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)

The early growth response gene 1 (Egr-1) is a member of the family of immediate early response genes. Egr-1 encodes a nuclear phosphoprotein that binds a specific nonameric DNA sequence through three zinc-finger domains and functions as a transcriptional activator. We tested whether the vasoactive agents platelet-derived growth factor (PDGF), arginine vasopressin (AVP), serotonin (5-HT), and angiotensin II (ANG II) induced Egr-1 mRNA in cultured rat mesangial cells (MCs) and investigated the role of protein kinase C (PKC) in mediating the induction process. PDGF, AVP, and 5-HT induced Egr-1 mRNA within 15 min, reaching peak levels at 45-60 min. After PDGF and 5-HT stimulation, Egr-1 mRNA levels returned to baseline within 4 h, whereas AVP induced a sustained increase for up to 8 h. There was a very close correlation between doses required for Egr-1 induction and induction of MC proliferation. ANG II was a very weak MC mitogen and induced only a small increase in Egr-1 mRNA. Comparison of control cells with cells depleted of PKC by 48 h of PMA treatment revealed that induction of Egr-1 by PDGF and 5-HT is independent of PKC. In contrast, however, the Egr-1 response to AVP was diminished in PKC-depleted cells. AVP induced Egr-1 mRNA 10.9-fold in control cells, compared with 7.8-fold in PKC-depleted cells. Egr-1 mRNA after AVP stimulation remained elevated in control cells for up to 8 h but returned to baseline after 120 min in PKC-depleted cells. Similar results were obtained using the PKC-inhibitor H-7. Using immunocytochemistry, PDGF and AVP were found to induce Egr-1 protein within 30 min localized to the nucleus. We conclude that there is a strong correlation between induction of Egr-1 after stimulation with PDGF, AVP, 5-HT, and ANG II and the proliferative response elicited by these agents in MCs. AVP induces Egr-1 by both PKC-dependent and PKC-independent pathways, whereas the effects of PDGF and 5-HT are independent of PKC.
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PMID:Effect of vasoactive agents on induction of Egr-1 in rat mesangial cells: correlation with mitogenicity. 141 34

CRE-BP1 is a transcriptional activator binding to the cyclic AMP response element, which has a putative metal finger structure and the leucine zipper motif linked to a cluster of basic amino acids in the amino and carboxyl-terminal regions, respectively. The activities of a number of transcription factors are known to be controlled through phosphorylation and dephosphorylation. At the first step for understanding of the regulation of CRE-BP1, phosphorylation of CRE-BP1 was studied in vitro. The human recombinant CRE-BP1 was phosphorylated by protein kinase C and cyclic AMP-dependent protein kinase. These two protein kinases recognized distinct seryl residues of CRE-BP1. Amino acid sequence analysis after phosphopeptide map indicated that two seryl residues, Ser-340 and Ser-367, located in the basic region of CRE-BP1 were identified as the major protein kinase C phosphorylation sites, whereas Ser-62 downstream of the metal finger structure was determined as the phosphorylation site by cyclic AMP-dependent protein kinase. The phosphorylation of CRE-BP1 by these two protein kinases may regulate the function of this transcriptional activator protein.
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PMID:Phosphorylation of CRE-BP1, a cyclic AMP response element binding protein, by protein kinase C and cyclic AMP-dependent protein kinase. 145 87

Transcription of the human vasoactive intestinal peptide (VIP) gene is regulated by both cyclic AMP and phorbol esters. A 17-nucleotide enhancer element within the human VIP gene mediates transcriptional activation by both phorbol esters and forskolin. Mutations of this element decrease responses to both agents, suggesting that the trans-acting proteins that mediate both modes of transcriptional regulation have similar DNA-binding characteristics. The response of the VIP enhancer element to forskolin, but not to 12-O-tetradecanoylphorbol-13-acetate, was attenuated by treatment with a recombinant inhibitor of the cAMP-dependent protein kinase, suggesting that the cAMP-dependent protein kinase and protein kinase C second messenger pathways that converge on this single enhancer element are distinct. The transcriptional activator cAMP-responsive element-binding (CREB) proteins and the c-fos.c-Jun complex interact with the VIP enhancer. The dual second messenger responses of the VIP gene may result from the interaction of this second messenger enhancer with different transcriptional activator proteins.
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PMID:Cyclic AMP- and phorbol ester-induced transcriptional activation are mediated by the same enhancer element in the human vasoactive intestinal peptide gene. 184 91

