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J. Biol. Chem., Vol. 281, Issue 29, 20383-20392, July 21, 2006

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Inhibition of Transforming Growth Factor -enhanced Serum Response Factor-dependent Transcription by SMAD7^*

Blanca Camoretti-Mercado¹, Darren J. Fernandes, Samantha Dewundara, Jason Churchill, Lan Ma, Paul C. Kogut, John F. McConville, Michael S. Parmacek, and Julian Solway

From the Department of Medicine, University of Chicago, Chicago, Illinois 60637 and the Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104

Transforming growth factor (TGF)- is present in large amounts in the airways of patients with asthma and with other diseases of the lung. We show here that TGF treatment increased transcriptional activation of SM22, a smooth muscle-specific promoter, in airway smooth muscle cells, and we demonstrate that this effect stems in part from TGF-induced enhancement of serum response factor (SRF) DNA binding and transcription promoting activity. Overexpression of Smad7 inhibited TGF-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. TGF treatment weakened Smad7 association with SRF, and conversely the Smad7-SRF interaction was increased by inhibition of the TGF pathway through overexpression of a dominant negative mutant of TGF receptor I or of Smad3 phosphorylation-deficient mutant. Our findings thus reveal that SRF-Smad7 interactions in part mediate TGF regulation of gene transcription in airway smooth muscle. This offers potential targets for interventions in treating lung inflammation and asthma.

Received for publication, March 23, 2006

^* This work was supported by grants from the Blowitz-Ridgeway Foundation, the American Lung Association (to B. C.-M.), the American Thoracic Society (to B. C.-M.), and the LAM Foundation (to B. C.-M.), by NHLBI Grant SCOR HL 56399 from the National Institutes of Health (to J. S. and B. C.-M.), and by Asthma and Allergic Diseases Research Center Grant AI 056352 (to J. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: University of Chicago, 5841 S. Maryland Ave., MC6026, Chicago, IL 60637. Tel.: 773-702-5448; Fax: 773-702-4736; E-mail: bcamoret{at}medicine.bsd.uchicago.edu.

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