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)

Three human T-lymphotropic viruses have been isolated and characterized in the past 5 years. The ability to culture target cells with T-cell growth factor and sensitive detection systems for the virally encoded polymerase reverse transcriptase permitted isolation of HTLV-I, which is strongly linked to the cause of adult T-cell leukemia and associated with other lymphoid malignancies in endemic areas. The same techniques, using a permissive human tumor cell line, allowed the isolation and characterization of HTLV-III/lymphadenopathy-associated virus, which is implicated as the primary cause of the acquired immunodeficiency syndrome (AIDS). This virus shares some features with HTLV-I and HTLV-II, such as additional genes not found in most retroviruses. One gene codes for a transcriptional activator protein and may be a feature of a larger group of related retroviruses. The clear identification of the primary cause of AIDS has resulted in the development of specific immunologic reagents, preventive and therapeutic proposals, and comprehensive identification of the clinical diseases associated with this virus.
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PMID:A human T-lymphotropic retrovirus (HTLV-III) as the cause of the acquired immunodeficiency syndrome. 299 99

The immunosuppressants cyclosporin and FK506 block the calcium-dependent signal-transduction pathway emanating from the T-cell receptor, thereby inhibiting the activation of helper T cells. Using these drugs as probes, chemists and biologists have uncovered several intracellular signaling molecules bridging the generation of second-messenger Ca2+ ion and the transcriptional activation of IL-2, among which are calmodulin, calcineurin and the nuclear factor of activated T cells (NF-AT). Hence, Ca2+ binds to calmodulin, leading to the binding of calmodulin to calcineurin; the activated calcineurin, in turn, may dephosphorylate the cytoplasmic subunit of NF-AT, resulting in its translocation from the cytoplasm into the nucleus to form a competent transcriptional activator. As described by Jun Liu these drugs manifest their effects in an unprecedented fashion. They do not directly intercept intracellular signaling molecules. Instead, they form tight complexes with two different classes of abundant cytosolic receptors called immunophilins upon entering the cell, and consequently inhibit their peptidyl prolyl cis-trans isomerase activities. The two structurally distinct immunophilin-drug complexes bind to, and inhibit, the phosphatase activity of calcineurin.
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PMID:FK506 and cyclosporin, molecular probes for studying intracellular signal transduction. 769 Oct 65

The immunosuppressants ciclosporin and FK506 block the Ca(2+)-dependent signal-transduction pathway emanating from the T-cell receptor, thereby inhibiting the activation of helper T cells. Using these drugs as probes, chemists and biologists have uncovered several intracellular signalling molecules bridging the generation of second-messenger Ca2+ ions and the transcriptional activation of IL-2, among which are calmodulin, calcineurin and the nuclear factor of activated T cells (NF-AT). Hence, Ca2+ binds to calmodulin, leading to the binding of calmodulin to calcineurin; the activated calcineurin, in turn, may dephosphorylate the cytoplasmic subunit of NF-AT, resulting in its translocation from the cytoplasm into the nucleus to form a competent transcriptional activator. As described by Jun Liu, these drugs manifest their effects in an unprecedented fashion. They do not directly intercept intracellular signalling molecules. Instead, they form tight complexes with two different classes of abundant cytosolic receptors called immunophilins upon entering the cell, and consequently inhibit their peptidyl prolyl cis-trans isomerase activities. The two structurally distinct immunophilin-drug complexes bind to, and inhibit, the phosphatase activity of calcineurin.
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PMID:FK506 and ciclosporin: molecular probes for studying intracellular signal transduction. 769 52

