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)

Copper is an essential cellular cofactor that becomes toxic at high levels. Copper homeostasis is tightly regulated by opposing mechanisms that control copper import, export, and copper binding capacity within the cell. High levels of copper induce the expression of metallothioneins, small sulfhydryl-rich proteins with high metal binding capabilities that serve as neutralizers of toxic levels of metals. In yeast, the CUP1 gene encodes a copper metallothionein that is strongly induced in response to metals and other stress and is subsequently rapidly down-regulated. Activation of CUP1 is mediated by the copper-responsive transcriptional activator AceI, and also requires the histone acetylase Spt10 for full induction. We have examined the role of histone H2A in the normal regulation of the CUP1 gene. We have shown that specific H2A mutations in combination with spt10 deletions result in aberrant regulation of CUP1 expression. Certain lysine mutations in H2A alleviate the transcriptional defect in spt10 Delta strains, though CUP1 activation is still delayed in these mutants; however, CUP1 shutdown is normal. In contrast, serine mutations in H2A prevent CUP1 shutdown when combined with spt10 deletions. In addition, swi/snf mutants exhibit both impaired CUP1 induction and failure to shut down CUP1 normally. Finally, different Spt10-dependent histone acetylation events correlate with induction and shutdown. Taken together, these data indicate that CUP1 transcriptional shutdown, like induction, is an active process controlled by the chromatin structure of the gene. These results provide new insights for the role of chromatin structure in metal homeostasis.
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PMID:Histone H2A and Spt10 cooperate to regulate induction and autoregulation of the CUP1 metallothionein. 1550 26

Aspergilli represent unique pathogens. Based on their saprophytic life style they are able to colonize a variety of ecological niches, among them the immunocompromised individual. Distinct fungal attributes that play a role in pathogenicity of aspergilli have been described, and primary metabolism indisputably has to be taken into account for contributing to the virulence potential of this fungal genus. Here we present an overview of studies that focus on this aspect of nutritional versatility. In the predominant pathogenic representative Aspergillus fumigatus regulation of nitrogen utilization and sensing of nitrogen sources have been scrutinized with respect to pathogenicity. The impact of distinct metabolic pathways on virulence capacities could be evaluated by inspection of auxotrophic mutant strains. Among them, para-aminobenzoic acid-requiring mutants revealed that this biosynthetic route is strictly required for pathogenicity. For amino acid anabolism only lysine biosynthesis has been investigated in this regard. Fungal amino acid biosynthesis is generally subject to strict regulation mediated by the Cross-Pathway Control system, a conserved regulatory circuit evolved to counteract conditions of nutritional stress. A clear influence of the system on pathogenicity could be observed by targeting its transcriptional activator CpcA. However, additional metabolic characteristics as well as regulatory instruments that compensate environmental challenges need to be addressed in future research with the aim to assess the significance of fungal primary metabolism for pathogenicity of aspergillus species.
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PMID:Nitrogen metabolism of Aspergillus and its role in pathogenicity. 1611 Jul 90

Human immunodeficiency virus type 1 (HIV-1) Tat is a potent transcriptional activator of the HIV-1 promoter and also has the ability to modulate a number of cellular regulatory circuits including apoptosis. Tat exerts its effects through interaction with viral as well as cellular proteins. Here, we studied the influence of p73, a protein that is implicated in apoptosis and cell cycle control, on Tat functions in the central nervous system. Protein interaction studies using immunoprecipitation followed by Western blot and glutathione S-transferase pull-down assays demonstrated the association of Tat with p73. Tat bound to the N-terminal region of p73 spanning amino acids 1 to 120, and this interaction required the cysteine-rich domain (amino acids 30 to 40) of Tat. Association of p73 with Tat prevented the acetylation of Tat on lysine 28 by PCAF. Functional studies including RNA interference showed that p73 inhibited Tat stimulation of the HIV-1 promoter. Furthermore, p73 prevented the interaction of Tat with cyclin T1 in vitro but not in vivo. These findings suggest possible new therapeutic approaches, using p73, for Tat-mediated AIDS pathogenesis.
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PMID:p73 Interacts with human immunodeficiency virus type 1 Tat in astrocytic cells and prevents its acetylation on lysine 28. 1613 3

