IRON REGULATION OF GENE EXPRESSION

本提案的目的是促进对《公约》的理解， 参与调节铁稳态的过程。铁是必需的 大多数生物的生存，并在许多生物中发挥作用， 包括氧和电子传递、固氮和 DNA合成游离铁是有毒的细胞，由于它的能力，形成 导致脂质膜过氧化和损伤的活性羟基 DNA.在人类中，过量细胞铁的积累可导致 组织损伤导致肝硬化、关节炎、心肌病、糖尿病 糖尿病和癌症风险增加。为了防止铁中毒，细胞 通过调节铁的摄入量来严格维持铁的水平 并由细胞储存。细胞铁稳态由铁- 调节蛋白1和2（IRP 1和IRP 2）。IRP是细胞溶质RNA- 结合蛋白结合特定的茎环结构，称为 铁响应元件（IRE）。IRE位于5'或3'端 编码参与摄取的蛋白质的mRNA的非翻译区， 铁的储存或利用。IRP 1表现出两个相互排斥的 活性取决于细胞内铁水平：当铁缺乏时 IRP 1与调节mRNA翻译或稳定性的IRE结合;当铁 丰富的IRP 1表现出顺乌头酸酶活性， 柠檬酸盐和异柠檬酸盐的相互转化。与IRP 1相比，IRP 2 仅作为RNA结合蛋白发挥作用。虽然IRP 1和IRP 2都 这些蛋白质在生物化学上不同， 铁通过不同的机制调节它们的活性。 目前还不知道为什么两个IRP进化不知道他们是否玩 在调节铁代谢中的不同作用。在这份提案中，我们计划 研究IRP 1和IRP 2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.