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J. Biol. Chem., Vol. 276, Issue 37, 34486-34494, September 14, 2001

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Identification of a Critical Sp1 Site within the Endoglin Promoter and Its Involvement in the Transforming Growth Factor- Stimulation^*

Luisa M. Botella, Tilman Sánchez-Elsner, Carlos Rius, Angel Corbí, and Carmelo Bernabéu^§

From the Centro de Investigaciones Biológicas, Consejo Superior de Investigaciones Científicas, Velázquez 144, 28006 Madrid, Spain

Endoglin, a component of the transforming growth factor- (TGF-) receptor complex expressed on endothelial cells, is involved in cardiovascular morphogenesis and vascular remodeling, as exemplified by the fact that the endoglin gene is the target for the autosomal dominant disorder known as hereditary hemorrhagic telangiectasia type 1. Since haploinsufficiency is the underlying mechanism for hereditary hemorrhagic telangiectasia type 1, understanding the regulation of endoglin gene expression appears to be a crucial step to correct the disease. In this study we have identified an Sp1 site at 37 as a critical element for the basal transcription of the endoglin TATA-less promoter. Since endoglin promoter activity is stimulated by TGF- and this stimulation is located at the Sp1-containing proximal region, we have investigated the possible involvement of Sp1 in the TGF--mediated induction. Mutation of the Sp1-binding sequence, or addition of the Sp1 inhibitor WP631, abolished both the basal transcription activity and the TGF- responsiveness of the endoglin promoter. Binding of Sp1 and Smad3 to the proximal promoter region 50/29 was evidenced by electrophoretic mobility shift assays and DNA affinity precipitation studies. Furthermore, synergistic cooperation on the promoter activity between Sp1 and TGF- or Smad3 could be demonstrated by co-transfection experiments of reporter promoter constructs. The molecular mechanism underlying this cooperation appears to involve a direct physical interaction between Sp1 and Smad3/Smad4.

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