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Papers In Press, published online ahead of print July 23, 2002
Medicine/Rheumatology, Thomas Jefferson University, Philadelphia, PA 19107
Corresponding Author: Sergio.Jimenez{at}mail.tju.edu
The Sp1 transcription factor plays a crucial role in COL1A1 transcriptional regulation of COL1A1 under normal and pathologic conditions and under the effects of transforming growth factor
J. Biol. Chem, 10.1074/jbc.M201742200
Submitted on February 20, 2002
Revised on July 23, 2002
Accepted on July 23, 2002
Inhibition of basal and transforming growth factor
-induced stimulation of COL1A1 transcription by the DNA intercalators, mithoxantrone and WP631, in cultured human dermal fibroblasts
(TGF). Sp1 activity is elevated in numerous diseases characterized by tissue fibrosis. Therefore, inhibition of Sp1 binding to COL1A1 regulatory elements may represent an effective treatment for these diseases. Here, we examined the effect of two DNA intercalators that prevent Sp1 binding on the expression of COL1A1 in human dermal fibroblasts. Cultured human adult dermal fibroblasts were treated with WP631 (50 pM/ml to 500 nM/ml) or mithoxantrone (5-500 nM/ml). Cytotoxicity, cellular apoptosis and collagen deposition were examined by fluorescence microscopy. Collagen production was examined by ELISA and metabolic labeling, COL1A1 steady-state mRNA levels and stability were assessed by Northern hybridizations, and COL1A1 transcription by in vitro nuclear transcription assays and transient transfections. Competition of the drugs for Sp1 binding and their effect on TGF-induced stimulation of COL1A1 transcription was also examined. Both drugs caused a dose-related inhibition of COL1A1 production and mRNA levels without cytotoxicity or apoptosis. COL1A1 transcriptional activity showed a profound reduction mediated by a short proximal promoter region containing an Sp1 binding element at –87 to –82 bp. Furthermore, both drugs inhibited Sp1 DNA complex formation and abrogated the stimulation of COL1A1 transcription induced by TGF. WP361 showed 10-fold higher potency than mithoxantrone. These data indicate that mithoxantrone and WP631 are very potent inhibitors of basal and TGF-stimulated COL1A1 expression and suggest that Sp1-DNA intercalators may be an effective and novel approach for the treatment of fibrotic diseases and modulation of profibrogenic effects of TGF.
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