Abstract

Cooperation between nuclear factor of activated T cells (NFAT) and AP-1 (Fos–Jun) proteins on composite NFAT–AP-1 DNA elements constitutes a powerful mechanism for signal integration of the calcium and protein kinase C/Ras pathways in the regulation of gene expression. Here we report that NFAT can induce expression of certain genes in T cells without the need for cooperative recruitment of Fos and Jun. Using NFAT1 mutant proteins that are unable to interact with Fos–Jun dimers but are unaffected in DNA binding or transcriptional activity, we show that expression of interleukin (IL)-2, granulocyte–macrophage colony-stimulating factor (GM-CSF), IL-3, IL-4, MIP1 and Fas ligand mRNAs is absolutely dependent on cooperation between NFAT and Fos–Jun; in contrast, NFAT induces tumor necrosis factor (TNF) mRNA and IL-13 promoter activity without any necessity to recruit Fos and Jun. Furthermore, we show that NFAT–Fos–Jun cooperation is also essential to elicit the NFAT-dependent program of activation-induced cell death. Our results support the hypothesis that even in a single cell type, NFAT activation can evoke two distinct biological programs of gene expression, dependent or independent of NFAT–AP-1 cooperation.