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)

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

The yeast transcriptional activator GCN4 is 1 of over 30 identified eukaryotic proteins containing the basic region leucine zipper (bZIP) DNA-binding motif. We have determined the crystal structure of the GCN4 bZIP element complexed with DNA at 2.9 A resolution. The bZIP dimer is a pair of continuous alpha helices that form a parallel coiled coil over their carboxy-terminal 30 residues and gradually diverge toward their amino termini to pass through the major groove of the DNA-binding site. The coiled-coil dimerization interface is oriented almost perpendicular to the DNA axis, giving the complex the appearance of the letter T. There are no kinks or sharp bends in either bZIP monomer. Numerous contacts to DNA bases and phosphate oxygens are made by basic region residues that are conserved in the bZIP protein family. The details of the bZIP dimer interaction with DNA can explain recognition of the AP-1 site by the GCN4 protein.
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PMID:The GCN4 basic region leucine zipper binds DNA as a dimer of uninterrupted alpha helices: crystal structure of the protein-DNA complex. 147 54

The cis-acting elements for the early and late promoters, as well as the enhancer in the prototype strains of human polyomavirus BK (BKV) are located within a 500 bp intergenic region. We previously studied the specificity of protein binding in this region in vitro and showed that the interaction of proteins of the nuclear factor-1 (NF-1) family is crucial for early promoter activity. We have now extended our study to the BKV late promoter. We show that the late promoter activity in HeLa cell extracts is poor compared to the activity of the early promoter. Using a high template to protein ratio, multiple start sites were detected by primer extension analysis. DNase I protection experiments revealed the presence of three NF-1 binding sites in the late side, in addition to those identified previously in the 68 bp repeats and C element. Competition transcription assays using binding sites for NF-1, AP-1, Sp-1 and a complete 68 bp repeat indicated that only the 68 bp repeat and the NF-1 binding site competed significantly with the late promoter activity. A point mutation in the NF-1 binding site, which destroys the ability of the oligonucleotide to bind NF-1, also impaired its capacity to compete with the late promoter. The ability of NF-1 to activate both the early and late promoters suggests that the proteins of this family act as a bidirectional transcriptional activator in this virus.
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PMID:Proteins of the nuclear factor-1 family act as an activator of the late promoter in human polyomavirus BK in vitro. 165 86

Human papillomavirus type 18 (HPV-18) infects genital squamous epithelium and is an etiological agent of cervical cancer. Cell-type-specific expression of HPV-18 is directed by the region upstream of the viral early genes that contains a transcriptional enhancer whose function is dependent solely on cellular factors. This element directs expression to high levels in squamous epithelial cells but is only weakly active in other cell types. We demonstrate by gel mobility-shift, methylation interference, and mutational analysis that the binding of two distinct factors to the enhancer is necessary for cell-type-specific transcriptional activation. One of these factors is identified as a keratinocyte-specific transcriptional activator, which we call KRF-1, while the other is a member of the AP-1 family. We also find that Oct-1 competes with KRF-1 for binding to enhancer sequences though it does not contribute to transcriptional activation. These results suggest a complex interplay of ubiquitous and cell-type-restricted transcriptional factors in the tissue- and differentiation-specific expression of HPV-18.
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PMID:A keratinocyte-specific transcription factor, KRF-1, interacts with AP-1 to activate expression of human papillomavirus type 18 in squamous epithelial cells. 165 60

