HORMONE-REGULATED EXPRESSION OF INSULIN RECEPTOR GENE

胰岛素调节大多数细胞的代谢和生长。 的行动 胰岛素的分泌是通过胰岛素受体介导的， 糖蛋白 功能性受体是由两个 两个亚基通过二硫桥连接。 α亚基， 含有胰岛素结合位点，暴露在细胞外 面 β-亚基含有细胞外，跨膜， 和胞内结构域。 在细胞内结构域中， 酪氨酸磷酸化位点，其在结合后自磷酸化 胰岛素。 自磷酸化激活酪氨酸激酶相关的 β亚基引发信号传导级联反应 包括各种细胞的磷酸化和去磷酸化 proteins. 非胰岛素依赖型糖尿病（NIDDM），一种异质性疾病 是糖尿病最常见的形式。 虽然分子机制 对于NIDDM发生的原因知之甚少，但通常认为， 胰岛素信号转导通路的遗传缺陷与环境 这些因素增加了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 在细胞表面上已经大大减少， 受体基因的转录。 因为胰岛素受体是 在胰岛素作用中，重要的是要了解其 表达是有规律的。 人胰岛素受体（hIR）基因编码 包含α和β亚基的单一转录物。 到 为了研究该基因的调控，我们建议定义顺式元件 所需的激素反应的合成，并确定 与这些元素结合的反式作用因子。 后续我们 将表征重要的反式作用因子并克隆 对应的基因。 这项研究应该提供重要的见解， 胰岛素受体基因是如何在细胞中调节的， 了解某些形式的胰岛素抵抗的原因

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.