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 (interle ukin (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 gam ma c promoter and define the minimal tissue-specific promoter region, progressive 5'-deletion constructs of a segment extending 1053 base pa irs upstream of the major transcription start site were generated and tested for promoter activity in various hematopoietic and nonhematopoi etic cell types, The -1053/+34 construct allowed promoter activity onl y in cells of hematopoietic origin, and tissue specificity was conserv ed in all other constructs tested, The region downstream of -90 appear ed critical for basal promoter activity. It contains two potential Ets binding sites conserved in the murine gamma c promoter gene, one of w hich was found essential for functional promoter activity as determine d by mutational analysis, The functional Ets binding site was found to bind Ets family proteins, principally GA-binding protein and Elf-1 an d could be transactivated by GABP alpha and -beta synergistically. The se results indicate that, as already reported for the IL2R beta promot er, GA-binding protein is an essential component of gamma c basal prom oter activity, Although GABP expression is not restricted to the hemat opoietic lineage, its interaction with other specific factors may cont ribute to the tissue-specific expression of the gamma c gene.