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)

RANTES is a basic 8-kDa polypeptide of the C-C chemokine subfamily with strong chemoattractant activity for T lymphocytes and monocytes/macrophages that are implicated in the pathogenesis of multiple sclerosis (MS) lesions. Glatiramer acetate is a drug recently approved for the treatment of MS. We therefore investigated the effect of glatiramer acetate on RANTES expression in glial cells in vitro. Treatment of human U-251 MG astroglial cells with glatiramer acetate blocks IL-1beta-induced RANTES chemokine production in a dose- and time-dependent manner. Glatiramer acetate also decreased steady-state levels of RANTES mRNA in these cells, which was attributable to reduced transcription, as assessed by nuclear run-on assays. In addition, we showed that NF-kappaB may be the transcriptional activator responsible for the IL-1beta-mediated RANTES gene expression in this system. Our data indicated that the IL-1beta-induced increase in RANTES was associated with an increase in in vitro nuclear extract binding activity specific for the NF-kappaB site in the promoter region of the RANTES gene. The increases in RANTES mRNA and protein expression were suppressed by the NF-kappaB inhibitors gliotoxin, isohelenin, and pyrrolidine dithiocarbamate (PDTC). Furthermore, we demonstrated that the increase in NF-kappaB DNA-binding activity was prevented by pretreatment with glatiramer acetate or the NF-kappaB inhibitors. Our results suggest that glatiramer acetate may inhibit IL-1beta-stimulated RANTES expression in human glial cells by blocking NF-kappaB activation, thus identifying part of the molecular basis for its anti-inflammatory and immunosuppressive effects in demyelinating diseases.
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PMID:Glatiramer acetate blocks interleukin-1-dependent nuclear factor-kappaB activation and RANTES expression in human U-251 MG astroglial cells. 1122 59

The choice between meiosis and alternative developmental pathways in budding yeast depends on the expression and activity of transcriptional activator Ime1. The transcription of IME1 is repressed in the presence of glucose, and a low basal level of IME1 RNA is observed in vegetative cultures with acetate as the sole carbon source. IREu, a 32-bp element in the IME1 promoter, exhibits upstream activation sequence activity depending on Msn2 and -4 and the presence of acetate. We show that in the presence of glucose IREu functions as a negative element and that Sok2 mediates this repression activity. We show that Sok2 associates with Msn2. Sok2 functions as a general repressor whose availability and activity depend on glucose. The activity of Sok2 as a repressor depends on phosphorylation of T598 by protein kinase A (PKA). Relief of repression of Sok2 depends on both the N-terminal domain of Sok2 and Ime1. In the absence of glucose and the presence of Ime1 Sok2 is converted to a weak activator. Overexpression of Sok2 or mild expression of Sok2 with its N-terminal domain deleted leads to a decrease in sporulation. Previously it was reported that overexpression of Sok2 suppresses the growth defect resulting from a temperature-sensitive PKA; thus Sok2 has a positive role in mitosis. We show that Candida albicans Efg1, a homolog of Sok2, complements sok2 Delta in repressing IREu. Our results demonstrate that Sok2, a positive regulator of mitosis, and Efg1, a positive regulator of filamentation, function as negative regulators of meiosis. We suggest that cells use the same regulators with opposing effects to ensure that meiosis will be an alternative to mitosis.
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PMID:A positive regulator of mitosis, Sok2, functions as a negative regulator of meiosis in Saccharomyces cerevisiae. 1123 97

We identified an open reading frame, designated phcS, downstream of the transcriptional activator gene (phcR) for the expression of multicomponent phenol hydroxylase (mPH) in Comamonas testosteroni R5. The deduced product of phcS was homologous to AphS of C. testosteroni TA441, which belongs to the GntR family of transcriptional regulators. The transformation of Pseudomonas aeruginosa PAO1c (phenol negative, catechol positive) with pROR502 containing phcR and the mPH genes conferred the ability to grow on phenol, while transformation with pROR504 containing phcS, phcR, and mPH genes did not confer this ability. The disruption of phcS in strain R5 had no effect on its phenol-oxygenating activity in a chemostat culture with phenol. The phenol-oxygenating activity was not expressed in strain R5 grown in a chemostat with acetate. In contrast, the phenol-oxygenating activity in the strain with a knockout phcS gene when grown in a chemostat with acetate as the limiting growth factor was 66% of that obtained in phenol-grown cells of the strain with a knockout in the phcS gene. The disruption of phcS and/or phcR and the complementation in trans of these defects confirm that PhcS is a trans-acting repressor and that the unfavorable expression of mPH in the phcS knockout cells grown on acetate requires PhcR. These results show that the PhcS protein repressed the gratuitous expression of phenol-metabolizing enzymes in the absence of the genuine substrate and that strain R5 acted by an unknown mechanism in which the PhcS-mediated repression was overcome in the presence of the pathway substrate.
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PMID:PhcS represses gratuitous expression of phenol-metabolizing enzymes in Comamonas testosteroni R5. 1141 63

