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)

CYP1(HAP1) is a transcriptional activator involved in the aerobic metabolism of the yeast Saccharomyces cerevisiae. The amino acid sequence of its DNA-binding domain suggests that it belongs to the "zinc cluster" class. This region is indeed characterized by a pattern known to form a bimetal thiolate cluster where two zinc ions are coordinated by six cysteine residues. Structures of two such domains, those from GAL4 and PPR1, have been solved as complexes with DNA. These domains consist of the zinc cluster connected to a dimerization helix by a linker peptide. They recognize, as a dimer, an inverted repeat of a CGG motif that is separated by a specific number of bases. Interestingly, the specificity of that interaction seems not to be due to the interaction between the cluster region and the DNA but rather to a fine tune between the structure of the linker peptide and the number of base-pairs separating the two CGGs. However, the CYP1 target sites fail to display such a consensus sequence. One of the two CGG sites is poorly conserved and some experiments suggest a direct rather than an inverted repeat. Using 1H, 15N and 113Cd NMR spectroscopy, we have undertaken the analysis of the structural properties of the CYP1(56-126) fragment that consists of the zinc-cluster region, the linker peptide and a part of the dimerization helix. We have demonstrated that the six cysteine residues of the peptide chelate two cadmium ions as in GAL4 and PPR1. Fifteen structures of the zinc-cluster region (residues 60 to 100) were calculated, the linker peptide and the dimerization helix being unstructured under the conditions of our study. This region possesses the same overall fold as in GAL4 and PPR1, and most of the side-chains involved in the interaction with DNA are structurally conserved. This suggests that the CYP1 zinc-cluster region recognizes a CGG triplet in the same way as GAL4 and PPR1. In this case, the particular properties of CYP1 seem to be due to the structure of the linker peptide and/or of the dimerization helix.
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PMID:1H, 15N resonance assignment and three-dimensional structure of CYP1 (HAP1) DNA-binding domain. 868 83

The coordinated cellular responses to physiological stress are known to be effected in part by the activation of heat-shock factor 1, a transcriptional activator protein capable of binding to, and inducing transcription from genes containing heat shock elements. Other stress responsive signal transduction pathways also exist including the stress activated protein kinase cascade that regulates the activity of the transcription factor AP1. We have examined the expression of the low molecular stress proteins, heat shock protein 27 and alpha B-crystallin in astrocytes in response to physiological stress of different types and asked what component of this induction is effected at the transcriptional level and whether activation of heat shock factor 1 and AP1 might account for these events. We have found that stress regulated induction of alpha B-crystallin has a strong transcriptional component and that it may be effected by at least two different transcriptional mechanisms. In one set of phenomena, represented here by cadmium exposure, alpha B-crystallin and heat shock protein 27 are coordinately regulated and this occurs in the presence of activated heat shock factor 1. In the second series of phenomena, represented here by hypertonic stress, alpha B-crystallin is induced in the absence of heat shock factor activation and in the absence of any corresponding change in heat shock protein 27 expression. Although hypertonic stress does activate an AP1-like binding activity, the AP1 consensus binding site in the alpha B-crystallin promoter does not appear to be a target for this hypertonic stress inducible activity. These data suggest that the hypertonic stress response is effected through a heat shock factor independent mechanism and that hypertonic stress regulated induction of alpha B-crystallin does not directly depend on the SAPK pathway and AP1 activity.
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PMID:Transcription regulation of alpha B-crystallin in astrocytes: analysis of HSF and AP1 activation by different types of physiological stress. 874 50

We have shown previously that the heavy metal-responsive transcriptional activator MTF-1 regulates the basal and heavy metal-induced expression of metallothioneins. To investigate the physiological function of MTF-1, we generated null mutant mice by targeted gene disruption. Embryos lacking MTF-1 die in utero at approximately day 14 of gestation. They show impaired development of hepatocytes and, at later stages, liver decay and generalized edema. MTF-1(-/-) embryos fail to transcribe metallothionein I and II genes, and also show diminished transcripts of the gene which encodes the heavy-chain subunit of the gamma-glutamylcysteine synthetase, a key enzyme for glutathione biosynthesis. Metallothionein and glutathione are involved in heavy metal homeostasis and detoxification processes, such as scavenging reactive oxygen intermediates. Accordingly, primary mouse embryo fibroblasts lacking MTF-1 show increased susceptibility to the cytotoxic effects of cadmium or hydrogen peroxide. Thus, MTF-1 may help to control metal homeostasis and probably cellular redox state, especially during liver development. We also note that the MTF-1 null mutant phenotype bears some similarity to those of two other regulators of cellular stress response, namely c-Jun and NF-kappaB (p65/RelA).
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PMID:Embryonic lethality and liver degeneration in mice lacking the metal-responsive transcriptional activator MTF-1. 958 78

