Modulation of cellular iron metabolism by hydrogen peroxide -: Effects of H2O2 on the expression and function of iron-responsive element-containing mRNAs in B6 fibroblasts
Modulation of cellular iron metabolism by hydrogen peroxide -: Effects of H2O2 on the expression and function of iron-responsive element-containing mRNAs in B6 fibroblasts
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DOI：
10.1074/jbc.m100245200
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发表时间：
2001-06-08
影响因子：
4.8
通讯作者：
Pantopoulos, K
中科院分区：
文献类型：
--
作者：
Caltagirone, A;Weiss, G;Pantopoulos, K
铁调节蛋白（IRP），IRP 1和IRP 2，与编码转铁蛋白受体（TfR）和铁蛋白的mRNA内的铁响应元件（IRE）结合，协调控制细胞铁的摄取和储存。在铁饥饿的条件下，IRP 1和IRP 2都以高亲和力结合同源IRE，从而稳定TfR并抑制铁蛋白mRNA的翻译。IRE/IRP调节系统通过氧化应激以H2 O2的形式接收额外的输入，这导致IRP 1的快速激活。在这里，我们表明，用100 μ M H2 O2脉冲处理小鼠B6成纤维细胞1小时足以以时间依赖性方式改变铁稳态的关键参数。首先，这种刺激会抑制铁蛋白合成至少8小时，导致细胞铁蛋白含量显着减少（50%）。其次，用H2 O2处理诱导TfR mRNA水平在2-6小时内增加约4倍，并且随后在4小时后新合成的蛋白质积累。这与TfR的细胞表面表达的显著增加、与荧光素标记的转铁蛋白的结合增强以及转铁蛋白介导的铁摄取进入细胞的刺激有关。在线粒体顺乌头酸酶和在bar转运体DMT 1下的bar三价（M）下的bar等（T）下的（D）的水平中没有观察到显著的改变，尽管两者都由两种表征较少的含IRE的mRNA编码。H2 O2处理的细胞表现出增加的能力，螯合铁-59在铁蛋白，尽管减少铁蛋白池，这导致在Fe-59细胞内分布的重排。我们的数据表明，过氧化氢调节细胞铁的收购和细胞内铁分布的IRP 1依赖和非依赖机制。
Cellular iron uptake and storage are coordinately controlled by binding of iron-regulatory proteins (IRP), IRP1 and IRP2, to iron-responsive elements (IREs) within the mRNAs encoding transferrin receptor (TfR) and ferritin. Under conditions of iron starvation, both IRP1 and IRP2 bind with high affinity to cognate IREs, thus stabilizing TfR and inhibiting translation of ferritin mRNAs, The IRE/IRP regulatory system receives additional input by oxidative stress in the form of H2O2 that leads to rapid activation of IRP1. Here we show that treating murine B6 fibroblasts with a pulse of 100 muM H2O2 for 1 h is sufficient to alter critical parameters of iron homeostasis in a time-dependent manner. First, this stimulus inhibits ferritin synthesis for at least 8 h, leading to a significant (50%) reduction of cellular ferritin content. Second, treatment with H2O2 induces a similar to4-fold increase in TfR mRNA levels within 2-6 h, and subsequent accumulation of newly synthesized protein after 4 h, This is associated with a profound increase in the cell surface expression of TfR, enhanced binding to fluorescein-tagged transferrin, and stimulation of transferrin-mediated iron uptake into cells, Under these conditions, no significant alterations are observed in the levels of mitochondrial aconitase and the (D) under bar ivalent (M) under bar etal (T) under bar ransporter DMT1, although both are encoded by two as yet lesser characterized IRE-containing mRNAs, Finally. H2O2-treated cells display an increased capacity to sequester Fe-59 in ferritin, despite a reduction in the ferritin pool, which results in a rearrangement of Fe-59 intracellular distribution. Our data suggest that H2O2 regulates cellular iron acquisition and intracellular iron distribution by both IRP1-dependent and -independent mechanisms.