We have measured the transcription of several genes that have been implicated as virulence factors in Aspergillus fumigatus, including fos-1, a histidine kinase, two-component signal protein, rhbA, a ras-related protein required for signaling, pksP, a polyketide synthase involved in biosynthesis of melanin, pabA synthetase, an enzyme catalyzing a late step in the biosynthesis of folate, lysF, a homoconitase related to lysine biosynthesis, and cpcA, the transcriptional activator of the cross-pathway control system of amino acid biosynthesis. Transcription levels were determined from in vitro grown organism as well as from lung tissue from mice infected with A. fumigatus. Our data indicate that fos-1 and rhbA transcription increased significantly during the infection in mice, compared to the other genes whose transcription remained the same (pksP, cpcA, pabA) or decreased slightly (lysF). In vitro measurements of transcription compared to transcription in infected lung tissue demonstrated low levels of fos-1 and rhbA, 20-40-fold increases (cpcA, lysF, pabA), while pksP was not detected from cultures. Our data demonstrate that transcription of these genes differs in vitro versus during disease.
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PMID:Expression of Aspergillus fumigatus virulence-related genes detected in vitro and in vivo with competitive RT-PCR. 1620 68

Sp1 is a ubiquitously expressed transcription factor that binds GC-rich cis elements. Many posttranslational modifications have been implicated in the regulation of Sp1 activity. We now provide evidence for a novel mechanism of Sp1 regulation involving the small ubiquitin-like modifier (SUMO-1). Western blot analysis revealed a high molecular mass Sp1 of 125 kDa that is stabilized by a selective SUMO hydrolase inhibitor and destabilized by a specific SUMO-1 hydrolase. The covalent modification of Sp1 by endogenous SUMO-1 and SUMO-1 that has been fused to green fluorescent protein was demonstrated using transient transfection assays. A high probability sumoylation consensus motif, VK(16)IE(18), is located within the N-terminal negative regulatory domain of Sp1. Either arginine substitution for lysine 16 (Sp1(K16R)) or alanine substitution for glutamic acid 18 (Sp1(E18A)), abrogated Sp1 sumoylation. In vitro SUMO-1 covalently bound affinity-purified GST-Sp1, but not GST-Sp1(K16R). In vivo Sp1 was determined to be N-terminally cleaved, while Sp1(K16R) could not be cleaved indicating that sumoylation and cleavage are coupled through the key regulatory lysine 16. This coupling was evident by the demonstration of an inverse relationship between cellular SUMO-modified Sp1 and N-terminally cleaved Sp1. Compared with Sp1, sumoylation-deficient Sp1(E18A) exhibited enhanced cleavage and was a better transcriptional activator, while constitutively SUMO-1-modified Sp1 was deficient in proteolytic processing and repressed Sp1 transcriptional activity. The repressive effect of sumoylation on Sp1 activity is emphasized through the use of a GAL4 based transactivation assay. A model is proposed defining a mechanism by which sumoylation preserves the integrity of a negative regulatory domain thereby allowing for the inhibition of Sp-dependent transcription.
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PMID:Sumoylation inhibits cleavage of Sp1 N-terminal negative regulatory domain and inhibits Sp1-dependent transcription. 1640 61

The transcriptional activator CadC in Escherichia coli, a member of the ToxR-like proteins, activates transcription of the cadBA operon encoding the lysine decarboxylase CadA and the lysine-cadaverine antiporter CadB. cadBA is induced under conditions of acidic external pH and exogenous lysine; anoxic conditions raise the expression level up to 10 times. To characterize the binding mechanism of CadC, procedures for the purification of this membrane-integrated protein and its reconstitution into proteoliposomes were established. The binding sites of CadC upstream of the cadBA promoter region were determined by in vitro DNaseI protection analysis. Two regions were protected during DNaseI digestion, one from -144 to -112 bp, designated Cad1, and another one from -89 to -59 bp, designated Cad2. Binding of purified CadC to Cad1 and Cad2 was further characterized by DNA-binding assays, indicating that CadC was able to bind to both DNA fragments. Genetic analysis with promoter-lacZ fusions confirmed that both sites, Cad1 and Cad2, are essential for activation of cadBA transcription. Moreover, these experiments revealed that binding of H-NS upstream of the CadC-binding sites is necessary for repression of cadBA expression at neutral pH and under aerobic conditions. Based on these results, a model for transcriptional regulation of the cadBA operon is proposed, according to which H-NS is involved in the formation of a repression complex under non-inducing conditions. This complex is dissolved by binding of CadC to Cad1 under inducing conditions. Upon binding of CadC to Cad2 cadBA expression is activated.
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PMID:CadC-mediated activation of the cadBA promoter in Escherichia coli. 1649 Oct 24

