The Role of Stat1 in Mitochondria

Stat1 在线粒体中的作用

• 批准号: 7670764
• 负责人: ANDREW Charles LARNER
• 金额: $ 18.27万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7670764
• 关键词: B-Lymphocytes; Binding; Cells; Cytosol; Data; Electron Transport; Family; Genes; Genetic Transcription; Growth Factor; Human; Infection; Interferon-alpha; Interferon-beta; Interferons; Knockout Mice; Localized; Mediating; Mitochondria; Mus; Nuclear; Nuclear Translocation; Null Lymphocytes; Play; Point Mutation; Proteins; Reporting; Respiration; Role; Series; Signal Transduction; Testing; Tyrosine Phosphorylation; Virus Diseases; cell type; cytokine; mitochondrial genome; transcription factor

DESCRIPTION (provided by applicant): The Stat family of transcription factors are well known to control the expression of nuclear encoded cellular genes. As a consequence of incubation of cells with a variety of cytokines and growth factors the Stats are activated by tyrosine phosphorylation resulting in their nuclear translocation. Previous studies have reported that the expression of several mitochondria encoded RNAs is inhibited as a result of incubation of cells with type one interferons (IFN alpha/beta). Preliminary data presented in this application indicates that Stat1 is constitutively present in the mitochondria of both human and mouse cells. In primary murine pro B cells and MEFs isolated from Stat1-null mice the expression of all RNAs that encode mitochondria synthesized proteins are elevated 3 to 8 fold compared to pro B cells or MEFs derived from wild type littermates. Furthermore, we are able to demonstrate that Stat1 binds to the D-loop region of the mitochondrial genome where transcription of the mitochondrially encoded genes is initiated. We hypothesize that Stat1 plays an important role in the expression of mitochondrial encoded mRNAs and possibly other functions involved in electron transport. To test this hypothesis we will perform the following specific aims: 1) Determine whether decreased expression of mitochondria-encoded RNAs is mediated by Stat1 localized in the mitochondria and identify the domains in Stat1 required for its localization in the mitochondria. 2) Determine whether viral infection or IFN beta treatment of cells alters expression of mitochondria-encoded mRNAs and mitochondria respiration.

描述（由申请人提供）：众所周知，转录因子Stat家族控制核编码细胞基因的表达。由于细胞与多种细胞因子和生长因子一起孵育，Stats 被酪氨酸磷酸化激活，导致细胞核转位。先前的研究报道，由于细胞与一型干扰素（IFN α/β）一起孵育，一些线粒体编码的 RNA 的表达受到抑制。本申请中提供的初步数据表明 Stat1 组成型存在于人和小鼠细胞的线粒体中。在从 Stat1 缺失小鼠中分离的原代小鼠 pro B 细胞和 MEF 中，与源自野生型同窝小鼠的 pro B 细胞或 MEF 相比，编码线粒体合成蛋白的所有 RNA 的表达升高了 3 至 8 倍。此外，我们能够证明 Stat1 与线粒体基因组的 D 环区域结合，线粒体编码基因的转录在此启动。我们假设 Stat1 在线粒体编码 mRNA 的表达以及可能涉及电子传递的其他功能中发挥重要作用。为了检验这一假设，我们将执行以下具体目标：1) 确定线粒体编码 RNA 表达的降低是否是由线粒体中定位的 Stat1 介导的，并确定 Stat1 中定位线粒体所需的结构域。 2) 确定细胞的病毒感染或 IFN beta 处理是否会改变线粒体编码 mRNA 的表达和线粒体呼吸。