Yeast cells deficient in the transcriptional activator Imp2p are viable, but display marked hypersensitivity to a variety of oxidative agents. We now report that imp2 null mutants are also extremely sensitive to elevated levels of the monovalent ions, Na+ and Li+, as well as to the divalent ions Ca2+, Mn2+, Zn2+, and Cu2+, but not to Cd2+, Mg2+, Co2+, Ni2+, and Fe2+, as compared to the parent strain. We next searched for multicopy suppressor genes that would allow the imp2Delta mutant to grow under high salt conditions. Two genes that independently restored normal salt-resistance to the imp2Delta mutant, ENA1 and HAL3, were isolated. ENA1 encodes a P-type ion pump involved in monovalent ion efflux from the cell, while HAL3 encodes a protein required for activating the expression of Ena1p. Neither ENA1 nor HAL3 gene expression was positively regulated by Imp2p. Moreover, the imp2 ena1 double mutant was exquisitely sensitive to Na+/Li+ cations, as compared to either single mutant, implying that Imp2p mediates Na+/Li+ cation homeostasis independently of Ena1p.
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PMID:The transcriptional activator Imp2p maintains ion homeostasis in Saccharomyces cerevisiae. 961 Dec

Heat shock factor (hsf) is the transcriptional activator that governs the transcriptional response of eukaryotic cells to stressful conditions. The structure and regulation of hsf is highly conserved. We describe deletion mutations in hsf+ that alter the ability of Schizosaccharomyces pombe to respond to different stressful conditions. One mutation causes increased sensitivity to cadmium while maintaining near normal sensitivity to heat stress, while another mutation confers increased sensitivity to heat stress but retains normal sensitivity to cadmium. Despite the differential sensitivity of these two strains to cadmium and heat stress, the mutant hsf proteins in each strain were activated by both cadmium and heat. However, we found that these mutations differentially affected the ability of hsf to activate different promoters: one mutated hsf activated the ssp1+ gene better than the wis2+ gene following either stress, while the other mutated hsf activated wis2+ better than ssp1+. We propose that the differential ability of strains that contain these mutant hsfs to survive cadmium and heat stress is not caused by differences in activation of hsf, but is caused instead by differential abilities of the mutant hsfs to activate the appropriate sets of genes needed for survival.
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PMID:Mutations in the Schizosaccharomyces pombe heat shock factor that differentially affect responses to heat and cadmium stress. 1007 Dec 22

The copZ gene of Bacillus subtilis encodes a copper chaperon CopZ that donates copper to the copper transporter CopA. Both genes copZ and copA are clustered to an operon and its promoter is regulated by Cu ions and CueR, a Mer-like transcriptional activator. Here we show that cadmium ions activate copZA expression as strong as copper ions. Northern hybridization analysis showed that copper and cadmium both induce the synthesis of a 2.7 kb copZA transcript and a 250 bp copZ transcript. A copA deletion mutant was sensitive to copper, whereas a copZ deletion resulted in an increased sensitivity to cadmium and copper. Transcription of the cadmium resistance gene cadA, which is adjacent to the copZA cluster, is extremely reduced in a copZ deletion strain. Transformation of copZ in trans restores wild type resistance to cadmium and copper in a copZ deletion strain. This excludes any polar effect and proves that the copZ encoded protein is important for copper and cadmium resistance.
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PMID:Metalloregulation in Bacillus subtilis: the copZ chromosomal gene is involved in cadmium resistance. 1521

Saccharomyces cerevisiae has developed several mechanisms to cope with exposure to cadmium. In particular, the sulfur compound glutathione plays a pivotal role in cadmium detoxification, and exposure to cadmium leads to a wide reorganization of S. cerevisiae transcriptome and proteome, resulting in a significant increase in glutathione synthesis. Met4, the transcriptional activator of the sulfur metabolism enzymes, is a critical actor in this reorganization. Recent work has uncovered a part of the mechanism of cadmium-induced Met4 regulation, and showed that it occurs trough the SCF ubiquitin ligase complex SCF(Met30). We discuss this regulation in S. cerevisiae and compare it with the regulation of two other transcriptional activators involved in cadmium detoxification: the Schizosaccharomyces pombe Zip1, regulated by SCF(Pof1), and the mammalian Nrf2, regulated by the SCF-like ubiquitin ligase Cul3:Rbx1:Keap1.
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PMID:Regulation of the cadmium stress response through SCF-like ubiquitin ligases: comparison between Saccharomyces cerevisiae, Schizosaccharomyces pombe and mammalian cells. 1658 27

