Trichostatin A blocks TGF-β-induced collagen gene expression in skin fibroblasts:: Involvement of Sp1

被引:77
|
作者
Ghosh, Asish K. [1 ]
Mori, Yasuji [1 ]
Dowling, Elizabeth [1 ]
Varga, John [1 ]
机构
[1] Northwestern Univ, Feinberg Sch Med, Div Rheumatol, Chicago, IL 60611 USA
关键词
fibroblasts; TGF-beta; type I collagen; fibrosis; histone deacetylase; histone acetyltransferase; trichostatin A; Smad; Sp1;
D O I
10.1016/j.bbrc.2006.12.204
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Transforming growth factor-beta (TGF-beta) stimulates Type I collagen synthesis by fibroblasts and is implicated in tissue fibrosis. Here, we demonstrate that historic deacetylase inhibitor Trichostatin A (TSA) suppresses the TGF-beta-induced Type I collagen synthesis but not induced PAI-1 synthesis suggesting the influence of TSA is gene specific. Results further reveal that there is no significant alteration in Smad activation and function in presence of TSA suggesting suppression of TGF-beta-induced collagen synthesis is not due to impaired Smad signaling. TGF-beta induces the levels of Spl, an essential transcription factor of Smad-dependent stimulation of collagen synthesis. However, in presence of TSA, TGF-beta fails to induce Sp1 levels, its interaction with Smad complex and Sp1 binding site in COL1A2 promoter. Furthermore, overexpressed Sp1 reverses the TSA-mediated inhibition of TGF-beta-induced collagen gene expression. Collectively, these results suggest that TSA-mediated suppression of Smad-dependent TGF-p-induced collagen synthesis is due to suppression of Sp1 activity in skin fibroblasts. (c) 2007 Elsevier Inc. All rights reserved.
引用
收藏
页码:420 / 426
页数:7
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