Showing papers on "Transcription factor published in 1995"
TL;DR: Observations suggest that Adenylate/uridylate-rich elements play a critical role in the regulation of gene expression during cell growth and differentiation and in the immune response.
1,955 citations
TL;DR: This review will examine how two receptor associated tyrosine kinases from the JAK family mediate the transduction of signal directly from receptor to nucleus.
Abstract: Cytokines and growth factors regulate multiple aspects of cell growth through their interactions with specific receptors. These receptors initiate signals directed at both the cytoplasmic and the nuclear compartments. Many of the nuclear signals culminate in the induction of new genes. Characterization of the ability of IFN-alpha to rapidly induce new genes has led to the identification of a new signaling paradigm, the JAK-STAT (Signal Transducers and Activators of Transcription) pathway. In the IFN-alpha pathway, two receptor associated tyrosine kinases from the JAK family, Jak1 and Tyk2, mediate the activation of two latent cytoplasmic transcription factors, Stat1 and Stat2. More recent studies have not only determined that this pathway is used extensively, but have led to the identification of additional components (e.g., Jak2, Jak3, Stat3, Stat4, Stat5, and Stat6). This review will examine how these components mediate the transduction of signal directly from receptor to nucleus.
1,878 citations
TL;DR: A model has been proposed for the cytokine‐induced E‐selectin enhancer that is similar to the stereospecific complex proposed forThe inter‐ feron‐β gene promoter, in which multiple DNA bending proteins facilitate the assembly of higher order complexes of transcriptional activators that interact as a unit with the basal transcriptional machinery.
Abstract: Transcription of endothelial-leukocyte adhesion molecule-1 (E-selectin or ELAM-1), vascular cell adhesion molecule-1 (VCAM-1), and intercellular adhesion molecule-1 (ICAM-1) is induced by the inflammatory cytokines interleukin-1 beta (IL-1 beta) and tumor necrosis factor-alpha (TNF alpha). The positive regulatory domains required for maximal levels of cytokine induction have been defined in the promoters of all three genes. DNA binding studies reveal a requirement for nuclear factor-kappa B (NF-kappa B) and a small group of other transcriptional activators. The organization of the cytokine-inducible element in the E-selectin promoter is remarkably similar to that of the virus-inducible promoter of the human interferon-beta gene in that both promoters require NF-kappa B, activating transcription factor-2 (ATF-2), and high mobility group protein I(Y) for induction. Based on this structural similarity, a model has been proposed for the cytokine-induced E-selectin enhancer that is similar to the stereospecific complex proposed for the interferon-beta gene promoter. In these models, multiple DNA bending proteins facilitate the assembly of higher order complexes of transcriptional activators that interact as a unit with the basal transcriptional machinery. The assembly of unique enhancer complexes from similar sets of transcriptional factors may provide the specificity required to regulate complex patterns of gene expression and correlate with the distinct patterns of expression of the leukocyte adhesion molecules.
1,706 citations
TL;DR: A role for the JNK signal transduction pathway in transcriptional responses mediated by ATF2 is demonstrated and mutations in this pathway inhibited ATF2-stimulated gene expression mediated by the retinoblastoma tumor suppressor and the adenovirus early region 1A (E1A) oncoprotein.
Abstract: Treatment of cells with pro-inflammatory cytokines or ultraviolet radiation causes activation of the c-Jun NH2-terminal protein kinase (JNK). Activating transcription factor-2 (ATF2) was found to be a target of the JNK signal transduction pathway. ATF2 was phosphorylated by JNK on two closely spaced threonine residues within the NH2-terminal activation domain. The replacement of these phosphorylation sites with alanine inhibited the transcriptional activity of ATF2. These mutations also inhibited ATF2-stimulated gene expression mediated by the retinoblastoma (Rb) tumor suppressor and the adenovirus early region 1A (E1A) oncoprotein. Furthermore, expression of dominant-negative JNK inhibited ATF2 transcriptional activity. Together, these data demonstrate a role for the JNK signal transduction pathway in transcriptional responses mediated by ATF2.
1,477 citations
TL;DR: Results suggest that phosphorylation at one or both of these residues is critical for activation of NF-kappa B, the transcription factor inhibited by I kappa B-alpha.
