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At least 19 recordsLinked to original sources
PubMed2002

Functional diversity of Xenopus lymphoid enhancer factor/T-cell factor transcription factors relies on combinations of activating and repressing elements.

Lymphoid enhancer factor/T-cell factor (LEF/TCF) high mobility group box transcription factors are the nuclear transducers of the Wnt/beta-catenin signaling cascade. In Xenopus, three members of the LEF/TCF family, XLEF-1, XTCF-3, and XTCF-4, with distinct but partially overlapping expression patterns have been identified. The individual Xenopus LEF/TCF family members differ extremely in their properties of target gene regulation. We observed that in contrast to LEF-1, neither XTCF-3 nor XTCF-4 can induce secondary axis formation upon ventral overexpression in Xenopus embryos. To identify functional motifs within the LEF/TCF transcription factors responsible for target gene activation or repression, we created various mutants and a set of XLEF-1/XTCF-3 chimeras. In overexpression studies, we asked whether these constructs can mimic an activated Wnt/beta-catenin pathway and lead to the formation of a secondary body axis. In addition, we examined their capacity to rescue a loss-of-function phenotype given by dominant negative LEF-1 expression. We further analyzed their ability to directly activate target genes in reporter gene assays using the LEF/TCF target promoters, siamois and fibronectin. We found that a region homologous to exon IVa of human TCF-1 is an activating element. This is flanked by two small repressing motifs, LVPQ and SXXSS. Our findings implicate that the motifs identified here play an essential role in determining cell type-specific activity of LEF/TCF transcription factors.

Amino Acid Motifs↗
PubMed2004

Engineered zinc finger-activating vascular endothelial growth factor transcription factor plasmid DNA induces therapeutic angiogenesis in rabbits with hindlimb ischemia.

BACKGROUND: Therapeutic angiogenesis seeks to promote blood vessel growth to improve tissue perfusion. Vascular endothelial growth factor (VEGF) exists in multiple isoforms. We investigated an engineered zinc finger-containing transcription factor plasmid designed to activate the endogenous VEGF gene (ZFP-VEGF). METHODS AND RESULTS: New Zealand White rabbits (n=56) underwent unilateral femoral artery ligation and excision. At day 10 postoperatively, the ischemic muscle received ZFP treatment (500 microg ZFP-VEGF plasmid) or no ZFP treatment (beta-galactosidase, empty, or no plasmid). Group 1 (n=13) was harvested 3 days after injection to examine VEGF mRNA by real-time polymerase chain reaction and protein by ELISA. Groups 2 (n=13) and 3 (n=10) were harvested 11 days after injection. Group 2 was studied by histology and group 3, by histology and changes in blood flow. Groups 4 and 5 (n=10 each) were harvested 22 and 32 days after injection, respectively, and studied for changes in blood flow. In group 1, VEGF mRNA copy numbers were significantly higher for VEGF121, VEGF165, VEGF189, and protein in the ZFP-VEGF-treatment versus no-ZFP-treatment arms. In groups 2 and 3, capillary density and proliferating cells were significantly greater and apoptosis significantly lower in the treatment versus no-treatment arms. Changes in the blood flow ratio of the ischemic to the nonischemic limb were significantly greater in the treatment versus no-ZFP-treatment groups (6.57+/-1.52% versus 3.38+/-0.87%, P<0.005; 13.15+/-1.77% versus 6.13+/-1.55%, P<0.001; and 20.16+/-2.84% versus 13.88+/-3.14%, P<0.01, for groups 3, 4, and 5, respectively). CONCLUSIONS: This engineered ZFP-VEGF-activating transcription factor may provide a novel approach to treat peripheral arterial disease.

Animals↗
PubMed2005

Making a tooth: growth factors, transcription factors, and stem cells.

