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.
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