Transcription factor

About: Transcription factor is a(n) research topic. Over the lifetime, 82881 publication(s) have been published within this topic receiving 5400448 citation(s). The topic is also known as: transcription factors.

Simple Combinations of Lineage-Determining Transcription Factors Prime cis-Regulatory Elements Required for Macrophage and B Cell Identities

Abstract: Genome-scale studies have revealed extensive, cell type-specific colocalization of transcription factors, but the mechanisms underlying this phenomenon remain poorly understood. Here, we demonstrate in macrophages and B cells that collaborative interactions of the common factor PU.1 with small sets of macrophage- or B cell lineage-determining transcription factors establish cell-specific binding sites that are associated with the majority of promoter-distal H3K4me1-marked genomic regions. PU.1 binding initiates nucleosome remodeling, followed by H3K4 monomethylation at large numbers of genomic regions associated with both broadly and specifically expressed genes. These locations serve as beacons for additional factors, exemplified by liver X receptors, which drive both cell-specific gene expression and signal-dependent responses. Together with analyses of transcription factor binding and H3K4me1 patterns in other cell types, these studies suggest that simple combinations of lineage-determining transcription factors can specify the genomic sites ultimately responsible for both cell identity and cell type-specific responses to diverse signaling inputs.

THE NF-κB AND IκB PROTEINS: New Discoveries and Insights

Abstract: ▪ Abstract The transcription factor NF-κB has attracted widespread attention among researchers in many fields based on the following: its unusual and rapid regulation, the wide range of genes that it controls, its central role in immunological processes, the complexity of its subunits, and its apparent involvement in several diseases. A primary level of control for NF-κB is through interactions with an inhibitor protein called IκB. Recent evidence confirms the existence of multiple forms of IκB that appear to regulate NF-κB by distinct mechanisms. NF-κB can be activated by exposure of cells to LPS or inflammatory cytokines such as TNF or IL-1, viral infection or expression of certain viral gene products, UV irradiation, B or T cell activation, and by other physiological and nonphysiological stimuli. Activation of NF-κB to move into the nucleus is controlled by the targeted phosphorylation and subsequent degradation of IκB. Exciting new research has elaborated several important and unexpected findings that...

A human homologue of the Drosophila Toll protein signals activation of adaptive immunity

Abstract: . Like Drosophila Toll, human Toll is a type I transmembrane protein with an extracellular domain consisting of a leucine-rich repeat (LRR) domain, and a cytoplasmic domain homologous to the cytoplasmic domain of the human interleukin (IL)-1 receptor. Both Drosophila Toll and the IL-1 receptor are known to signal through the NF-kB pathway 5-7 . We show that a constitutively active mutant of human Toll transfected into human cell lines can induce the activation of NF-kB and the expression of NF-kB-controlled genes for the inflammatory cyto- kines IL-1, IL-6 and IL-8, as well as the expression of the co- stimulatory molecule B7.1, which is required for the activation of naive T cells. The Toll protein controls dorsal-ventral patterning in Drosophila embryos and activates the transcription factor Dorsal upon binding to its ligand Spatzle 8 . In adult Drosophila, the Toll/Dorsal signalling pathway participates in an anti-fungal immune response 2 . Signal- ling through Toll parallels the signalling pathway induced by the IL- 1 receptor (IL-1R) in mammalian cells: IL-1R signals through the NF-kB pathway, and Dorsal and its inhibitor Cactus are homo- logous to NF-kB and I-kB proteins, respectively 5,6 . Moreover, the cytoplasmic domain of Drosophila Toll is homologous to the cytoplasmic domain of IL-1R (ref. 9). Remarkably, the tobacco- virus-resistance gene that encodes N-protein is also similar to Toll in that it contains both a Toll signalling domain and an LRR domain 10 . It thus appears that the immune-response system mediated by Toll represents an ancient host defence mechanism 6 (Fig. 1). To inves- tigate the possibility that this pathway has been retained in the immune system of vertebrates, we used sequence and pattern searches 11 of the expressed-sequence tag (EST) database at the fragment was used to probe northern blots containing poly(A) + RNA from several organs. Most organs expressed two mRNA species: one of ,5 kilobases (kb) was predominant in most tissues except peripheral blood leukocytes (PBL), and corresponded to the length of the cDNA that we cloned. The lower band was ,4 kb long and this band was predominant in the PBL. The 4-kb band was not detectable in kidney, and liver did not contain any mRNA at all (Fig. 3). We also tested different mouse and human cell lines for expression of hToll mRNA by using PCR with reverse transcription (RT-PCR). We found mRNA for hToll in monocytes, macrophages, dendritic cells, g/d T cells, Th1 and Th2 a/b T cells, a small intestinal epithelial cell line, and a B-cell line (data not shown). The hToll gene is expressed most strongly in spleen and PBL (Fig. 3); its expression in other tissues may be due to the presence of macrophages and dendritic cells, in which it could act as an early-warning system for infection. Alternatively, hToll may be widely expressed because hToll signals through the conserved NF-kB pathway (see below) and NF- kB is a ubiquitous transcription factor. To characterize hToll functions and see whether it can induce transcription of immune response genes like dToll, we generated a dominant-positive mutant of hToll because the natural ligand of hToll is unknown. To produce a constitutively active mutant of hToll, we made use of genetic information from dToll: analysis of ventra- lizing mutants in Drosophila embryos had identified the function of the ectodomain C-flanking cysteine-rich region in dToll 16 as control- ling the activity of dToll in signal transduction. In three dominant

Molecular mechanisms of epithelial–mesenchymal transition

Abstract: The transdifferentiation of epithelial cells into motile mesenchymal cells, a process known as epithelial-mesenchymal transition (EMT), is integral in development, wound healing and stem cell behaviour, and contributes pathologically to fibrosis and cancer progression. This switch in cell differentiation and behaviour is mediated by key transcription factors, including SNAIL, zinc-finger E-box-binding (ZEB) and basic helix-loop-helix transcription factors, the functions of which are finely regulated at the transcriptional, translational and post-translational levels. The reprogramming of gene expression during EMT, as well as non-transcriptional changes, are initiated and controlled by signalling pathways that respond to extracellular cues. Among these, transforming growth factor-β (TGFβ) family signalling has a predominant role; however, the convergence of signalling pathways is essential for EMT.

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

Abstract: 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.