Mammalian tooth development is largely dependent on sequential and reciprocal epithelial-mesenchymal interactions. These processes involve a series of inductive and permissive interactions that result in the determination, differentiation, and organization of odontogenic tissues. Multiple signaling molecules, including BMPs, FGFs, Shh, and Wnt proteins, have been implicated in mediating these tissue interactions. Transcription factors participate in epithelial-mesenchymal interactions via linking the signaling loops between tissue layers by responding to inductive signals and regulating the expression of other signaling molecules. Adult stem cells are highly plastic and multipotent. These cells including dental pulp stem cells and bone marrow stromal cells could be reprogrammed into odontogenic fate and participated in tooth formation. Recent progress in the studies of molecular basis of tooth development, adult stem cell biology, and regeneration will provide fundamental knowledge for the realization of human tooth regeneration in the near future.

Animals↗
PubMed2000

Regulation of RANTES chemokine gene expression requires cooperativity between NF-kappa B and IFN-regulatory factor transcription factors.

Virus infection of host cells activates a set of cellular genes, including cytokines, IFNs, and chemokines, involved in antiviral defense and immune activation. Previous studies demonstrated that virus-induced transcriptional activation of a member of the human CC-chemokine RANTES required activation of the latent transcription factors IFN-regulatory factor (IRF)-3 and NF-kappa B via posttranslational phosphorylation. In the present study, we further characterized the regulatory control of RANTES transcription during virus infection using in vivo genomic footprinting analyses. IRF-3, the related IRF-7, and NF-kappa B are identified as important in vivo binding factors required for the cooperative induction of RANTES transcription after virus infection. Using fibroblastic or myeloid cells, we demonstrate that the kinetics and strength of RANTES virus-induced transcription are highly dependent on the preexistence of IRFs and NF-kappa B. Use of dominant negative mutants of either I kappa B-alpha or IRF-3 demonstrate that disruption of either pathway dramatically abolishes the ability of the other to bind and activate RANTES expression. Furthermore, coexpression of IRF-3, IRF-7, and p65/p50 leads to synergistic activation of RANTES promoter transcription. These studies reveal a model of virus-mediated RANTES promoter activation that involves cooperative synergism between IRF-3/IRF-7 and NF-kappa B factors.

Base Sequence↗
PubMed1992

Yeast GCN4 as a probe for oncogenesis by AP-1 transcription factors: transcriptional activation through AP-1 sites is not sufficient for cellular transformation.

The Jun and Fos oncoproteins belong to the AP-1 family of transcriptional activators and are believed to induce cellular transformation by inappropriately activating genes involved in cell replication. To determine whether transcriptional activation through AP-1 sites is sufficient for transforming activity, we examined the properties of an autonomous and heterologous AP-1 protein, yeast GCN4, in rat embryo fibroblasts. GCN4 induces transcriptional activation through AP-1 sites but, unlike Jun and Fos, fails to induce cellular transformation, in cooperation with Ha-ras. Jun-GCN4 and Fos-GCN4 homodimers independently induce cellular transformation indicating that the amino-terminal regions of Jun and Fos each contain regulatory functions that are required for oncogenesis but are distinct from generic transcriptional activation domains. In addition, these observations have implications for the nature of the oncogenically relevant target genes that respond to Jun and Fos.

Base Sequence↗
PubMed1995

Activation of the STAT3/acute phase response factor transcription factor by interleukin-5.

The receptor for interleukin-5 (IL-5R) is composed of a unique alpha chain (IL-5R alpha) expressed on eosinophils and basophils, associated with a beta c subunit, which is shared by the receptors for IL-3 and granulocyte macrophage-colony stimulating factor. One of the molecular events activated via the IL-5R is the JAK/STAT signaling pathway. Recent reports have shown that IL-5 induces tyrosine phosphorylation of JAK2 followed by the subsequent cell type-specific activation of either STAT1 alpha or STAT5. To identify additional STAT proteins activated by IL-5, we co-transfected the IL-5R with STAT cDNAs in COS cells. We found that IL-5 induces binding of STAT3 to the intercellular adhesion molecule-1 pIRE, and activates STAT3-dependent transcription. Moreover, endogenous STAT3 was tyrosine phosphorylated and activated in human IL-5-stimulated BaF3 cells ectopically expressing the human IL-5R (BaF3/IL5R). These data imply that multiple STAT proteins are involved in gene regulation by IL-5 in a cell type-specific manner. We further demonstrate using C-terminal truncations of the alpha and beta c subunits of the IL-5R that the membrane-proximal STAT activation. Interestingly, a beta c receptor mutant lacking intracellular tyrosine residues is able to mediate STAT3 activation, suggesting that tyrosine phosphorylation of the beta c receptor is not essential for STAT3 activation.

