Published ahead of print on July 20, 2006, doi:10.1165/rcmb.2006-0043OC
Am. J. Respir. Cell Mol. Biol., Volume 36, Number 1, January 2007, 78-84
A more recent version of this article appeared on January 1, 2007
Submitted on January 27, 2006
Revised on July 20, 2006
Gut-enriched Kruppel-like Factor Interaction with Smad3 Inhibits Myofibroblast Differentiation
Biao Hu1, Zhe Wu1, Tianju Liu1, Matthew R Ullenbruch1, Hong Jin1, and Sem H Phan1*
1 Department of Pathology, University of Michigan Medical School, Ann Arbor, MI, USA
* To whom correspondence should be addressed. E-mail: shphan{at}umich.edu.
Gut-enriched Kruppel-like factor (GKLF) has been reported to partially inhibit  -smooth muscle actin (-SMA) gene transcription by competing for binding to the TGF control element (TCE) with known activators such as Sp1 and other KLFs. This incomplete inhibition via the TCE suggests an additional mechanism, which was evaluated in this study. The results showed that an -SMA promoter mutated in the TCE remained susceptible to inhibition by GKLF in rat lung fibroblasts consistent with the existence of an additional TCE independent mechanism. Since TGF-induced -SMA expression is Smad3-dependent, potential interaction between GKLF and Smad3 was examined as a basis for this additional inhibitory mechanism. Co-immunoprecipitation and yeast two-hybrid assays revealed that GKLF could bind Smad3 through the Smad3 MH2 domain. Electrophoretic mobility shift assays and ChIP assay indicated that this GKLF-Smad3 interaction inhibited Smad3 binding to the Smad3 binding element (SBE) in the -SMA promoter, and the activity of an SBE containing artificial promoter. Further analysis using smad3(-/-) fibroblasts confirmed that the TCE independent inhibition by GKLF was dependent on Smad3. These data taken together suggest that in addition to inhibition via the TCE, GKLF represses -SMA gene expression by interacting with Smad3 to prevent Smad3 binding to the SBE. It represents the first evidence to directly link GKLF with Smad3, a key intracellular mediator of TGF signaling, which should lead to a clearer understanding of the mechanism of how GKLF regulates TGF-induced gene expression.
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Copyright © 2006 American Thoracic Society.
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