REGULATION OF THE IGF-I RECEPTOR GENE BY WT1

描述（改编自申请人的摘要）：总体目标 这项研究旨在评估IGF-IR基因表达在 正常肾脏发育及其对肾脏疾病的影响 如Wilms肿瘤。 WT 1的产物，肾母细胞瘤 抑制基因是一种锌指转录因子，通常 抑制其靶基因。 WT-1表达是正常肾脏所必需的 WT-1基因座的发育和突变或缺失通常与 肾母细胞瘤。 研究者先前提出WT-1调节 IGF-IR基因的突变是后肾发育的重要因素， 并且这种控制机制的改变导致异常的肾脏 发展 调查员现在提议审查涉及的机制 WT-1对IGF-IR表达的调节作用。 主要的假设是 将测试WT-1的各种同种型控制IGF-IR基因表达 通过差异结合和蛋白质-蛋白质相互作用， 转录因子 提出了四个具体目标。 1)证明 293例人胚胎内源性IGF-IR基因表达的调控 通过调节内源性WT-1基因表达和/或WT-1 行动上 2)评估自然发生和临床上的影响 WT-1的相关突变形式对IGF-IR基因表达的调节， 缺乏WT-1的肾衍生细胞系。 3)为了研究 WT-1蛋白与转录激活因子Sp-1的结合， 基础IGF-IR启动子活性，可能是一个必要的组成部分， WT-1介导的IGF-IR基因表达抑制。 4)以识别 可能与WT-1相互作用并有助于其活性的其他蛋白质; 这些可能包括修饰WT-1的其他转录因子或蛋白质 结构

DESCRIPTION (Adapted from the applicant's abstract): The overall goal of the proposed research is to assess the role of IGF-IR gene expression in normal renal development and its contribution to disorders of kidney development such as Wilms tumor. The product of WT1, the Wilms tumor suppressor gene, is a zinc-finger transcription factor that generally represses its target genes. WT-1 expression is necessary for normal kidney development and mutation or loss of the WT-1 locus is often associated with Wilms tumor. The investigator has proposed previously that WT-1 regulation of the IGF-IR gene is an important factor in metanephrogenic development, and that alterations in this control mechanism result in aberrant kidney development. The investigator now proposes to examine mechanisms involved in regulation of IGF-IR expression by WT-1. The main hypothesis to be tested will be that various isoforms of WT-1 control IGF-IR gene expression through differential binding and protein-protein interactions with other transcription factors. Four Specific Aims are proposed. 1) To demonstrate regulation of endogenous IGF-IR gene expression in 293 human embryonic kidney cells by modulation of endogenous WT-1 gene expression and/or WT-1 action. 2) To assess the effects of naturally occurring and clinically relevant mutant forms of WT-1 on regulation of IGF-IR gene expression in a kidney derived cell line that lacks WT-1. 3) To investigate the interaction of WT-1 proteins with the transcriptional activator Sp-1, which is required for basal IGF-IR promoter activity, and which may be a necessary component for WT-1 mediated repression of IGF-IR gene expression. 4) To identify other proteins that may interact with WT-1 and contribute to its activity; these may include other transcription factors or proteins that modify WT-1 structure.