Lipopolysaccharide (LPS) increases the production of interleukin-12 (IL-12) from mouse macrophages via a B site within the IL-12 p40 promoter. In this study, we found that retinoids inhibit this LPS-stimulated production of IL-12 in a dose-dependent manner. The NFB components p50 and p65 bound retinoid X receptor (RXR) in a ligand-independent manner in vitro, and the interaction interfaces involved the p50 residues 1-245, the p65 residues 194 -441, and the N-terminal A/B/C domains of RXR. Activation of macrophages by LPS resulted in markedly enhanced binding activities to the B site, which significantly decreased upon addition of retinoids, as demonstrated by the electrophoretic mobility shift assays. In cotransfections of CV-1 and HeLa cells, RXR also inhibited the NFB transactivation in a ligand-dependent manner, whereas a mutant RXR lacking the AF2 transactivation domain, which serves as ligand-dependent binding sites for transcription integrators SRC-1 and p300, was without any effect. In addition, coexpression of increasing amounts of SRC-1 or p300 relieved the retinoid-mediated inhibition of the NFB transactivation. From these results, we propose that retinoid-mediated suppression of the IL-12 production from LPS-activated macrophages may involve both inhibition of the NFB-DNA interactions and competitive recruitment of transcription integrators between NFB and RXR.
The activation protein-1 (AP-1) 1 transcription factors are immediate early response genes involved in a diverse set of transcriptional regulatory processes (1). The AP-1 complex consists of a heterodimer of a Fos family member and a Jun family member. This complex binds the consensus DNA sequence (TGAGTCA) (termed AP-1) sites found in a variety of promoters (2, 3). The Fos family contains four proteins (c-Fos, Fos-B, Fra-1, and Fra-2) (4 -6), whereas the Jun family is composed of three (c-Jun, Jun-B, and Jun-D) (7-10). Fos and Jun are members of the bZIP family of sequence-specific dimeric DNA-binding proteins (11). The C-terminal half of the bZIP domain is amphipathic, containing a heptad repeat of leucines that is critical for the dimerization of bZIP proteins (12,13). The N-terminal half of the long bipartite helix is the basic region that is critical for sequence-specific DNA binding (14 -16).Transcription coactivators bridge transcription factors and the components of the basal transcriptional apparatus (17). Functionally conserved proteins CREB-binding protein (CBP) and p300 have been shown to be essential for the activation of transcription by a large number of regulated transcription factors, including nuclear receptors (18 -21), , NFB (25,26), basic helix-loop-helix factors (27), STATs (28,29), and AP-1 (30, 31). In particular, the nuclear receptor superfamily is a group of ligand-dependent transcriptional regulatory proteins that function by binding to specific DNA sequences named hormone response elements in promoters of target genes (reviewed in Ref. 32). Transcriptional regulation by nuclear receptors depends primarily upon a ligand-dependent activation function, AF-2, located in the C terminus and predicted to undergo an allosteric change upon ligand binding (32). Consistent with this, CBP and p300 have been found to interact directly with nuclear receptors in a ligand-and AF-2-dependent manner (18 -21). In addition, a series of factors that exhibit ligand-and AF-2-dependent binding to nuclear receptors have been identified both biochemically and by expression cloning. Among these, a group of highly related proteins have been shown to form a complex with CBP and p300 and enhance transcriptional activation by several nuclear receptors, i.e. steroid receptor coactivator-1 (SRC-1) (20, 33), xSRC-3 (34), AIB1 (35), TIF2 (36), RAC3 (37), ACTR (38), TRAM-1 (39), and p/CIP (40). Interestingly, SRC-1 (41) and its homologue ACTR (38), along with CBP and p300 (42,43), were recently shown to contain potent histone acetyltransferase activities themselves and associate with yet another histone acetyltransferase protein p/CAF (44). In contrast, it was shown that SMRT (45) and N-CoR (46), nuclear receptor corepressors, form complexes with Sin3 and histone deacetylase proteins (47,48). From these results, it was suggested that chromatin remodeling by cofactors may contribute, through histone acetylation-deacetylation, to transcription factor-mediated transcriptional regulation.In light of the fact that SRC-1 is ...
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