Tissue-specific activity of the gamma c chain gene promoter depends upon an Ets binding site and is regulated by GA-binding protein

The gamma c 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 gamma c leads to the X-linked severe combined immunodeficiency characterized by a block in T cell differentiation. In order to better characterize the human gamma c 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 gamma c 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 GABP alpha and -beta synergistically. These results indicate that, as already reported for the IL2R beta promoter, GA-binding protein is an essential component of gamma c 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 gamma c gene.