On its upstream side, the human interferon-beta gene is flanked by a 7-kb SAR (scaffold-attached region) DNA element. The core of this element is determined and subjected to in vitro reassociations with isolated scaffolds. Binding properties of SAR fragments with decreasing length are quantified and related to consensus sequences like the topoisomerase II box and an ATATTT motif. Characteristics as the stoichiometry, affinity, and cooperativity of the binding process are shown to depend on the length of SAR DNA and suggest a model involving a multiple-site attachment to protein scaffolds. We propose a rational approach for predicting the SAR mediated transcriptional enhancements in vivo from their binding properties in a standardized in vitro assay. The efficiency of this approach is demonstrated for a marker (huIFN-beta) and a selector gene (neor).

Hierarchical Binding of DNA Fragments Derived from Scaffold-Attached Regions: Correlation of Properties in Vitro and Function in Vivo+,$

Role of endogenous interferon-beta in lipopolysaccharide-triggered activation of the inducible nitric-oxide synthase gene in a mouse macrophage cell line, J774.

Macrophages induce the innate immunity by recognizing pathogens through Toll-like receptors (TLRs), which sense pathogen-associated molecular patterns. Myeloid differentiation factor 88 (MyD88), which is an essential adaptor molecule for most TLRs, mediates the induction of inflammatory cytokines through nuclear factor κB (NF-κB). Trichothecene mycotoxin deoxynivalenol (DON) shows immunotoxic effects by interrupting inflammatory mediators produced by activated macrophages. The present study investigates the effect of DON on NF-κB in activated macrophages through MyD88-dependent pathways. DON inhibited NF-κB-dependent reporter activity induced by MyD88-dependent TLR agonists. In addition, lipopolysaccharide-induced phosphorylation of interleukin-1 receptor-associated kinase 1 and inhibitor κBα were attenuated by DON. Furthermore, DON downregulated the expression level of MyD88. These results suggest that DON inhibits NF-κB activation in macrophages stimulated with TLR ligands via MyD88-dependent TLR signals. Therefore exposure to DON may lead to the inhibition of MyD88-dependent pathway of TLR signaling.

NF-κB activation via MyD88-dependent Toll-like receptor signaling is inhibited by trichothecene mycotoxin deoxynivalenol

Luminescence assays are generally based on measurements of light intensity alone. Inclusion of colour as an additional parameter of the assay could increase the information content. Colour variation in luminescence is particularly prevalent among beetle luciferases. To study the relationship between enzyme structure and colour, luciferases from a Jamalcan click beetle were examined as a model system. These luciferases emit light ranging from green to orange, though their amino acid sequences differ by less than 5%. Through mutation of their respective cDNA clones, the amino acids responsible for the colour variation were identified. These specific amino acids are few, and they act upon colour independently with respect to the enzyme structure. Analysis of their effects indicates that the potential for colour variation among beetle luciferases is greater than is evident among the click beetle luciferase. Because of the subtle changes of enzyme structure that effect colour, luciferases that emit different colours may be useful as paired genetic reporters. They should interact equivalently with the intracellular environment of a host, but could be distinguished by colour in their assay. Such paired reporters could be used to observed simultaneous events, or to provide internal control for luminescence measurements.

Luc genes: introduction of colour into bioluminescence assays.

The interferons (IFNs) are a family of cytokines that elicit pleiotropic biological effects (Pestka et al. 1987; DeMaeyer and DeMaeyer-Guignard 1988; Sen and Lengyel 1992). Although best known (and named) for their ability to inhibit viral replication in treated cells, IFNs are also capable of regulating cellular proliferation, differentiation, and immunological responses (Lengyel 1982; Pestka et al. 1987; Baron et al. 1992; Vilcek and Sen 1996). Over the past 40 years, studies of IFN expression, structure, and function have provided a number of important scientific breakthroughs. The IFNs were the first cytokines to be cloned and characterized, and the first to be used therapeutically. The study of how the transcription of the IFN genes is regulated has provided insight into the complexities of inducible gene expression in eukaryotic organisms, and the analysis of IFN-induced proteins has uncovered a number of important regulators of many physiological processes. Perhaps the most far-reaching discovery to have emerged from analysis of the IFN system has been the identification of the JAK and STAT signaling components, a finding that has ushered in a new era of cytokine and growth factor signal transduction research.

Mechanisms of interferon action.

A murine cosmid clone harboring the single-copy interferon-β1 (IFN-β1) gene and extended flanking sequences was isolated. The functional IFN-β1 promoter is contained within a 170-bp DNA fragment located 5′ of the coding sequence. This was shown by fusion of this fragment to a heterologous reporter gene and transient as well as stable expression in mouse L and monkey CV-1 cells. With the help of these functional assays, it could be demonstrated that the 5′-flanking sequences are the target for the typical regulatory action of common type I IFN activators. DNA sequencing reveals a considerable homology to the human IFN-β1 promoter within the 280 upstream base pairs. The homology is particularly pronounced within the DNA region containing the virus responsive element (VRE). This phenomenon may explain the similarity of both genes in the mode of regulation. The mouse promoter fragment compared with the human equivalent was shown to be several times more efficient in transcriptional activation in muri...

Isolation and Functional Characterization of the Murine Interferon-β1 Promoter

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Isolation and Functional Characterization of the Murine Interferon-β1 Promoter