In natural killer (NK) cells, interleukin-2 (IL-2) differentially regulates the expression of several transcription factors, including JunB and c-fos. The cAMP response element binding protein, CREB, is a key transcriptional regulator of a large number of genes containing the octanucleotide CRE consensus sequence in their upstream regulatory regions. We studied here the functional role of CREB in the IL-2-mediated transcriptional regulation of c-fos in human NK cells. Our results show that IL-2 activates CREB in human NK cells and that CREB activation hasa prominent regulatory role on the IL-2-induced expression of functional c-fos and AP-1 in NK cells. We identify two domains of the c-fos promoter, containing three CRE sites, which are critical for the transcriptional activity induced by IL-2. The first domain is located within the first 220 nucleotides of the c-fos promoter, while the second encompasses the nucleotides - 440 and - 220. Our results show that CREB has a relevant role in the cytokine-mediated activation of NK cells, and are particularly remarkable in the light of the several genes that are positively regulated by c-fos and AP-1, such as IFN-gamma, IL-2 and GM-CSF genes.
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