Induction of ferritin expression by oxalomalate
Induction of ferritin expression by oxalomalate
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DOI：
10.1016/j.bbamcr.2004.01.004
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发表时间：
2004-05-03
影响因子：
5.1
通讯作者：
Colonna, A
中科院分区：
文献类型：
--
作者：
Santamaria, R;Irace, C;Colonna, A
铁蛋白是细胞内普遍存在的铁储存蛋白，其生物合成主要受铁调节蛋白（IRP 1和IRP 2）在转录后水平的调控。这种调节防止铁过量促进活性氧（ROS）的形成。IRP 1是由这样的因素，如细胞内铁水平，氧化剂H2 O2和NO.我们最近证明，顺丁烯二酸（OMA，α-羟基-β-草酰琥珀酸），乌头酸酶的竞争性抑制剂，这是一种酶的柠檬酸循环，显着降低IRP 1的结合活性。本研究的目的是研究这种分子是否可以影响铁蛋白的表达。用凝胶阻滞法检测IRP 1的RNA结合活性，发现用5 mM OMA处理几种细胞系后IRP 1的RNA结合活性降低，6 h后最大降低约3倍。这种影响几乎保持不变，直到48小时后，它恢复到基础水平。细胞内铁蛋白水平，通过蛋白质印迹分析，增加与OMA诱导的IRP 1结合活性的降低。此外，用OMA处理细胞引起铁蛋白mRNA水平的升高。有趣的是，在暴露于铁挑战的细胞中，OMA诱导的铁蛋白过表达阻止了ROS和细胞脂质过氧化的形成。这些数据表明，乌头酸酶的抑制剂，OMA，除了参与能量代谢，是能够控制铁蛋白的表达，可能通过转录后调节或转录调节的分子机制，与有利的后果细胞。(C)2004 Elsevier B.V保留所有权利。
Ferritin is a ubiquitous protein required for intracellular iron storage; its biosynthesis is mainly regulated by iron-regulatory proteins (IRP1 and IRP2) at post-transcriptional level. This regulation prevents iron excess from promoting the formation of reactive oxygen species (ROS). IRP1 is regulated by such factors as intracellular iron levels, the oxidants H2O2 and NO. We recently demonstrated that oxalomalate (OMA, alpha-hydroxy-beta-oxalosuccinic acid), a competitive inhibitor of aconitase, which is an enzyme of the citric acid cycle, remarkably decreases the binding activity of IRP1. The aim of the present study was to investigate whether this molecule could affect the expression of ferritin. The RNA-binding activity of IRP1, evaluated by gel retardation assay, decreased after treatment of several cell lines with 5 mM OMA, with a maximal decrease of about 3-fold after 6 h. This effect remained almost constant up to 48 h after which it returned to basal levels. Intracellular ferritin levels, determined by Western blot analysis, increased in correlation with the OMA-induced decrease of IRP1 binding activity. Furthermore, treatment of cells with OMA caused a rise in ferritin mRNA levels. Interestingly, in cells exposed to iron challenge, OMA-induced overexpression of ferritin prevented formation of ROS and cellular lipid peroxidation. These data show that an inhibitor of aconitase, OMA, besides being involved in energetic metabolism, is able to control ferritin expression, probably through molecular mechanisms of either post-transcriptional regulation or transcriptional modulation, with advantageous consequences for the cell. (C) 2004 Elsevier B.V All rights reserved.