Heme oxygenase-1 (HO-1) degrades heme into biliverdin, iron and CO. The enzyme participates in adaptive and protective responses to oxidative stress and various inflammatory stimuli, and is induced in response to reactive oxygen species (ROS). 2',7'-Dichlorodihydrofluorescin diacetate (DCFH-DA) is a common reagent used to detect ROS by the oxidation of 2',7'-dichlorodihydrofluorescin (DCFH) to fluorescent dichlorodihydrofluorescein. We previously found that rapid oxidation of DCFH occurred with heme-compounds as well as ROS [Ohashi, T. et al. (2002) FEBS Lett. 511, 21-27], and then examined the effect of DCFH-DA on the induction of HO-1 expression by arsenite, cadmium and hemin, which induce oxidative stress and cytotoxicity. We found suppression of the arsenite-, cadmium- and hemin-dependent induction of HO-1 with DCFH-DA. The suppression occurred at the transcriptional level since the promoter activity of the Maf-recognition site of the HO-1 gene decreased with the DCFH-DA treatment. DCFH abolished the phosphorylation of extracellular signal-regulated kinase, the nuclear translocation of a transcriptional activator Nrf2, and cell death. An antioxidant, N-acetylcysteine (NAC), also suppressed the induction by arsenite and cadmium, but not that by hemin, indicating that DCFH blocked a different site in the stress signal pathway from NAC. Considering that the oxidation of DCFH diminishes ROS generated by various stressors, our findings provide a potential strategy for protection of cells from toxic insults using DCFH-like molecules.
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PMID:The antioxidant role of a reagent, 2',7'-dichlorodihydrofluorescin diacetate, detecting reactive-oxygen species and blocking the induction of heme oxygenase-1 and preventing cytotoxicity. 1695 97

Adult T-cell leukemia (ATL) is a highly aggressive mature CD4+ T-cell malignancy that is etiologically associated with human T-lymphotropic virus Type 1 (HTLV-1). ATL is characterized by frequent infiltration of lymph nodes, spleen, liver, skin and gut. Previously, we and others have shown that the majority of ATL cases are strongly positive for CCR4, which may explain the frequent skin invasion of ATL. Here, we examined whether ATL cells express CCR9, which is involved in T-cell homing to the gastrointestinal tract. Human T cell lines carrying HTLV-1 consistently expressed CCR9 together with the HTLV-1-encoded transcriptional activator Tax. Although ATL cells freshly isolated from peripheral blood hardly expressed CCR9, ATL cells cultured for 1 day consistently expressed CCR9 in parallel with the upregulation of Tax. Induction of Tax by Cd2+ in JPX-9, a subline of Jurkat human T cell line carrying Tax under the control of metallothionein promoter, led to upregulation of CCR9. A luciferase reporter gene under the control of the CCR9 promoter was expressed by cotransfection of an expression vector for Tax or in Cd2+-treated JPX-9 cells. Furthermore, immunohistochemical staining demonstrated that ATL cells infiltrating gastrointestinal tract were frequently positive for CCR9. Collectively, CCR9 is inducible in ATL cells expressing Tax and may play a role in the gastrointestinal involvement of ATL.
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PMID:Expression of CCR9 in HTLV-1+ T cells and ATL cells expressing Tax. 1720 12

In this work we have cloned and characterized the Kluyveromyces lactis HAP1 gene and we have found that, contrary to data previously described for the homologous gene of Saccharomyces cerevisiae, i.) the function of this gene does not affect growth in media with carbon sources used by fermentative or respiratory pathways ii) in aerobiosis, KlHap1p is not a transcriptional activator of the expression of genes related to respiration, cholesterol biosynthesis or oxidative stress defence analyzed in this study. The comparison of homology between specific regions of ScHap1p and KlHap1p reveals that the dimerization domain is poorly conserved and we have verified that this domain, cloned in the two plasmids of the two hybrid system, does not reconstitute S. cerevisiae Gal4p activity. Since the COOH-terminal transcriptional activation domain of KlHap1p is active when fused to the Gal4p-DNA binding domain, we hypothesize that differences in the capacity to form dimers could contribute to allow different functions of the protein in K. lactis and S. cerevisiae. Transcriptional expression of KlHAP1 is dependent on oxygen availability, increasing its expression in hypoxia. Deletion of KlHAP1 increases the resistance to oxidative stress or cadmium and the induction of KlYAP1 and KlTSA1 by the addition of 0.5 mM H(2)O(2) is repressed by KlHap1p. These data are discussed in reference to the evolution of respiro-fermentative metabolism in yeasts.
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PMID:Functional characterization of KlHAP1: a model to foresee different mechanisms of transcriptional regulation by Hap1p in yeasts. 1794 45


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