Abstract: I kappa B-alpha inhibits transcription factor NF-kappa B by retaining it in the cytoplasm. Various stimuli, typically those associated with stress or pathogens, rapidly inactivate I kappa B-alpha. This liberates NF-kappa B to translocate to the nucleus and initiate transcription of genes important for the defense of the organism. Activation of NF-kappa B correlates with phosphorylation of I kappa B-alpha and requires the proteolysis of this inhibitor. When either serine-32 or serine-36 of I kappa B-alpha was mutated, the protein did not undergo signal-induced phosphorylation or degradation, and NF-kappa B could not be activated. These results suggest that phosphorylation at one or both of these residues is critical for activation of NF-kappa B.
1,457 citations
TL;DR: It is demonstrated that curcumin (diferuloylmethane), a known anti-inflammatory and anticarcinogenic agent, is a potent inhibitor of NF-κB activation.
1,326 citations
TL;DR: Results establish SRF as a nuclear target of a novel Rho-mediated signaling pathway that does not correlate with activation of the MAP kinases ERK, SAPK/JNK, or MPK2/p38.
1,306 citations
TL;DR: This review shall concentrate on transcriptional responses to cell surface receptor-activated signaling pathways; however, much of the discussion is also applicable to signals induced by environmental stresses or to extracellular signals that act directly on transcription factors, such as steroid hormones.
1,258 citations
TL;DR: Recent progress is reviewed in understanding the mechanisms involved in the activation of NF-KB, the function of individual Rel family proteins, and synergistic interactions between Rel proteins and other families of transcription factors, leading to specific gene activation.
1,250 citations
TL;DR: It is suggested that the concept of ‘persistent oxidative stress in cancer’ may open up a new research area, explaining part of the characteristic tumor biology of cancer such as activated transcription factors and proto‐oncogenes, genomic instability, chemotherapy‐resistance, invasion and metastasis.
1,210 citations
TL;DR: Data support the role of NF-kappa B as a vital transcription factor for both specific and nonspecific immune responses, but do not indicate a developmental role for the factor.
TL;DR: A wide variety of normal and malignant cell types generate and release superoxide or hydrogen peroxide in vitro either in response to specific cytokine/growth factor stimulus or constitutively in the case of tumour cells.
TL;DR: The expression pattern of mouse p21 correlated with terminal differentiation of multiple cell lineages including skeletal muscle, cartilage, skin, and nasal epithelium in a p53-independent manner, demonstrating that p21 expression does not require these transcription factors.
Abstract: Terminal differentiation is coupled to withdrawal from the cell cycle. The cyclin-dependent kinase inhibitor (CKI) p21Cip1 is transcriptionally regulated by p53 and can induce growth arrest. CKIs are therefore potential mediators of developmental control of cell proliferation. The expression pattern of mouse p21 correlated with terminal differentiation of multiple cell lineages including skeletal muscle, cartilage, skin, and nasal epithelium in a p53-independent manner. Although the muscle-specific transcription factor MyoD is sufficient to activate p21 expression in 10T1/2 cells, p21 was expressed in myogenic cells of mice lacking the genes encoding MyoD and myogenin, demonstrating that p21 expression does not require these transcription factors. The p21 protein may function during development as an inducible growth inhibitor that contributes to cell cycle exit and differentiation.
TL;DR: Cell culture models (e.g. 3T3-L1 cells) have been developed and transcription factors coordinate the expression of genes involved in creating and maintaining the adipocyte phenotype including the insulin-responsive glucose transporter (GLUT4), stearoyl CoA desaturase 1 (SCD1), and the fatty acid binding protein (422/aP2).
Abstract: Cell culture models (e.g. 3T3-L1 cells) have been developed for studying the process of adipocyte differentiation. Differentiation can be induced by adding insulin-like growth factor I, glucocorticoid, fatty acids, and an agent that increases intracellular cAMP level. The adipocyte differentiation program is regulated by transcriptional activators such as CCAAT/enhancer binding protein alpha (C/EBP alpha), peroxisomal proliferator activated receptor gamma 2 (PPAR gamma 2), fatty acid activated receptor (FAAR), and transcriptional repressors such as preadipocyte repressor element binding protein (PRE) and C/EBP undifferentiated protein (CUP). These transcription factors coordinate the expression of genes involved in creating and maintaining the adipocyte phenotype including the insulin-responsive glucose transporter (GLUT4), stearoyl CoA desaturase 1 (SCD1), and the fatty acid binding protein (422/aP2).
TL;DR: It is proposed that expression of the type II sodium channel gene in neurons reflects a default pathway that is blocked in nonneuronal cells by the presence of REST.
