The c-rel Protooncogene Product Represses NF-κB p65-Mediated Transcriptional Activation of the Long Terminal Repeat of Type 1 Human Immunodeficiency Virus

• Published in: Proceedings of the National Academy of Sciences - PNAS 1993-02, Vol.90 (3), p.1023-1027
• Main Authors: Doerre, S, Sista, P, Sun, S C, Ballard, D W, Greene, W C
• Format: Article
• Language: English
• Subjects: AIDS/HIV; Base Sequence; Biological and medical sciences; Chloramphenicol O-Acetyltransferase - genetics; Complementary DNA; COS cells; DNA Mutational Analysis; Enhancer Elements, Genetic - genetics; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Viral - drug effects; HIV; HIV 1; HIV Long Terminal Repeat - genetics; HIV-1 - genetics; human immunodeficiency virus 1; Human T lymphotropic virus 1; Humans; Interleukin-2 - genetics; Molecular and cellular biology; Molecular genetics; Molecular Sequence Data; NF-kappa B - metabolism; Plasmids; Promoter Regions, Genetic - genetics; Proteins; Proto-Oncogene Proteins - pharmacology; Proto-Oncogene Proteins c-rel; Repression; Repressor Proteins - pharmacology; T lymphocytes; Transcription, Genetic - drug effects; Transcription. Transcription factor. Splicing. Rna processing; Transfection
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.90.3.1023

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 α subunit (IL-2Rα) share functional κB enhancer elements involved in the regulation of these inducible transcription units during T-cell activation. These κB 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-κB complex, which is rapidly translocated from the cytoplasm to the nucleus during T-cell activation. This intracellular signaling complex potently stimulates κB-directed transcription from either the HIV-1 LTR or the IL-2Rα 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 α 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 κB enhancer element. Together, these findings suggest that one function of c-Rel is as a physiologic repressor of the HIV-1 LTR and IL-2Rα promoters, serving to efficiently counter the strong transcriptional activating effects of p65.