H2O2 and tumor necrosis factor-alpha activate intercellular adhesion molecule 1 (ICAM-1) gene transcription through distinct cis-regulatory elements within the ICAM-1 promoter.
H2O2 and tumor necrosis factor-alpha activate intercellular adhesion molecule 1 (ICAM-1) gene transcription through distinct cis-regulatory elements within the ICAM-1 promoter.
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发表时间：
1995
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通讯作者：
K. Roebuck;A. Rahman;V. Lakshminarayanan;K. Janakidevi;A. B. Malik
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作者：
K. Roebuck;A. Rahman;V. Lakshminarayanan;K. Janakidevi;A. B. Malik
我们研究了 H2O2 增加内皮细胞中细胞间粘附分子 1 (ICAM-1; CD54) 表达的机制。 H2O2 诱导的 ICAM-1 mRNA 增加受到放线菌素 D、抗氧化剂 N-乙酰半胱氨酸和 3-氨基苯甲酰胺（阻断氧化剂诱导的 AP-1 活性）的抑制，但吡咯烷二硫代氨基甲酸酯（阻断氧化剂诱导的 NF-κ B 活性）则不抑制。 ICAM-1 启动子构建体的核连续转染和瞬时转染表明，H2O2 通过激活 ICAM-1 启动子的不同区域来刺激 ICAM-1 基因转录。 H2O2 响应元件定位于-981 和-769 之间的序列（相对于起始密码子）。该区域内有两个 16 碱基对重复序列，每个重复序列均包含转录因子 AP-1 和 Ets 的结合位点。从巨噬细胞清道夫受体基因中分离出的类似复合 AP-1/Ets 元件赋予了对最小启动子的 H2O2 反应性。 ICAM-1启动子内16个碱基对重复序列的突变阻止了H2O2诱导的DNA结合活性，并且它们的缺失消除了H2O2诱导的转录活性。相反，TNF α 通过激活 -393 和 -176 之间的启动子序列（具有 C/EBP 和 NF-κ B 结合位点的区域）诱导 ICAM-1 转录。结果表明，H2O2 通过 ICAM-1 启动子内的 AP-1/Ets 元件激活 ICAM-1 转录，这与 TNF α 诱导的 NF-κ B 介导的 ICAM-1 表达不同。
We investigated the mechanisms by which H2O2 increases intercellular adhesion molecule 1 (ICAM-1; CD54) expression in endothelial cells. The H2O2-induced increase in ICAM-1 mRNA was inhibited by actinomycin D, by the antioxidant N-acetylcysteine, and by 3-amino-benzamide (which blocks oxidant-induced AP-1 activity), but not by pyrrolidine dithiocarbamate (which blocks oxidant-induced NF-kappa B activity). Nuclear run-on and transient transfections of ICAM-1 promoter constructs indicated that H2O2 stimulated ICAM-1 gene transcription by activation of a distinct region of the ICAM-1 promoter. The H2O2-responsive element was localized to sequences between -981 and -769 (relative to start codon). Located within this region are two 16-base pair repeats, each containing binding sites for the transcription factors AP-1 and Ets. A similar composite AP-1/Ets element isolated from the macrophage scavenger receptor gene conferred H2O2 responsiveness to a minimal promoter. Mutation of the 16-base pair repeats within the ICAM-1 promoter prevented H2O2-induced DNA binding activity, and their deletion abrogated the H2O2-induced transcriptional activity. In contrast, TNF alpha induced ICAM-1 transcription via activation of promoter sequences between -393 and -176, a region with C/EBP and NF-kappa B binding sites. The results indicate that H2O2 activates ICAM-1 transcription through AP-1/Ets elements within the ICAM-1 promoter, which are distinct from NF-kappa B-mediated ICAM-1 expression induced by TNF alpha.