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.

该提议的目的是为理解 铁稳态调节涉及的过程。需要铁 大多数生存生物都在许多生物学中发挥作用 包括氧和电子传输，氮固定和电子传输的过程 DNA合成。游离铁由于其形成能力而对细胞有毒 导致脂质膜过氧化和损伤的反应性羟基 脱氧核糖核酸。在人类中，过量的细胞铁的积累可能导致 组织损伤导致肝硬化，关节炎，心肌病，糖尿病 Mellitus和癌症风险增加。为了防止铁毒性，细胞 通过调节被吸收的铁的量严格维持铁水平 并由细胞存储。细胞铁稳态受铁 - 调节蛋白1和2（IRP1和IRP2）。 IRP是胞质RNA- 结合与特定干循环结构结合的蛋白质称为 铁反应元件（IRE）。 IRES位于5'或3' 编码参与摄取的蛋白质的mRNA的未翻译区域， 铁的储存或利用。 IRP1展示了两个相互排斥的 活动取决于细胞内铁的水平：当铁稀缺时 IRP1与调节mRNA翻译或稳定性的IRES结合；当铁 大量的IRP1表现出刺激性的刺激性IRP1活性 柠檬酸盐和异位酸的互连。与IRP1相反，IRP2 仅充当RNA结合蛋白。虽然IRP1和IRP2都 调节含IRE的mRNA这些蛋白质在生化上不同， 结构上和铁通过不同的机制调节其活动。 尚不知道为什么两个IRP不进化 在调节铁代谢方面的作用不同。在此提案中，我们计划 解决IRP1和IRP2在铁代谢中的不同作用。