THE C-REL PROTOONCOGENE PRODUCT REPRESSES NF-KAPPA-B P65-MEDIATED TRANSCRIPTIONAL ACTIVATION OF THE LONG TERMINAL REPEAT OF TYPE-1 HUMAN-IMMUNODEFICIENCY-VIRUS

The long terminal repeat (LTR) of the type 1 human immunodeficiency virus (HIV-1) and the 5' regulatory region of the gene encoding the interleukin 2 receptor alpha subunit (IL-2Ralpha) share functional kappaB enhancer elements involved in the regulation of these inducible transcription units during T-cell activation. These kappaB enhancer elements are recognized by a structurally related family of interactive proteins that includes p50, p65, and the product of the c-rel protooncogene (c-Rel). Recent biochemical studies have shown that p65 and p50 form the prototypical NF-kappaB complex, which is rapidly translocated from the cytoplasm to the nucleus during T-cell activation. This intracellular signaling complex potently stimulates kappaB-directed transcription from either the HIV-1 LTR or the IL-2Ralpha promoter via the strong transactivation domain present in p65. We now demonstrate that nuclear expression of human c-Rel, which is induced by either phorbol ester or tumor necrosis factor alpha with delayed kinetics relative to p65, markedly represses p65-mediated activation of these transcription units. These inhibitory effects of c-Rel correlate with its DNA-binding activity but not with its ability to heterodimerize with p50, suggesting that c-Rel inhibition involves competition with p50/p65 for occupancy of the kappaB enhancer element. Together, these findings suggest that one function of c-Rel is as a physiologic repressor of the HIV-1 LTR and IL-2Ralpha promoters, serving to efficiently counter the strong transcriptional activating effects of p65.