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

Molecular, biochemical and epidemiological evidence implicate HTLV-I as an etiologic agent of adult T cell leukemia (ATL). The Tax protein of HTLV-I, a positive transcriptional activator of HTLV-I gene expression, is a viral oncogene that also increases transcription of cellular genes including GM-CSF, IL-2R alpha and IL-2. One of the cellular targets of the trans-activating effects of Tax is the NF-kappa B/Rel family of transcription factors, pleiotropic regulators of immunoregulatory, cytokine and viral gene expression. In this report, we demonstrate that NFKB2 (lyt-10) and c-Rel are overexpressed in HTLV-I infected and Tax-expressing cells and, together, account for the majority of the constitutive NF-kappa B binding activity in these cells before and after PMA stimulation. Most importantly, we show a Tax-dependent correlation between expression of NFKB2(p100) and processing to the DNA binding NFKB2(p52) form, induction of c-Rel, and trans-activation of NF-kappa B-mediated gene expression. Furthermore, the NFKB2 precursor is physically associated with c-Rel and with Tax in HTLV-I infected cells. We propose that NFKB2 synthesis and processing allows continuous nuclear expression of an otherwise cytoplasmic protein and, in conjunction with overexpression of c-Rel, NFKB2 alters the NF-kappa B signalling pathway and contributes to leukemic transformation of T cells by HTLV-I.
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PMID:Overproduction of NFKB2 (lyt-10) and c-Rel: a mechanism for HTLV-I Tax-mediated trans-activation via the NF-kappa B signalling pathway. 810 27

AP-1 is a transcriptional activator composed of homo- and heterodimers of Jun and Fos proteins. It is involved in activation of genes, such as collagenase, stromelysin, IL-2 and TGF beta 1, by tumour promoters, growth factors and cytokines. AP-1 activity is also elevated in response to transforming oncogenes and is required for cell proliferation. AP-1 activity is subject to complex regulation both transcriptionally and post-transcriptionally. Transcriptional control of jun and fos gene expression determines the amount and composition of the AP-1 complex. The jun and fos genes are regulated both positively and negatively and are highly inducible in response to extracellular stimuli. Post translational control is also important. Both cJun and cFos are subject to regulated phosphorylation. In the case of cJun, phosphorylation of sites near the DNA-binding domain inhibits DNA-binding, while dephosphorylation reverses this inhibition. Phosphorylation of cJun on sites within the N-terminal activation domain increases its ability to activate transcription. The protein kinase phosphorylating these sites is stimulated by cytokines and growth factors. Another mechanism modulating AP-1 activity is transcriptional interference by members of the nuclear receptor family and is relevant for the pathophysiology of rheumatoid arthritis (RA). In RA, chronic inflammation leads to increased AP-1 activity in T cells,macrophages and synoviocytes as a response to secretion of cytokines such as IL-1 and TNF alpha. While the IL-2 gene plays a major role in T cell activation, another AP-1 target gene encodes an enzyme, collagenase, responsible for destruction of bone and tendon.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Various modes of gene regulation by nuclear receptors for steroid and thyroid hormones. 831 34

Nuclear factor of activated T cells (NF-AT) is a transcriptional activator involved in the induction of IL-2 gene expression. The response element for NF-AT is a sequence localized between -285/-254 in the IL-2 regulatory region. The composition of NF-AT protein is still not fully elucidated. We demonstrate that, in normal human T cells, an AP-1 protein is a component of the NF-AT protein complex. This was evidenced by the ability of the AP-1 site to compete with the NF-AT site for binding to NF-AT and by the capacity of immobilized anti-Jun and anti-Fos antibodies to deplete NF-AT-binding activity from nuclear extracts of activated T cells. There was no detectable binding of in vitro translated Jun/Fos heterodimer (AP-1) to the NF-AT sequence, and the NF-AT sequence was unable to inhibit the binding of Jun/Fos to the AP-1 sequence. The presence of an AP-1 protein in the NF-AT protein complex may regulate NF-AT-binding activity through protein-protein interaction.
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PMID:A protein of the AP-1 family is a component of nuclear factor of activated T cells. 846 70