Here we define a function of metastasis-associated protein 1 (MTA1), a presumed corepressor of estrogen receptor alpha (ERalpha), as a transcriptional activator of Breast Cancer Amplified Sequence 3 (BCAS3), a gene amplified and overexpressed in breast cancers. We identified BCAS3 as a MTA1 chromatin target in a functional genomic screen. MTA1 stimulation of BCAS3 transcription required ERalpha and involved a functional ERE half-site in BCAS3. Furthermore, we discovered that MTA1 is acetylated on lysine 626, and that this acetylation is necessary for a productive transcriptional recruitment of RNA polymerase II complex to the BCAS3 enhancer sequence. BCAS3 expression was elevated in mammary tumors from MTA1 transgenic mice and 60% of the human breast tumors, and correlated with the coexpression of MTA1 as well as with tumor grade and proliferation of primary breast tumor samples. These findings reveal a previously unrecognized function of MTA1 in stimulating BCAS3 expression and suggest an important role for MTA1-BCAS3 pathway in promoting cancerous phenotypes in breast tumor cells.
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PMID:MTA1, a transcriptional activator of breast cancer amplified sequence 3. 1661 2

The unstructured N-terminal domain of the transcriptional cofactor PC4 contains multiple phosphorylation sites that regulate activity. The phosphorylation status differentially influences the various biochemical functions performed by the structured core of PC4. Binding to ssDNA is slightly enhanced by phosphorylation of one serine residue, which is not augmented by further phosphorylation. The presence of at least two phosphoserines decreases DNA-unwinding activity and abrogates binding to the transcriptional activator VP16. Phosphorylation gradually decreases the binding affinity for dsDNA. These phosphorylation-dependent changes in PC4 activities correlate with the sequential functions PC4 fulfils throughout the transcription cycle. MS and NMR revealed that up to eight serines are progressively phosphorylated towards the N-terminus, resulting in gradual environmental changes in the C-terminal direction of the following lysine-rich region. Also within the structured core, primarily around the interaction surfaces, environmental changes are observed. We propose a model for co-ordinated changes in PC4 cofactor functions, mediated by phosphorylation status-dependent gradual masking of the lysine-rich region causing shielding or exposure of interaction surfaces.
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PMID:Gradual phosphorylation regulates PC4 coactivator function. 1668 30

Adaptation to low oxygen tension (hypoxia) in cells and tissues leads to the transcriptional induction of a series of genes that participate in angiogenesis, iron metabolism, glucose metabolism, and cell proliferation/survival. The primary factor mediating this response is the hypoxia-inducible factor-1 (HIF-1), an oxygen-sensitive transcriptional activator. HIF-1 consists of a constitutively expressed subunit HIF-1beta and an oxygen-regulated subunit HIF-1alpha (or its paralogs HIF-2alpha and HIF-3alpha). The stability and activity of the alpha subunit of HIF are regulated by its post-translational modifications such as hydroxylation, ubiquitination, acetylation, and phosphorylation. In normoxia, hydroxylation of two proline residues and acetylation of a lysine residue at the oxygen-dependent degradation domain (ODDD) of HIF-1alpha trigger its association with pVHL E3 ligase complex, leading to HIF-1alpha degradation via ubiquitin-proteasome pathway. In hypoxia, the HIF-1alpha subunit becomes stable and interacts with coactivators such as cAMP response element-binding protein binding protein/p300 and regulates the expression of target genes. Overexpression of HIF-1 has been found in various cancers, and targeting HIF-1 could represent a novel approach to cancer therapy.
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PMID:Hypoxia-inducible factor-1 (HIF-1). 1688 34

In Salmonella enterica serovar Typhimurium, the membrane-localized CadC is a transcriptional activator of the cadBA operon, which contributes to the acid tolerance response. Unlike in Escherichia coli, in which transcription of cadC is constitutive, in S. enterica serovar Typhimurium cadC expression is induced by low pH and lysine. Inactivation of cadC suppresses the acid-sensitive phenotype of a cadA mutation, suggesting the existence of other CadC-dependent genes in addition to the cadBA operon. Using a proteomic approach, we identified 8 of the putative CadC-induced proteins and 15 of the putative CadC-repressed proteins. The former include porin proteins OmpC and OmpF. The latter include proteins involved in glycolysis, energy production, and stress tolerance. To better understand the altered levels of OmpC and OmpF, we compared expression of ompR in S. enterica serovar Typhimurium wild-type and cadC mutant strains and determined that CadC exerted a negative influence on ompR transcription. Taken together, our findings strongly suggest that CadC may be a global regulator involved in the OmpR regulatory system during acid adaptation.
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PMID:CadC has a global translational effect during acid adaptation in Salmonella enterica serovar Typhimurium. 1720 22


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