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Isoprenoid-Mediated Control of SMAD3 Expression in a Cultured Model of Cystic Fibrosis Epithelial Cells

Departments of Pediatrics and Pharmacology, Case Western Reserve University, and Rainbow Babies and Children's Hospital, Cleveland, Ohio

Address correspondence to: Thomas J. Kelley, Ph.D., Department of Pediatrics, Case Western Reserve University, 8th floor BRB, 10900 Euclid Ave., Cleveland, OH 44106-4948. E-mail: tjk12{at}po.cwru.edu

Several cellular signaling alterations have been identified in cystic fibrosis (CF) epithelium. One of these alterations is reduced SMAD3 protein expression and a corresponding reduction in SMAD3-mediated transforming growth factor-ß1 (TGF-ß1) signaling in CF epithelial cells compared with wild-type (wt) controls. The goal of this study was to identify a mechanism leading to reduced SMAD3 protein expression in CF epithelium. Based on previous work demonstrating isoprenoid-mediated regulation of CF-related alterations in signal transducer and activator of transcription-1 (Stat1) and inducible nitric oxide synthase (NOS2) expression, the hypothesis of this study is that inhibition of isoprenoid-dependent signaling will restore SMAD3 expression and signaling in a model of CF epithelium. Presented data will demonstrate that inhibition of both farnesyl and geranylgeranyl transferase activities partially restores SMAD3-mediated TGF-ß1 signaling and normalizes SMAD3 protein expression in one cultured model of CF cells. Analysis of the human SMAD3 promoter demonstrates that isoprenoid regulation of SMAD3 expression is dependent on Sp1/Sp3 activity, although farnesyl-mediated pathways may be acting through a secondary mechanism as well. Isoprenoid-mediated regulation of SMAD3 expression, coupled with previous data demonstrating isoprenoid control of Stat1 and NOS2 expression, suggest that the isoprenoid/cholesterol synthesis pathway is a critical intermediate in influencing CF-related cell signaling changes.

Abbreviations: cystic fibrosis, CF • CF transmembrane conductance regulator, CFTR • plasminogen activator inhibitor-1, PAI-1 • phosphate-buffered saline, PBS • transforming growth factor, TGF • wild-type, wt

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