Inhibition of transforming growth factor β-enhanced serum response factor-dependent transcription by SMAD7

Abstract

Transforming growth factor (TGF)-β is present in large amounts in the airways of patients with asthma and with other diseases of the lung. We show here that TGFβ treatment increased transcriptional activation of SM22α, a smooth muscle-specific promoter, in airway smooth muscle cells, and we demonstrate that this effect stems in part from TGFβ-induced enhancement of serum response factor (SRF) DNA binding and transcription promoting activity. Overexpression of Smad7 inhibited TGFβ-induced stimulation of SRF-dependent promoter function, and chromatin immunoprecipitation as well as co-immunoprecipitation assays established that endogenous or recombinant SRF interacts with Smad7 within the nucleus. The SRF binding domain of Smad7 mapped to the C-terminal half of the Smad7 molecule. TGFβ treatment weakened Smad7 association with SRF, and conversely the Smad7-SRF interaction was increased by inhibition of the TGFβ pathway through overexpression of a dominant negative mutant of TGFβ receptor I or of Smad3 phosphorylation-deficient mutant. Our findings thus reveal that SRF-Smad7 interactions in part mediate TGFβ regulation of gene transcription in airway smooth muscle. This offers potential targets for interventions in treating lung inflammation and asthma. © 2006 by The American Society for Biochemistry and Molecular Biology, Inc.