Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51532 (transcriptional activator)
 6,546 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In uremia, muscle wasting involves increased glucocorticoid production and activation of the ubiquitin-proteasome proteolytic pathway, including increased expression of ubiquitin. Previously, we reported that glucocorticoids stimulate ubiquitin transcription by a mechanism involving Sp1 in L6 muscle cells (Marinovic AC, Zheng B, Mitch WE, Price SR. J Biol Chem 277: 16673-16681, 2002). This finding was surprising because Sp1 is a general transcriptional activator. To better understand the mechanism of glucocorticoid-induced ubiquitin (UbC) gene transcription, we examined whether this response occurs in many organs or uniquely in skeletal muscle. Glucocorticoid-responsive cells of different organs were transfected with a human UbC promoter-luciferase reporter plasmid; dexamethasone stimulated UbC reporter activity 220% (P < 0.05) in L6 skeletal muscle cells but not in HepG2 hepatocytes, NRK kidney cells, CaCo-2 colon cells, or H9c2 cardiomyocytes. Transactivation of the Sp1-responsive SV40 viral promoter was also increased in muscle but not in other nonmuscle cells. The muscle-specific nature of the UbC response was confirmed in vivo in rats with insulin deficiency, a condition associated with high glucocorticoid production: UbC mRNA was elevated in skeletal muscle but not in liver, kidney, intestine, or heart. Electrophoretic mobility shift assays and in vivo genomic footprinting demonstrated that insulin deficiency increased Sp1 binding to GC-rich elements in the UbC promoter. Thus glucocorticoids increase UbC transcription by a mechanism involving Sp1 that is unique to muscle.
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PMID:Tissue-specific regulation of ubiquitin (UbC) transcription by glucocorticoids: in vivo and in vitro analyses. 1695 42

Our previous studies have identified a minimal Sp1-driven promoter region (nt -36/+116) directing NHE2 expression in mouse renal epithelial cells. However, this minimal promoter region was not sufficient to support active transcription of NHE2 gene in the intestinal epithelial cells, suggesting the need for additional upstream regulatory elements. In the present study, we used nontransformed rat intestinal epithelial (RIE) cells as a model to identify the minimal promoter region and transcription factors necessary for the basal transcription of rat NHE2 gene in the intestinal epithelial cells. We identified a region within the rat NHE2 gene promoter located within nt -67/-43 upstream of transcription initiation site as indispensable for the promoter function in intestinal epithelial cells. Mutations at nt -56/-51 not only abolished the DNA-protein interaction in this region, but also completely abolished NHE2 gene promoter activity in RIE cells. Supershift assays revealed that Sp1 and Sp3 interact with this promoter region, but, contrary to the minimal promoter indispensable for renal expression of NHE2, both transcription factors expressed individually in Drosophila SL2 cells activated rat NHE2 gene promoter. Moreover, Sp1 was a weaker transactivator and when coexpressed in SL2 cells it reduced Sp3-mediated NHE2 basal promoter activity. Furthermore, DNase I footprinting confirmed that nt -58/-51 is protected by nuclear protein from RIE cells. We conclude that the mechanism of basal control of rat NHE2 gene promoter activity is different in the renal and intestinal epithelium, with Sp3 being the major transcriptional activator of NHE2 gene transcription in the intestinal epithelial cells.
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PMID:Sp1 and Sp3 mediate NHE2 gene transcription in the intestinal epithelial cells. 1737 26

The basic helix-loop-helix transcription factor NeuroD1 is required for late events in neuronal differentiation, for maturation of pancreatic beta cells, and for terminal differentiation of enteroendocrine cells expressing the hormone secretin. NeuroD1-null mice demonstrated that this protein is essential for expression of the secretin gene in the murine intestine, and yet it is a relatively weak transcriptional activator by itself. The present study shows that Sp1 and NeuroD1 synergistically activate transcription of the secretin gene. NeuroD1, but not its widely expressed dimerization partner E12, physically interacts with the C-terminal 167 amino acids of Sp1, which include its DNA binding zinc fingers. NeuroD1 stabilizes Sp1 DNA binding to an adjacent Sp1 binding site on the promoter to generate a higher-order DNA-protein complex containing both proteins and facilitates Sp1 occupancy of the secretin promoter in vivo. NeuroD-dependent transcription of the genes encoding the hormones insulin and proopiomelanocortin is potentiated by lineage-specific homeodomain proteins. The stabilization of binding of the widely expressed transcription factor Sp1 to the secretin promoter by NeuroD represents a distinct mechanism from other NeuroD target genes for increasing NeuroD-dependent transcription.
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PMID:The basic helix-loop-helix transcription factor NeuroD1 facilitates interaction of Sp1 with the secretin gene enhancer. 1787 29

