KAPPA-B SITE-DEPENDENT ACTIVATION OF THE INTERLEUKIN-2 RECEPTOR ALPHA-CHAIN GENE PROMOTER BY HUMAN C-REL

The cis-acting control elements of the interleukin-2 receptor alpha-chain (IL-2R-alpha) gene contain a potent kappa-B-like enhancer whose activity can be induced by various mitogenic stimuli. Recent cloning of the p50 and p65 subunits of the kappa-B-binding protein NF-kappa-B complex revealed a striking sequence homology of these proteins with the c-rel proto-oncogene product (c-Rel). On the basis of this homology, we examined the potential role of c-Rel in controlling IL-2R-alpha transcription. We now demonstrate that the recombinant human c-Rel protein binds to the kappa-B element in the IL-2R-alpha promoter and results in alteration of the DNA structure in the adjacent downstream regulatory elements containing the CArG box and the GC box. We found that human c-Rel can activate transcription from the IL-2R-alpha promoter, but not the kappa-B-containing human immunodeficiency virus type 1 promoter, upon cotransfection into Jurkat T cells. Furthermore, truncation of the carboxyl terminus of c-Rel results in a c-Rel mutant (Rel(NA)) that (i) localizes exclusively in the nucleus and (ii) acts in synergy with wild-type c-Rel in activating transcription from the KB site of the IL-2R-alpha promoter. Finally, induction of surface IL-2R-alpha expression coincides with the induced levels of endogenous c-Rel and induced c-Rel binding to the IL-2R-alpha-kappa-B site. Our study identified c-Rel as one component of the Rel/NF-kappa-B-family proteins involved in the kappa-B-dependent activation of IL-2R-alpha gene expression. Furthermore, our results suggest that a Rel(NA)-like cellular factor (e.g., NF-kappa-B p50 or p49 subunit) acts in synergy with c-Rel during T-cell activation.