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

The Fc receptor γ-chain (FcRγ), 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 FcRγ 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 FcRγ promoter. Furthermore, inactivation of the GABP-binding site by nucleotide substitutions as well as repression of GABPα expression by RNA interference reduced Sp1-mediated transactivation of the FcRγ promoter, demonstrating that Sp1 and GABP synergistically activated the FcRγ promoter. This synergistic activation was suggested to require physical interaction between the two transcription factors, because the Ets domain of GABPα was demonstrated to directly bind Sp1. On the other hand, GABP and Elf-1, whose recognition sequences overlapped, were shown to bind the FcRγ gene with similar affinity in the context of chromatin, although Elf-1 exerted weaker enhancer activity for FcRγ 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 FcRγ promoter activity. Such functional and physical interactions among transcription factors involved in the cooperative regulation of FcRγ gene expression as revealed in this study will become promising targets for medical applications against various immune diseases involving FcRγ.