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血红素控制铁蛋白 1（FPN1）转录，涉及 Bach1、Nrf2 和 FPN1 启动子位置-7007 的 MARE/ARE 序列基序。

Heme controls ferroportin1 (FPN1) transcription involving Bach1, Nrf2 and a MARE/ARE sequence motif at position -7007 of the FPN1 promoter.

机构信息

Department of Pediatric Oncology, University of Heidelberg, Im Neuenheimer Feld 153, 69120 Heidelberg, Germany.

出版信息

Haematologica. 2010 Aug;95(8):1261-8. doi: 10.3324/haematol.2009.020123. Epub 2010 Feb 23.

DOI:10.3324/haematol.2009.020123
PMID:20179090
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC2913073/
Abstract

BACKGROUND: Macrophages of the reticuloendothelial system play a key role in recycling iron from hemoglobin of senescent or damaged erythrocytes. Heme oxygenase 1 degrades the heme moiety and releases inorganic iron that is stored in ferritin or exported to the plasma via the iron export protein ferroportin. In the plasma, iron binds to transferrin and is made available for de novo red cell synthesis. The aim of this study was to gain insight into the regulatory mechanisms that control the transcriptional response of iron export protein ferroportin to hemoglobin in macrophages. DESIGN AND METHODS: Iron export protein ferroportin mRNA expression was analyzed in RAW264.7 mouse macrophages in response to hemoglobin, heme, ferric ammonium citrate or protoporphyrin treatment or to siRNA mediated knockdown or overexpression of Btb And Cnc Homology 1 or nuclear accumulation of Nuclear Factor Erythroid 2-like. Iron export protein ferroportin promoter activity was analyzed using reporter constructs that contain specific truncations of the iron export protein ferroportin promoter or mutations in a newly identified MARE/ARE element. RESULTS: We show that iron export protein ferroportin is transcriptionally co-regulated with heme oxygenase 1 by heme, a degradation product of hemoglobin. The protoporphyrin ring of heme is sufficient to increase iron export protein ferroportin transcriptional activity while the iron released from the heme moiety controls iron export protein ferroportin translation involving the IRE in the 5'untranslated region. Transcription of iron export protein ferroportin is inhibited by Btb and Cnc Homology 1 and activated by Nuclear Factor Erythroid 2-like involving a MARE/ARE element located at position -7007/-7016 of the iron export protein ferroportin promoter. CONCLUSIONS: This finding suggests that heme controls a macrophage iron recycling regulon involving Btb and Cnc Homology 1 and Nuclear Factor Erythroid 2-like to assure the coordinated degradation of heme by heme oxygenase 1, iron storage and detoxification by ferritin, and iron export by iron export protein ferroportin.

摘要

背景：网状内皮系统中的巨噬细胞在从衰老或受损红细胞的血红蛋白中回收铁方面发挥着关键作用。血红素加氧酶 1 降解血红素部分并释放出无机铁，这些铁被储存在铁蛋白中或通过铁输出蛋白 ferroportin 输出到血浆中。在血浆中，铁与转铁蛋白结合，以供新的红细胞合成使用。本研究的目的是深入了解控制铁输出蛋白 ferroportin 对巨噬细胞中血红蛋白的转录反应的调节机制。

设计和方法：分析 RAW264.7 小鼠巨噬细胞中铁输出蛋白 ferroportin mRNA 的表达，以响应血红蛋白、血红素、柠檬酸铁铵或原卟啉处理，或通过 siRNA 介导的 Btb 和 Cnc 同源结构域 1 敲低或过表达或核因子红细胞 2 样蛋白的核积累。使用包含铁输出蛋白 ferroportin 启动子特定缺失或新鉴定的 MARE/ARE 元件突变的报告构建体分析铁输出蛋白 ferroportin 启动子活性。

结果：我们表明，铁输出蛋白 ferroportin 与血红素氧合酶 1 一起通过血红素转录调控，血红素是血红蛋白的降解产物。血红素的原卟啉环足以增加铁输出蛋白 ferroportin 的转录活性，而从血红素部分释放的铁控制铁输出蛋白 ferroportin 的翻译，涉及 5'非翻译区中的 IRE。Btb 和 Cnc 同源结构域 1 抑制铁输出蛋白 ferroportin 的转录，而核因子红细胞 2 样蛋白通过位于铁输出蛋白 ferroportin 启动子-7007/-7016 位的 MARE/ARE 元件激活铁输出蛋白 ferroportin 的转录。

结论：这一发现表明，血红素控制涉及 Btb 和 Cnc 同源结构域 1 和核因子红细胞 2 样蛋白的巨噬细胞铁回收调节子，以确保血红素氧合酶 1 对血红素的协同降解、铁蛋白的铁储存和解毒以及铁输出蛋白 ferroportin 的铁输出。

相似文献

[1]
Heme controls ferroportin1 (FPN1) transcription involving Bach1, Nrf2 and a MARE/ARE sequence motif at position -7007 of the FPN1 promoter.

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[2]
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本文引用的文献

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J Biol Chem. 2007-11-23

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Mol Cell Biol. 2007-10

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