Transcriptional regulation of the human FasL promoter-enhancer region

The human FasL enhancer region was cloned and functionally characterized in transformed and primary T cells, Within the 2.3 kilobase pairs of the FasL, untranslated region, the distal 3' 300-base pair portion contains a single transcription initiation site and confers basal and inducible transcriptional activity. Stimuli that increase [Ca2+](i) such as CD3 cross-linking or ionomycin, but not activation of protein kinase C, were found to induce FasL enhancer transcription in a cyclosporin-sensitive manner. Moreover, calcineurin and NFAT, but not AP1, were identified as necessary and sufficient effectors in driving FasL, transcription through an NFAT cis-acting motif (GGAAA), Additional modes of T cell activation such as CD4 cross-linking were also found to induce NFAT binding to the FasL enhancer region and to functionally transactivate its transcription, These results indicate that the induction of FasL gene transcription in T cells after CD3 or CD4 activation is selectively mediated by calcineurin and NFAT.