REGULATION OF THE POLYMERIC IMMUNOGLOBULIN RECEPTOR

聚合免疫球蛋白受体的调节

• 批准号: 2683498
• 负责人: Charlotte S Kaetzel
• 金额: $ 15.11万
• 依托单位: UNIVERSITY OF KENTUCKY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-04-01 至 1999-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2683498
• 关键词: DNA binding protein; DNA footprinting; MHC class II antigen; antibody receptor; cell differentiation; gel mobility shift assay; gene expression; genetic promoter element; genetic regulation; genetic regulatory element; genetic transcription; immunoglobulin A; immunoglobulin genes; immunoregulation; interferon gamma; interferon inducers; intestinal mucosa; neoplastic growth; nucleoproteins; plasmids; receptor expression; reporter genes; secretory immune system; tissue /cell culture; transfection

DESCRIPTION: IgA is transported into external fluids by the polymeric immunoglobulin receptor (pIgR), whose expression is tissue specific and cytokine regulated. Expression of pIgR is abnormally regulated during colon carcinogenesis and has been used a prognostic variable in colon cancer. Investigators have demonstrated that pIgR is expressed in well differentiated human intestinal adenoma and carcinoma cell lines, but not in a human liver cell line or in less differentiated colon carcinoma cell lines and that it is upregulated by interferon gamma. The investigators have located a segment of promoter-proximal region of the pIgR gene which is necessary and sufficient to confer cell-type specificity and interferon gamma inducibility on a reporter gene. They have identified a putative tissue-specific cis-acting element, the pIgR Xbox; binding of nucleoproteins to this element is positively correlated with pIgR expression and transcription activity of pIgR promoter. They have also identified an interferon gamma responsive element which binds interferon regulatory factor I (IRF-I). Deletion of the IRF-I site abolishes interferon gamma inducibility with the pIgR promoter. Significantly the IRF-I site is located within the first exon of the pIgR gene rather than in the 5 prime flanking region. This is the first demonstration of an IRF-I binding site in a promoter-proximal exon and suggests a novel mechanism for transcriptional regulation by interferon gamma. The central hypothesis of this proposed research is that binding of IRF-I to the interferon gamma response element and binding of tissue specific transcription factors to the Xbox element are important mechanisms for regulating transcription of the polymeric immunoglobulin receptor gene. Three specific aims are proposed: 1. The investigators will characterize the role of the IRF-I element in the interferon gamma inducibility of the human pIgR promoter, especially in its unique location within the first exon. 2. The investigator will characterize the role of Xbox element in tissue specific expression of the human pIgR promoter. 3. The investigators will characterize the biochemical and functional properties of proteins that bind the Xbox element both in vitro and in the nuclei of living cells. These studies offer the potential for identifying novel molecular mechanisms which relate expression of the pIgR gene which may offer insights into: a. Immune regulation in the human intestine. b. Specific gene regulation. c. Novel mechanisms of gene regulation by interferon gamma. d. Regulation of gene expression during colon carcinogenesis.

描述：伊加通过聚合物转运到外部液体中， 免疫球蛋白受体（pIgR），其表达是组织特异性的， 细胞因子调节。pIgR的表达在哺乳动物中受到异常调节， 结肠癌发生，并已被用作结肠癌的预后变量 癌 研究人员已经证明，pIgR在细胞中表达良好， 分化的人肠腺瘤和癌细胞系，但 而不是在人肝细胞系或低分化结肠癌中 细胞系，并且其被干扰素γ上调。的 研究人员已经定位了一段启动子近端区域， pIgR基因，其是赋予细胞类型所必需且足够的 特异性和干扰素γ诱导。他们 已经鉴定了一种假定的组织特异性顺式作用元件，pIgR 核蛋白与该元素的结合呈正相关 pIgR启动子的表达和转录活性。他们 还鉴定了一种干扰素γ应答元件， 干扰素调节因子I（IRF-I）。IRF-I位点缺失 用pIgR启动子消除干扰素γ诱导。 值得注意的是，IRF-I位点位于第一外显子内。 pIgR基因，而不是在5总理侧翼区。这是第一 在启动子近端外显子中证明IRF-I结合位点， 提出了一种新的机制，转录调控干扰素 γ的这项研究的核心假设是， IRF-I与干扰素γ应答元件的结合和组织的结合 Xbox元件的特异性转录因子是重要的 调节多聚免疫球蛋白转录的机制 受体基因提出了三个具体目标：1。调查人员 将表征IRF-I元件在干扰素γ中的作用， 人pIgR启动子的诱导，特别是其独特的 在第一个外显子中的位置。2.研究者将描述 Xbox元件在人pIgR组织特异性表达中的作用 启动子3.研究人员将描述生物化学和 结合Xbox元素的蛋白质的功能特性， 在体外和活细胞的细胞核中。 这些研究为鉴定新的分子生物学提供了可能。 与pIgR基因表达相关的机制， 深入了解：a. 人体肠道的免疫调节。B.具体 基因调控C. 干扰素基因调控的新机制 γ的D.结肠癌发生过程中基因表达的调控。