Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UNIPROT:P51532 (transcriptional activator)
6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Transcription of the skeletal alpha-actin gene is selectively activated in rat myocardiocytes undergoing hypertrophy both in vivo and in vitro. In most of these models, transient expression of certain proto-oncogene transcription factors precedes hypertrophy and sarcomeric gene induction. Using expression vectors encoding Fos and Jun, the main constituents of transcriptional activator protein AP-1, we analyzed the role of these oncoproteins in mediating the transcriptional induction of skeletal alpha-actin by adrenergic stimulation. Both c-fos and c-jun were induced early after beta-adrenergic stimulation, with peak mRNA levels preceding skeletal alpha-actin induction by several hours. A second peak of c-jun mRNA coincided with skeletal alpha-actin induction. Co-transfection assays in cardiac myocytes and P19 teratocarcinoma cells demonstrated that over-expression of c-jun, or c-fos plus c-jun, transactivated the skeletal alpha-actin promoter by about 5-fold. Comparable activation was not seen for alpha-myosin heavy chain or cardiac alpha-actin promoters. Skeletal alpha-actin promoter sequences between -153 and -36 were required for maximal transactivation by c-fos/c-jun, and purified Fos and Jun were bound specifically within this region. A direct physiological role is suggested for the AP-1 transcription factor complex in regulating skeletal alpha-actin gene expression and alpha-actin isoform switching during the onset of signal-mediated cardiac myocyte hypertrophy.
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PMID:Positive regulation of the skeletal alpha-actin gene by Fos and Jun in cardiac myocytes. 146 48

In order to identify genes that may play a role in the onset of the differentiation program elicited by retinoic acid, we analyzed, in P19 embryonal carcinoma cells, the expression of genes that are part of the early response of mouse fibroblasts to growth factor stimulation. In this paper, we show that a sequence-specific transcriptional activator, Krox-24, is rapidly induced, under conditions that promote differentiation of P19 cells. Expression of three other serum- and retinoic acid-stimulated genes (clones AC36, C1, and G39) was also studied. Induction of these genes occurs during the first 48 h of exposure of cells to retinoic acid, a period that precedes cell type determination. Our results suggest that different mechanisms regulate the expression of the Krox-24 gene in differentiating P19 cells. A labile repressor seems to be responsible for control of Krox-24 expression in P19 embryonal carcinoma cells. Inactivation of this repressor following retinoic acid treatment resulted in several peaks of activation of the Krox-24 gene, mediated by different mechanisms, some of which did not require de novo protein synthesis. In contrast, activation of AC36 required de novo protein synthesis, and that of C1 and G39 did not. The four genes are differentially expressed in several mouse tissues and during mouse embryonic development.
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PMID:Regulated expression of Krox-24 and other serum-responsive genes during differentiation of P19 embryonal carcinoma cells. 179 34

Transcription of the vascular cell adhesion molecule 1 (VCAM-1) gene in endothelial cells is induced by lipopolysaccharide and the inflammatory cytokines interleukin-1 beta and tumor necrosis factor alpha (TNF-alpha). Previous studies have demonstrated that tandem binding sites for the inducible transcription factor NF-kappa B are necessary but not sufficient for full cytokine-mediated transcriptional activation. Herein, we demonstrate that full cytokine-induced accumulation of VCAM1 transcript requires protein synthesis. We report the definition of a functional regulatory element in the VCAM1 promoter interacting with the transcriptional activator interferon regulatory factor 1 (IRF-1). DNA-protein binding studies with endothelial nuclear extracts revealed that IRF-1 is cytokine inducible and binds specifically to a consensus sequence motif located 3' of the TATA element. We have identified heterodimeric p65 and p50 as the NF-kappa B species binding to the VCAM1 promoter in TNF-alpha-activated endothelial cells. Experiments with recombinant proteins showed that p50/p65 and high-mobility-group I(Y) protein cooperatively facilitated the binding of IRF-1 to the VCAM1 IRF binding site and that IRF-1 physically interacted with p50 and with high-mobility-group I(Y) protein. Transient transfection assay in endothelial cells showed that overexpressed IRF-1 resulted in superinduction of TNF-alpha-stimulated transcription. Site-directed mutations in the IRF binding element decreased TNF-alpha-induced activity and totally abolished superinduction. Cotransfection assays in P19 embryonal carcinoma cells revealed that IRF-1 synergized with p50/p65 NF-kappa B to activate the VCAM1 promoter or heterologous promoter constructs bearing isolated VCAM1 NF-kappa B and IRF binding motifs. Cytokine inducibility of VCAM1 in endothelial cells utilizes the interaction of heterodimeric p50/p65 proteins with IRF-1.
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PMID:Endothelial interferon regulatory factor 1 cooperates with NF-kappa B as a transcriptional activator of vascular cell adhesion molecule 1. 753 51

