Cooperative Regulation of Fc Receptor γ-Chain Gene Expression by Multiple Transcription Factors, Including Sp1, GABP, and Elf-1

Abstract

The Fc receptor gamma-chain (FcRgamma), which was first identified as a constituent of the high affinity IgE receptor, associates with various cell surface receptors to mediate intracellular signals. We identified three transcriptional enhancer elements in the 5' region of the human FcRgamma gene; one of the cis-elements was recognized by the transcription factor Sp-1 and another was recognized by GABP or Elf-1. The sequence of the other element was similar to a binding motif of the C/EBP family. Overexpression experiments showed that these transcription factors cooperatively activated the FcRgamma promoter. Furthermore, inactivation of the GABP-binding site by nucleotide substitutions as well as repression of GABPalpha expression by RNA interference reduced Sp1-mediated transactivation of the FcRgamma promoter, demonstrating that Sp1 and GABP synergistically activated the FcRgamma promoter. This synergistic activation was suggested to require physical interaction between the two transcription factors, because the Ets domain of GABPalpha was demonstrated to directly bind Sp1. On the other hand, GABP and Elf-1, whose recognition sequences overlapped, were shown to bind the FcRgamma gene with similar affinity in the context of chromatin, although Elf-1 exerted weaker enhancer activity for FcRgamma gene expression than did GABP. Both were thought to compete for binding to the element, because additional expression of Elf-1 in combination with Sp1 and GABP reduced FcRgamma promoter activity. Such functional and physical interactions among transcription factors involved in the cooperative regulation of FcRgamma gene expression as revealed in this study will become promising targets for medical applications against various immune diseases involving FcRgamma.