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)

Drug resistance as a result of overexpression of drug transporter genes presents a major obstacle in the treatment of cancers and infections. The molecular mechanisms underlying transcriptional up-regulation of drug transporter genes remains elusive. Employing Saccharomyces cerevisiae as a model, we analyzed here transcriptional regulation of the drug transporter gene PDR5 in a drug-resistant pdr1-3 strain. This mutant bears a gain-of-function mutation in PDR1, which encodes a transcriptional activator for PDR5. Similar to the well studied model gene GAL1, we provide evidence showing that PDR5 belongs to a group of genes whose transcription requires the Spt-Ada-Gcn5 acetyltransferase (SAGA) complex. We also show that the drugindependent PDR5 transcription is associated with enhanced promoter occupancy of coactivator complexes, including SAGA, Mediator, chromatin remodeling SWI/SNF complex, and TATA-binding protein. Analyzed by chromatin immunoprecipitations, loss of contacts between histones and DNA occurs at both promoter and coding sequences of PDR5. Consistently, micrococcal nuclease susceptibility analysis revealed altered chromatin structure at the promoter and coding sequences of PDR5. Our data provide molecular description of the changes associated with constitutive PDR5 transcription, and reveal the molecular mechanism underlying drug-independent transcriptional up-regulation of PDR5.
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PMID:On the mechanism of constitutive Pdr1 activator-mediated PDR5 transcription in Saccharomyces cerevisiae: evidence for enhanced recruitment of coactivators and altered nucleosome structures. 1529 7

The SoxR protein of Escherichia coli responds to redox signals by activating the transcription of soxS, which encodes another transcription activator that directly stimulates oxidative stress genes. In contrast, Pseudomonas aeruginosa has an open reading frame (ORF) encoding a putative protein homologous to E. coli SoxR, but not to SoxS. Instead of a soxS homolog, ORFs encoding an unknown hypothetical protein and soxR are arranged divergently with their 5' ends separated by a 78 bp region containing a sequence homologous to the SoxR-binding soxS promoter. In this study, we report the overproduction and purification of SoxR from P. aeruginosa to investigate the mechanism of gene activation by SoxR. The spectroscopic properties of the purified SoxR protein indicate that it contains a redox active iron-sulfur [2Fe-2S] cluster. Redox titration of the SoxR protein revealed a midpoint potential of -290 mV. The SoxR protein specifically binds a fragment of the SoxS promoter-like region in a concentration-dependent fashion, as shown by both gel mobility shift and fluorescence polarization assays. The purified SoxR stimulates the in vitro transcription of the gene encoding the hypothetical protein in P. aeruginosa. This activity was lost following reduction of the SoxR [2Fe-2S] clusters. The levels of mRNA in the hypothetical protein increased in paraquat-treated cells. These results indicate that P. aeruginosa SoxR is a direct transcriptional activator of the hypothetical protein, and suggest that SoxR proteins may play multiple regulatory roles as a transcription factor in addition to its protective role in oxidative stress.
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PMID:Activation of SoxR-dependent transcription in Pseudomonas aeruginosa. 1563

Major insights into the regulation of chromatin organization have stemmed from biochemical studies using Gal4-VP16, a chimeric transcriptional activator in which the DNA binding domain of Gal4p is fused to the activation domain of viral protein VP16. Unexpectedly, given previous intensive efforts to understand how Gal4-VP16 functions in the context of chromatin, we have uncovered a new mode of chromatin reorganization that is dependent on Gal4-VP16. This reorganization is performed by an activity in a crude DEAE (CD) fraction from budding yeast which also supports ATP-dependent assembly of physiologically spaced nucleosome arrays. Biochemical analysis reveals that the activity tightly associates with chromatin and reorganizes nucleosome arrays by a mechanism which is insensitive to ATP depletion after nucleosome assembly. It generates a chromatin organization in which a nucleosome is stably positioned immediately adjacent to Gal4p binding sites in the template DNA. Individual deletion of genes previously implicated in chromatin assembly and remodeling, namely, the histone chaperones NAP1, ASF1, and CAC1 and the SNF2-like DEAD/H ATPases SNF2, ISW1, ISW2, CHD1, SWR1, YFR038w, and SPT20, does not significantly perturb reorganization. Therefore, Gal4-VP16-directed chromatin reorganization in yeast can occur by an ATP-independent mechanism that does not require SAGA, SWI/SNF, Isw1, or Isw2 chromatin remodeling complexes.
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PMID:Gal4-VP16 directs ATP-independent chromatin reorganization in a yeast chromatin assembly system. 1576 86