zif268/egr-1 is an immediate early response gene that is involved in regulation of growth and differentiation. Its mRNA encodes a sequence-specific transcriptional activator containing three zinc fingers that act as the DNA-binding domain. Although zif268/egr-1 is expressed in the nervous system during neuronal excitation, no target gene has yet been identified. Here we report that the zif268/egr-1 protein bound in vitro to two sites in the proximal regulatory region of the human synapsin I gene. The zif268/egr-1 protein was also shown to stimulate transcription from this control region in transactivation assays. Additionally, the presence of a putative neural-restrictive silencer element next to one of the zif268/egr-1-binding sites interfered with transactivation in a tissue-independent manner. An analysis of the temporal expression pattern of zif268/egr-1 and synapsin I during neuronal differentiation of P19 embryonal carcinoma cells revealed that zif268/egr-1 mRNA was induced on day 5 and synapsin I mRNA on day 8 after retinoic acid treatment. From this data we conclude that the synapsin I gene is a target of the zif268 transcription factor; however, intermediate factors may also be involved in the activation.
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PMID:Regulation of synapsin I gene expression by the zinc finger transcription factor zif268/egr-1. 819 67

Interferon regulatory factors (IRFs) bind to the interferon-stimulated response element (ISRE) and regulate interferon- and virus-mediated gene expression. IRF-1 acts as a transcriptional activator, while IRF-2 acts as a repressor. Here we show that IRF-1 and IRF-2 bind to both cellular TFIIB, a component of the basal transcription machinery, and recombinant TFIIB (rTFIIB) and that this protein-protein interaction facilitates binding of IRFs to the ISRE. A functional interaction between TFIIB and IRF was assessed by a newly established in vitro transcription assay in which recombinant IRF-1 (rIRF-1) stimulated transcription specifically from an ISRE-containing template. With this assay we show that rIRF-1 and rTFIIB cooperatively enhance the ISRE promoter in vitro. We found that the activity of an ISRE-containing promoter was cooperatively enhanced upon cotransfection of TFIIB and IRF-1 cDNAs into P19 embryonal carcinoma cells, further demonstrating functional interactions in vivo. The cooperative enhancement by TFIIB and IRF-1 was independent of the TATA sequence in the ISRE promoter but dependent on the initiator sequence (Inr) and was abolished when P19 cells were induced to differentiate by retinoic acid treatment. In contrast, cotransfection of TFIIB and IRF-1 into NIH 3T3 cells resulted in a dose-dependent repression of promoter activation which occurred in a TATA-dependent manner. Our results indicate the presence of a cell type-specific factor that mediates the functional interaction between IRFs and TFIIB and that acts in conjunction with the requirement of TATA and Inr for promoter activation.
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PMID:Interferon regulatory factors and TFIIB cooperatively regulate interferon-responsive promoter activity in vivo and in vitro. 888 61

GATA-4 is a cardiac-specific member of the GATA family of zinc finger transcription factors. During embryogenesis, GATA-4 expression is detected very early in the cardiogenic area and persists later in the developing heart. Studies have shown that GATA-4 is a potent transcriptional activator of several cardiac muscle-specific genes and a key regulator of the cardiomyocyte gene program. Consistent with a role for GATA-4 in cardiomyocyte formation, inhibition of GATA-4 expression by antisense transcripts interferes with expression of cardiac muscle genes and blocks development of beating cardiomyocytes in P19 embryonic stem cells. In order to better define the function of GATA-4 in cardiogenesis, we have carried out molecular analysis of early stages of cardiomyocyte differentiation in GATA-4-deficient P19 cell lines and in P19 cells stably overexpressing GATA-4. The results indicate that GATA-4 is not required for either endodermal or mesodermal commitment or for initiation of the cardiac pathway. However, in the absence of GATA-4, differentiation is blocked at the precardiac (cardioblasts) stage and cells are lost through extensive apoptosis. In contrast, ectopic expression of GATA-4 in P19 cells accelerates cardiogenesis and markedly increases (over 10-fold) the number of terminally differentiated beating cardiomyocytes following cell aggregation. Together, these findings suggest that, in addition to its role in activation of the cardiac genetic program, GATA-4 may be the nuclear target of inductive and/or survival factors for precardiac cells.
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PMID:Enhanced cardiogenesis in embryonic stem cells overexpressing the GATA-4 transcription factor. 919 65

The ZAN75 cDNA was first identified in NIH 3T3 cells and codes for a DNA-binding protein with two zinc finger motifs. In this study, we characterized the nuclear localization signal of ZAN75, tested if ZAN75 regulates transcription, and examined its expression during embryonic development and neuronal differentiation of P19 mouse embryonal carcinoma cells. By examining the cellular localization of deletion mutants of ZAN75 fused to green fluorescence protein, ZAN75 was revealed to have a bipartite nuclear localization signal sequence upstream of the zinc finger domains. The N-terminal region of ZAN75, when fused to the GAL4 DNA-binding domain, strongly activated transcription. The expression of ZAN75 mRNA was found to be developmentally regulated, showing the highest expression in E11.5 embryos. In situ hybridization experiments using E11.5 embryos showed a high expression of the transcripts in neuronal tissues such as brain and neural tube. The expression of ZAN75 was transiently increased at both the mRNA and the protein levels when P19 cells were treated with retinoic acid to induce neuronal differentiation. Taken together, these results indicate that ZAN75 is a transcriptional activator with a bipartite nuclear localization signal and may play a role in neuronal differentiation.
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PMID:Characterization of a zinc finger protein ZAN75: nuclear localization signal, transcriptional activator activity, and expression during neuronal differentiation of P19 cells. 1079 46

