A novel splice variant of the transcription factor Nrf1 interacts with the TNF  promoter and stimulates transcription

Abstract

Common signaling chains of various receptor families, despite some similarities, are able to provoke quite different cellular responses. This suggests that they are linked to different cascades and transcription factors, dependent on the context of the ligand binding moiety and the cell type. The ITAM (immunoreceptor tyrosine-based activation motif) containing gamma chain of the FcepsilonRI, FcgammaRI, FcgammaRIII and the T-cell receptor is one of these shared signaling molecules. Here, we show that in the context of the FcgammaRIII, the gamma chain activates the transcription factor Nrf1 or a closely related protein that specifically interacts with the extended kappa3 site in the TNFalpha promoter. A novel splice variant of Nrf1 with a 411 bp deletion of the serine-rich region, resulting in an overall structure reminiscent of the BTB and CNC homology (Bach) proteins, was isolated from the corresponding DC18 cells. In a gel shift analysis, this bacterially expressed splice variant binds to the TNFalpha promoter site after in vitro phosphorylation by casein kinase II (CKII). In addition, cotransfection studies demonstrate that this splice variant mediates induced transcription at the TNFalpha promoter after stimulation/activation in a heterologous system.

Nuclear Factor-E2-related Factor-1 Mediates Ascorbic Acid Induction of Osterix Expression via Interaction with Antioxidant-Responsive Element in Bone Cells

“…Upon antioxidant stimulation, however, Nrf1 is released from the cytoplasm and trafficked into the nucleus. The abundance of activated, and possibly phosphorylated, Nrf1 then interacts with small Maf or other transcription factors, binding to ARE as a heterodimer to activate the target genes (28,43,46). We will test this model in bone-specific Nrf1 conditional knock-out mice.…”

Curcumin: an orally bioavailable blocker of TNF and other pro‐inflammatory biomarkers

“…TNF suppression primarily occurs at the transcriptional level. The factors known to be involved in TNF transcription include the transcription factor ETS (Kramer et al, 1995), activating transcription factor 2 (ATF2)/ Jun (Leitman et al, 1991;Newell et al, 1994;Tsai et al, 1996a,b), Sp1 (Kramer et al, 1994), nuclear factor of activated T-cell transcription factor (NFAT) (McCaffrey et al, 1994;Tsai et al, 1996a,b), NF-kB (Udalova et al, 1998;Kuprash et al, 1999), early growth response protein-1 (Kramer et al, 1994), cAMP response element binding protein (CREB) (Geist et al, 1997), CCAAT/enhancer binding protein b (C/EBPb) (Pope et al, 1994;Wedel et al, 1996;Zagariya et al, 1998), NF-E2-related factor 1 Prieschl et al, 1998) and LPS-induced TNF-a factor (LITAF) (Takashiba et al, 1995;Myokai et al, 1999) (Figure 1). Hence, different transcription factors appear to be involved in the stimulation of TNF expression by various stimuli and in different cell types.…”

Is there a future for TNF promoter polymorphisms?

“…18 No SNPs have been identified in this proximal portion of the promoter, where they might be expected to be able to influence transcription, while those that have been reported, all occur in regions that have no clearly established functional significance. Most of the factors that have been convincingly described as being involved in TNF transcription, including CREB, 157 C/EBPa þ b, [158][159][160] NFATp, [161][162][163] SP-1, Egr-1, 164 ATF2/JUN, 162,163,165,166 Nrf-1, 167,168 and Ets, 169 bind within the 200 bp proximal promoter. Although functional binding sites in the À600 region have been reported for NF-kB 170,171 and Litaf, 172,173 these regions harbour no known SNP.…”