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IFN- and Its Receptor Subunit IFNGR1 Are Recruited to the IFN--Activated Sequence Element at the Promoter Site of IFN--Activated Genes: Evidence of Transactivational Activity in IFNGR1¹

Department of Microbiology and Cell Science, University of Florida, Gainesville, FL 32611

We have shown previously that IFN- and one of its receptor subunits, IFNGR1, are translocated to the nucleus, together with STAT1 as one macromolecular complex, via the classical importin-dependent pathway. In this study, we have identified the nuclear targets of IFN- and IFNGR1. By chromatin immunoprecipitation followed by PCR, IFN-, its receptor subunit IFNGR1, and STAT1 were found to be associated with the IFN--activated sequence (GAS) in the promoter of two of the genes stimulated by IFN-. Immunoprecipitated chromatin also showed the association of the IFN-, IFNGR1, and STAT1 on the same DNA sequence. Examination of nuclear extracts from WISH cells treated with IFN- revealed the specific binding of IFN-, IFNGR1, and STAT1 to biotinylated GAS nucleotide sequence. Association of IFN-, IFNGR1, and STAT1 with the GAS promoter was also demonstrated by EMSA. Transfection with a GAS-luciferase gene together with the IFNGR1 and nonsecreted IFN- resulted in enhanced reporter activity. In addition, IFNGR1 fused to the yeast GAL4 DNA binding domain resulted in enhanced transcription from a GAL4 response element, suggesting the presence of a trans activation domain in IFNGR1. Our observations put IFN- and its receptor subunit, IFNGR1, in direct contact with the promoter region of IFN--activated genes with associated increased activity, thus suggesting a transcriptional/cotranscriptional role for IFN-/IFNGR1 as well as a possible role in determining the specificity of IFN- action.

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