Noradrenergic neuronal identity and differentiation are controlled by cascades of transcription factors acting downstream of BMP4, including the basic helix-loop-helix DNA binding protein HAND2 and the homeodomain factor Phox2a. Dopamine-beta-hydroxylase (DBH) is the penultimate enzyme required for synthesis of norepinephrine and is thus a noradrenergic cell type-specific marker. We have examined the interaction of HAND2 and Phox2a at the DBH promoter. Using transient transfection of P19 or NT-2 cells, HAND2 is shown to synergistically enhance Phox2a-driven transcriptional activity at the DBH promoter, an effect that is enhanced by cAMP. While mutation of the Phox2a homeodomain binding sites HD1, HD2, and HD3 results in the loss of HAND2/Phox2a transactivation of DBH, it is the interaction of HAND2/Phox2a at the CRE/AP1-HD1/2 domains in the DBH enhancer that are required for synergistic activation by HAND2. We find that HAND2 functions as a transcriptional activator without directly binding to E-box sequences in the DBH promoter, suggesting that HAND2-mediated DBH activity occurs by protein-protein interactions with other transcriptional regulators. Although we were unable to detect interaction of HAND2 and Phox2a in IP/Western blots, HAND2 synergistic activation of DBH is blocked by E1A, suggesting that HAND2 interacts with CBP (cAMP response element binding protein) in this transcriptional complex. In the presence of the putative HAND2 dimerization partner, E12, synergistic activation of DBH transcription is titrated away, suggesting that HAND2 does not functionally dimerize with E12 in the DBH transcription complex. Our data suggest that HAND2 regulates cell type-specific expression of norepinephrine in concert with Phox2a by a novel mechanism.
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PMID:HAND2 synergistically enhances transcription of dopamine-beta-hydroxylase in the presence of Phox2a. 1451 28

The molecular mechanisms involved in neuronal/astroglial cell fate decisions during the development of the mammalian central nervous system are poorly understood. Here, we report that PRP19beta, a splice variant of mouse PRP19alpha corresponding to the yeast PRP19 protein, can function as a neuron-astroglial switch during the retinoic acid-primed neural differentiation of P19 cells. The beta-variant possesses an additional 19 amino acid residues in-frame in the N-terminal region of the alpha-variant. The forced expression of the alpha-variant RNA caused the down-regulation of oct-3/4 and nanog mRNA expression during the 12-48 h of the late-early stages of neural differentiation and was sufficient to convert P19 cells into neurons (but not glial cells) when the cells were cultured in aggregated form without retinoic acid. In contrast, the forced expression of the beta-variant RNA suppressed neuronal differentiation and conversely stimulated astroglial cell differentiation in retinoic acid-primed P19 cells. Based on yeast two-hybrid screening, cyclophilin A was identified as a specific binding partner of the beta-variant. Luciferase reporter assay mediated by the oct-3/4 promoter revealed that cyclophilin A could act as a transcriptional activator and that its activity was suppressed by the beta-variant, suggesting that cyclophilin A takes part in the induction of oct-3/4 gene expression, which might lead to neuroectodermal otx2 expression within 12 h of the immediate-early stages of retinoic acid-primed neural differentiation. These results show that the alpha-variant gene plays a pivotal role in neural differentiation and that the beta-variant participates in neuronal/astroglial cell fate decisions.
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PMID:Involvement of the mouse Prp19 gene in neuronal/astroglial cell fate decisions. 1635 98

Proteins of the LIM family play important roles in a variety of fundamental biological processes including cell lineage specification and organ development. Here we examined the function in cardiogenesis of a new member of the LIM family, hhLIM, by molecular analysis of early stages of cardiomyocyte differentiation in hhLIM-deficient P19 cell line and P19 cells stably overexpressing hhLIM. The results indicate that hhLIM is a potent transcriptional activator of several cardiac muscle-specific genes. Inhibition of hhLIM expression by antisense transcripts can interfere with expression of cardiac muscle genes and block development of beating cardiomyocytes in P19 embryonic stem cells. Overexpression of hhLIM in P19 cells can enhance expression of cardiac marker genes Nkx2.5 and GATA-4 and potentiate development of cardiomyocyte-like morphology. These findings suggest that, in addition to its role in activation of the cardiac genetic program, hhLIM may be the nuclear target of inductive factor for precardiac cells.
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PMID:hhLIM is involved in cardiomyogenesis of embryonic stem cells. 1648 72


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