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J. Biol. Chem., Vol. 282, Issue 44, 32000-32014, November 2, 2007

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Human Collagen Krox Up-regulates Type I Collagen Expression in Normal and Scleroderma Fibroblasts through Interaction with Sp1 and Sp3 Transcription Factors^*

Magdalini Kypriotou¹, Gallic Beauchef²³, Christos Chadjichristos², Russell Widom, Emmanuelle Renard, Sergio A. Jimenez^¶, Joseph Korn, François-Xavier Maquart^||, Thierry Oddos^**, Otto Von Stetten^**, Jean-Pierre Pujol, and Philippe Galéra^**4

From the Laboratoire de Biochimie du Tissu Conjonctif, Université de Caen/Basse-Normandie, IFR ICORE 146, FacultédeMédecine, CHU Niveau 3, Avenue de la Côte de Nacre, 14032 Caen Cedex, France, the Department of Medicine, Arthritis Center, Boston University School of Medicine and Boston Veterans Affairs Medical Center, Boston, Massachusetts 02118, the ^¶Departments of Medicine and Biochemistry and Molecular Biology, Jefferson Medical College, Thomas Jefferson University, Philadelphia, Pennsylvania 19017, ^||Laboratoire de Biochimie Médicale et de Biologie Moléculaire, CNRS FRE-2534, IFR-53 Biomolécules, UFR de Médecine, 51095 Reims, France, and ^**Johnson & Johnson Consumer France, R & D Europe, Campus de Maigremont, 27100 Val de Reuil, France

Despite several investigations, the transcriptional mechanisms that regulate the expression of both type I collagen genes (COL1A1 and COL1A2) in either physiological or pathological situations, such as scleroderma, are not completely known. We have investigated the role of hc-Krox transcription factor on type I collagen expression by human dermal fibroblasts. hc-Krox exerted a stimulating effect on type I collagen protein synthesis and enhanced the corresponding mRNA steady-state levels of COL1A1 and COL1A2 in foreskin fibroblasts (FF), adult normal fibroblasts (ANF), and scleroderma fibroblasts (SF). Forced hc-Krox expression was found to up-regulate COL1A1 transcription through a –112/–61-bp sequence in FF, ANF, and SF. Knockdown of hc-Krox by short interfering RNA and decoy strategies confirmed the transactivating effect of hc-Krox and decreased substantially COL1A1 transcription levels in all fibro-blast types. The –112/–61-bp sequence bound specifically hc-Krox but also Sp1 and CBF. Attempts to elucidate the potential interactions between hc-Krox, Sp1, and Sp3 revealed that all of them co-immunoprecipitate from FF cellular extracts when a c-Krox antibody was used and bind to the COL1A1 promoter in chromatin immunoprecipitation assays. Moreover, hc-Krox DNA binding activity to its COL1A1-responsive element is increased in SF, cells producing higher amounts of type I collagen compared with ANF and FF. These data suggest that the regulation of COL1A1 gene transcription in human dermal fibroblasts involves a complex machinery that implicates at least three transcription proteins, hc-Krox, Sp1, and Sp3, which could act in concert to up-regulate COL1A1 transcriptional activity and provide evidence for a pro-fibrotic role of hc-Krox.

Received for publication, June 25, 2007

^* This work was supported by the Regional Council of Lower Normandy, the French Ministry of Regional Development, and Johnson & Johnson Consumer France. 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 supplemental Figs. S1–S3.

¹ Fellow of the Regional Council of Lower Normandy and the French Ministry of Regional Development.

² Both authors contributed equally to this work.

³ Fellow of the Regional Council of Lower Normandy and of Johnson & Johnson Consumer France Laboratories (Campus de Maigremont, 27100 Val de Reuil, France).

⁴ To whom correspondence should be addressed. Tel.: 33-6-31063106 (Ext. 8003); Fax: 33-6-31068224; E-mail: philippe.galera{at}unicaen.fr.

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