Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF-2alpha) is a well-characterized mechanism regulating protein synthesis in response to environmental stresses. In the yeast Saccharomyces cerevisiae, starvation for amino acids induces phosphorylation of eIF-2alpha by Gcn2 protein kinase, leading to elevated translation of GCN4, a transcriptional activator of more than 50 genes. Uncharged tRNA that accumulates during amino acid limitation is proposed to activate Gcn2p by associating with Gcn2p sequences homologous to histidyl-tRNA synthetase (HisRS) enzymes. Given that eIF-2alpha phosphorylation in mammals is induced in response to both carbohydrate and amino acid limitations, we addressed whether activation of Gcn2p in yeast is also controlled by different nutrient deprivations. We found that starvation for glucose induces Gcn2p phosphorylation of eIF-2alpha and stimulates GCN4 translation. Induction of eIF-2alpha phosphorylation by Gcn2p during glucose limitation requires the function of the HisRS-related domain but is largely independent of the ribosome binding sequences of Gcn2p. Furthermore, Gcn20p, a factor required for Gcn2 protein kinase stimulation of GCN4 expression in response to amino acid starvation, is not essential for GCN4 translational control in response to limitation for carbohydrates. These results indicate there are differences between the mechanisms regulating Gcn2p activity in response to amino acid and carbohydrate deficiency. Gcn2p induction of GCN4 translation during carbohydrate limitation enhances storage of amino acids in the vacuoles and facilitates entry into exponential growth during a shift from low-glucose to high-glucose medium. Gcn2p function also contributes to maintenance of glycogen levels during prolonged glucose starvation, suggesting a linkage between amino acid control and glycogen metabolism.
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PMID:Glucose limitation induces GCN4 translation by activation of Gcn2 protein kinase. 1073 73

Protein kinase GCN2 regulates translation initiation by phosphorylating eukaryotic initiation factor 2alpha (eIF2alpha), impeding general protein synthesis but specifically inducing translation of GCN4, a transcriptional activator of amino acid biosynthetic genes in Saccharomyces cerevisiae. GCN2 activity is stimulated in amino acid-deprived cells through binding of uncharged tRNA to a domain related to histidyl tRNA synthetase. We show that GCN2 is phosphorylated by another kinase on serine 577, located N-terminal to the kinase domain. Mutation of Ser-577 to alanine produced partial activation of GCN2 in nonstarved cells, increasing the level of phosphorylated eIF2alpha, derepressing GCN4 expression, and elevating the cellular levels of tryptophan and histidine. The Ala-577 mutation also increased the tRNA binding affinity of purified GCN2, which can account for the elevated kinase activity of GCN2-S577A in nonstarved cells where uncharged tRNA levels are low. Whereas Ser-577 remains phosphorylated in amino acid-starved cells, its dephosphorylation could mediate GCN2 activation in other stress or starvation conditions by lowering the threshold of uncharged tRNA required to activate the protein.
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PMID:Serine 577 is phosphorylated and negatively affects the tRNA binding and eIF2alpha kinase activities of GCN2. 1207 Jan 58

Yeast protein kinase GCN2 stimulates the translation of transcriptional activator GCN4 by phosphorylating eIF2alpha in response to amino acid starvation. Kinase activation requires binding of uncharged tRNA to a histidyl tRNA synthetase-related domain in GCN2. Phosphorylation of serine 577 (Ser 577) in GCN2 by another kinase in vivo inhibits GCN2 function in rich medium by reducing tRNA binding activity. We show that rapamycin stimulates eIF2alpha phosphorylation by GCN2, with attendant induction of GCN4 translation, while reducing Ser 577 phosphorylation in nonstarved cells. The alanine 577 (Ala 577) mutation in GCN2 (S577A) dampened the effects of rapamycin on eIF2alpha phosphorylation and GCN4 translation, suggesting that GCN2 activation by rapamycin involves Ser 577 dephosphorylation. Rapamycin regulates the phosphorylation of Ser 577 and eIF2alpha by inhibiting the TOR pathway. Rapamycin-induced dephosphorylation of Ser 577, eIF2alpha phosphorylation, and induction of GCN4 all involve TAP42, a regulator of type 2A-related protein phosphatases. Our results add a new dimension to the regulation of protein synthesis by TOR proteins and demonstrate cross-talk between two major pathways for nutrient control of gene expression in yeast.
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PMID:Translational control by TOR and TAP42 through dephosphorylation of eIF2alpha kinase GCN2. 1265 28

p38 is associated with a macromolecular tRNA synthetase complex. It has an essential role as a scaffold for the complex, and genetic disruption of p38 in mice causes neonatal lethality. Here we investigated the molecular mechanisms underlying lethality of p38-mutant mice. p38-deficient mice showed defects in lung differentiation and respiratory distress syndrome. p38 was found to interact with FUSE-binding protein (FBP), a transcriptional activator of c-myc. Binding of p38 stimulated ubiquitination and degradation of FBP, leading to downregulation of c-myc, which is required for differentiation of functional alveolar type II cells. Transforming growth factor-beta (TGF-beta) induced p38 expression and promoted its translocation to nuclei for the regulation of FBP and c-myc. Thus, this work identified a new activity of p38 as a mediator of TGF-beta signaling and its functional importance in the control of c-myc during lung differentiation.
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PMID:Downregulation of FUSE-binding protein and c-myc by tRNA synthetase cofactor p38 is required for lung cell differentiation. 1281 82