A new esterase-encoding gene was found in the draft genome sequence of Lactobacillus casei BL23 (CECT5275). It is located in an operon together with genes encoding the EIIA, EIIB, EIIC, and EIID proteins of a mannose class phosphoenolpyruvate:sugar phosphotransferase system. After overproduction in Escherichia coli and purification, the esterase could hydrolyze acetyl sugars, hence the operon was named esu for esterase-sugar uptake genes. Upstream of the genes encoding the EII components (esuABCD) and the esterase (esuE), two genes transcribed in the opposite sense were found which encode a Bacillus subtilis LevR-like transcriptional activator (esuR) and a sigma54-like transcriptional factor (rpoN). As compared with the wild-type strain, elevated fructose phosphorylation was detected in L. casei mutants constitutively expressing the esu operon. However, none of the many sugars tested could induce the esu operon. The fact that EsuE exhibits esterase activity on acetyl sugars suggests that this operon could be involved in the uptake and metabolism of esterified sugars. Expression of the esu operon is similar to that of the B. subtilis lev operon: it contains a -12,-24 consensus promoter typical of sigma54-regulated genes, and EsuR and RpoN are essential for its transcription which is negatively regulated by EIIB(Esu). The esuABCDE transcription unit represents the first sigma54-regulated operon in lactobacilli. Furthermore, replacement of His852 in the phosphoenolpyruvate:sugar phosphotransferase system regulation domain II of EsuR with Ala indicated that the transcription activator function of EsuR is inhibited by EIIB(Esu)-mediated phosphorylation at His852.
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PMID:An esterase gene from Lactobacillus casei cotranscribed with genes encoding a phosphoenolpyruvate:sugar phosphotransferase system and regulated by a LevR-like activator and sigma54 factor. 1592 3

Calbindin-D(28k) has been reported to be a facilitator of calcium diffusion and to protect against apoptotic cell death. Most recently, we found that the presence of calbindin-D(28k) results in reduced calcium influx through voltage-dependent L-type Ca(2+) channels and enhanced sensitivity of the channels to calcium dependent inactivation. Co-immunoprecipitation and GST pull down assays indicate that calbindin-D(28k) interacts with the C-terminus of the L-type calcium channel alpha(1c) subunit (Ca(v)1.2). This is the first report of the binding of calbindin to a calcium channel and provides new insight concerning mechanisms by which calbindin acts to modulate intracellular calcium. Besides calbindin, another major target of 1,25(OH)(2)D(3) is 24(OH)ase, which is involved in the catabolism of 1,25(OH)(2)D(3). We reported that C/EBPbeta is a major transcriptional activator of 24(OH)ase that cooperates with CBP/p300 in regulating VDR mediated 24(OH)ase transcription. Recently, we found, in addition to p160 coactivators, that SWI/SNF complexes (that facilitate transcription by remodeling chromatin using the energy of ATP hydrolysis) are also involved in VDR mediated 24(OH)ase transcription and functionally cooperate with C/EBPbeta in regulating 24(OH)ase. These findings define novel mechanisms that may be of fundamental importance in understanding how 1,25(OH)(2)D(3) mediates its multiple biological effects.
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PMID:New insights into the function and regulation of vitamin D target proteins. 1725 25

It has been reported that mouse Lbh (limb-bud and heart) can regulate cardiac gene expression by modulating the combinatorial activities of key cardiac transcription factors, as well as their individual functions in cardiogenesis. Here we report the cloning and characterization of the human homolog of mouse Lbh gene, hLBH, from a human embryonic heart cDNA library. The cDNA of hLBH is 2927 bp long, encoding a protein product of 105 amino acids. The protein is highly conserved in evolution across different species from zebra fish, to mouse, to human. Northern blot analysis indicates that a 2.9 kb transcript specific for hLBH is most abundantly expressed in both embryonic and adult heart tissue. In COS-7 cells, hLBH proteins are localized to both the nucleus and the cytoplasm. hLBH is a transcription activator when fused to Gal-4 DNA-binding domain. Deletion analysis indicates that both the N-terminal containing proline-dependent serine/threonine kinase group and the C-terminal containing ERK D-domain motif are required for transcriptional activation. Overexpression of hLBH in COS-7 cells activates the transcriptional activities of activator protein-1 (AP-1) and serum response element (SRE). These results suggest that hLBH proteins may act as a transcriptional activator in mitogen-activated protein kinase signaling pathway to mediate cellular functions.
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PMID:A human homolog of mouse Lbh gene, hLBH, expresses in heart and activates SRE and AP-1 mediated MAPK signaling pathway. 1739 Feb 36

