ACTIVATION OF THE IL-2 GENE PROMOTER BY HTLV-I TAX INVOLVES INDUCTIONOF NF-AT COMPLEXES BOUND TO THE CD28-RESPONSIVE ELEMENT

The tax gene product of the type I human T-cell leukemia virus (HTLV-I ) is a potent transcriptional activator of various growth-related cell ular genes, including that encoding interleukin-2 (IL-2). Tax activati on of many of these target genes appears to be mediated by the NF-kapp a B/Rel and CREB/ATF family of cellular transcription factors. However , the mechanism by which Tax transactivates the IL-2 gene remains uncl ear. In the present study, we demonstrate that neither NF-kappa B/Rel nor CREB/ATF is sufficient for Tax-mediated activation of the IL-2 pro moter. Two novel nuclear protein complexes are induced by Tax and spec ifically bind to an IL-2 gene enhancer, the CD28-responsive element (C D28RE). Immunobiochemical analyses suggest that these DNA binding comp lexes contain at least two members of the nuclear factor of activated T cells, NF-ATp and NF-ATc. However, the CD28 binding NF-AT complexes do not contain Jun and Fos family proteins that have been proposed to serve as NF-AT partners in the activation of the IL-2 NF-AT motif. Tra nsient transfection studies demonstrate that the in vivo expressed NF- ATp binds to the CD28RE probe and enhances Tax-mediated activation of this critical IL-2 enhancer. We demonstrate further that binding of NF -AT to CD28RE is critical for Tax activation of the IL-2 promoter. Tog ether, these results suggest a novel mechanism of Tax-mediated activat ion of the IL-2 gene, which involves the induction of NF-AT-containing CD28RE binding complexes.