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)

Interleukin 1 (IL 1) is a protein produced by monocytes in response to certain antigens which produces a wide variety of cellular responses in various tissues. We have studied the regulation of the human proIL-1 beta gene in THP-1 human monocytic leukemia cells. Lipopolysaccharide (LPS) induction of this gene results in an immediate and transient increase of message that rapidly falls to a low, but constant, level within 6 hr. This decrease results from a specific repression of transcription by 2 hr after stimulation. Cycloheximide inhibition of new protein synthesis causes a superinduction of IL 1 message, but does not alter the initial kinetics of message production. This presumably delays the synthesis of a labile transcriptional repressor protein and implies that the proIL-1 beta gene is under the control of both a transcriptional activator and a newly synthesized transcriptional repressor. The transient increase in mRNA production and the sustained low-level synthesis beyond the initial transient response suggest that the IL 1 protein itself may act intracellularly in a manner analogous to that described for several proto-oncogenes and cellular competence factors.
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PMID:Transcriptional regulation of the human prointerleukin 1 beta gene. 349 77

The third component of the interleukin (IL) 2 receptor, gamma chain, is essential not only for IL-2- but also for IL-4-, IL-7-, IL-9-, and IL-15-induced proliferation of lymphocytes. To elucidate the mechanisms by which the gamma chain is expressed, we have analyzed the promoter region of the gamma chain gene. The 633-base pair fragment upstream of the initiation codon showed the promoter activity in human hematopoietic cell lines, Jurkat and THP-1, when linked to the luciferase gene. With a series of 5'-deletion mutants, the basal promoter activity was found in a fragment from nucleotide 80 to 58 upstream from the RNA start site, including an Ets binding sequence. Treatment of cells with either 12-O-tetradecanoylphorbol-13-acetate or phytohemagglutinin but not forskolin induced transcription from the gamma chain gene promoter. A viral trans-acting transcriptional activator, Tax, of human T-cell leukemia virus type I elevated expression of the gamma chain gene. In contrast, IL-2 decreased transcription from the IL-2 receptor gamma chain promoter. These results suggest that expression of the gamma chain is regulated at the transcription level by extracellular stimuli and may be implicated in immune response.
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PMID:Functional analysis of the human interleukin 2 receptor gamma chain gene promoter. 770 94

The interaction of IFN-alpha and IFN-gamma with monocytes results in several actions that significantly influence the course of an immune response. Many of these effects are proinflammatory and can contribute to the degree of tissue injury at a site of inflammation. Whereas recent investigations target IL-4 as a T cell product that can antagonize some of the responses induced by IFN, little is known regarding the mechanisms involved. We have taken advantage of two well defined systems: the transcriptional activation of the cellular genes ISG-54 by IFN-alpha and IP-10 by IFN-gamma. IL-4 treatment of both the monocytic leukemia cell line, THP-1, and normal peripheral blood monocytes resulted in inhibition of IFN-induced RNA levels for both genes. Nuclear run-on assays in THP-1 cells indicated that the effects of IL-4 were due to the inhibition of the transcriptional activation of these genes by both IFN-alpha and IFN-gamma. This inhibition was not due to alteration in the binding characteristics of IFN-alpha or IFN-gamma to the cell. In the IFN-alpha system, we were able to show that IL-4 treatment resulted in reduced formation of the transcriptional activator, IFN-stimulated gene factor 3. This reduction appears to be the result of a defect in the ability of IFN alpha to activate the IFN-stimulated gene factor 3 alpha component of IFN-stimulated gene factor 3.
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PMID:IL-4 attenuates the transcriptional activation of both IFN-alpha and IFN-gamma-induced cellular gene expression in monocytes and monocytic cell lines. 843 26

