Submitted on December 18, 2003
Revised on March 25, 2004
Isoprenoid-mediated control of SMAD3 expression in one model of cystic fibrosis epithelial cells
Jenny Y Lee1, Heather L Elmer1, Kristie R Ross1, and Thomas J Kelley1*
1 Departments of Pediatrics and Pharmacology, Case Western Reserve University, Cleveland, Ohio, USA
* To whom correspondence should be addressed. E-mail: tjk12{at}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-
1 (TGF-1) signaling in CF epithelial cells compared to wild type (wt) controls. The goal of this manuscript is 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-1 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.
