At high concentrations, free radicals and radical-derived, nonradical reactive species are hazardous for living organisms and damage all major cellular constituents. At moderate concentrations, how...

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Free Radicals in the Physiological Control of Cell Function

▪ Abstract The transcription factor NF-κB, more than a decade after its discovery, remains an exciting and active area of study. The involvement of NF-κB in the expression of numerous cytokines and adhesion molecules has supported its role as an evolutionarily conserved coordinating element in the organism's response to situations of infection, stress, and injury. Recently, significant advances have been made in elucidating the details of the pathways through which signals are transmitted to the NF-κB:IκB complex in the cytosol. The field now awaits the discovery and characterization of the kinase responsible for the inducible phosphorylation of IκB proteins. Another exciting development has been the demonstration that in certain situations NF-κB acts as an anti-apoptotic protein; therefore, elucidation of the mechanism by which NF-κB protects against cell death is an important goal. Finally, the generation of knockouts of members of the NF-κB/IκB family has allowed the study of the roles of these protein...

NF-kappa B and Rel proteins: evolutionarily conserved mediators of immune responses

NF-kappa B is a ubiquitous transcription factor. Nevertheless, its properties seem to be most extensively exploited in cells of the immune system. Among these properties are NF-kappa B's rapid posttranslational activation in response to many pathogenic signals, its direct participation in cytoplasmic/nuclear signaling, and its potency to activate transcription of a great variety of genes encoding immunologically relevant proteins. In vertebrates, five distinct DNA binding subunits are currently known which might extensively heterodimerize, thereby forming complexes with distinct transcriptional activity, DNA sequence specificity, and cell type- and cell stage-specific distribution. The activity of DNA binding NF-kappa B dimers is tightly controlled by accessory proteins called I kappa B subunits of which there are also five different species currently known in vertebrates. I kappa B proteins inhibit DNA binding and prevent nuclear uptake of NF-kappa B complexes. An exception is the Bcl-3 protein which in addition can function as a transcription activating subunit in th nucleus. Other I kappa B proteins are rather involved in terminating NF-kappa B's activity in the nucleus. The intracellular events that lead to the inactivation of I kappa B, i.e. the activation of NF-kappa B, are complex. They involve phosphorylation and proteolytic reactions and seem to be controlled by the cells' redox status. Interference with the activation or activity of NF-kappa B may be beneficial in suppressing toxic/septic shock, graft-vs-host reactions, acute inflammatory reactions, acute phase response, and radiation damage. The inhibition of NF-kappa B activation by antioxidants and specific protease inhibitors may provide a pharmacological basis for interfering with these acute processes.

Function and activation of NF-kappa B in the immune system.

Hydrogen peroxide and oxygen radicals are agents commonly produced during inflammatory processes. In this study, we show that micromolar concentrations of H2O2 can induce the expression and replication of HIV-1 in a human T cell line. The effect is mediated by the NF-kappa B transcription factor which is potently and rapidly activated by an H2O2 treatment of cells from its inactive cytoplasmic form. N-acetyl-L-cysteine (NAC), a well characterized antioxidant which counteracts the effects of reactive oxygen intermediates (ROI) in living cells, prevented the activation of NF-kappa B by H2O2. NAC and other thiol compounds also blocked the activation of NF-kappa B by cycloheximide, double-stranded RNA, calcium ionophore, TNF-alpha, active phorbol ester, interleukin-1, lipopolysaccharide and lectin. This suggests that diverse agents thought to activate NF-kappa B by distinct intracellular pathways might all act through a common mechanism involving the synthesis of ROI. ROI appear to serve as messengers mediating directly or indirectly the release of the inhibitory subunit I kappa B from NF-kappa B.

Reactive oxygen intermediates as apparently widely used messengers in the activation of the NF-kappa B transcription factor and HIV-1.

Sixteen years have passed since the description of the nuclear factor-кB (NF-кB) as a regulator of к light-chain gene expression in murine B lymphocytes (Sen & Baltimore, 1986a) During that time, over 4,000 publications have appeared, characterizing the family of Rel/NF-кB transcription factors involved in the control of a large number of normal and pathological cellular processes The physiological functions of NF-кB proteins include immunological and inflammatory responses, developmental processes, cellular growth and modulating effects on apoptosis In addition, these factors are activated in a number of diseases, including cancer, arthritis, acute and chronic inflammatory states, asthma, as well as neurodegenerative and heart diseases

Activators and target genes of Rel/NF-kappaB transcription factors.

The DNA binding subunit of NF-κB is identical to factor KBF1 and homologous to the rel oncogene product

NF-κB and related proteins: Rel/dorsal homologies meet ankyrin-like repeats

The Maf transcription factors: regulators of differentiation

Bacterial chemotaxis provides a simple model system for the more complex sensory responses of multicellular eukaryotic organisms1. In Escherichia coli, methylation and demethylation of four related membrane proteins, the methyl-accepting chemotaxis proteins (or MCPs), is central to chemotactic sensing and signal transduction2. Three of these proteins, Tar, Tsr and Trg, have been assigned specific roles in chemotaxis. However, the role of the fourth MCP, Tap, has remained obscure3. We demonstrate here that Tap functions as a conventional signal transducer, enabling the cell to respond chemotactically to dipeptides. This provides the first evidence of specific bacterial chemotaxis towards peptides. Peptide taxis requires the function of a periplasmic component of the dipeptide permease. This protein represents the first example of a periplasmic chemoreceptor that does not have a sugar substrate.

Peptide chemotaxis in E. coli involves the Tap signal transducer and the dipeptide permease.

The transcription factor NF-kappa B binds to DNA as a heterodimer composed of two subunits of 50 kDa (p50) and 65 kDa (p65). p50 contains a DNA binding and dimerization domain and represents a truncated form of a 105 kDa (p105) precursor molecule. We show here that in different cell types the p105 precursor as well as the processed p50 coexist in the cytoplasm, but that only the latter enters the nucleus. The cytoplasmic retention of the precursor molecule is controlled by a small region in its C-terminal part. We show that this region is responsible for the observed lack of DNA binding of the p50 precursor and controls the extent of processing of the precursor to the mature form. We also present evidence that a stretch of four basic amino acids, similar to a sequence found in the other proteins belonging to the rel/NF-kappa B family, is required for translocation of the processed p50 protein into the nucleus and thus could be the target for the retention mechanism.

Volker Blank

Papers

The DNA binding subunit of NF-κB is identical to factor KBF1 and homologous to the rel oncogene product

NF-κB and related proteins: Rel/dorsal homologies meet ankyrin-like repeats

The Maf transcription factors: regulators of differentiation

Peptide chemotaxis in E. coli involves the Tap signal transducer and the dipeptide permease.

Cytoplasmic retention, DNA binding and processing of the NF-kappa B p50 precursor are controlled by a small region in its C-terminus.