Myc is a transcriptional activator whose deregulated expression not only promotes proliferation but also induces or sensitizes cells to apoptosis. Here we demonstrate that c-myc plays a role in triggering apoptosis in CEM T leukaemia cells exposed to progressive medium exhaustion. Indeed starved cells undergo apoptosis in the presence of constitutively elevated c-myc expression and the phorbol ester, phorbol 12-miristate 13-acetate (PMA), which rescues cells from apoptosis, induces complete c-myc down-regulation. We also investigate the hypothesis that ornithine decarboxylase (ODC), a transcriptional target of c-myc, is a down-stream mediator of c-myc driven apoptosis. We demonstrate that PMA induces in starved cells an earlier and larger decrease in ODC expression (mRNA and activity) and intracellular polyamine content, compared to untreated starved cells. Moreover we show that alpha-difluoromethylornithine (DFMO), an irreversible inhibitor of ODC enzymatic activity, effectively reduces, while exogenous added polyamines enhance apoptosis in starved cells. All these data indicate that ODC and polyamines may act as facilitating factors in triggering apoptosis induced by growth/survival factors withdrawal.
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PMID:Down-modulation of c-myc expression by phorbol ester protects CEM T leukaemia cells from starvation-induced apoptosis: role of ornithine decarboxylase and polyamines. 1159 94

The Neurospora crassa homologue of the Aspergillus nidulans regulatory gene facB has been cloned. The gene encodes a putative transcriptional activator of 865 amino acids that contains a DNA-binding domain with a Zn(II)(2)Cys(6) binuclear cluster, a linker region and a leucine zipper-like heptad repeat. Two internal amino acid sequences are identical to peptide sequences determined from proteolytic fragments of a DNA-binding protein complex specific for genes involved in acetate utilisation and expressed in acetate-induced mycelia of N. crassa. Recombinant expression of the predicted DNA-binding domain demonstrates that it is capable of independent recognition of a subset of the promoter sequences that bind the protein complex from N. crassa. A duplication-induced mutation in the corresponding gene results in an acetate non-utilising phenotype that is characterised by inefficient induction of the enzymes required for acetate utilisation. The new gene does not fall into any existing complementation group and has been designated acu-15.
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PMID:A regulator gene for acetate utilisation from Neurospora crassa. 1211 57

Spumaviruses, commonly called foamy viruses (FV), are complex retroviruses that establish lifelong persistent infections without any accompanying pathologies. In tissue culture, cells can be either lytically or latently infected, depending on cell type. Regulation of FV replication is controlled by two promoters: the LTR and a second promoter within the env gene termed the internal promoter (IP). The IP directs expression of the transcriptional activator, Tas, and a second accessory protein, Bet, whose function has been elusive. In this study, we report that expression of exogenous Tas is sufficient to initiate a switch from latent to lytic replication. We also show that treatment with the phorbol ester phorbol 12-myristate 13-acetate (PMA) can lead to an increase in transcription from the IP, and that Bet protein expression abrogates this effect. Finally, we demonstrate that Bet expression severely limits the ability of PMA to activate transcription of latent FV genomes, and that replication of a Bet(-) virus is more easily activated than wild-type FV. Taken together, these data suggest that viral transcription is regulated by a sensitive switch, and that Bet functions as a negative regulator of basal IP activity.
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PMID:Reactivation of a complex retrovirus is controlled by a molecular switch and is inhibited by a viral protein. 1241 20

ACT is a LIM-only protein expressed exclusively in round spermatids, where it cooperates with transcriptional activator CREM in regulating various postmeiotic genes. Targeted inactivation of CREM leads to a complete block of mouse spermiogenesis. We sought to identify the regulatory steps controlling the functional interplay between CREM and ACT. We found that ACT selectively associates with KIF17b, a kinesin highly expressed in male germ cells. The ACT-KIF17b interaction is restricted to specific stages of spermatogenesis and directly determines the intracellular localization of ACT. Sensitivity to leptomycin B indicates that KIF17b can be actively exported from the nucleus through the Crm1 receptor. Thus, a kinesin directly controls the activity of a transcriptional coactivator by a tight regulation of its intracellular localization.
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PMID:CREM-dependent transcription in male germ cells controlled by a kinesin. 1249 14

