A regulatory domain within the virus-response element of the interferon alpha 1 gene acts as a transcriptional repressor sequence and determinant of cell-specific gene expression.
Type-I interferons are encoded by a multigene family, the major members of which are at least 13 IFN A subtypes and a single IFN B gene. IFNs A and B are induced in response to similar stimuli, such as virus infection and double-stranded RNA, but in different cell types: the induction of IFN A is almost exclusively restricted to cells of lymphoid origin, while IFN B has been found to be induced in a variety of cell types including fibroblasts. The virus-responsive enhancer element in the promoter region of IFN A family members is largely responsible for the differential expression of individual subtypes in responsive cells. In this paper we describe experiments which address the issue of the differential expression of IFN A and IFN B in different cell types. We show that IFN-beta is induced in a variety of cells of different origin, while not all of these are able to secrete IFN-alpha. By transfection of reporter gene constructs comprising the virus-responsive enhancer from the IFN A1 and IFN B genes, we show that this differential response is mediated at the level of transcription via these control elements. More detailed analysis of the function of these regions identifies specific sequences within the IFN A1 virus response element that has an inhibitory effect on expression in cells that are normally inducible, and is also implicated in the overall suppression of IFN A induction in non-inducible cells.
Dent
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CL
Division of Biology, Wellcome Research Laboratories, Beckenham, UK.
Gewert
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D000469:Alkaline Phosphatase / Q000096:biosynthesis; D001483:Base Sequence; D002460:Cell Line; D017931:DNA Primers; D004742:Enhancer Elements, Genetic; D015967:Gene Expression Regulation, Viral; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis* / Q000235:genetics*; D016899:Interferon-beta / Q000096:biosynthesis* / Q000235:genetics; D008969:Molecular Sequence Data; D005810:Multigene Family; D009928:Organ Specificity; D010222:Parainfluenza Virus 1, Human / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D021382:Protein Sorting Signals / Q000096:biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000096:biosynthesis; D012045:Regulatory Sequences, Nucleic Acid; D013489:Suppression, Genetic; D014158:Transcription, Genetic; D014162:Transfection; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D016898:Interferon-alpha; D021382:Protein Sorting Signals; D012333:RNA, Messenger; D011994:Recombinant Proteins; D016899:Interferon-beta; D000469:Alkaline Phosphatase