Interaction of anthracyclines with iron responsive element mRNAs.
Interaction of anthracyclines with iron responsive element mRNAs.
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DOI：
10.1093/nar/gkn774
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发表时间：
2008-12
影响因子：
14.9
通讯作者：
Oyelere AK
中科院分区：
文献类型：
--
作者：
Canzoneri JC;Oyelere AK
mRNA的双链部分通常是各种蛋白质和小分子相互作用的邀请位点。在这些位点的相互作用可用于调节或破坏编码蛋白质产物的稳态。这种配体靶位点作为发夹环结构存在于参与铁稳态的几种蛋白质（包括铁蛋白重链和轻链）的mRNA中，并且被称为铁响应元件（IRE）。这些IRE通过与铁调节蛋白（IRP）的相互作用作为细胞中铁代谢的主要控制机制。IRE/IRP相互作用的破坏可以极大地影响铁代谢。在这里，我们报告说，蒽环类药物，一类临床上有用的化疗药物，包括阿霉素和柔红霉素，专门与铁蛋白重链和轻链的IRES相互作用。我们通过UV熔解、荧光猝灭和药物-RNA足迹来表征这种相互作用。野生型和突变型IRE的足迹实验结果表明，蒽环类药物优先结合在UG摆动对侧翼的不对称凸出的C-残基，保守的基础，是必不可少的IRE-IRP相互作用。此外，根据荧光猝灭实验计算了高纳摩尔范围内的药物-RNA亲和力（表观Kds），而UV熔解研究显示熔解温度（ΔTm）的变化高达10°C。这种蒽环类抗生素-IRE相互作用可能导致蒽环类抗生素暴露导致的细胞内铁稳态的畸变。
Double-stranded sections of mRNA are often inviting sites of interaction for a wide variety of proteins and small molecules. Interactions at these sites can serve to regulate, or disrupt, the homeostasis of the encoded protein products. Such ligand target sites exist as hairpin–loop structures in the mRNAs of several of the proteins involved in iron homeostasis, including ferritin heavy and light chains, and are known as iron responsive elements (IREs). These IREs serve as the main control mechanism for iron metabolism in the cell via their interaction with the iron regulatory proteins (IRPs). Disruption of the IRE/IRP interaction could greatly affect iron metabolism. Here, we report that anthracyclines, a class of clinically useful chemotherapeutic drugs that includes doxorubicin and daunorubicin, specifically interact with the IREs of ferritin heavy and light chains. We characterized this interaction through UV melting, fluorescence quenching and drug–RNA footprinting. Results from footprinting experiments with wild-type and mutant IREs indicate that anthracyclines preferentially bind within the UG wobble pairs flanking an asymmetrically bulged C-residue, a conserved base that is essential for IRE–IRP interaction. Additionally, drug–RNA affinities (apparent Kds) in the high nanomolar range were calculated from fluorescence quenching experiments, while UV melting studies revealed shifts in melting temperature (ΔTm) as large as 10°C. This anthracycline–IRE interaction may contribute to the aberration of intracellular iron homeostasis that results from anthracycline exposure.
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影响因子：
2.9
作者：
GRAVES, DE;KRUGH, TR
通讯作者：
KRUGH, TR
影响因子：
2.9
作者：
Chaires, JB;Satyanarayana, S;Priebe, W
通讯作者：
Priebe, W
影响因子：
14.9
作者：
JAFFREY, SR;HAILE, DJ;HARFORD, JB
通讯作者：
HARFORD, JB
影响因子：
5.1
作者：
Haj, HTB;Salerno, M;Garnier-Suillerot, A
通讯作者：
Garnier-Suillerot, A
DOI：
10.1073/pnas.85.7.2171
发表时间：
1988-04-01
影响因子：
11.1
作者：
LEIBOLD, EA;MUNRO, HN
通讯作者：
MUNRO, HN