IL-1, like other agents that have been shown a capacity to induce protein kinase C, is a potent transcriptional activator of the metalloproteinase, stromelysin, in synovial and other fibroblasts. cAMP has been shown to inhibit stromelysin transcription in fibroblasts of nonsynovial origin, and is regarded as an important second messenger for IL-1. In addition to stimulating metalloproteinase transcription, IL-1 also induces PGE2 production in synoviocytes. We determined that rIL-1 alpha led to the time-dependent accumulation of intracellular cAMP in serum-starved rheumatoid synovial fibroblasts, and that the effect was blocked by indomethacin. The cAMP agonists forskolin, 3-isobutyl-1-methylxanthine, and PGE2 suppressed the IL-1 induction of stromelysin; conversely, indomethacin superinduced IL-1-elicited stromelysin mRNA. These results were recapitulated on the transcriptional level in cells transfected with the rat transin/stromelysin promoter in a reporter (CAT) construct. 2',5'-Dideoxyadenosine, an inhibitor of adenylate cyclase, also augmented the IL-1 induction of stromeylsin mRNA, as did H-8, a specific inhibitor of the cAMP-dependent protein kinase A. Staurosporine and H-7, inhibitors of protein kinase C, blocked the IL-1 induction of stromelysin mRNA. We conclude that IL-1 appears to stimulate at least two transduction pathways in synovial fibroblasts from patients with rheumatoid arthritis, and that these have antagonistic effects on the regulation of stromelysin transcription.
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PMID:IL-1 regulation of transin/stromelysin transcription in rheumatoid synovial fibroblasts appears to involve two antagonistic transduction pathways, an inhibitory, prostaglandin-dependent pathway mediated by cAMP, and a stimulatory, protein kinase C-dependent pathway. 217 73

The HBx protein of hepatitis B virus (HBV) is a transcriptional activator that is required for infection and may play an important role in HBV-associated hepatocarcinogenesis. Recently, we and others have shown that HBx stimulates the Ras-Raf-MAP kinase cascade, which leads to enhanced cell proliferation and the activation of transcription factors AP-1 and NF-kappa B. Other studies have shown that HBx can activate transcription by interacting directly with nuclear components of the transcription machinery. Therefore we examined the basis for the different reported activities of HBx. Here, we show that HBx is a complex protein, displaying independent activities in different intracellular locations. The intracellular distribution of HBx protein was first investigated using scanning confocal laser immunomicroscopy and by genetic studies. Our work has established that HBx expressed in cultured cells is found authentically in both the cytoplasm and the nucleus. HBx is not strongly associated with any intracellular structures, but some preferential accumulation was observed near the cell surface. Next, HBx variants were constructed containing a functional or mutant nuclear localization sequence. We show that when HBx is engineered to relocate exclusively to the nucleus, it no longer activates the Ras-Raf-MAP kinase cascade, nor does it activate transcription factors AP-1 and NF-kappa B. Surprisingly, nuclear HBx fully retains the ability to stimulate HBV enhancer I, which is activated independently of the Ras and protein kinase C pathways. Therefore HBx protein stimulates signal transduction pathways in the cytoplasm and transactivates transcription elements in the nucleus. Furthermore, SV40 T antigen is shown to induce the nuclear sequestration of HBx protein and to block its activation of NF-kappa B, demonstrating that HBx is regulated by proteins that alter its intracellular distribution. The conflicting functions of HBx protein in viral infection and possibly carcinoma may involve the regulation of its differential distribution in the cell.
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PMID:The hepatitis B virus HBx protein is a dual specificity cytoplasmic activator of Ras and nuclear activator of transcription factors. 758 4