Acute-Phase Reaction↗
PubMedDate not supplied

The interferon system and interferon regulatory factor transcription factors -- studies from gene knockout mice.

Interferon regulatory factors (IRFs) were initially identified as regulators of IFN-alpha/beta genes and to date nine members have been determined in human and mouse. They share a conserved DNA-binding domain in the N-terminal portion that recognizes similar DNA sequences. Despite their similar DNA binding specificity, the IRFs show diverse functions in response to extra cellular stimuli. Although the study of IRFs was started with respect to regulation of the IFN-alpha/beta gene expression, recent studies have revealed other aspects of IRF functions. In this review, we summarize our current knowledge of the functions of IRF family members revealed by our gene targeting study in mice, focusing on the regulation of the IFN system.

Animals↗
PubMed2006

Bacterial lipopolysaccharide stimulates the thyrotropin-dependent thyroglobulin gene expression at the transcriptional level by involving the transcription factors thyroid transcription factor-1 and paired box domain transcription factor 8.

The bacterial lipopolysaccharide (LPS) is a biological activator that induces expression of multiple genes in several cell types. LPS has been proposed as an etiopathogenic agent in autoimmune diseases. However, whether LPS affects the expression of autoantigens has not been explored. Thyroglobulin (TG) is a key protein in thyroid hormonogenesis and one of the major thyroid autoantigens. This study aimed to analyze the action of LPS on TG gene expression in Fisher rat thyroid cell line FRTL-5 thyroid cells. We demonstrate that LPS increases the TSH-induced TG protein and mRNA level. Evidence that the effect of LPS is exerted at the transcriptional level was obtained by transfecting the minimal TG promoter. The C element of the TG promoter, which contains sequences for paired box domain transcription factor 8 (Pax8) and thyroid transcription factor (TTF)-1 binding, is essential for full TG promoter expression under TSH stimulation. The transcriptional activity of a construct containing five tandem repeats of the C site is increased by LPS, indicating a possible involvement of the C site in the LPS-induced TG gene transcription. We demonstrate that the TG promoter mutated at the Pax8 or TTF-1 binding element in the C site does not respond to LPS. In band shift assays, binding of Pax8 and TTF-1 to the C site is increased by LPS. The Pax8 and TTF-1 mRNA and protein levels are augmented by LPS. The half-lives of TG, Pax8, and TTF-1 are increased in endotoxin-treated cells. Our results reveal the ability of LPS to stimulate the expression of TG, a finding of potential pathophysiological implication.

Animals↗
PubMed1999

Persistent phosphorylation of cyclic AMP responsive element-binding protein and activating transcription factor-2 transcription factors following transient cerebral ischemia in rat brain.

The transcription factors cyclic AMP responsive element-binding protein (CREB) and activating transcription factor-2 were studied in rat brains subjected to 15 min ischemia followed by varied periods of reperfusion using western blot and immunocytochemical analyses. The total amounts of both CREB and activating transcription factor-2 were not altered in the hippocampus after ischemia. In contrast, levels of the phosphorylated forms of both transcription factors decreased during ischemia but rebounded following reperfusion. The phospho-forms of CREB and activating transcription factor-2 showed regional and temporal differences in their expression. Phospho-CREB was increased relative to control levels at 30 min, and continued to increase for at least three days postischemia, mainly in dentate granule cells. The level of phospho-activating transcription factor-2 appeared to be higher in CAI pyramidal cells than in dentate granule cells after ischemia. The present findings suggest that the signaling pathways for phosphorylation of CREB may be neuroprotective for dentate cells, which are relatively resistant to ischemic insults. The increased phospho-activating transcription factor-2 may reflect increased stresses in these neurons. The more modest activation of CREB pathways in CA1 neurons may not be enough to overcome the increased stresses in these neurons, contributing to delayed neuronal death.

