Ets transcription factors cooperate with Sp1 to activate the human Tenascin-C promoter

Tenascin-C (TN-C), an extracellular matrix glycoprotein is expressed during embryonic development, but is present only at low levels in normal adult t issues. TN-C is re-expressed during wound healing, fibrotic diseases and in cancer. To better understand the mechanisms that control TN-C gene express ion, we examined the regulation of the human TN-C promoter in human fibrobl asts. We demonstrate that a short segment of the TN-C promoter between bp - 133 and -27 contains three evolutionarily conserved Ets binding sites (EBS) . These three EBSs bind in vitro expressed Fli1 protein and mediate transac tivation of the TN-C gene by Fli1. Furthermore, two proximal EBSs contribut e significantly to basal activity of the TN-C promoter. GABP, which is pres ent in human fibroblast nuclear extracts, interacts with the two proximal E BSs, In addition, several Spl and Sp3 binding sites have been located in cl ose proximity to the EBSs within this promoter region. The studies performe d in Drosophila cells demonstrate that either Fli1 or GABP alpha + beta 1 f unctionally interact with Spl resulting in a synergistic stimulation of the TN-C promoter activity. In conclusion, this study shows for the first time that the TN-C gene is regulated by Ets proteins, which together with Spl a ct as potent activators of TN-C expression.