Interleukin-6-induced tethering of STAT3 to the LAP/C/EBPβ promoter suggests a new mechanism of transcriptional regulation by STAT3
Interleukin-6-induced tethering of STAT3 to the LAP/C/EBPβ promoter suggests a new mechanism of transcriptional regulation by STAT3
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DOI：
10.1074/jbc.m009284200
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发表时间：
2001-03-23
影响因子：
4.8
通讯作者：
Trautwein, C
中科院分区：
文献类型：
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作者：
Niehof, M;Streetz, K;Trautwein, C
EBP/C/EBP β是C/EBP家族转录因子的成员，并有助于调节肝细胞中的急性期反应。在这里，我们表明，IL-6控制的IL/C/EBP β基因转录，并确定IL-6的反应元件在IL/C/EBP β启动子，其中不包含STAT 3 DNA结合基序。然而，荧光素酶报告基因测定表明，通过gp 130信号转导分子激活STAT 3参与介导IL-6依赖性LAP/C/EBP β转录。Southwestern分析表明，IL-6诱导68-kDa蛋白质与最近表征的CREA/C/EBP β启动子中的CREA样元件结合。使用具有突变的CRE样元件的启动子构建体的转染实验揭示了这些位点赋予IL-6响应性。使用STAT 1/STAT 3嵌合体的进一步分析确定了IL-6依赖性增加IL-6/C/EBP β基因转录所需的蛋白质的特定结构域; STAT 3氨基末端结构域的过表达阻断了IL-6介导的应答，表明STAT 3氨基末端在IL-8介导的IL-8/C/EBP β基因转录中具有重要功能。这些数据导致了一个模型，如何拴STAT 3的DNA结合的复合物有助于IL-6依赖性的EBP/C/β基因转录。我们的分析描述了STAT 3控制基因转录的一种新机制，该机制对肝细胞的急性期反应有直接影响。
LAP/C/EBP beta is a member of the C/EBP family of transcription factors and contributes to the regulation of the acute phase response in hepatocytes. Here we show that IL-6 controls LAP/C/EBP beta gene transcription and identify an IL-6 responsive element in the LAP/C/EBP beta promoter, which contains no STAT3 DNA binding motif. However, luciferase reporter gene assays showed that STAT3 activation through the gp130 signal transducer molecule is involved in mediating IL-6-dependent LAP/C/EBP beta transcription. Southwestern analysis indicated that IL-6 induces binding of a 68-kDa protein to the recently characterized CRE-like elements in the LAP/C/EBP beta promoter. Transfection experiments using promoter constructs with mutated CRE-like elements revealed that these sites confer IL-6 responsiveness. Further analysis using STAT1/STAT3 chimeras identified specific domains of the protein that are required for the IL-6-dependent increase in LAP/C/EBP beta gene transcription; Overexpression of the amino-terminal domain of STAT3 blocked the IL-6-mediated response, suggesting that the STAT3 amino terminus has an important function in IL-8-mediated transcription of the LAP/C/EBP beta gene. These data lead to a model of how tethering STAT3 to a DNA-bound complex contributes to IL-6-dependent LAP/C/EBP beta gene transcription. Our analysis describes a new mechanism by which STAT3 controls gene transcription and which has direct implication for the acute phase response in liver cells.