The activation of natural killer (NK) cells, cytotoxic lymphocytes capable of major histocompatibility complex (MHC)-unrestricted killing and early antiviral defense, is temporally related to the increased interferon (IFN)-alpha/beta production that is seen in the viral infection of mice. Type I IFN (IFN-alpha/beta) are expressed in many cell types early after primary viral infection and have been shown to mediate resistance against a variety of viruses. In this study, the role of the transcriptional activator IFN regulatory factor-1 (IRF-1) in murine NK cell activity was assessed. IRF-1-deficient mice displayed a normal frequency of NK marker-positive cells, but exhibited greatly reduced NK cell-mediated cytotoxicity after both virus infection and stimulation with the IFN inducer polyinosinic:polycytidilic acid in vivo. In vitro, cytolytic activity in IRF-1-deficient NK cells remained defective after stimulation with IFN-beta, IL-2, and IL-12. IRF-1-deficient mice were unable to eliminate syngeneic MHC class I-negative tumor cells in vivo, and had a reduced ability to reject parental semi-allogeneic donor cells from the circulation. Thus, IRF-1 is essential for the induction of NK cell-mediated cytotoxicity and for the in vivo effector functions that are mediated by this activity.
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PMID:The transcription factor interferon regulatory factor-1 is essential for natural killer cell function in vivo. 892 Aug 93

Constitutive expression of the IL-2 receptor (IL-2R) on adult T-cell leukemia (ATL) cells and the presence of permanent IL-2-dependent ATL cell lines indicate that the signal transduction system via IL-2R is a key element for the development of this disease. IL-2R is a member of the common gamma-chain (gammac)-receptor family and shares gamma with IL-4R, IL-7R, IL-9R, and IL-15R. In addition to IL-2R, ATL cells express IL-15R and respond to IL-15. In the present study, we examined other members of this receptor family. ATL cells showed various levels of IL-4Ralpha (CD124) and IL-7Ralpha (CD127) expression, and responded to these cytokines. In contrast, ATL cells hardly responded to IL-9. As primary samples were a mixed population and the results may have been modified by contaminating normal cells, we used ATL cell lines as pure ATL cell populations. Here, we report that IL-2-dependent ATL cell lines also express IL-4Ralpha and respond to IL-4, which was verified by the activation of cytoplasmic transcriptional activator Stat6 protein. Moreover, a novel ATL cell line that grows stably in an IL-7-dependent manner was established from one of the cell lines, and IL-7 induced Stat5 activation in this cell line. These results indicated that ATL cells have the potential to express all gammac-receptors except IL-9R. Overlapping and switching of cytokine receptors supported the idea that ATL cells can rapidly select the appropriate gammac-receptor according to conditions.
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PMID:Multiple gammac-receptor expression in adult T-cell leukemia. 1222 94

NF45/ILF2 associates with NF90/ILF3 in the nucleus and regulates IL-2 gene transcription at the antigen receptor response element (ARRE)/NF-AT DNA target sequence (P.N. Kao, L. Chen, G. Brock, J. Ng, A.J. Smith, B. Corthesy, J. Biol. Chem. 269 (1994) 20691-20699). NF45 is widely expressed in normal tissues, especially testis, brain, and kidney, with a predominantly nuclear distribution. NF45 mRNA expression is increased in lymphoma and leukemia cell lines. The human and murine NF45 proteins differ only by substitution of valine by isoleucine at amino acid 142. Fluorescence in situ hybridization localized the human NF45 gene to chromosome 1q21.3, and mouse NF45 gene to chromosome 3F1. Promoter analysis of 2.5 kB of the murine NF45 gene reveals that significant activation is conferred by factors, possible including NF-Y, that bind to the CCAAT-box sequence. The function of human NF45 in regulating IL-2 gene expression was characterized in Jurkat T-cells stably transfected with plasmids directing expression of NF45 cDNA in sense or antisense orientations. NF45 sense expression increased IL-2 luciferase reporter gene activity 120-fold, and IL-2 protein expression 2-fold compared to control cells. NF45 is a highly conserved, regulated transcriptional activator, and one target gene is IL-2.
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PMID:NF45/ILF2 tissue expression, promoter analysis, and interleukin-2 transactivating function. 1581 56


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