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Post‐transcriptional regulation of plasminogen activator inhibitor‐1 by intracellular iron in cultured human lung fibroblasts—interaction of an 81‐kDa nuclear protein with the 3′‐UTR
Author(s) -
RADHA K. S.,
SUGIKI M.,
HARISH KUMAR M.,
OMURA S.,
MARUYAMA M.
Publication year - 2005
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/j.1538-7836.2005.01272.x
Subject(s) - intracellular , chemistry , activator (genetics) , plasminogen activator , microbiology and biotechnology , human lung , lung , biochemistry , biology , gene , medicine , endocrinology
Summary. The proteinase inhibitor, type‐1 plasminogen activator inhibitor (PAI‐1), is a major regulator of the plasminogen activator system involved in plasmin formation and fibrinolysis. The present study explores the effects of intracellular iron on the expression of PAI‐1 and associated cell‐surface plasmin activity in human lung fibroblasts; and reports the presence of a novel iron‐responsive protein. ELISA revealed a dose‐dependent increase in PAI‐1 antigen levels expressed in the conditioned medium of cells treated with deferoxamine, in the three cell lines studied. A concomitant increase in mRNA levels was also observed by Northern analyses. Presaturation with ferric citrate quenched the effect of deferoxamine. Experiments with transcription and translation inhibitors on TIG 3‐20 cells demonstrated that intracellular iron modulated PAI‐1 expression at the post‐transcriptional level with the requirement of de‐novo protein synthesis. Electrophoretic mobility shift assay and UV crosslinking assays revealed the presence of an ∼ 81‐kDa nuclear protein that interacted with the 3′‐UTR of PAI‐1 mRNA in an iron‐sensitive manner. Finally, we demonstrated that the increased PAI‐1 is functional in suppressing cell‐surface plasmin activity, a process that can affect wound healing and tissue remodeling.