TL;DR: The results suggest that cell-permeable synthetic peptides carrying a functional cargo can be applied to control signal transduction-dependent subcellular traffic of transcription factors mediating the cellular responses to different agonists and can be used to study other intracellular processes involving proteins with functionally distinct domains.
TL;DR: Evidence that transcriptional activation of the human interferon-beta (IFN beta) gene requires the assembly of a higher order transcription enhancer complex (enhanceosome) is presented and HMG I(Y) plays an essential role in the assembly and function of the IFN beta gene enhanceosome.
TL;DR: It is shown by targeted gene disruption in mice that tal-1 is essential for embryonic blood formation in vivo and resembles loss of the erythroid transcription factor GATA-113,14 or the LIM protein rbtn215 .
Abstract: CHROMOSOMAL translocations associated with malignancies often result in deregulated expression of genes encoding transcription factors1. In human T-cell leukaemias such regulators belong to diverse protein families and may normally be expressed widely (for example, Ttg-1/rbtnl, Ttg-2/rbtn2) 2,3, exclusively outside the haematopoietic system (for example, Hoxll) 4, or specifically in haematopoietic cells and other selected sites (for example, tal-1/ SCL, lyl-1) 5,6. Aberrant expression within T cells is thought to interfere with programmes of normal maturation. The most frequently activated gene in acute T-cell leukaemias, tal-1 (also called SCL) 7,8, encodes a candidate regulator of haematopoietic development9, a basic-helix-loop-helix protein5, related to critical myogenic10 and neurogenic11 factors. Here we show by targeted gene disruption in mice12 that tal-1 is essential for embryonic blood formation in vivo. With respect to embryonic erythropoiesis, tal-1 deficiency resembles loss of the erythroid transcription factor GATA-113,14 or the LIM protein rbtn215 .Profound reduction in myeloid cells cultured in vivo from tal-1 null yolk sacs suggests a broader defect manifest at the myelo-erythroid or multipotential progenitor cell level.
TL;DR: The ternary complex factor (TCF) subfamily of ETS-domain transcription factors bind with serum response factor (SRF) to the serum response element (SRE) and mediate increased gene expression and integrates MAP kinase signaling pathways in vivo to coordinate biological responses to different extracellular stimuli.
Abstract: The ternary complex factor (TCF) subfamily of ETS-domain transcription factors bind with serum response factor (SRF) to the serum response element (SRE) and mediate increased gene expression. The TCF protein Elk-1 is phosphorylated by the JNK and ERK groups of mitogen-activated protein (MAP) kinases causing increased DNA binding, ternary complex formation, and transcriptional activation. Activated SRE-dependent gene expression is induced by JNK in cells treated with interleukin-1 and by ERK after treatment with phorbol ester. The Elk-1 transcription factor therefore integrates MAP kinase signaling pathways in vivo to coordinate biological responses to different extracellular stimuli.
TL;DR: It is discovered that ectopic expression of C/EBP beta in multipotential NIH-3T3 cells results in their conversion into committed adipoblasts capable, upon hormonal stimulation, of synchronous and uniform differentiation into fat-laden adipocytes.
Abstract: Terminal differentiation of cultured 3T3-L1 fibroblasts to the adipogenic phenotype is potently stimulated by dexamethasone (DEX) and methylisobutylxanthine (MIX). Previous studies have shown that these hormones induce the expression of genes encoding two members of the CCAAT/enhancer binding protein (C/EBP) family of transcription factors. In the absence of new protein synthesis DEX activates the gene encoding C/EBP~. Likewise, MIX is a direct inducer of C/EBP~ gene expression. Optimal conditions for differentiation entail a 2-day period wherein confluent fibroblasts are exposed to DEX and MIX, followed by removal of the hormones and subsequent culture in the presence of insulin and fetal bovine serum. During the early phase of differentiation, high levels of C/EBP6 and C/EBP~ accumulate. These transcription factors diminish during the terminal phase of differentiation and come to be replaced by a third member of the C/EBP family, C/EBP~. Conclusive evidence has already shown that C/EBPot regulates terminal adipocyte differentiation, turning on the battery of fat-specific genes required for the synthesis, uptake, and storage of long chain fatty acids. Here we provide evidence that C/EBP~ and C/EBP~ play early catalytic roles in the differentiation pathway, relaying the effects of the hormonal stimulants DEX and MIX in a cascade-like fashion, leading to the activation of the gene encoding C/EBP~. Conditions facilitating the precocious expression of either C/EBP6 or C/EBPI3 were observed to accelerate adipogenesis and, in the case of C/EBPI3, relieve dependence on the early hormonal stimulants. Likewise, conditions that prevented the expression of functional C/EBP~ effectively blocked terminal differentiation. Finally, we have discovered that ectopic expression of C/EBPI3 in multipotential NIH-3T3 cells results in their conversion into committed adipoblasts capable, upon hormonal stimulation, of synchronous and uniform differentiation into fat-laden adipocytes.