Activating Transcription Factor 2↗
PubMed2001

The molecular biology and nomenclature of the activating transcription factor/cAMP responsive element binding family of transcription factors: activating transcription factor proteins and homeostasis.

The mammalian ATF/CREB family of transcription factors represents a large group of basic region-leucine zipper (bZip) proteins which was originally defined in the late 1980s by their ability to bind to the consensus ATF/CRE site 'TGACGTCA'. Over the past decade, cDNA clones encoding identical or homologous proteins have been isolated by different laboratories and given different names. These proteins can be grouped into subgroups according to their amino acid similarity. In this review, we will briefly describe the classification of these proteins with a historical perspective of their nomenclature. We will then review three members of the ATF/CREB family of proteins: ATF3, ATF4 and ATF6. We will address four issues for each protein: (a) homologous proteins and alternative names, (b) dimer formation with other bZip proteins, (c) transcriptional activity, and (d) potential physiological functions. Although the name Activating Transcription Factor (ATF) implies that they are transcriptional activators, some of these proteins are transcriptional repressors. ATF3 homodimer is a transcriptional repressor and ATF4 has been reported to be either an activator or a repressor. We will review the reports on the transcriptional activities of ATF4, and propose potential explanations for the discrepancy. Although the physiological functions of these proteins are not well understood, some clues can be gained from studies with different approaches. When the data are available, we will address the following questions. (a) How is the expression (at the mRNA level or protein level) regulated? (b) How are the transcriptional activities regulated? (c) What are the interacting proteins (other than bZip partners)? (d) What are the consequences of ectopically expressing the gene (gain-of-function) or deleting the gene (loss-of-function)? Although answers to these questions are far from being complete, together they provide clues to the functions of these ATF proteins. Despite the diversity in the potential functions of these proteins, one common theme is their involvement in cellular responses to extracellular signals, indicating a role for these ATF proteins in homeostasis.

Activating Transcription Factor 2↗
PubMed2003

[Construction of a SV40 promoter specific artificial transcription factor].

Transcriptions are regulated by transcription factors. Natural transcription factors usually consist of at least two functional domains: a DNA-binding domain and an effector domain. According to this, novel artificial transcription factors are designed to up or down regulate transcription and expression of a target gene. The Cys2-His2 zinc finger domain is a DNA-binding module that has been widely used as the DNA-binding domain in artificial transcription factors. Each zinc finger domain, which comprises about 30 amino acids that adopt a compact structure by chelating a zinc ion, typically functions by binding 3 base pairs of DNA sequence. Several zinc fingers linked together would bind proportionally longer DNA sequences. According to the "bipartite complementary" library strategy, a pair of zinc finger phage display libraries were constructed. After construction of the libraries, a 9bp sequence (5'-GCAGAGGCC-3') on the promoter of SV40 was chosen as a target for next step. After parallel selection, PCR amplification, desired fragments recovery, re-ligation, and additional rounds of selection, phage enzyme-linked ELISA experiments were performed to identify specific binding clones displaying the zinc fingers with predetermined sequence-specificity to our target sequence. Then two clones with strong ELISA signals were chosen to be tested for binding both to its full target site (5'-GCAGAGGCC-3') and to sites containing single transition mutations. The binding specificity of one of the two clones (clone 3) was shown to be fairly good. The three-finger DNA-binding domain targeted to SV40 promoter, that is, zinc finger sequences on clone 3, was fused to KOX1 suppression domain KRAB and cloned into pcDNA3.1 (+) (which expression product was artificial transcription factor). The zinc fingers (which expression product was the DNA-binding domain of artificial transcription factor) and KRAB domain only (which expression product was effector domain of artificial transcription factor) were also cloned separately into the same expression vector. All constructs contained an N-terminal nuclear localization signal. Every of the vectors (including pcDNA3.1 (+) without inserting sequences) were cotransfected with pGL3-Control and pRL-TK and the activity of luciferase was used to indicate the function of product from transfected expression vectors. Our artificial transcription factor was proved to repress the expression of reporter gene efficiently,while with only DNA-binding domain or effector domain the repression was not remarkable. By adding different effector domains and changing the DNA-binding domain, artificial transcription factor would have a wide range of potential applications.

