Nrf2 mediates the induction of ferritin H in response to xenobiotics and cancer chemopreventive dithiolethiones
Nrf2 mediates the induction of ferritin H in response to xenobiotics and cancer chemopreventive dithiolethiones
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DOI：
10.1074/jbc.m210664200
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发表时间：
2003-01-24
影响因子：
4.8
通讯作者：
Torti, SV
中科院分区：
文献类型：
--
作者：
Pietsch, EC;Chan, JY;Torti, SV
铁蛋白是一种普遍存在的细胞内铁储存蛋白，由24个H和L型亚基组成。螯合铁参与氧自由基形成的能力与铁蛋白的细胞保护作用一致。在这里，我们证明，铁蛋白H和L诱导β-萘酮（β-NF）和化学预防性二硫代硫酮处理的细胞。β-NF和二硫杂环戊烯硫酮oltipraz和1，2-二硫杂环戊烯-3-酮（D3 T）对铁蛋白H的诱导通过由铁蛋白H亲电体/抗氧化剂响应元件（EpRE/ARE）介导的转录机制发生。鼠铁蛋白H基因在其5 '启动子区含有5个潜在的外源性反应元件（XRE）序列。然而，缺失分析表明，这些XRE序列在诱导响应于β-NF的铁蛋白H中没有功能。电泳迁移率变动分析表明，铁蛋白H EpRE/ARE结合Nrf 2。用Nrf 2表达载体和Nrf 2显性失活突变体转染嵌合铁蛋白H报告基因表明，Nrf 2在EpRE/ARE处起介导铁蛋白H转录激活的作用。在Nrf 2敲除细胞中未观察到铁蛋白H和L的诱导，表明该转录因子是响应于多环芳香族异生物质和化学预防剂诱导铁蛋白所需的。Nrf 2也可能在铁蛋白H和L的基础转录中起作用。这些结果提供了铁储存蛋白铁蛋白的调节和癌症化学预防反应之间的机制联系。
Ferritin is a ubiquitous intracellular iron storage protein that consists of 24 subunits of the H and L type. The ability to sequester iron from participation in oxygen free radical formation is consistent with a cytoprotective role for ferritin. Here we demonstrate that ferritins H and L are induced in cells treated with beta-napthoflavone (beta-NF) and chemopreventive dithiolethiones. Induction of ferritin H by beta-NF and the dithiolethiones oltipraz and 1,2-dithiole-3-thione (D3T) occurs via a transcriptional mechanism that is mediated by the ferritin H electrophile/antioxidant-responsive element (EpRE/ARE). The murine ferritin H gene contains five potential xenobiotic-responsive element (XRE) sequences in its 5'-promoter region. However, deletion analysis demonstrates that these XRE sequences are not functional in inducing ferritin H in response to beta-NF. Electrophoretic mobility shift assays demonstrate that the ferritin H EpRE/ARE binds Nrf2. Transfection of chimeric ferritin H reporter genes with Nrf2 expression vectors and Nrf2 dominant-negative mutants indicate that Nrf2 functions at the EpRE/ARE to mediate transcriptional activation of ferritin H. Induction of ferritin H and L was not seen in Nrf2 knockout cells, demonstrating that this transcription factor is required for the induction of ferritin in response to polycyclic aromatic xenobiotics and chemopreventive agents. Nrf2 may also play a role in basal transcription of both ferritin H and L. These results provide a mechanistic link between regulation of the iron storage protein ferritin and the cancer chemopreventive response.