An important step in the herpesvirus life cycle is the switch from latency to lytic reactivation. In order to study the life cycle of Kaposi's sarcoma-associated herpesvirus (KSHV), we developed a gene expression system in KSHV-infected primary effusion lymphoma cells. This system uses Flp-mediated efficient recombination and tetracycline-inducible expression. The Rta transcriptional activator, which acts as a molecular switch for lytic reactivation of KSHV, was efficiently integrated downstream of the Flp recombination target site, and its expression was tightly controlled by tetracycline. Like stimulation with tetradecanoyl phorbol acetate (TPA), the ectopic expression of Rta efficiently induced a complete cycle of viral replication, including a well-ordered program of KSHV gene expression and production of infectious viral progeny. A striking feature of Rta-mediated lytic gene expression was that Rta induced KSHV gene expression in a more powerful and efficient manner than TPA stimulation, indicating that Rta plays a central, leading role in KSHV lytic gene expression. Thus, our streamlined gene expression system provides a novel means not only to study the effects of viral gene products on overall KSHV gene expression and replication, but also to understand the natural viral reactivation process.
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PMID:Global changes in Kaposi's sarcoma-associated virus gene expression patterns following expression of a tetracycline-inducible Rta transactivator. 1263 78

The ErbB-4 receptor protein-tyrosine kinase is proteolytically processed by membrane proteases in response to the ligand or 12-O-tetradecanoylphorbol-13-acetate stimulation resulting in the cytoplasmic fragment translocating to the cell nucleus. The WW domain-containing co-transcriptional activator Yes-associated protein (YAP) associates physically with the full-length ErbB-4 receptor and functionally with the ErbB-4 cytoplasmic fragment in the nucleus. The YAP.ErbB4 complex is mediated by the first WW domain of YAP and the most carboxyl-terminal PPXY motif of ErbB-4. In human tissues, we documented the expression of YAP1 with a single WW domain and YAP2 with two WW domains. It is known that the COOH-terminal fragment of ErbB4 does not have transcriptional activity by itself; however, we show here that in the presence of YAP its transcriptional activity is revealed. There is a difference in the extent of transactivation activity among YAP isoforms: YAP2 is the stronger activator compared with YAP1. This transactivation is abolished by mutations that abrogate the YAP.ErbB4 complex formation. The unphosphorylatable mutation that increases the nuclear localization of YAP increases transcription activity. The COOH-terminal fragment of ErbB-4 and full-length YAP2 overexpressed in cells partially co-localize to the nucleus. Our data indicate that YAP is a potential signaling partner of the full-length ErbB4 receptor at the membrane and of the COOH-terminal fragment of ErbB-4 that translocates to the nucleus to regulate transcription.
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PMID:WW domain-containing protein YAP associates with ErbB-4 and acts as a co-transcriptional activator for the carboxyl-terminal fragment of ErbB-4 that translocates to the nucleus. 1280 3

We have cloned two novel, alternatively spliced messages of human cyclin D-binding Myb-like protein (hDMP1). The known, full-length protein has been named hDMP1alpha and the new isoforms, hDMP1beta and hDMP1gamma. The hDMP1alpha, -beta, and -gamma splice variants have unique expression patterns in normal hematopoietic cells; hDMP1beta mRNA transcripts are strongly expressed in quiescent CD34+ cells and freshly isolated peripheral blood leukocytes, as compared with hDMP1alpha. In contrast, activated T-cells and developing myeloid cells, macrophages, and granulocytes express low levels of hDMP1beta transcripts, and hDMP1gamma is ubiquitously and weakly expressed. Mouse Dmp1 has been shown to activate CD13/aminopeptidase N (APN) and p19ARF gene expression via binding to canonical DNA recognition sites in the respective promoters. Assessment of CD13/APN promoter responsiveness demonstrated that hDMP1alpha but not hDMP1beta and -gamma, is a transcriptional activator. Furthermore, hDMP1beta was found to inhibit the CD13/APN promoter transactivation ability of hDMP1alpha. Stable, ectopic expression of hDMP1beta and, to a lesser extent hDMP1gamma, reduced endogenous cell surface levels of CD13/APN in U937 cells. Moreover, stable, ectopic expression of hDMP1beta altered phorbol 12-myristate 13-acetate-induced terminal differentiation of U937 cells to macrophages and resulted in maintenance of proliferation. These results demonstrate that hDMP1beta antagonizes hDMP1alpha activity and suggest that cellular functions of hDMP1 may be regulated by cellular hDMP1 isoform levels.
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PMID:Alternative splicing of the human cyclin D-binding Myb-like protein (hDMP1) yields a truncated protein isoform that alters macrophage differentiation patterns. 1291 99


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