Brain-specific homeobox (Bsx) is specifically expressed at the early embryonic stages during brain development. Several studies show that Bsx plays important roles in brain development; however, the mechanisms of its transcriptional regulation remain to be established. In this study, we show that binding of repressor element silencing transcription factor (REST) to the neuron restrictive silencer element (NRSE) represses Bsx transcription in non-neuronal P19 cells. The Bsx promoter contains several putative binding sites for transcription factors, including NRSE for REST and the GC box for the transcriptional activator, Sp1. Upon neuronal differentiation of P19 cells with retinoic acid, Bsx gene expression increased, whereas that of the REST gene decreased. Electrophoretic mobility shift analyses demonstrated that recombinant REST proteins bound the NRSE region of the Bsx promoter. In neuronal NS20Y cells, transcriptional activity of the Bsx promoter was decreased upon expression of REST. Moreover, dominant-negative REST derepressed Bsx transcription in P19 cells. Sp1-mediated transcriptional activity of the Bsx promoter was attenuated by treatment with mithramycin A, a GC box-binding drug, but was enhanced upon mutation of NRSE. Co-immunoprecipitation and chromatin immunoprecipitation assays showed that the Bsx promoter appeared to be modulated by direct interactions between REST and Sp1. The CpG sites of NRSE and GC box were completely unmethylated, signifying no interference of DNA methylation. Our results suggest that binding of REST to NRSE suppresses the Sp1-mediated activation of Bsx in non-neuronal cells.
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PMID:REST is a key regulator in brain-specific homeobox gene expression during neuronal differentiation. 1794 79

NFBD1/MDC1 is a large nuclear protein with an anti-apoptotic potential which participates in DNA damage response. Recently, we have demonstrated that NFBD1 has an inhibitory effect on pro-apoptotic p53 and DNA damage-induced transcriptional repression of NFBD1 plays an important role in p53-dependent apoptotic response. In this study, we have found that NFBD1 promoter region contains canonical Sp1-, STAT-1- and NF-Y-binding sites and finally we have identified Sp1 as a transcriptional activator for NFBD1. The 5'-RACE and bioinformatic analyses revealed that NFBD1 encodes at least four transcriptional variants arising from distinct transcriptional start sites. Luciferase reporter assays using a series of NFBD1 promoter deletion mutants demonstrated that the proximal Sp1-binding site is required for the transcriptional activation of NFBD1. Indeed, the endogenous Sp1 was recruited onto the proximal Sp1-binding site as examined by chromatin immunoprecipitation (ChIP) assay and siRNA-mediated knockdown of the endogenous Sp1 in HeLa cells reduced the expression levels of NFBD1, which renders cells sensitive to adriamycin (ADR). In support of this notion, mithramycin A (MA, Sp1 inhibitor) treatment resulted in a significant down-regulation of NFBD1. Taken together, our present findings suggest that Sp1-mediated transcriptional regulation of NFBD1 plays an important role in the regulation of DNA damage response.
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PMID:Sp1-mediated transcriptional regulation of NFBD1/MDC1 plays a critical role in DNA damage response pathway. 1817 47

Generation of new adipocytes plays a major role in the development of obesity. We previously have shown that transcriptional repressor factor that binds to IST (FBI)-1 exerts a dual effect in the process of adipogenesis by inhibiting proliferation and promoting differentiation of preadipocytes. The aim of the present study was to identify FBI-1 regulated molecular effectors that could account for these effects. Overexpressing FBI-1 in preadipocytes resulted in reduced expression of the cell cycle regulator cyclin A, which may explain FBI-1 induced inhibition of proliferation. Interestingly, FBI-1 repressed cyclin A promoter activity through an indirect mechanisms that did not involve direct binding of FBI-1 to the promoter sequence, but rather FBI-1 inhibition of transcriptional activator Sp1 binding to a regulatory element at -452 to -443. We also show that FBI-1 promotes terminal preadipocyte differentiation through a mechanism involving decreased levels of expression of the PPARgamma inhibitor E2F-4. FBI-1 significantly reduced E2F-4 promoter activity. Contrary to cyclin A, we found FBI-1-induced repression of E2F-4 is mediated by a direct mechanism via a FBI-1 regulatory element at -11 to -5. As function of transcriptional repressors normally depends on the presence of regulatory co-factors we also performed expression profiling of potential FBI-1 co-repressors throughout adipogenesis. In these experiments Sin3A and histon deacetylase (HDAC)-1 showed a similar expression pattern compared to FBI-1. Strikingly, co-immunoprecipitation studies revealed that FBI-1 binds Sin3A and HDAC-1 to form a repressor complex. Furthermore, by mutational analysis the amino terminal Poxvirus (POZ) domain of FBI-1 was found to be important for Sin3A and HDAC-1 binding. Taken together, FBI-1 is the first transcriptional repressor shown to act as a dual regulator in adipogenesis exerting repressor activities on target genes by both, direct and indirect mechanisms.
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PMID:Transcription factor FBI-1 acts as a dual regulator in adipogenesis by coordinated regulation of cyclin-A and E2F-4. 1836 81

