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J. Biol. Chem., Vol. 282, Issue 24, 17665-17675, June 15, 2007

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Scleraxis and NFATc Regulate the Expression of the Pro-1(I) Collagen Gene in Tendon Fibroblasts^*

Véronique Léjard¹, Gaëlle Brideau², Frédéric Blais, Ruchanee Salingcarnboriboon^¶, Gerhard Wagner^||, Michael H. A. Roehrl^**, Masaki Noda^¶, Delphine Duprez, Pascal Houillier, and Jerome Rossert³

From the INSERM U652 and Paris-Descartes University, 75006 Paris, France, CNRS UMR 7622 and Pierre and Marie Curie University, 75005 Paris, France, the ^¶Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, 101-0062 Tokyo, Japan, the ^||Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, and the ^**Department of Pathology and Laboratory Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02114

The combinatorial action of separate cis-acting elements controls the cell-specific expression of type I collagen genes. In particular, we have shown that two short elements located between -3.2 and -2.3 kb and named TSE1 and TSE2 are needed for expression of the mouse COL1a1 gene in tendon fibroblasts. In this study, we analyzed the trans-acting factors binding to TSE1 and TSE2. Gel shift experiments showed that scleraxis (SCX), which is a basic helix-loop-helix transcription factor that is expressed selectively in tendon fibroblasts, binds TSE2, preferentially as a SCX/E47 heterodimer. In transfection experiments, overexpression of SCX and E47 strongly enhanced the activity of reporter constructs harboring either four copies of TSE2 cloned upstream of the COL1a1 minimal promoter or a 3.2-kb segment of the COL1a1 proximal promoter. Analysis of TSE1 showed that it contains a consensus binding site for NFATc transcription factors. This led us to show that the NFATc4 gene is expressed in tendons of developing mouse limbs and in TT-D6 cells, a cell line that has characteristics of tendon fibroblasts. In gel shift assays, TSE1 bound NFATc proteins present in nuclear extracts from TT-D6 cells. In transfection experiments, overexpression of NFATc transactivated a reporter construct harboring four copies of TSE1 cloned upstream of the COL1a1 minimal promoter. By contrast, inhibition of the nuclear translocation of NFATc proteins in TT-D6 cells strongly inhibited the expression of the COL1a1 gene. Taken together, these results suggest that SCX and NFATc4 cooperate to activate the COL1a1 gene specifically in tendon fibroblasts.

Received for publication, October 30, 2006 , and in revised form, March 29, 2007.

^* This work was supported in part by Grant GIS 2004 from the French Ministry of Research (to J. R.). 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 Recipient of a fellowship from the French Ministry of Research and from the Fondation pour la Recherche Médicale.

² Present address: Dept. of Medical Biochemistry and Molecular Biology, University of Oulu, 90014 Oulu, Finland.

³ To whom correspondence should be addressed: Cordeliers Biomedical Institute, INSERM U652, 15 Rue de l'É_cole de Médecine, 75006 Paris, France. Tel.: 33 1 44 41 37 10/19; Fax: 33 1 44 41 37 17; E-mail: jerome.rossert{at}egp.aphp.fr.

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