Tissue-specific Activity of the γc Chain Gene Promoter Depends upon an Ets Binding Site and Is Regulated by GA-binding Protein

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The γc chain is a subunit of multiple cytokine receptors (interleukin (IL)-2, IL-4, IL-7, IL-9, and IL-15), the expression of which is restricted to hematopoietic lineages. A defect in γc leads to the X-linked severe combined immunodeficiency characterized by a block in T cell differentiation. In order to better characterize the human γc promoter and define the minimal tissue-specific promoter region, progressive 5′-deletion constructs of a segment extending 1053 base pairs upstream of the major transcription start site were generated and tested for promoter activity in various hematopoietic and nonhematopoietic cell types. The −1053/+34 construct allowed promoter activity only in cells of hematopoietic origin, and tissue specificity was conserved in all other constructs tested. The region downstream of −90 appeared critical for basal promoter activity. It contains two potential Ets binding sites conserved in the murine γc promoter gene, one of which was found essential for functional promoter activity as determined by mutational analysis. The functional Ets binding site was found to bind Ets family proteins, principally GA-binding protein and Elf-1 and could be transactivated by GABPα and -β synergistically. These results indicate that, as already reported for the IL2Rβ promoter, GA-binding protein is an essential component of γc basal promoter activity. Although GABP expression is not restricted to the hematopoietic lineage, its interaction with other specific factors may contribute to the tissue-specific expression of the γc gene. The γc chain is a subunit of multiple cytokine receptors (interleukin (IL)-2, IL-4, IL-7, IL-9, and IL-15), the expression of which is restricted to hematopoietic lineages. A defect in γc leads to the X-linked severe combined immunodeficiency characterized by a block in T cell differentiation. In order to better characterize the human γc promoter and define the minimal tissue-specific promoter region, progressive 5′-deletion constructs of a segment extending 1053 base pairs upstream of the major transcription start site were generated and tested for promoter activity in various hematopoietic and nonhematopoietic cell types. The −1053/+34 construct allowed promoter activity only in cells of hematopoietic origin, and tissue specificity was conserved in all other constructs tested. The region downstream of −90 appeared critical for basal promoter activity. It contains two potential Ets binding sites conserved in the murine γc promoter gene, one of which was found essential for functional promoter activity as determined by mutational analysis. The functional Ets binding site was found to bind Ets family proteins, principally GA-binding protein and Elf-1 and could be transactivated by GABPα and -β synergistically. These results indicate that, as already reported for the IL2Rβ promoter, GA-binding protein is an essential component of γc basal promoter activity. Although GABP expression is not restricted to the hematopoietic lineage, its interaction with other specific factors may contribute to the tissue-specific expression of the γc gene.