To understand transcriptional regulation of the human mitotic centromere-associated kinesin (MCAK) promoter, the 1,151-bp promoter region of the human MCAK gene in Jurkat T cells was cloned by polymerase chain reaction (PCR). Although a bioinformatic analysis of the promoter sequence predicted several putative transcription factor binding sites for E2F, Sp1, c-Myb, p53, p300, NF-1, AML-1a, Ap-1, E-box factor, and C/EBPalpha/beta with no consensus TATA-box motif, deletion constructs of the promoter region revealed that the core positive promoter activity resided at -266/-66, containing three GC-motifs for binding Sp1. Site-directed disruption and chromatin immunoprecipitation analysis indicated that Sp1-binding to the GC-motifs was crucial for promoter activation, but the E2F1-binding to the E2F-motif (-57/-50) was crucial for promoter repression. Cotransfection of the luciferase reporter with either Sp1- or E2F1-expression plasmid further verified the role of Sp1 as a transcriptional activator and E2F1 as a transcriptional repressor in the human MCAK promoter.
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PMID:Regulation of the human mitotic centromere-associated kinesin (MCAK) promoter by the transcription factors Sp1 and E2F1. 1844 Mar 23

Many macrophage-specific promoters lack classical transcriptional start site elements such as TATA boxes and Sp1 sites. One example is the CSF-1 receptor (CSF-1R, CD115, c-fms), which is used as a model of the transcriptional regulation of macrophage genes. To understand the molecular basis of start site recognition in this gene, we identified cellular proteins binding specifically to the transcriptional start site (TSS) region. The mouse and human csf1r TSS were identified using cap analysis gene expression (CAGE) data. Conserved elements flanking the TSS cluster were analyzed using EMSAs to identify discrete DNA-binding factors in primary bone marrow macrophages as candidate transcriptional regulators. Two complexes were identified that bind in a highly sequence-specific manner to the mouse and human TSS proximal region and also to high-affinity sites recognized by myeloid zinc finger protein 1 (Mzf1). The murine proteins were purified by DNA affinity isolation from the RAW264.7 macrophage cell line and identified by mass spectrometry as EWS and FUS/TLS, closely related DNA and RNA-binding proteins. Chromatin immunoprecipitation experiments in bone marrow macrophages confirmed that EWS, but not FUS/TLS, was present in vivo on the CSF-1R proximal promoter in unstimulated primary macrophages. Transfection assays suggest that EWS does not act as a conventional transcriptional activator or repressor. We hypothesize that EWS contributes to start site recognition in TATA-less mammalian promoters.
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PMID:The Ewing sarcoma protein (EWS) binds directly to the proximal elements of the macrophage-specific promoter of the CSF-1 receptor (csf1r) gene. 1845 93

Immediate early response 3 interacting protein 1 (IER3IP1) is an endoplasmic reticulum protein with its potential cellular function involved in cell differentiation and cell death processes. In this report, we investigated the molecular mechanism by which the expression of IER3IP1 gene is regulated by cloning the 5' flanking region of the human IER3IP1 gene for various promoter studies. Deletion analysis was used to identify the basal promoter activity retained at -298/-59 region and mutation analysis proved that Sp1 is a transcriptional activator of this gene expression. As an early response gene, IER3IP1 showed an increase in transcription in response to tumor necrosis factor alpha (TNF-alpha) in a time- and dose-dependent manner. This inducible response to TNF-alpha is mediated by the demonstration of nuclear factor kappaB (NF-kappaB) responsive element on IER3IP1 promoter sequence. From our results, we suggest that IER3IP1 gene is involved in TNF-alpha-mediated cellular response to stressful conditions.
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PMID:Transcriptional regulation of IER3IP1 gene by tumor necrosis factor-alpha and Sp family proteins. 1988 54

The varicella-zoster virus (VZV) IE62 protein is the major transcriptional activator. IE62 is capable of associating with DNA both nonspecifically and in a sequence-specific manner via a consensus binding site (5'-ATCGT-3'). However, the function of the consensus site is poorly understood, since IE62 efficiently transactivates promoter elements lacking this sequence. In the work presented here, sequence analysis of the VZV genome revealed the presence of 245 IE62 consensus sites throughout the genome. Some 54 sites were found to be present within putative VZV promoters. Electrophoretic mobility shift assay (EMSA) experiments using an IE62 fragment containing the IE62 DNA-binding domain and duplex oligonucleotides that did or did not contain the IE62 consensus binding sequence yielded K(D) (equilibrium dissociation constant) values in the nanomolar range. Further, the IE62 DNA binding domain was shown to have a 5-fold-increased affinity for its consensus site compared to nonconsensus sequences. The effect of consensus site presence and position on IE62-mediated activation of native VZV and model promoters was examined using site-specific mutagenesis and transfection and superinfection reporter assays. In all promoters examined, the consensus sequence functioned as a distance-dependent repressive element. Protein recruitment assays utilizing the VZV gI promoter indicated that the presence of the consensus site increased the recruitment of IE62 but not Sp1. These data suggest a model where the IE62 consensus site functions to down-modulate IE62 activation, and interaction of IE62 with this sequence may result in loss or decrease of the ability of IE62 to recruit cellular factors needed for full promoter activation.
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PMID:Role of the IE62 consensus binding site in transactivation by the varicella-zoster virus IE62 protein. 2013 51


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