In the yeast Saccharomyces cerevisiae, starvation for amino acids induces phosphorylation of the alpha subunit of eukaryotic initiation factor 2alpha by Gcn2 protein kinase, leading to elevated translation of GCN4. Gcn4p is a transcriptional activator of hundreds of genes involved in remedying nutrient deprivation. In addition to a conserved kinase domain, Gcn2p has a regulatory region homologous to histidyl tRNA synthetase enzymes that binds uncharged tRNA that accumulates during amino acid starvation. Flanking the carboxyl terminus of the histidyl-tRNA synthetase-related domain is a region spanning 162 residues that participates in the activation of the protein kinase. Gel filtration and chemical cross-linking analysis of the recombinant carboxyl-terminal Gcn2 protein revealed that this region is a stable homodimer that is highly resistant to high concentrations of salt. Residue alterations in three hydrophobic segments and one segment with a proposed amphipathic alpha-helix in this Gcn2p carboxyl terminus blocked oligomerization, supporting the role of hydrophobic interactions in the dimerization interface of Gcn2p. Introduction of residue substitutions that impaired dimerization into the full-length protein prevented the ability of Gcn2p to phosphorylate its substrate eukaryotic initiation factor-2alpha and induce GCN4 translational expression in yeast cells subjected to a variety of stresses including amino acid limitation or exposure to rapamycin or high levels of NaCl. This latter stress can be overcome by addition of increasing amounts of K+ ions, indicating that the Na+/K+ ion balance is central to this stress induction. We conclude that dimerization involving hydrophobic segments in the carboxyl-terminal region is required for activation of Gcn2p in response to a multitude of stresses.
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PMID:Dimerization is required for activation of eIF2 kinase Gcn2 in response to diverse environmental stress conditions. 1501 Apr 61

The general amino acid control (GAAC) enables yeast cells to overcome amino acid deprivation by activation of the alpha subunit of translation initiation factor 2 (eIF2alpha) kinase GCN2 and consequent induction of GCN4, a transcriptional activator of amino acid biosynthetic genes. Binding of GCN2 to GCN1 is required for stimulation of GCN2 kinase activity by uncharged tRNA in starved cells. Here we show that YIH1, when overexpressed, dampens the GAAC response (Gcn- phenotype) by suppressing eIF2alpha phosphorylation by GCN2. The overexpressed YIH1 binds GCN1 and reduces GCN1-GCN2 complex formation, and, consistent with this, the Gcn- phenotype produced by YIH1 overexpression is suppressed by GCN2 overexpression. YIH1 interacts with the same GCN1 fragment that binds GCN2, and this YIH1-GCN1 interaction requires Arg-2259 in GCN1 in vitro and in full-length GCN1 in vivo, as found for GCN2-GCN1 interaction. However, deletion of YIH1 does not increase eIF2alpha phosphorylation or derepress the GAAC, suggesting that YIH1 at native levels is not a general inhibitor of GCN2 activity. We discovered that YIH1 normally resides in a complex with monomeric actin, rather than GCN1, and that a genetic reduction in actin levels decreases the GAAC response. This Gcn- phenotype was partially suppressed by deletion of YIH1, consistent with YIH1-mediated inhibition of GCN2 in actin-deficient cells. We suggest that YIH1 resides in a YIH1-actin complex and may be released for inhibition of GCN2 and stimulation of protein synthesis under specialized conditions or in a restricted cellular compartment in which YIH1 is displaced from monomeric actin.
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PMID:YIH1 is an actin-binding protein that inhibits protein kinase GCN2 and impairs general amino acid control when overexpressed. 1512

We used genome-wide expression analysis in Saccharomyces cerevisiae to explore whether and how the expression of protein-coding, RNA polymerase (Pol) II-transcribed genes is influenced by a decrease in RNA Pol III-dependent transcription. The Pol II transcriptome was characterized in four thermosensitive, slow-growth mutants affected in different components of the RNA Pol III transcription machinery. Unexpectedly, we found only a modest correlation between altered expression of Pol II-transcribed genes and their proximity to class III genes, a result also confirmed by the analysis of single tRNA gene deletants. Instead, the transcriptome of all of the four mutants was characterized by increased expression of genes known to be under the control of the Gcn4p transcriptional activator. Indeed, GCN4 was found to be translationally induced in the mutants, and deleting the GCN4 gene eliminated the response. The Gcn4p-dependent expression changes did not require the Gcn2 protein kinase and could be specifically counteracted by an increased gene dosage of initiator tRNA(Met). Initiator tRNA(Met) depletion thus triggers a GCN4-dependent reprogramming of genome expression in response to decreased Pol III transcription. Such an effect might represent a key element in the coordinated transcriptional response of yeast cells to environmental changes.
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PMID:Modulation of yeast genome expression in response to defective RNA polymerase III-dependent transcription. 1616 43