TL;DR: A transcriptionally inactive mutant of the murine oestrogen receptor is used which is unable to bind oestrogens yet retains normal affinity for the synthetic ligand, 4-hydroxytamoxifen.
Abstract: A number of proteins have been rendered functionally oestrogen-dependent by fusion with the hormone-binding domain of the oestrogen receptor. There are, however, several significant disadvantages with such fusion proteins. First, their use in cells in vitro requires phenol red-free medium and laborious stripping of steroid hormones from serum in order to avoid constitutive activation. Secondly, control of oestrogen receptor fusion proteins in vivo is precluded by high endogenous levels of circulating oestrogens. Thirdly, the hormone-binding domain of the oestrogen receptor functions as a hormone-dependent transcriptional activation domain making interpretation of fusions with transcription factors problematical. In order to overcome these drawbacks we have used a transcriptionally inactive mutant of the murine oestrogen receptor which is unable to bind oestrogen yet retains normal affinity for the synthetic ligand, 4-hydroxytamoxifen. When the hormone-binding domain of this mutant oestrogen receptor is fused to the C-terminus of the c-Myc protein, Myc-induced proliferation and apoptosis in fibroblasts becomes dependent on 4-hydroxytamoxifen, but remains refractory to 17 beta-oestradiol.
TL;DR: When microinjected into sympathetic neurons, an expression vector for a c-Jun dominant negative mutant protects them against NGF withdrawal-induced death, indicating that AP-1 activity is essential for neuronal cell death.
TL;DR: This work has shown that transcription factors are kept in a latent state in the cytoplasm and are translocated into the nucleus upon activation, where they phosphorylate target transcription factors.
TL;DR: It is proposed that the induction and stabilization of IκBα by NO are important mechanisms by which NO inhibits NF-κB and attenuate atherogenesis.
TL;DR: It is shown that EBF is necessary for the generation of immunoglobulin-expressing B cells in EBF-deficient mice, and that various non-lymphoid tissues that express EBF are apparently normal in homozygous mutant mice, including olfactory neurons in which EBF was identified as Olf-1.
Abstract: Early B-cell factor (EBF) is a cell type-specific transcription factor that is expressed at all antigen-independent stages of B-lymphocyte differentiation and participates in the regulation of the mb-1 gene. Here we show, by targeted gene disruption in mice, that EBF is necessary for the generation of immunoglobulin-expressing B cells. EBF-deficient mice lack B cells that have rearranged their immunoglobulin D and JH gene segments, but contain B220+CD43+ progenitor cells that express germline mu and IL-7 receptor transcripts. Various non-lymphoid tissues that express EBF are apparently normal in homozygous mutant mice, including olfactory neurons in which EBF was identified as Olf-1 (refs 5, 6). Together, these data suggest that EBF plays a specific and important role in the transcriptional control of B-cell differentiation at a stage before Ig (immunoglobulin) gene rearrangement but after commitment of cells to the B-lymphoid lineage.
TL;DR: It is demonstrated that Elk‐1, a protein closely related to p62TCF in function, is a nuclear target of two members of the MAP kinase family, ERK1 and ERK2, which increases the yield of ternary complex in vitro.
Abstract: Induction of the human c-fos proto-oncogene by mitogens depends on the formation of a ternary complex by p62TCF with the serum response factor (SRF) and the serum response element (SRE). We demonstrate that Elk-1, a protein closely related to p62TCF in function, is a nuclear target of two members of the MAP kinase family, ERK1 and ERK2. Phosphorylation of Elk-1 increases the yield of ternary complex in vitro. At least five residues in the C-terminal domain of Elk-1 are phosphorylated upon growth factor stimulation of NIH3T3 cells. These residues are also phosphorylated by purified ERK1 in vitro, as determined by a combination of phosphopeptide sequencing and 2-D peptide mapping. Conversion of two of these phospho-acceptor sites to alanine impairs the formation of ternary complexes by the resulting Elk-1 proteins. Removal of these serine residues also drastically diminishes activation of the c-fos promoter in epidermal growth factor-treated cells. Analogous mutations at other sites impair activation to a lesser extent without affecting ternary complex formation in vitro. Our results indicate that phosphorylation regulates ternary complex formation by Elk-1, which is a prerequisite for the manifestation of its transactivation potential at the c-fos SRE.