The transcriptional mechanisms which contribute to the regulation of nerve growth factor (NGF) production are still largely unknown. We previously expressed the NGF promoter region in transgenic mice to localize cis regulatory elements to within 5 kb of the promoter. To further map these elements, and to begin to study the corresponding transacting factors, we here assayed the effects of 5' deletions and point mutations and examined the binding of nuclear factors to the NGF promoter region using L929 cell fibroblasts. Sequential deletions delineated regions upstream from the promoter which stimulated and inhibited transcription. DNAse-1 footprinting experiments identified four upstream segments, designated F2, F4, F6 and F8, which bound L929 cell nuclear proteins. F2 and F4 mapped to stimulatory and F6 and F8 to inhibitory regions. Competition experiments using a heptanucleotide present in both F2 and F4 segments suggested that they may be bound by related factors. Gel shift assays showed that the F8 binding proteins are less abundant in L929 cells than in NIH 3T3 fibroblasts and B16 melanoma cells. In addition to the upstream segments, a downstream AP-1 consensus sequence bound L929 nuclear proteins. Mutation of the AP-1 consensus sequence eliminated binding of nuclear proteins and reduced transcriptional activity. Our results indicate that transcriptional activator as well as suppressor regions surround the NGF gene promoter. The regulation of NGF production is likely to involve cis elements within these regions and transacting factors that bind to them.
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PMID:Structural and functional identification of regulatory regions and cis elements surrounding the nerve growth factor gene promoter. 166 23

Protein-DNA recognition is often mediated by a small domain containing a recognizable structural motif, such as the helix-turn-helix or the zinc-finger. These motifs are compact structures that dock against the DNA double helix. Another DNA recognition motif, found in a highly conserved family of eukaryotic transcription factors including C/EPB, Fos, Jun and CREB, consists of a coiled-coil dimerization element the leucine-zipper and an adjoining basic region which mediates DNA binding. Here we describe circular dichroism and 1H-NMR spectroscopic studies of another family member, the yeast transcriptional activator GCN4. The 58-residue DNA-binding domain of GCN4, GCN4-p, exhibits a concentration-dependent alpha-helical transition, in accord with previous studies of the dimerization properties of an isolated leucine-zipper peptide. The GCN4-p dimer is approximately 70% helical at 25 degrees C, implying that the basic region adjacent to the leucine zipper is largely unstructured in the absence of DNA. Strikingly, addition of DNA containing a GCN4 binding site (AP-1 site) increases the alpha-helix content of GNC4-p to at least 95%. Thus, the basic region acquires substantial alpha-helical structure when it binds to DNA. A similar folding transition is observed on GCN4-p binding to the related ATF/CREB site, which contains an additional central base pair. The accommodation of DNA target sites of different lengths clearly requires some flexibility in the GCN4 binding domain, despite its high alpha-helix content. Our results indicate that the GCN4 basic region is significantly unfolded at 25 degrees C and that its folded, alpha-helical conformation is stabilized by binding to DNA.
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PMID:Folding transition in the DNA-binding domain of GCN4 on specific binding to DNA. 221 76

The BZLF1 or zta immediate-early gene of Epstein-Barr virus (EBV) encodes a 33-kilodalton phosphorylated nuclear protein that is a specific transcriptional activator of the EBV lytic cycle when introduced into latently infected B lymphocytes. We have shown previously that the divergent EBV DSL target promoter contains two zta-response regions, one within the minimal promoter and the other in an upstream lymphocyte-dependent enhancer region. In this study, we used footprinting and gel mobility retardation assays to reveal that bacterially synthesized Zta fusion proteins bound directly to six TGTGCAA-like motifs within DSL. Four of the Zta-binding sites lay adjacent to cellular TATA and CAAT factor-binding sites within the minimal promoter, and two mapped within the enhancer region. Single-copy oligonucleotides containing these Zta-binding sites conferred Zta responsiveness to heterologous promoters. In addition, the Zta protein, which possesses a similar basic domain to the conserved DNA-binding region of the c-Fos, c-Jun, GCN4, and CREB protein family, proved to bind directly to the consensus AP-1 site in the collagenase 12-O-tetradecanoylphorbol-13-acetate response element. Cotransfection with zta also trans activated a target reporter gene containing inserted wild-type 12-O-tetradecanoylphorbol-13-acetate response element oligonucleotides. Cellular AP-1 binding activity proved to be low in latently EBV-infected Raji cells but was induced (together with the Zta protein) after activation of the lytic cycle with 12-O-tetradecanoylphorbol-13-acetate. We conclude that EBV may have captured and modified a cellular gene encoding a c-jun-like DNA-binding protein during its evolutionary divergence from other herpesviruses and that this protein is used to specifically redirect transcriptional activity toward expression of EBV lytic-cycle genes in infected cells.
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PMID:The zta transactivator involved in induction of lytic cycle gene expression in Epstein-Barr virus-infected lymphocytes binds to both AP-1 and ZRE sites in target promoter and enhancer regions. 215 99

