IRON REGULATION OF GENE EXPRESSION

这项建议的目的是帮助理解 参与铁稳态调节的过程。需要熨斗 由大多数生物赖以生存，并在许多生物中发挥作用 包括氧气和电子传输、固氮和 DNA合成。游离铁因其形成能力而对细胞有毒 引起脂膜过氧化和损害的活性羟基 DNA在人类中，过多的细胞铁积累会导致 组织损伤导致肝硬变、关节炎、心肌病、糖尿病 罹患糖尿病和癌症风险增加。为了防止铁中毒，细胞 通过调节铁摄入量来严格维持铁水平 并由细胞存储。细胞内的铁稳态受铁- 调节蛋白1和2(IRP1和IRP2)。IRP是胞质RNA- 与特定的茎环结构相结合的结合蛋白，称为 铁响应元件(IRE)。IRES位于5‘或3’ 编码参与摄取的蛋白质的mRNAs的非翻译区， 铁的储存或利用。IRP1展示了两个互斥的 取决于细胞内铁水平的活动：缺铁时 Irp1与调节mRNA翻译或稳定性的IRES结合；当铁 丰富的Irp1显示出乌头酸酶活性，催化 柠檬酸和异柠檬酸的相互转化。与IRP1相比，IRP2 仅作为一种RNA结合蛋白发挥作用。虽然IRP1和IRP2都 调节含有IRE的mRNAs这些蛋白质在生化上和 在结构上，铁通过不同的机制调节它们的活动。 不知道为什么两个IRP进化了，也不知道他们是否在玩 在调节铁代谢中的不同作用。在这份提案中，我们计划 探讨IRP1和IRP2在铁代谢中的不同作用。

The aim of this proposal is to contribute to an understanding of the processes involved in regulation of iron homeostasis. Iron is required by most organisms for survival and plays a role in many biological processes including oxygen and electron transport, nitrogen fixation, and DNA synthesis. Free iron is toxic to cells due to its ability to form reactive hydroxyls that cause peroxidation of lipid membranes and damage DNA. In human, the accumulation of excess cellular iron can result in tissue damage leading to cirrhosis, arthritis, cardiomyopathy, diabetes mellitus and increased risk of cancer. To prevent iron toxicity, cells tightly maintain iron levels by regulating the amount of iron taken up and stored by cells. Cellular iron homeostasis is regulated by the iron- regulatory proteins 1 and 2 (IRP1 and IRP2). IRPs are cytosolic RNA- binding proteins that bind to a specific stem-loop structure termed the iron responsive element (IRE). IREs are located in the 5' or 3' untranslated regions of mRNAs that encode proteins involved in uptake, storage or utilization of iron. IRP1 exhibits two mutually exclusive activities depending on intracellular iron levels: when iron is scarce IRP1 binds to IREs regulating mRNA translation or stability; when iron is abundant IRP1 exhibits aconitase activity catalyzing the interconversion of citrate and isocitrate. In contrast to IRP1, IRP2 functions solely as an RNA-binding protein. Although IRP1 and IRP2 both regulate IRE-containing mRNAs these proteins differ biochemically and structurally and iron regulates their activities by different mechanisms. It is not known why two IRPs evolved not is it know whether they play different roles in regulating iron metabolism. In this proposal, we plan to address the different roles of IRP1 and IRP2 in iron metabolism.