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J. Biol. Chem., Vol. 283, Issue 3, 1324-1333, January 18, 2008

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Transforming Growth Factor-β (TGF-β1) Down-regulates Notch3 in Fibroblasts to Promote Smooth Muscle Gene Expression^*

From the Vascular Biology Center and Department of Obstetrics and Gynecology, Medical College of Georgia, Augusta, Georgia, 30912

Select signaling pathways have emerged as key players in regulating smooth muscle gene expression during myofibroblast and smooth muscle differentiation, an event that is important for wound healing and vascular remodeling. These include the transforming growth factor-β (TGF-β1) signaling cascade, which has been assigned multiple roles in these cells, and the Notch pathway. Notch family members have been implicated in governing cell fate in a variety of cells; however, the mechanisms are not well understood. We sought to explore how these prominent signaling mediators regulate differentiation, and in particular, how they might converge to control the transcription of smooth muscle genes. Using TGF-β1 to induce the differentiation of 10T1/2 fibroblasts, we investigated the specific function of Notch3. Overexpression of activated Notch3 caused repression of TGF-β1-induced smooth muscle-specific genes, whereas knockdown of Notch3 by small interfering RNA did not convincingly alter their expression. Surprisingly, the addition of TGF-β1 caused a significant decrease in Notch3 RNA and protein and a reciprocal increase in Hes1 gene transcription. The repression of Notch3 was mediated by SMAD activity and p38 mitogen-activated protein (MAP) kinase, whereas analysis of the Hes1 promoter revealed direct activation by Smad2 but not Smad3. Furthermore, the Hes1 repressor protein augmented Smad3 transactivation of the SM22 promoter. These results offer a novel mechanism by which TGF-β1 promotes the expression of smooth muscle differentiation genes through the inhibition of Notch3 and activation of Hes1.

Received for publication, August 10, 2007 , and in revised form, October 1, 2007.

^* This work was supported by National Institutes of Health Grant NHLBI00086 (to B. L.). 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.

The on-line version of this article (available at http://www.jbc.org) contains a supplemental figure.

¹ To whom correspondence should be addressed: Medical College of Georgia, 1459 Laney Walker Blvd., Augusta, GA, 30912. Tel.: 706-721-8862; Fax: 706-721-9799; E-mail: blilly{at}mcg.edu.

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