Staf was originally identified as the transcriptional activator of Xenopus tRNA(Sec) and small nuclear (sn) RNA-type genes. Recently, transcription of seven human (h) protein coding genes was reported to be activated by the human ortholog hStaf/ZNF143. Here we have used a combined in silico and biochemical approach to identify 1175 conserved hStaf/ZNF143-binding sites (SBS) distributed in 938 promoters of four mammalian genomes. The SBS shows a significant positional preference and occurs mostly within 200 bp upstream of the transcription start site. Chromatin immunoprecipitation assays with 295 of the promoters established that 90% contain bona fide SBS. By extrapolating the values of this mapping to the full sizes of the mammalian genomes, we can infer the existence of at least 2500 SBS distributed in 2000 promoters. This unexpected large number strongly suggests that SBS constitutes one of the most widespread transcription factor-binding sites in mammalian promoters. Furthermore, we demonstrated that the presence of the SBS alone is sufficient to direct expression of a luciferase reporter gene, suggesting that hStaf/ZNF143 can recruit per se the transcription machinery.
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PMID:A genome scale location analysis of human Staf/ZNF143-binding sites suggests a widespread role for human Staf/ZNF143 in mammalian promoters. 1709 45

Zinc-finger protein 143 (ZNF143) is a human homolog of Xenopus transcriptional activator staf that is involved in selenocystyl tRNA transcription. We previously showed that ZNF143 expression is induced by treatment with DNA-damaging agents and that it preferentially binds to cisplatin-modified DNA. In this study, the potential function of ZNF143 was investigated. ZNF143 was overexpressed in cisplatin-resistant cells. ZNF143 knockdown in prostate cancer caused increased sensitivity for cisplatin, but not for oxaliplatin, etoposide and vincristine. We also showed that ZNF143 is associated with tumor suppressor gene product p73 but not with p53. p73 could stimulate the binding of ZNF143 to both ZNF143 binding site and cisplatin-modified DNA, and modulate the function of ZNF143. We provide a direct evidence that both Rad51 and flap endonuclease-1 are target genes of ZNF143 and overexpressed in cisplatin-resistant cells. Taken together, these experiments demonstrate that an interplay of ZNF143, p73 and ZNF143 target genes is involved in DNA repair gene expression and cisplatin resistance.
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PMID:ZNF143 interacts with p73 and is involved in cisplatin resistance through the transcriptional regulation of DNA repair genes. 1729 37

In Streptomyces coelicolor, bldA encodes the only tRNA for a rare leucine codon, UUA. This tRNA is unnecessary for growth, but is required for some aspects of secondary metabolism and morphological development, as revealed by the phenotypes of bldA mutants in diverse streptomycetes. This article is a comprehensive review of out understanding of this unusual situation. Based on information from four sequenced genomes it now appears that, typically, about 2 approximately 3% of genes in any one streptomycete contain a TTA codon, most having been acquired through species-specific horizontal gene transfer. Among the few widely conserved TTA-containing genes, mutations in just one, the pleiotropic regulatory gene adpA, give an obvious phenotype: such mutants are defective in aerial growth and sporulation, but vary in the extent of their impairment in secondary metabolism in different streptomycetes. The TTA codon in adpA is largely responsible for the morphological phenotype of a bldA mutant of S. coelicolor. AdpA-dependent targets include several genes involved in the integrated action of extracellular proteases that, at least in some species, are involved in the conversion of primary biomass into spores. The effects of bldA mutations on secondary metabolism are mostly attributable to the presence of TTA codons in pathway-specific genes, particularly in transcriptional activator genes. This is not confined to S. coelicolor-it is true for about half of all known antibiotic biosynthetic gene sets from streptomycetes. Combined microarray and proteomic analysis of liquid (and therefore non-sporulating) S. coelicolor bldA mutant cultures revealed effects of the mutation during rapid growth, during transition phase, and in stationary phase. Some of these effects may be secondary consequences of changes in the pattern of ppGpp accumulation. It is argued that the preferential accumulation of the bldA tRNA under conditions in which growth is significantly constrained has evolved to favour the expression of genes that confer adaptive benefits in intermittently encountered sub-optimal environments. The evolution of this system may have been a secondary consequence of the selective pressure exerted by bacteriophage attack. Some biotechnological implications of bldA phenomenology are considered.
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PMID:The use of the rare UUA codon to define "expression space" for genes involved in secondary metabolism, development and environmental adaptation in streptomyces. 1833 85


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