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C-Rel与C/EBPβ的相互作用增强了C/EBPβ与C反应蛋白基因启动子的结合。

The interaction of C-Rel with C/EBPbeta enhances C/EBPbeta binding to the C-reactive protein gene promoter.

作者信息

Cha-Molstad Hyunjoo, Young Duprane Pedaci, Kushner Irving, Samols David

机构信息

Department of Biochemistry, Case Western Reserve University, Cleveland, OH 44106, USA.

出版信息

Mol Immunol. 2007 Apr;44(11):2933-42. doi: 10.1016/j.molimm.2007.01.015. Epub 2007 Feb 28.

Abstract

C-reactive protein (CRP) is a plasma protein primarily synthesized in the liver following inflammatory stimuli as part of the acute phase response. Expression of CRP is tightly regulated in hepatocytes. Normally very little CRP mRNA is transcribed, but inflammatory stimuli are followed by a dramatic increase in mRNA synthesis and accumulation. Interleukins -6 and 1 (IL-6 and IL-1) are believed to be the major cytokines responsible for induction of acute phase protein biosynthesis. We previously demonstrated that in vivo c-Rel plays a novel regulatory role in that it appears to be in complex with C/EBPbeta when C/EBPbeta is bound to the CRP gene promoter following cytokine stimulation, but is not itself bound to DNA. In this study we found that recombinant c-Rel((1-300)) (truncated c-Rel protein missing the transactivation domain) increased the affinity of recombinant C/EBPbeta for a CRP-derived C/EBP site (-53) at least 10-fold. This effect was independent of a previously described p50 binding site at -43 and of binding of c-Rel to DNA. C/EBPbeta and c-Rel((1-300)) were found to physically interact in solution, and overexpression of c-Rel (either full length or truncated (1-300)) in the presence of overexpressed C/EBPbeta stimulated CRP transcription. We conclude that c-Rel((1-300)) binding to C/EBPbeta increases the affinity of C/EBPbeta for the C/EBP binding site at -53 on the CRP promoter, and that the transactivation domain of c-Rel is not necessary for this effect, which depends on protein: protein contacts with C/EBPbeta.

摘要

C反应蛋白(CRP)是一种血浆蛋白,主要在肝脏中合成,是炎症刺激后急性期反应的一部分。CRP在肝细胞中的表达受到严格调控。正常情况下,CRP mRNA转录很少,但炎症刺激后,mRNA合成和积累会急剧增加。白细胞介素-6和白细胞介素-1(IL-6和IL-1)被认为是诱导急性期蛋白生物合成的主要细胞因子。我们之前证明,在体内c-Rel发挥了一种新的调节作用,即当细胞因子刺激后C/EBPβ与CRP基因启动子结合时,c-Rel似乎与C/EBPβ形成复合物,但它本身并不与DNA结合。在本研究中,我们发现重组c-Rel((1-300))(缺失反式激活结构域的截短c-Rel蛋白)使重组C/EBPβ对CRP衍生的C/EBP位点(-53)的亲和力增加了至少10倍。这种效应与之前描述的位于-43的p50结合位点以及c-Rel与DNA的结合无关。发现C/EBPβ和c-Rel((1-300))在溶液中发生物理相互作用,并且在过表达的C/EBPβ存在的情况下,过表达c-Rel(全长或截短的(1-300))会刺激CRP转录。我们得出结论,c-Rel((1-300))与C/EBPβ结合增加了C/EBPβ对CRP启动子上-53处C/EBP结合位点的亲和力,并且c-Rel的反式激活结构域对于这种效应不是必需的,该效应取决于与C/EBPβ的蛋白质:蛋白质相互作用。

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