via the inhibition of an EGFR-dependent signal transduction pathway activated by MMPs.
URI
http://hdl.handle.net/YU.REPOSITORY/28584http://dx.doi.org/10.1007/s11033-011-1251-y
ISSN
0301-4851
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약학대학 > 약학부 > Articles
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