IRON REGULATION OF GENE EXPRESSION

铁对基因表达的调节

• 批准号: 2734682
• 负责人: Elizabeth Ann Leibold
• 金额: $ 20.83万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-01-01 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2734682
• 关键词: RNA binding protein; Xenopus oocyte; aconitate hydratase; affinity chromatography; complementary DNA; developmental genetics; embryonic stem cell; enzyme mechanism; gene expression; genetic regulation; genetically modified animals; homeostasis; iron metabolism; laboratory mouse; messenger RNA; mutant; polymerase chain reaction; protein degradation; protein structure function; proteolysis

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.

该提案的目的是促进对 参与铁稳态调节的过程。需要铁 大多数生物体为了生存而生存，并在许多生物中发挥作用 过程包括氧和电子传输、固氮和 DNA合成。游离铁由于其形成能力而对细胞有毒 反应性羟基导致脂质膜过氧化和损伤 脱氧核糖核酸。在人类中，过量细胞铁的积累会导致 组织损伤导致肝硬化、关节炎、心肌病、糖尿病 和增加患癌症的风险。为了防止铁中毒，细胞 通过调节铁的吸收量来严格维持铁水平 并由细胞储存。细胞铁稳态受铁调节 调节蛋白 1 和 2（IRP1 和 IRP2）。 IRP 是胞质 RNA 与特定茎环结构结合的结合蛋白 铁反应元件（IRE）。 IRE 位于 5' 或 3' 编码参与摄取的蛋白质的 mRNA 非翻译区， 铁的储存或利用。 IRP1展示了两个互斥的 活动取决于细胞内铁水平：当铁缺乏时 IRP1 与 IRE 结合，调节 mRNA 翻译或稳定性；当熨斗 丰富的IRP1表现出乌头酸酶活性，催化 柠檬酸盐和异柠檬酸盐的相互转化。与 IRP1 相比，IRP2 仅作为 RNA 结合蛋白发挥作用。虽然 IRP1 和 IRP2 都 调节含有 IRE 的 mRNA，这些蛋白质在生化方面有所不同，并且 在结构上，铁通过不同的机制调节其活性。 不知道为什么两个IRP会进化，也不知道它们是否发挥作用 调节铁代谢的不同作用。在这个提案中，我们计划 解决 IRP1 和 IRP2 在铁代谢中的不同作用。