HORMONE-REGULATED EXPRESSION OF INSULIN RECEPTOR GENE

胰岛素受体基因的激素调节表达

• 批准号: 2144225
• 负责人: SOPHIA Y. TSAI
• 金额: $ 14.87万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-01-01 至 1995-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2144225
• 关键词: DNA footprinting; RNase protection assay; corticosteroid receptors; gel mobility shift assay; gene induction /repression; genetic promoter element; genetic regulation; genetic regulatory element; genetic transcription; glucocorticoids; hormone regulation /control mechanism; human genetic material tag; immunoprecipitation; insulin receptor; laboratory rabbit; molecular cloning; mutant; northern blottings; nucleic acid sequence; phorbols; phosphorylation; polymerase chain reaction; protein purification; protein sequence; receptor expression; site directed mutagenesis; transcription factor; transfection; western blottings

Insulin regulates the metabolism and growth of most cells. The action of insulin is mediated through insulin receptor, an integral membrane glycoprotein. The functional receptor is a tetramer composed of two pairs of both subunits linked via disulfide bridges. The alpha-subunit, containing the insulin binding site, is exposed on the extracellular surface. The beta-subunit contains an extracellular, a transmembrane, and an intracellular domain. Within the intracellular domain there is a tyrosine phosphorylation site which is autophosphorylated upon binding of insulin. Autophosphorylation activates the tyrosine kinase associated with the beta-subunit which triggers a signal transduction cascade involving the phosphorylation and dephosphorylation of various cellular proteins. Noninsulin-dependent diabetes mellitus (NIDDM), a heterogeneous disorder is the most common form of diabetes. Although the molecular mechanism by which NIDDM occurs is poorly understood, it is generally believed that genetic defects in insulin signal transduction pathway and environmental factors increase the risk of developing NIDDM. In a rare form of extreme insulin resistance (Leprechaun-Minn-1), the levels of insulin receptors on the cell surface have been greatly reduced due to decrease in transcription of the receptor gene. Since the insulin receptor is a key player in insulin action, it is important to understand how its expression is regulated. The human insulin receptor (hIR) gene encodes a single transcript containing both the alpha and beta-subunits. To study the regulation of this gene, we propose to define the cis-elements required for the hormone responsiveness of its synthesis and to identify the trans-acting factors binding to these elements. Subsequently, we will characterize the important trans-acting factor(s) and clone the corresponding gene(s). This study should provide important insights into how the insulin receptor gene is regulated in the cell and help understand the cause of some forms of insulin resistance.

胰岛素调节大多数细胞的新陈代谢和生长。行动 胰岛素是通过胰岛素受体介导的，胰岛素受体是一种完整的膜 糖蛋白。功能性受体是一种四聚体，由两个 通过二硫键连接的两个亚基对。阿尔法亚单位， 含有胰岛素结合部位，暴露在细胞外 浮出水面。β亚基含有胞外、跨膜、 和一个胞内结构域。在细胞内域中，有 结合后自动磷酸化的酪氨酸磷酸化位点 胰岛素。自身磷酸化激活酪氨酸激酶相关蛋白 与触发信号转导级联的β亚基一起 涉及不同细胞的磷酸化和去磷酸化 蛋白质。 非胰岛素依赖型糖尿病(NIDDM)，一种异质性疾病 是最常见的糖尿病形式。虽然分子机制 人们对NIDDM的发病机制知之甚少，但普遍认为 胰岛素信号转导途径的遗传缺陷与环境 这些因素增加了患NIDDM的风险。以一种罕见的极端形式 胰岛素抵抗(Leprechaun-Minn-1)，胰岛素受体水平 已经大大减少了，因为在细胞表面 受体基因的转录。因为胰岛素受体是一个关键 在胰岛素的作用中，重要的是要了解它是如何 表达是受调控的。人类胰岛素受体(Hir)基因编码 同时包含α和β亚基的单一转录本。至 研究该基因的调控，我们建议定义顺式元件 它的合成所需的激素反应性和识别 与这些元素结合的反式作用因子。随后，我们 将表征重要的反式作用因子(S)，并克隆 相应基因(S)。这项研究应该为以下方面提供重要的见解 胰岛素受体基因在细胞中是如何调节的，并有助于 了解某些形式的胰岛素抵抗的原因。