We examined the biological function of a nonstructural regulatory protein, NS1, of human parvovirus B19. Because of the cytotoxic activity of NS1, human hematopoietic cell lines, K562, Raji, and THP-1, were established as transfectants which produce the viral NS1 protein upon induction by using bacterial lactose repressor/operator system. NS1 was significantly produced in the three transfectant cells in an inducer dose- and time-dependent manner. Surprisingly, these three transfectants secreted an inflammatory cytokine, interleukin-6 (IL-6), in response to induction. However, no production of other related cytokines, IL-1beta, IL-8, or tumor necrosis factor alpha, was seen. Moreover, NS1-primed IL-6 induction was transiently demonstrated in primary human endothelial cells. Analysis with luciferase reporter plasmids carrying IL-6 promoter mutant fragments demonstrated that NS1 effect is mediated by a NF-kappaB binding site in the IL-6 promoter region, strongly implying that NS1 functions as a trans-acting transcriptional activator on the IL-6 promoter. Our novel finding, IL-6 induction by NS1, supports the possible relationship between parvovirus B19 infection and polyclonal activation of B cells in rheumatoid arthritis and indicates that NS1 protein may play a significant role in the pathogenesis of some B19-associated diseases by modulating the expression of host cellular genes.
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PMID:A cytotoxic nonstructural protein, NS1, of human parvovirus B19 induces activation of interleukin-6 gene expression. 897 Sep 71

TFEC is a transcriptional repressor originally identified in rat chondrosarcoma and contains a basic helix-loop-helix and leucine zipper (bHLH/LZ) structure. TFEC shares a closely related bHLH/LZ structure with microphthalmia-associated transcription factor (MITF) and TFE3. In the course of cDNA cloning for a factor structurally related to MITF which is also a regulator for cell differentiation, we have isolated cDNA clones from a THP-1 human monocytic leukemia cell line. These cDNAs encode a protein of 347 amino acids, termed TFECL, a human homolog of a putative rat TFEC isoform. TFECL contains an acidic domain that corresponds to a transcriptional activation domain of TFE3 but its equivalent region is deleted in rat TFEC. We explored a function of TFECL using a melanocyte-specific tyrosinase gene and a ubiquitously expressed heme oxygenase-1 gene, each promoter containing the cis-acting CANNTG motifs. By transient coexpression assays, we showed that TFECL is able to activate or inhibit transcription of a reporter gene linked to either the tyrosinase or the heme oxygenase-1 gene promoter, depending on cell types. These results suggest that TFECL may function as a transcriptional activator under certain conditions.
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PMID:Molecular cloning of cDNA encoding a human TFEC isoform, a newly identified transcriptional regulator. 925 61

The AIR-1-encoded CIITA transcriptional activator is crucial for both constitutive and IFN-gamma-induced MHC class II gene transcription. We show here that the MHC class II negative phenotype of the human hepatocarcinoma cell lines Alexander and HepG2 remains unmodified after treatment with IFN-gamma, although MHC class I expression is up-modulated. This correlates with absence of CIITA mature transcripts. Transfection of an expressible CIITA cDNA in Alexander cells resulted in a very high cell surface expression of all three human class II subsets, HLA-DR, -DP and -DQ, indicating that normally observed induction of CIITA expression by IFN-gamma is probably blocked, in the hepatocarcinoma cell lines, at the level of CIITA transcription and not at the level of IFN-gamma receptor binding and signal transduction mechanisms. To assess whether MHC class II expression on CIITA-transfected Alexander cells could have functional relevance, we tested their capacity to present antigenic peptides to an HLA-DR-restricted T cell line specific for a peptide of Mycobacterium tuberculosis Ag85 protein. It was found that the transfected cells could not only present the exogenously supplemented peptide but also process Ag85 protein to generate the specific epitope recognized by the HLA-DR-restricted T cell line. Similar results were obtained with CIITA-transfected CFPAC-1 pancreatic adenocarcinoma cells, which differed from Alexander cells in that they were inducible by IFN-gamma. These results suggest new strategies to act on CIITA for increasing the potential of a tumor cell to present putative tumor Ags to the immune system.
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PMID:HLA class II expression in uninducible hepatocarcinoma cells after transfection of AIR-1 gene product CIITA: acquisition of antigen processing and presentation capacity. 967 Sep 58