Enzyme-Linked Immunosorbent Assay↗
PubMed1999

A binding site for the transcription factor Grainyhead/Nuclear transcription factor-1 contributes to regulation of the Drosophila proliferating cell nuclear antigen gene promoter.

The Drosophila proliferating cell nuclear antigen promoter contains multiple transcriptional regulatory elements, including upstream regulatory element (URE), DNA replication-related element, E2F recognition sites, and three common regulatory factor for DNA replication and DNA replication-related element-binding factor genes recognition sites. In nuclear extracts of Drosophila embryos, we detected a protein factor, the URE-binding factor (UREF), that recognizes the nucleotide sequence 5'-AAACCAGTTGGCA located within URE. Analyses in Drosophila Kc cells and transgenic flies revealed that the UREF-binding site plays an important role in promoter activity both in cultured cells and in living flies. A yeast one-hybrid screen using URE as a bait allowed isolation of a cDNA encoding a transcription factor, Grainyhead/nuclear transcription factor-1 (GRH/NTF-1). The nucleotide sequence required for binding to GRH was indistinguishable from that for UREF detected in embryo nuclear extracts. Furthermore, a specific antibody to GRH reacted with UREF in embryo nuclear extracts. From these results we conclude that GRH is identical to UREF. Although GRH has been thought to be involved in regulation of differentiation-related genes, this study demonstrates, for the first time, involvement of a GRH-binding site in regulation of the DNA replication-related proliferating cell nuclear antigen gene.

Animals↗
PubMed2006

The expression of transcription factor activating transcription factor 3 in the human prostate and its regulation by androgen in prostate cancer.

PURPOSE: ATF3 is a member of the basic leucine zipper/cyclic adenosine monophosphate responsive element binding protein family of transcription factors. There is overwhelming evidence that it is a stress inducible factor acting in a signal-type and cell-type dependent manner, and it is involved in cell proliferation and survival. We found that ATF3 was differently expressed in an in vitro prostate cancer tumor progression model and we investigated the possible role of ATF3 in prostate cancer. MATERIALS AND METHODS: ATF3 up-regulation in vivo/in vitro and androgen regulation were assessed by immunohistochemistry and immunoblot analysis. Results after forced ATF3 transfection were evaluated by proliferation assay and cell cycle analysis. RESULTS: Immunohistochemistry and immunoblot analysis revealed ATF3 up-regulation in prostate cancer in vitro and in vivo, and stimulation of expression by androgens. Antiandrogen treatment decreased ATF3 expression in androgen sensitive cells but acted as a stimulator in long-term androgen ablated cells representing a model for therapy refractory disease. Expression in tumors increased with higher Gleason scores and highest expression was observed in samples of therapy refractory tumor tissue. Forced ATF3 over expression in a prostate cancer cell line induced cell proliferation and accelerated cell cycle progression from G1 to S-phase. CONCLUSIONS: These data provide new insight into the role of ATF3 in prostate cancer development and/or progression. They indicate that ATF3 is an androgen regulated gene that is highly expressed in prostate tumors and stimulating cell proliferation. It represents a possible target for prostate cancer therapy.

Activating Transcription Factor 3↗
PubMed1995

Plant transcription factors.

Transcriptional regulation of gene expression relies on the recognition of promoter elements by transcription factors. In the past several years, a considerable number of (putative) transcription factors have been identified in plants. Some genes coding for these factors were isolated by south-western screening with oligonucleotides as a probe or by homology-based screening, and others were initially isolated by genetic means and subsequently identified as the genes for transcription factors. These transcription factors often form families of structurally related proteins with similar DNA-binding specificities and in addition, they are sometimes involved in related phenomena. Some groups of factors homo- and/or heterodimerize to increase the length and variability of the target sequences. Transcriptional activators, in general, comprise a modular activation domain. The activities of the transcription factors are controlled by post-translational modification, like phosphorylation and glycosylation, as well as at the levels of nuclear transport, oligomerization, etc. In this review, we will summarize the current knowledge of plant transcription factors to help understand the mechanistic aspects of the transcriptional regulation of genes.