We describe a core gene cluster, comprised of eight genes (designated CTB1-8), and associated with cercosporin toxin production in Cercospora nicotianae. Sequence analysis identified 10 putative open reading frames (ORFs) flanking the previously characterized CTB1 and CTB3 genes that encode, respectively, the polyketide synthase and a dual methyltransferase/monooxygenase required for cercosporin production. Expression of eight of the genes was co-ordinately induced under cercosporin-producing conditions and was regulated by the Zn(II)Cys(6) transcriptional activator, CTB8. Expression of the genes, affected by nitrogen and carbon sources and pH, was also controlled by another transcription activator, CRG1, previously shown to regulate cercosporin production and resistance. Disruption of the CTB2 gene encoding a methyltransferase or the CTB8 gene yielded mutants that were completely defective in cercosporin production and inhibitory expression of the other CTB cluster genes. Similar 'feedback' transcriptional inhibition was observed when the CTB1, or CTB3 but not CTB4 gene was inactivated. Expression of four ORFs located on the two distal ends of the cluster did not correlate with cercosporin biosynthesis and did not show regulation by CTB8, suggesting that the biosynthetic cluster was limited to CTB1-8. A biosynthetic pathway and a regulatory network leading to cercosporin formation are proposed.
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PMID:Molecular analysis of the cercosporin biosynthetic gene cluster in Cercospora nicotianae. 1746 21

p53 is a sequence-specific DNA-binding transcription factor and key regulator of cell cycle arrest and apoptosis. p53 is mutated in most human cancers and these mutations generally impair its ability to activate transcription. When expressed in Saccharomyces cerevisiae, p53 acts as a strong transcriptional activator allowing yeast to be used as a model system to study the effects of p53 mutations on activity. However, little is known about the exact mechanisms by which p53 functions in yeast. Using 76 mutant yeast strains, we have evaluated the effect of deleting components of the ADA, COMPASS, INO80, ISW1, Mediator, RSC, SAGA, SAS, SLIK, SWI/SNF, and SWR1 transcriptional regulatory complexes on p53-dependent transcription. In addition, we examined the role of histone H2B ubiquitylation by Rad6/Bre1 on p53 activation. Overall, our analysis indicates that there are several remarkable similarities between p53-dependent transcription in yeast and mammalian cells, suggesting that yeast can serve as a valid model system for at least some aspects of p53 function.
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PMID:Coactivator requirements for p53-dependent transcription in the yeast Saccharomyces cerevisiae. 1795 87

The peripheral nervous system is required for animals to detect and to relay environmental stimuli to central nervous system for the information processing. In Drosophila, the precise spatial and temporal expression of two proneural genes achaete (ac) and scute (sc), is necessary for development of the sensory organs. Here we present an evidence that the transcription co-repressor, dCtBP acts as a negative regulator of sensory organ prepattern. Loss of dCtBP function mutant exhibits ectopic sensory organs, while overexpression of dCtBP results in a dramatic loss of sensory organs. These phenotypes are correlated with mis-emerging of sensory organ precursors and perturbated expression of proneural transcription activator Ac. Mammalian CtBP-1 was identified via interaction with the consensus motif PXDLSX(K/R) of adenovirus E1A oncoprotein. We demonstrated that dCtBP binds directly to PLDLS motif of Drosophila Friend of GATA-1 protein, U-shaped and sharpens the adult sensory organ development. Moreover, we found that dCtBP mediates multivalent interaction with the GATA transcriptional activator Pannier and acts as a direct co-repressor of the Pannier-mediated activation of proneural genes. We demonstrated that Pannier genetically interacts with dCtBP-interacting protein HDAC1, suggesting that the dCtBP-dependent regulation of Pannier activity could utilize a repressive mechanism involving alteration of local chromatine structure.
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PMID:Drosophila C-terminal binding protein, dCtBP is required for sensory organ prepattern and sharpens proneural transcriptional activity of the GATA factor Pnr. 1877 87

Recently, the anti-tumor activity of N-myc downstream-regulated gene 2 (NDRG2) was elucidated, but the molecular mechanism of how NDRG2 works as a tumor suppressor is not well known. To determine the function of NDRG2 as a tumor suppressor, we established stable cell lines expressing NDRG2 protein or its mutant forms, and studied their effects on tumor cell growth. Interestingly, constitutive expression of wild-type NDRG2 induced the growth retardation of SW620 colon carcinoma cells. Introduction of NDRG2 into SW620 cells induced the decrease of c-Jun phosphorylation at Ser63, followed by the attenuation of activator protein-1 (AP-1) function as a transcriptional activator. Subsequently, the down-regulation of cyclin D1, which is known as a major target for AP-1 transcription activator, resulted in cell cycle arrest at G1/S phase. Additionally, treatment of NDRG2-siRNA on NDRG2-expressing cells has induced the recovery of c-Jun phosphorylation and cyclin D1 expression. Cell proliferation of those cells was also increased compared with untreated cells. NDRG2 mutants of which the phosphorylation sites at C-terminal region were removed by deletion or site-directed mutagenesis have shown no effect on cyclin D1 expression and could not induce cell growth retardation. In conclusion, NDRG2 modulates intracellular signals to control cell cycle through the regulation of cyclin D1 expression via phosphorylation pathway.
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PMID:NDRG2 suppresses cell proliferation through down-regulation of AP-1 activity in human colon carcinoma cells. 1884 21


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