ROLE FOR NF-KAPPA-B IN THE REGULATION OF FERRITIN-H BY TUMOR-NECROSIS-FACTOR-ALPHA
ROLE FOR NF-KAPPA-B IN THE REGULATION OF FERRITIN-H BY TUMOR-NECROSIS-FACTOR-ALPHA
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DOI：
10.1074/jbc.270.25.15285
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发表时间：
1995-06-23
影响因子：
4.8
通讯作者：
TORTI, FM
中科院分区：
文献类型：
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作者：
KWAK, EL;LAROCHELLE, DA;TORTI, FM
铁蛋白是一种普遍存在的铁结合蛋白，在细胞铁稳态中起关键作用。它由两个亚基组成，分别称为H（重或心脏）和L（轻或肝脏）。在成纤维细胞和其他细胞中，细胞因子肿瘤坏死因子- α (TNF)特异性地诱导铁蛋白H亚基的合成。利用核径流试验，我们证明了这种依赖于tnf的铁蛋白H的增加是由铁蛋白H转录的选择性增加介导的。将含有小鼠铁蛋白H 5'侧区与人类生长激素报告基因融合的嵌合基因转染小鼠成纤维细胞，发现介导这种反应的cia作用元件位于转录起始位点远端的4.8千碱基处。缺失分析将tnf反应区划分为位于核苷酸-4776和-4736之间的40个核苷酸序列，我们称之为FER-2。电泳迁移率转移测定和位点特异性突变表明，该区域包含两个独立的元素：一个包含一个结合NF-kappa B转录因子家族成员的序列，另一个包含一个部分符合NF-kappa B共识序列的新序列，并可能结合NF-kappa B/Rel转录因子家族的不同成员，因此，炎症细胞因子对铁蛋白的影响是由一个对氧化应激反应的转录因子家族介导的。
Ferritin is a ubiquitously distributed iron-binding protein that plays a key role in cellular iron homeostasis. It is composed of two subunits, termed H (heavy or heart) and L (light or liver), In fibroblasts and other cells, the cytokine tumor necrosis factor-alpha (TNF) specifically induces synthesis of the ferritin H subunit. Using nuclear run-off assays, we demonstrate that this TNF-dependent increase in ferritin H is mediated by a selective increase in ferritin H transcription. Transfection of murine fibroblasts with chimeric genes containing the 5'-flanking region of murine ferritin H fused to the human growth hormone reporter gene reveals that the cia-acting element that mediates this response is located similar to 4.8 kilobases distal to the start site of transcription. Deletion analyses delimit the TNF-responsive region to a 40-nucleotide sequence located between nucleotides -4776 and -4736, which we term FER-2. Electrophoretic mobility shift assays and site-specific mutations indicate that this region contains two independent elements: one contains a sequence that binds a member of the NF-kappa B family of transcription factors, and a second contains a novel sequence that partially conforms to the NF-kappa B consensus sequence and may bind a different member of the NF-kappa B/Rel transcription factor family, Thus, effects of an inflammatory cytokine on ferritin are mediated by a family of transcription factors responsive to oxidative stress.