Iron Regulation of Gene Expression

说明(申请人提供)：铁是细胞生长和增殖所必需的，因为它是DNA合成和能量代谢所需蛋白质中的修复基团。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，而围产期或出生后缺铁可导致神经认知障碍，成人缺铁会导致贫血。因此，所有的有机体都发展了感知、获取和储存铁的机制。在脊椎动物中，铁的代谢由铁调节蛋白2(IRP2)控制。IRP2是一种与RNA结合的蛋白质，与铁摄取、截留和输出相关的蛋白质中的铁反应元件(IRES)结合。IRP2与IRES的结合调节mRNAs的翻译或稳定性。IRP2缺乏会破坏多种组织的铁稳态，导致血液学、神经退行性和代谢紊乱。我们已经确定了调控IRP2功能的新途径和蛋白质：铁调节的FBXL5泛素连接酶对铁的依赖的蛋白分解，以及细胞周期中细胞周期蛋白依赖的激酶1(CDK1)的磷酸化对RNA结合活性的铁不依赖的调节。我们的目标是确定铁如何调节IRP2的稳定性，以及IRP2的磷酸化如何调节细胞周期进程。 公共卫生相关性：数百万患者患有与铁超载和缺铁有关的疾病。铁的营养需求是由于它的作用，如细胞分裂和能量产生等基本的细胞过程。铁的失调会导致血液、代谢和神经退行性疾病，并增加患癌症的风险。由于铁紊乱对健康的不利影响，了解细胞和组织对铁超载和铁缺乏的反应对于治疗这些紊乱很重要。铁调节蛋白2(IRP2)是细胞铁代谢的关键调节因子。我们发现了在增殖细胞和铁超载细胞中调节IRP2的两种新机制。增加对IRP2调节铁平衡和细胞增殖机制的了解，对于开发可用于靶向癌细胞和治疗铁紊乱的疗法非常重要。

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.