REGULATION OF THE POLYMERIC IMMUNOGLOBULIN RECEPTOR

聚合免疫球蛋白受体的调节

• 批准号: 6350096
• 负责人: Charlotte S Kaetzel
• 金额: $ 23.33万
• 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 2004-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6350096
• 关键词: antibody receptor; binding sites; colon neoplasms; cytokine; gastrointestinal absorption /transport; genetic regulation; genetic regulatory element; immunogenetics; immunoglobulin A; immunoregulation; intestinal mucosa; laboratory mouse; receptor expression; secretory immune system; tissue /cell culture; transcription factor

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：免疫球蛋白通过聚合物输送到外部流体中。 免疫球蛋白受体(PIgR)，其表达具有组织特异性和 细胞因子受调控。PIgR的表达受到异常调节 结肠癌的发生，并已被用作结肠癌的预后变量 癌症。研究人员已经证明，pIgR在Well中表达 分化的人类肠腺瘤和癌细胞系，但 在人类肝细胞系或分化较低的结肠癌中不存在 而且干扰素-伽马能上调其表达。这个 研究人员已经定位了一段启动子-近端区域 赋予细胞类型所必需且充分的pIgR基因 报告基因的特异性和干扰素伽马诱导性。他们 已经确定了一种可能的组织特异性顺式作用元件，即pIgR 核蛋白与该元件的结合呈正相关 PIgR的表达和pIgR启动子的转录活性。他们 还发现了一种干扰素伽马反应元件，它能结合 干扰素调节因子I(IRF-I)。删除IRF-I网站 取消pIgR启动子对干扰素伽马的诱导作用。 值得注意的是，IRF-I位点位于 PIgR基因，而不是在5号素侧翼区。这是第一次 启动子-近端外显子中IRF-I结合位点的证明 提示干扰素转录调控的一种新机制 伽马。这项拟议研究的中心假设是约束性 IRF-I对干扰素-γ反应元件和组织结合的影响 Xbox元件的特定转录因子很重要 多聚体免疫球蛋白转录调控机制的研究 受体基因。提出了三个具体目标：1.调查人员 将描述IRF-I元件在干扰素伽马中的作用 人pIgR启动子的诱导性，特别是在其独特的 位于第一个外显子内。2.调查员将描述 Xbox元件在人pIgR组织特异性表达中的作用 推动者。3.调查人员将对生物化学和 结合Xbox元件的蛋白质的功能特性 在体外和活细胞的核中。 这些研究为识别新的分子提供了可能性。 PIgR基因表达的相关机制可能提供 洞察：a。人体肠道的免疫调节。B.具体情况 基因调控。C.干扰素基因调控的新机制 伽马。D.结肠癌发生过程中基因表达的调控。