Tissue factor (TF) is the primary initiator of the coagulation protease cascades. This cell surface glycoprotein is the receptor and essential cofactor for the serine protease factor VIIa. TF is constitutively expressed in some extravascular cell types and is transiently induced in monocytes, endothelial cells, and fibroblasts. Inducible expression is implicated in cellular immune responses, inflammation, and intravascular coagulation. Transcriptional regulation of the TF promoter was analyzed in COS-7 cells under conditions of (i) high-level expression and (ii) serum induction. The region comprising nucleotides -209 to +121 (relative to the transcription start site) supports high-level transcriptional activity and can be divided into two distinct regions: a region (-111 to +121) that exhibited low promoter activity and a region (-209 to -112) that enhanced transcriptional activity to a high level. The role of further upstream sequences is still to be established, although two consensus binding sites for the transcriptional activator protein AP-1 did enhance low-level promoter activity. In serum-starved COS-7 cells TF expression was transiently increased 20-fold by serum. All transcriptionally active constructs were responsive to serum, indicating the presence of at least one serum response element, whose function was retained in the immediate 5' aspect of the gene, at -111 to +14. Based on this functional map, we propose that the elaborate pattern of TF expression by cells results from a relatively complex promoter.
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PMID:Functional analysis of the human tissue factor promoter and induction by serum. 231 17

The jun family of transcriptional activators includes mammalian AP-1 as well as the yeast regulatory protein GCN4. Recently, an additional transcriptional activator has been found in yeast that recognizes the TGACTCA sequence element common in GCN4/AP-1 sites. This factor was designated yAP-1. The structural gene for yAP-1 has now been isolated and characterized. The deduced amino acid sequence predicts a protein of 650 residues, considerably larger than GCN4 or c-Jun. The amino terminus of yAP-1 is homologous to the carboxy-terminal DNA-binding domains of GCN4 and c-Jun. Disruption of the YAP1 gene demonstrates this gene is not essential but is required for AP-1 recognition element-dependent transcriptional activation. DNA-affinity blots of proteins from YAP1 cells suggest the presence of additional TGACTCA-binding proteins other than GCN4 and yAP-1. Furthermore, expression of at least one of these related DNA-binding proteins appears to be under control of yAP-1.
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PMID:Yeast YAP1 encodes a novel form of the jun family of transcriptional activator proteins. 254 25

When expressed in Epstein-Barr virus (EBV) latently infected B cells, the EBV early protein EB1 trans-activates as many EBV early genes as does TPA. Several EB1 responsive elements (ZRE) have been identified in EBV early promoters and are located at relatively short distances from the TATA box. One of them (ZRE-M) overlaps with a consensus TPA responsive element (TRE) defined as an AP-1/c-jun/c-fos binding site and is located in an EBV promoter controlling the expression of the post-transcriptional activator EB2. Another (ZREZ) is located in the promoter controlling the expression of EB1 and does not respond to TPA. These two ZREs have no apparent sequence homology. Although EB1 activates transcription from the AP-1 enhancer sequence and from the ZREZ, the activation is severely impaired by distance, suggesting that EB1 is more likely to be a promoter factor than an enhancer factor. These properties also suggest that EB1 is not functionally related to c-jun and c-fos. However, since EB1 can activate transcription from AP-1 binding sites when properly positioned, the role of this factor in the oncogenic properties of EBV should be considered.
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PMID:The Epstein-Barr virus early protein EB1 activates transcription from different responsive elements including AP-1 binding sites. 254 44


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