TL;DR: Electrophoretic mobility shift assays suggest that inhibition of NFκB activation may be an important mechanism for IL-10 supression of cytokine gene transcription in human monocytes.
TL;DR: RNA in situ hybridization and reverse transcriptase-PCR demonstrate a stage- and tissue-specific distribution for the expression of Th1, a member of a new family of basic helix-loop-helix (bHLH) transcription factors with a reduced binding specificity.
Abstract: With modified two-hybrid technology, we have isolated a member of a new family of basic helix-loop-helix (bHLH) transcription factors. Thing1 (Th1) was identified in a screen of a mouse embryo cDNA library as a partner for theDrosophilaE protein daughterless. RNA in situ hybridization and reverse transcriptase-PCR demonstrate a stage- and tissue-specific distribution for the expression of Th1. Although tissue specific, the expression pattern ofTh1is fairly complex. During development,Th1mRNA is widely expressed in extraembryonictissues,portionsoftheheart,autonomicganglia,thegut,andpharyngealarches.Atembryonicday7.5 (E7.5), extraembryonic derivatives show robust Th1 expression. By E8.5, expression in the embryonic heart becomesdetectable.Duringthenext2daysofdevelopment,thesignalalsoincludesgutandpharyngealarches. Predominant expression at E13.5 is in neural crest derivatives, especially the autonomic nervous system and adrenal medulla. Expression ofTh1persists in the adult, in which it is localized to the smooth muscle cells of the gut. In vitro, Th1 protein recognizes a set of DNA sites that are more degenerate than has been determined for other bHLH factors, indicating a reduced binding specificity. Transient transfection of NIH 3T3 cells with GAL4-Th1 fusions reveals a repression activity mediated by the Th1 bHLH domain. In combination, these properties define Th1 as a new bHLH protein with a unique set of properties. Duringdevelopment,specificgeneticprogramsareactivated by transcription factors which are often stage and tissue specific in their distribution. Understanding the combinatorial code of factors which defines each cell fate during the differentiation process requires identification of new factors with restricted spatial activity. One group of factors with pivotal roles during development are the basic helix-loop-helix (bHLH) proteins. These factors are important in differentiation processes as diverse as skeletal myogenesis, neurogenesis, andhematopoiesis(forreviews,seereferences2,12,13,43,59,
TL;DR: Analysis of bandshift complexes with available antibodies to the known STATs suggests that IL‐3 activates the DNA‐binding ability of STAT5, a protein which was originally characterized as a prolactin‐responsive transcription factor in sheep.
Abstract: Interleukin-3 (IL-3) is an important regulator of hemopoiesis and considerable effort has been directed towards the study of its mechanism of signal transduction. In this paper, we describe the first molecular identification of a STAT transcription factor that is activated by IL-3. STATs exist in a cytoplasmic, transcriptionally inactive form which, in response to extracellular signals, become tyrosine phosphorylated and translocate to the nucleus where they bind to specific DNA elements. Several of these DNA elements were found which bind proteins in an IL-3-responsive manner. Analysis of these bandshift complexes with available antibodies to the known STATs suggests that IL-3 activates the DNA-binding ability of STAT5, a protein which was originally characterized as a prolactin-responsive transcription factor in sheep. IL-5 and granulocyte-macrophage colony stimulating factor (GM-CSF), which share a common signaling receptor subunit with IL-3, also activate STAT5. Unexpectedly, two murine STAT5 homologs, 96% identical to each other at the amino acid level, were isolated and IL-3-dependent GAS binding could be reconstituted in COS cells transfected with IL-3 receptor and either STAT5 cDNA. In IL-3-dependent hemopoietic cells, both forms of STAT5 are expressed and activated in response to IL-3.
TL;DR: The purification of an ATP-dependent nucleosome remodeling factor (NURF) from Drosophila embryo extracts suggests that two distinct systems may be involved in remodeling chromatin for transcription.