Inhibition of NF-κB by ZAS3, a zinc-finger protein that also binds to the κB otif
Inhibition of NF-κB by ZAS3, a zinc-finger protein that also binds to the κB otif
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DOI：
10.1073/pnas.2133048100
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发表时间：
2003-10-14
影响因子：
11.1
通讯作者：
Wu, LC
中科院分区：
文献类型：
--
作者：
Hong, JW;Allen, CE;Wu, LC
ZAS蛋白是大型锌指转录蛋白，与生长、信号转导和淋巴细胞发育有关。含有两个DNA结合结构域之一的重组ZAS融合蛋白已被证明能特异性结合κB基序，但内源性ZAS蛋白及其生理功能在很大程度上是未知的。κB基序GGGACTTTCC是一种基因调控元件，存在于参与免疫、炎症和生长的基因的启动子和增强子中。NF - κB的Rel家族，主要是p65.p50和p50.p50，是在急性期反应期间通过与κB基序相互作用诱导基因表达而闻名的转录因子。ZAS和NF - κB这两个不同的κB结合蛋白家族之间的功能联系源于我们之前的体外研究，该研究表明一个代表性成员ZAS3与肿瘤坏死因子信号传导中的衔接分子TRAF2结合，以抑制NF - κB的激活。本文提供的生化和遗传学证据表明，ZAS3编码B淋巴细胞中主要的κB结合蛋白，并且在ZAS3缺陷的B细胞中NF - κB被组成性激活。数据表明，ZAS3在维持细胞内稳态方面起着关键作用，至少部分是通过以下三种机制抑制NF - κB：抑制p65的核转位、竞争κB基因调控元件以及抑制靶基因转录。
The ZAS proteins are large zinc-finger transcriptional proteins implicated in growth, signal transduction, and lymphoid development. Recombinant ZAS fusion proteins containing one of the two DNA-binding domains have been shown to bind specifically to the kappaB motif, but the endogenous ZAS proteins or their physiological functions are largely unknown. The kappaB motif, GGGACTTTCC, is a gene regulatory element found in promoters and enhancers of genes involved in immunity, inflammation, and growth. The Rel family of NF-kappaB, predominantly p65.p50 and p50.p50, are transcription factors well known for inducing gene expression by means of interaction with the kappaB motif during acute-phase responses. A functional link between ZAS and NF-kappaB, two distinct families of kappaB-binding proteins, stems from our previous in vitro studies that show that a representative member, ZAS3, associates with TRAF2, an adaptor molecule in tumor necrosis factor signaling, to inhibit NF-kappaB activation. Biochemical and genetic evidence presented herein shows that ZAS3 encodes major kappaB-binding proteins in B lymphocytes, and that NF-kappaB is constitutively activated in ZAS3-deficient B cells. The data suggest that ZAS3 plays crucial functions in maintaining cellular homeostasis, at least in part by inhibiting NF-kappaB by means of three mechanisms: inhibition of nuclear translocation of p65, competition for kappaB gene regulatory elements, and repression of target gene transcription.