Iron Regulation of Gene Expression

描述（由申请人提供）：铁是细胞生长和增殖所必需的，因为它在DNA合成和能量代谢所需的蛋白质中起着辅助基团的作用。在人类中，细胞铁超载可导致糖尿病和神经退行性疾病，并与癌症风险增加有关，而围产期或产后缺铁可导致神经认知障碍，成年人缺铁可导致贫血。因此，所有生物都发展了感知、获取和储存铁的机制。在脊椎动物中，铁代谢是由铁调节蛋白2 （IRP2）控制的。IRP2是一种rna结合蛋白，与铁响应元件（IREs）结合，这些元件位于参与铁摄取、隔离和输出的蛋白质的mrna中。IRP2结合IREs调控mrna的翻译或稳定性。小鼠IRP2缺乏会损害多种组织中的铁稳态，并导致血液、神经退行性和代谢紊乱。我们已经确定了调节IRP2功能的新途径和蛋白质：铁调节的FBXL5泛素连接酶的铁依赖性蛋白水解和细胞周期中细胞周期蛋白依赖性激酶1 （CDK1）磷酸化对rna结合活性的铁非依赖性调节。我们的目标是确定铁如何调节IRP2的稳定性以及IRP2磷酸化如何调节细胞周期进程。

DESCRIPTION (provided by applicant): Iron is essential for cell growth and proliferation due to its role as prosthetic group in proteins required for DNA synthesis and energy metabolism. In humans, cellular iron overload can result in diabetes mellitus and neurodegenerative disease, and is associated with an increased risk of cancer, while iron deficiency perinatally or postnatally can cause neurocognitive impairment, and deficiency in adults cause anemia. All organisms have therefore developed mechanisms to sense, acquire and store iron. In vertebrates, iron metabolism is controlled by iron-regulatory protein 2 (IRP2). IRP2 is a RNA-binding protein that binds to iron-responsive elements (IREs) located in mRNAs of proteins involved in iron uptake, sequestration and export. IRP2 binding to IREs regulates the translation or stability of mRNAs. IRP2 deficiency in mice impairs iron homeostasis in multiple tissues, and leads to hematological, neurodegenerative and metabolic disorders. We have identified novel pathways and proteins regulating IRP2 function: iron-dependent proteolysis by an iron-regulated FBXL5 ubiquitin ligase and iron-independent regulation of RNA-binding activity by cyclin-dependent kinase 1 (CDK1) phosphorylation during the cell cycle. Our goals are to determine how iron regulates IRP2 stability and how IRP2 phosphorylation regulates cell cycle progression. PUBLIC HEALTH RELEVANCE: Millions of patients suffer from diseases involving iron overload and deficiency. The nutritional requirement for iron is due to its role such essential cellular processes as cell division and energy production. Iron dysregulation leads to hematological, metabolic and neurodegenerative diseases, and increases the risk of cancer. Because of the adverse impact of iron disorders on health, understanding how cells and tissues respond to iron overload and deficiency is important for treating these disorders. Iron regulatory protein 2 (IRP2) is a key regulator of cellular iron metabolism. We have discovered two novel mechanisms that regulate IRP2 in proliferating cells and in iron overloaded cells. Increased knowledge of the mechanism by which IRP2 regulates iron balance and cell proliferation is important for developing therapeutics that can be used to target cancer cells and treat iron disorders.