Amino Acid Sequence↗
PubMed2002

The use of inducible engrailed fusion proteins to study the cellular functions of eukaryotic transcription factors.

Transcription factors determine cell lineages, control cell fate, and regulate cellular responses to stimuli. Many methods are currently used to study the function of transcription factors in a cellular context and several of these involve overexpressing a constitutively active form of the protein and studying its effects. Here we outline an alternative approach involving the inducible expression of dominant-negative transcription factors in human cell lines. Dominant-negative transcription factors can be used to investigate the effect of signaling pathways on complex cellular processes that are regulated by a particular transcription factor. Potent dominant-negative transcription factors can be created by using fusions to the engrailed repressor domain. These fusion proteins can be coupled to inducible expression systems such as the ecdysone-inducible system. The ability to control protein expression has several benefits including the ability to create stable cell lines that express potentially cytotoxic proteins. Therefore when used in tandem, these two methods constitute a new and improved approach for dissecting the cellular role and transcriptional targets of many transcription factors. Here we illustrate this integrated approach by using a conditional dominant-negative Elk-1 protein to identify candidate Elk-1-regulated target genes.

Animals↗
PubMed2006

[Novel approaches to the background of developmental abnormalities: clinical genetics of transcription factors].

Transcription factors are highly conserved proteins with preserved structure and function for up to a hundred million years. They regulate protein formation and function by binding to DNA and controlling gene expression. Mutations are generally lethal, but can play role in endocrine disorders and tumor genesis. They are necessary for cell growth, proliferation, differentiation and are required in tissue and organ development during normal embryogenesis. Consequently, transcription factors are essential in developmental processes and homeostasis. Mutations of genes encoding transcriptional regulators have been shown to be involved in a number of various genetic diseases, in particular malformation of the skeletal system, cranium, limbs, as well as some congenital syndromes with anomalies of these organs and somatic/mental retardation. Evidences accumulate to support the need of transcription factor mutation identification in the clinical practice. The present study reviews the most important congenital malformations and genetic syndromes which are thought to be related to mutations in classic transcription factors, and in which determination of transcription factors might be of clinical significance, even in the near future, for exact causative diagnosis and genetic counseling in affected families. In addition, studies of the transcription factors may lead to a better understanding of human embryogenesis.

Bone Diseases, Developmental↗
PubMed1999

Angiotensin peptides and inducible transcription factors.

Transcription factors are DNA-binding proteins which are able to identify specific nucleotide sequences and by binding to them may regulate the expression of genes at the level of transcription. In addition to the general transcription factors, which are basically the same for each gene transcribed by eukaryotic RNA polymerase II, more than 100 specific transcription factors have been identified so far. These specific transcription factors regulate the expression patterns of various sets of inducible genes during growth and development and enable the adjustment of cells and tissues to environmental changes. Especially the AP-1 proteins have found increasing interest, since members of these families such as c-Fos and c-Jun seem to be involved in trophic changes in peripheral organs. Many studies have also used them as marker proteins for activated neurons in the central nervous system to identify functional pathways and connections between brain nuclei. The renin-angiotensin system is implicated both in the hormonal and the central regulation of blood pressure and volume homeostasis. By binding to their specific receptors angiotensin peptides, namely angiotensin (Ang) II, have also been reported to induce the expression of a variety of inducible transcription factors (ITF) of the AP-1 and other families in peripheral organs such as kidney and blood vessels and in specific brain regions. By activating ITF, transient ligand receptor signals are transformed into long-lasting genetic changes. While the Ang II induced expression of ITF in peripheral organs seems to be associated with trophism, the physiological significance of this expression in brain nuclei with their postmitotic cells is much less clear. This contribution reviews the Ang II induced ITF expression in various tissues and discusses the possible physiological and pathophysiological consequences of the resulting changes in genetic patterns.

Adrenal Glands↗