Role of NonO–histone interaction in TNFα-suppressed Prolyl-4-hydroxylase α1
- 作者：Cheng Zhang ; Ming-Xiang Zhang ; Ying H. Shen ; Jared K. Burks ; Xiao-Nan Li ; Scott A. LeMaire ; Koichi Yoshimura ; Hiroki Aoki ; Masunori Matsuzaki ; Feng-Shuang An ; David A. Engler ; Risë ; K. Matsunami
- 关键词：Inflammation ; Histone ; P4H
//www.sciencedirect.com/scidirimg/entities/204e.gif" alt="greek small letter alpha" title="greek small letter alpha" border="0">1 ; TNF
- 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Cell Research
- 出版年：2008
- 期刊代码：20_01674889
- 类别：bio
- 出版时间：August 2008
- 卷：1783
- 期：8
- 页码：1517-1528
- 文件大小：1754 K
摘要
Inflammation is a key process in cardiovascular diseases. The extracellular matrix (ECM) of the vasculature is a major target of inflammatory cytokines, and TNF
regulates ECM metabolism by affecting collagen production. In this study, we have examined the pathways mediating TNF-induced suppression of prolyl-4 hydroxylase alpha1 (P4H1), the rate-limiting isoform of P4H responsible for procollagen hydroxylation, maturation, and organization. Using human aortic smooth muscle cells, we found that TNF activated the MKK4-JNK1 pathway, which induced histone (H) 4 lysine 12 acetylation within the TNF response element in the P4H1 promoter. The acetylated-H4 then recruited a transcription factor, NonO, which, in turn, recruited HDACs and induced H3 lysine 9 deacetylation, thereby inhibiting transcription of the P4H1 promoter. Furthermore, we found that TNF oxidized DJ-1, which may be essential for the NonO–P4H1 interaction because treatment with gene specific siRNA to knockout DJ-1 eliminated the TNF-induced NonO–P4H1 interaction and its suppression. Our findings may be relevant to aortic aneurysm and dissection and the stability of the fibrous cap of atherosclerotic plaque in which collagen metabolism is important in arterial remodeling. Defining this cytokine-mediated regulatory pathway may provide novel molecular targets for therapeutic intervention in preventing plaque rupture and acute coronary occlusion.
regulates ECM metabolism by affecting collagen production. In this study, we have examined the pathways mediating TNF-induced suppression of prolyl-4 hydroxylase alpha1 (P4H1), the rate-limiting isoform of P4H responsible for procollagen hydroxylation, maturation, and organization. Using human aortic smooth muscle cells, we found that TNF activated the MKK4-JNK1 pathway, which induced histone (H) 4 lysine 12 acetylation within the TNF response element in the P4H1 promoter. The acetylated-H4 then recruited a transcription factor, NonO, which, in turn, recruited HDACs and induced H3 lysine 9 deacetylation, thereby inhibiting transcription of the P4H1 promoter. Furthermore, we found that TNF oxidized DJ-1, which may be essential for the NonO–P4H1 interaction because treatment with gene specific siRNA to knockout DJ-1 eliminated the TNF-induced NonO–P4H1 interaction and its suppression. Our findings may be relevant to aortic aneurysm and dissection and the stability of the fibrous cap of atherosclerotic plaque in which collagen metabolism is important in arterial remodeling. Defining this cytokine-mediated regulatory pathway may provide novel molecular targets for therapeutic intervention in preventing plaque rupture and acute coronary occlusion.