TRANSCRIPTIONAL REGULATION OF THE HUMAN FASL PROMOTER-ENHANCER REGION

The human FasL enhancer region was cloned and functionally characteriz ed in transformed and primary T cells, Within the 2.3 kilobase pairs o f the FasL, untranslated region, the distal 3' 300-base pair portion c ontains a single transcription initiation site and confers basal and i nducible transcriptional activity. Stimuli that increase [Ca2+](i) suc h as CD3 cross-linking or ionomycin, but not activation of protein kin ase C, were found to induce FasL enhancer transcription in a cyclospor in-sensitive manner. Moreover, calcineurin and NFAT, but not AP1, were identified as necessary and sufficient effectors in driving FasL, tra nscription through an NFAT cis-acting motif (GGAAA), Additional modes of T cell activation such as CD4 cross-linking were also found to indu ce NFAT binding to the FasL enhancer region and to functionally transa ctivate its transcription, These results indicate that the induction o f FasL gene transcription in T cells after CD3 or CD4 activation is se lectively mediated by calcineurin and NFAT.