Apoptosis is implicated in the generation and resolution of inflammation in response to bacterial pathogens. All bacterial pathogens produce lipoproteins (BLPs), which trigger the innate immune response. BLPs were found to induce apoptosis in THP-1 monocytic cells through human Toll-like receptor-2 (hTLR2). BLPs also initiated apoptosis in an epithelial cell line transfected with hTLR2. In addition, BLPs stimulated nuclear factor-kappaB, a transcriptional activator of multiple host defense genes, and activated the respiratory burst through hTLR2. Thus, hTLR2 is a molecular link between microbial products, apoptosis, and host defense mechanisms.
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PMID:Cell activation and apoptosis by bacterial lipoproteins through toll-like receptor-2. 1042 96

Human macrophage and T cell lines were stably transfected with HIV-1 wild-type Tat or Tat mutants in the cysteine-rich region displaying trans-dominant negative effects on HIV-1 life cycle. The expression of HLA class I and class II molecules was not affected by wild-type Tat. Tat mutants, instead, profoundly down-regulated in a dose-dependent fashion the expression of class II, but not of class I, in both cell types by acting at the transcriptional level. Down-regulation was manifested on constitutive and IFN-gamma-induced class II gene expression and did not correlate with reduced transcription of the AIR-1 gene product CIITA, the major transcriptional activator of class II genes, indicating that Tat mutants did not act by inhibiting AIR-1 gene expression. Class II down-modulation had important functional implications in macrophages, as both antigen processing and presenting capacity were inhibited. These results represent the first evidence that a modified HIV-1 Tat product can act as a potent immunosuppressor by inhibiting the HLA class II expression necessary for triggering both cellular and humoral responses against pathogens. The use of these HIV-1 Tat mutants also discloses new opportunities to investigate the molecular mechanisms underlying the coordinate HLA class II gene transcription.
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PMID:HIV-1 Tat mutants in the cysteine-rich region downregulate HLA class II expression in T lymphocytic and macrophage cell lines. 1060 23

The expression of HLA class II genes is under the control of a transcriptional activator, CIITA, encoded by the AIR-1 locus. Here we show that CIITA inhibits HIV-1 LTR transactivation mediated by Tat. The inhibition occurred when CIITA and Tat were transiently expressed in cells after transfection and, most importantly, when tat cDNA was transfected in cells expressing CIITA in a constitutive fashion and at physiological levels. Furthermore, CIITA inhibited the HIV-1 LTR transactivation mediated by extracellular Tat protein. CIITA inhibition of Tat function could be reversed by overexpression of Cyclin T1, the cellular cofactor used by Tat to facilitate elongation of viral transcripts. CIITA inhibition of Tat function had a dramatic effect on HIV-1 productive infection of human T cells because CIITA(+) T cells supported very poorly, if any, viral replication. These results indicate that sustained expression of CIITA in HIV-1-susceptible targets may down-regulate viral expression both in cells actively replicating the virus and in silently infected cells requiring exogenous Tat to reactivate virus from latency.
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PMID:The HLA class II transcriptional activator blocks the function of HIV-1 Tat and inhibits viral replication. 1235 30

The human T-cell leukemia virus type 2 (HTLV-2), an oncogenic retrovirus closely related to HTLV-1, produces a lifelong infection whose possible association to certain human diseases is still debated. Although some viral products can influence the expression and action of cellular genes, very little is known about the molecular mechanisms involved. Here we show that the AIR-1-encoded human major histocompatibility complex (MHC) class II transactivator (CIITA) strongly inhibits viral replication, but not virus entry, in human B- and T-cell susceptible targets. This effect results from CIITA inhibiting the Tax-mediated transactivation of the HTLV-2 long-term repeat. Further molecular analysis shows that the N-terminal region of CIITA encompassing the first 321 amino acids is responsible for the inhibitory effect on viral replication. This region is crucial for the transactivation of human MHC class II genes and includes the activation domain as well as domains interacting with coactivators that also are used by the viral transactivator Tax to modulate cellular functions. These results represent the first evidence that a cellular transcriptional activator, controlling the coordinate expression of the entire family of MHC class II antigen-presenting molecules, inhibits HTLV-2 viral replication by a distinct mechanism. In this new role CIITA may represent a new tool for therapeutic strategies aimed at counteracting HTLV-2 replication and spreading.
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PMID:The MHC class II transcriptional activator (CIITA) inhibits HTLV-2 viral replication by blocking the function of the viral transactivator Tax-2. 1452 69


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