Nuclear factor of activated T-cells (NFAT) is a transcriptional activator that binds to the interleukin-2 promoter and is believed to be responsible for T-cell-specific interleukin-2 gene expression. Here we demonstrate using electrophoretic mobility shift assays that nuclear NFAT can be induced in the rat basophilic leukemia (RBL-2H3) mast cell line and rat bone marrow-derived mast cells upon cross-linkage of the high affinity receptor (Fc epsilon RI) for immunoglobulin E (IgE). Receptor-dependent activation of NFAT was mimicked by the combination of the protein kinase C activator phorbol myristate acetate and the calcium ionophore ionomycin. The induced binding activity was specific for the NFAT recognition motif because competition with nonradioactive NFAT oligonucleotide abolished the DNA binding activity, whereas nonradioactive oligonucleotides recognized by the transcription factors NF kappa B, glucocorticoid receptors, and TFIID did not. An oligonucleotide representing the AP-1 recognition sequence also blocked the NFAT DNA binding activity, as did a combination of anti-Fos and anti-Jun antibodies. Using electrophoretic mobility shift assays, AP-1-binding proteins were found to be induced in RBL-2H3 cells under the same conditions as was the NFAT binding activity. Together these data suggest that the NFAT complex in mast cells contains Fos and Jun proteins as does NFAT in T-cells. The appearance of nuclear NFAT binding activity was dependent in part upon calcium mobilization, as buffering the antigen-induced calcium rise with intracellular BAPTA strongly inhibited NFAT activation. Prevention of calcium influx with external EGTA also inhibited NFAT activation, indicating that release of calcium from internal stores was insufficient for sustained activation of mast cell NFAT. Cyclosporin A, a potent inhibitor of the calmodulin-dependent phosphatase calcineurin, blocked the induction of NFAT-DNA binding activity, implicating calcineurin as a key signaling enzyme in this pathway. These results suggest that NFAT is present in the mast cell line RBL-2H3 and in primary bone marrow-derived mast cells, is similar in subunit composition to the T-cell NFAT, and may play a role in calcium-dependent signal transduction in mast cells.
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PMID:Fc epsilon RI-mediated induction of nuclear factor of activated T-cells. 760 2

LAP (NF-IL6 or C/EBP beta), is a liver transcriptional activator protein that confers liver-specific gene expression. Because LAP has a characteristic phosphoacceptor sequence for cAMP-dependent protein kinase A (PKA), we tested if in vitro phosphorylation of LAP by PKA modulates its interaction with specific DNA sequences. The major PKA phosphorylation site of LAP was identified as Ser105, which is a predicted PKA site. As expected, this PKA phosphorylation site disappears after mutation of Ser105 to Ala. Kinetic studies with LAP and LAP Asp105 (which mimics a phosphoserine residue) demonstrated that phosphorylation of Ser105 itself has no effect on DNA binding. Phosphorylation of other sites by PKA, identified in the region between Ser173 and Ser223 and at Ser240, by analysis of truncated and mutated LAP peptides, resulted in an inhibition of DNA binding. LAP was also phosphorylated by purified protein kinase C in vitro, and the major phosphoacceptor was shown to be Ser240 within the DNA-binding domain of LAP. Phosphorylation of LAP at this residue or introduction of a Ser240 to Asp mutation resulted in marked decrease in its binding to DNA. These results suggest that site-specific phosphorylations of LAP modulate transactivation of its target genes.
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PMID:Protein kinase A and C site-specific phosphorylations of LAP (NF-IL6) modulate its binding affinity to DNA recognition elements. 820 Sep 92

