Biological Function of Iron Responsive Elements

铁反应元件的生物学功能

基本信息

批准号：
7678621
负责人：
Richard S. Eisenstein
金额：
$ 31.8万
依托单位：
UNIVERSITY OF WISCONSIN-MADISON
依托单位国家：
美国
项目类别：
财政年份：
2005
资助国家：
美国
起止时间：
2005-09-30 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7678621
关键词：
5&apos Untranslated Regions Aconitate Hydratase Acquired Immunodeficiency Syndrome Affect Affinity Age American Animals Area Binding Biological Process Cell Maintenance Cell physiology Cells Chemicals Citric Acid Cycle Code Deficiency Diseases Development Dietary Iron Disease Elements Enzymes Eukaryotic Initiation Factors Face Ferritin Gender Gene Expression Regulation Genes Genetic Translation Goals Health Homeostasis Human Indium Individual Iron Iron Overload Iron Regulatory Protein 1 Iron-Regulatory Proteins L-ferritin Lead Maca Maintenance Malignant Neoplasms Malnutrition Mammals Messenger RNA Metabolic Metabolism Mitochondria Molecular Mutation NMR Spectroscopy Nerve Degeneration Nutrient Organ Organism Pathway interactions Pattern Formation Physiological Post-Translational Protein Processing Process Proteins RNA RNA Splicing RNA-Binding Proteins RNA-Protein Interaction Regulation Regulatory Element Relative (related person)Research Role Site Solutions Stem cells Structure Thermodynamics Time Transcriptional Regulation Transfer RNA Translational Regulation Translations Untranslated Regions Viral Work absorption base cell type combinatorial fitness in vivo iron metabolism meetings mutant nervous system disorder novel protein expression response synthetic protein translation factor uptake

项目摘要

DESCRIPTION (provided by applicant): Iron is an essential but potentially toxic nutrient for nearly all organisms. Iron deficiency is the most common human nutritional deficiency disease with 2 to 22% of Americans suffering from it depending on age and gender. At the same time excessive iron stores are associated with neurological disorders and certain cancers. Mammalian iron metabolism is modulated by two regulatory RNA binding proteins, iron regulatory protein 1 (IRP1) and IRP2. IRPs bind to iron responsive elements (IRE) in up to seven different mRNA encoding proteins critical for the maintenance of iron homeostasis or for other pathways needed during the adaptive response to iron deficiency. This includes proteins involved in the transport, use and storage of iron as well as the TCA cycle enzyme mitochondrial aconitase. It is clear that IRE-containing mRNA are differentially regulated by IRP in order to meet the physiological demands of various cell types yet relatively little is known as to how IRPs discriminate between different mRNA. Because IRPs are pivotal regulators of iron metabolism, and dysregulation of the expression of proteins encoded by IRE-containing mRNA contributes to neurodegenerative, iron overload and other diseases, it is important to elucidate the mechanisms through which IRE-containing mRNA are selectively regulated. Our overall goal is to understand how iron metabolism is controlled through the hierarchical regulation of IRE-containing mRNA. We demonstrate that mRNA with one IRE in their 5' untranslated region are differentially regulated by IRP; we propose several novel hypotheses to explain this hierarchical regulation and we propose to: 1) determine the structure of the 5' IRE region of mitochondrial aconitase (macon) mRNA and the role of IRP and specific translation factors as well as flanking sequences in the structure and/or thermodynamic stability of this region; 2) determine the role of specific translation factors, cellular protein synthetic capacity and individual IRP in the selective regulation of the use of IRE-containing mRNA; 3) elucidate the role of IRE and flanking sequences in the hierarchical regulation of the translation in vivo of mRNA containing functionally strong or weak IRE-regions in the 5' UTR. Our studies provide a comprehensive approach from the molecular to the cellular level that will: a) delineate the mechanisms that define the breadth of the IRP regulatory spectrum; b) demonstrate how target site diversity amongst RNA regulatory elements controls mRNA fate; and c) serve as a paradigm for understanding how combinatorial mRNA regulation controls fundamental biological processes.

描述（由申请人提供）：铁是几乎所有生物体必需但潜在有毒的营养物质。缺铁是最常见的人类营养缺乏疾病，根据年龄和性别，2% 至 22% 的美国人患有缺铁。同时，过多的铁储存与神经系统疾病和某些癌症有关。哺乳动物铁代谢由两种调节 RNA 结合蛋白：铁调节蛋白 1 (IRP1) 和 IRP2 调节。 IRP 与多达七种不同 mRNA 编码蛋白中的铁反应元件 (IRE) 结合，这些蛋白对于维持铁稳态或对铁缺乏的适应性反应期间所需的其他途径至关重要。这包括参与铁的运输、使用和储存的蛋白质以及 TCA 循环酶线粒体乌头酸酶。很明显，IRP 对含有 IRE 的 mRNA 进行差异性调节，以满足各种细胞类型的生理需求，但对于 IRP 如何区分不同 mRNA 的了解相对较少。由于 IRP 是铁代谢的关键调节因子，并且含有 IRE 的 mRNA 编码的蛋白质表达失调会导致神经退行性、铁过载和其他疾病，因此阐明选择性调节含有 IRE 的 mRNA 的机制非常重要。我们的总体目标是了解如何通过含有 IRE 的 mRNA 的分层调控来控制铁代谢。我们证明，5'非翻译区有一个 IRE 的 mRNA 受到 IRP 的差异调节；我们提出了几个新的假设来解释这种分层调节，我们建议：1）确定线粒体乌头酸酶（macon）mRNA 5'IRE区域的结构以及IRP和特定翻译因子以及结构中的侧翼序列的作用和/或该区域的热力学稳定性； 2)确定特定翻译因子、细胞蛋白质合成能力和个体IRP在选择性调节含有IRE的mRNA的使用中的作用； 3) 阐明IRE和侧翼序列在5'UTR中包含功能强或弱IRE区域的mRNA体内翻译的分级调节中的作用。我们的研究提供了从分子到细胞水平的综合方法，该方法将： a) 描述定义 IRP 监管范围广度的机制； b) 证明 RNA 调控元件之间的靶位点多样性如何控制 mRNA 的命运； c) 作为理解组合 mRNA 调控如何控制基本生物过程的范例。