We have analyzed the effect of antibodies (Abs) directed against major histocompatibility complex (MHC) class II Abs on the proliferation of Theileria parva-infected (Tpi) T cells. Anti-MHC class II Abs exert a direct effect on Tpi T cells causing an acute block in their proliferation. The inhibition does not involve apoptosis and is also entirely reversible. The rapid arrest of DNA synthesis caused by anti-MHC class II Abs is not due to interference with the state of activation of the T cells since the transcriptional activator NF-kappa B remains activated in arrested cells. In addition, interleukin 2 (IL-2), IL-2R, and c-myc gene expression are also unaffected. By analyzing the cell-cycle phase distribution of inhibited cells, it could be shown that cells in all phases of the cell cycle are inhibited. The signal transduction pathway that results in inhibition was shown to be independent of protein kinase C and extracellular Ca2+. Tyrosine kinase inhibitors, however, partly reduced the level of inhibition and, conversely, phosphatase inhibitors enhanced it. The possible relevance of this phenomenon in other systems is discussed.
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PMID:Antibodies against major histocompatibility complex class II antigens directly inhibit the growth of T cells infected with Theileria parva without affecting their state of activation. 835 52

Inducible gene expression in eukaryotes is mainly controlled by the activity of transcriptional activator proteins, such as NF-kappa B (refs 1-3), a factor activated upon treatment of cells with phorbol esters, lipopolysaccharide, interleukin-1 and tumour necrosis factor-alpha. Activation of NF-kappa B involves release of the inhibitory subunit I kappa B from a cytoplasmic complex with the DNA-binding subunits Rel-A (formerly p65) and p50 (refs 6, 7). Cell-free experiments have suggested that protein kinase C and other kinases transfer phosphoryl groups onto I kappa B causing release of I kappa B and subsequent activation of NF-kappa B. Here we report that I kappa B-alpha (formerly MAD-3) is degraded in cells after stimulation with phorbol ester, interleukin-1, lipopolysaccharide and tumour necrosis factor-alpha, an event coincident with the appearance of active NF-kappa B. Treatment of cells with various protease inhibitors or an antioxidant completely prevented the inducible decay of I kappa B-alpha as well as the activation of NF-kappa B. Our findings suggest that the activation of NF-kappa B relies on an inducible degradation of I kappa B-alpha through a cytoplasmic, chymotrypsin-like protease. In intact cells, phosphorylation of I kappa B-alpha is apparently not sufficient for activation of NF-kappa B.
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PMID:Rapid proteolysis of I kappa B-alpha is necessary for activation of transcription factor NF-kappa B. 837 61

NF-kappa B is a potent transcriptional activator that resides in latent form in the cytoplasm complexed to its inhibitor I kappa B. Phosphorylation of I kappa B by protein kinase C (PKC) releases NF-kappa B, enabling its translocation to the nucleus. Since PKC can activate NF-kappa B and PKC is activated by long-term potentiation (LTP), we investigated NF-kappa B expression after hippocampal LTP induced in vivo. We first described the expression of the NF-kappa B subunits, p50 and p65, and I kappa B alpha mRNAs, in each cell field of the hippocampus. In other brain locations I kappa B alpha mRNA exhibited a more selective expression than p50 and p65. We then demonstrated specific NF-kappa B-like DNA-binding activity in hippocampal whole-cell extracts and in synaptosomes using electrophoretic mobility shift assays by the following criteria: (1) latent binding was revealed after deoxycholate treatment; (2) binding was competed off by unlabeled kappa B oligonucleotides; and (3) antibodies to either p50 or p65 blocked binding. Since p50 gene expression is auto-regulated by NF-kappa B, we used its expression as a reporter for NF-kappa B activity using quantitative in situ hybridization. Both p50 and p65 increased their expression in response to either LTP-inducing or low-frequency control stimulation, although the increase in p65 mRNA levels was greater after LTP than control stimulation. In contrast to p50 and p65, I kappa B alpha hybridization levels were not increased, but were inversely correlated with the magnitude of LTP. Since NF-kappa B subunit gene expression in the hippocampus is increased by augmented synaptic activity, NF-kappa B activation may contribute to alterations in target gene expression that accompany activity-dependent synaptic plasticity, but only in a combinatorial fashion with other transcription factors.
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PMID:Gene expression of the transcription factor NF-kappa B in hippocampus: regulation by synaptic activity. 879 6


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