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)

The Aspergillus nidulans amyR gene and its cDNA were cloned and sequenced. The genomic gene comprised 2,092 bp, interrupted by two short introns, and encoded a cys-6 zinc transcriptional activator (AMYR) of 662 amino acid residues with a calculated molecular mass of 72,862 Da. Disruption of the amyR gene caused defects in the utilization of maltose and starch and abolished expression of the taaG2 gene encoding A. oryzae Taka-amylase A, which is inducibly and abundantly expressed in the wild-type A. nidulans. Expression of the amyR gene was under the control of the carbon catabolite repressor, CREA. The growth defect of the malA1 mutant on maltose was complemented by the amyR gene; and the amyR gene derived from the mutant possessed a single mutation, from A to T, at position 1,483, resulting in a substitution of His478 to Leu. These results indicate that the amyR gene is identical to the genetically defined malA gene. AMYR possessed five domains (Zn and MH1-MH4) homologous to Mal63p, a transcriptional activator for the genes involved in maltose utilization in Saccharomyces cerevisiae. The His478 to Leu substitution lay within the MH3 domain, corresponding to the negative regulatory domain of Mal63p which relieves the inhibitory effect on the activation function in response to maltose.
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PMID:Characterization of the amyR gene encoding a transcriptional activator for the amylase genes in Aspergillus nidulans. 1131 1

CpG-binding protein is a transcriptional activator that exhibits a unique DNA binding specificity for unmethylated CpG motifs. CpG-binding protein contains a cysteine-rich CXXC domain that is conserved in DNA methyltransferase 1, methyl binding domain protein 1, and human trithorax. In vitro DNA binding assays reveal that CpG-binding protein contains a single DNA binding domain comprised of the CXXC domain and a short carboxyl extension. Specific mutation to alanine of individual conserved cysteine residues within the CXXC domain abolishes DNA binding activity. Denaturation/renaturation experiments in the presence of various metal cations demonstrate that the CXXC domain requires zinc for efficient DNA binding activity. Ligand selection of high affinity binding sites from a pool of degenerate oligonucleotides reveals that CpG-binding protein interacts with a variety of sequences that contains the CpG dinucleotide with a consensus binding site of (A/C)CpG(A/C). Mutation of the CpG motif(s) present within ligand-selected oligonucleotides ablates the interaction with CpG-binding protein, and mutation to thymine of the nucleotides flanking the CpG motifs reduces the affinity of CpG-binding protein. Hence, a CpG motif is necessary and sufficient to comprise a binding site for CpG-binding protein, although the immediate flanking sequence affects binding affinity.
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PMID:Identification and characterization of the DNA binding domain of CpG-binding protein. 1157 67

Little is known about the factors that control the specification of the mid-hindbrain domain (MHD) within the vertebrate embryonic neural plate. Because the head-trunk junction of the Drosophila embryo and the MHD have patterning similarities, we have searched for vertebrate genes related to the Drosophila head gap gene buttonhead (btd), which in the fly specifies the head-trunk junction. We report here the identification of a zebrafish gene which, like btd, encodes a zinc-finger transcriptional activator of the Sp-1 family (hence its name, bts1 for btd/Sp-related-1) and shows a restricted expression in the head. During zebrafish gastrulation, bts1 is transcribed in the posterior epiblast including the presumptive MHD, and precedes in this area the expression of other MHD markers such as her5, pax2.1 and wnt1. Ectopic expression of bts1 combined to knock-down experiments demonstrate that Bts1 is both necessary and sufficient for the induction of pax2.1 within the anterior neural plate, but is not involved in regulating her5, wnt1 or fgf8 expression. Our results confirm that early MHD development involves several genetic cascades that independently lead to the induction of MHD markers, and identify Bts1 as a crucial upstream component of the pathway selectively leading to pax2.1 induction. In addition, they imply that flies and vertebrates, to control the development of a boundary embryonic region, have probably co-opted a similar strategy: the restriction to this territory of the expression of a Btd/Sp-like factor.
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PMID:The zebrafish buttonhead-like factor Bts1 is an early regulator of pax2.1 expression during mid-hindbrain development. 1164 Dec 25

Metal-response element (MRE)-binding transcription factor-1 (MTF-1) is a zinc-regulated transcriptional activator of metallothionein (MT) genes in mammalian cells. The MRE-binding domain of MTF-1 (MTF-zf) has six canonical Cys(2)-His(2) zinc finger domains that are distinguished on the basis of their apparent affinities for zinc and their specific roles in MRE-binding. In this paper, pulsed alkylation of the zinc-liganding cysteine thiolate pairs with the sulfhydryl-specific alkylating reagent d(5)-N-ethylmaleimide (d(5)-NEM) is used as a residue-specific probe of the relative stabilities of the individual zinc finger coordination complexes in Zn(6) MTF-zf. A chase with excess H(5)-N-ethylmaleimide (H(5)-NEM) to fully derivatize MTF-zf concomitant with complete proteolysis, followed by MALDI-TOF mass spectrometry allows quantitation of the mole fraction of d(5),d(5)-, d(5),H(5)-, and H(5),H(5)-NEM derivatized peptides corresponding to each individual zinc finger domain as a function of d(5)-NEM pulse time. This experiment establishes the hierarchy of cysteine thiolate reactivity in MTF-zf as F5 > F6 >> F1 > F2 approximately F3 approximately F4. The apparent second-order rate of reaction of F1 thiolates is comparable to that determined for the DNA binding domain of Sp1, Zn(3) Sp1-zf, under identical solution conditions. The reactivities of all Cys residues in MTF-zf are significantly reduced when bound to an MREd-containing oligonucleotide. An identical experiment carried out with Zn(5) MTF-zf26, an MTF-zf domain lacking the N-terminal F1 zinc finger, reveals that MTF-zf26 binds to the MREd very weakly, and is characterized by strongly increased reactivity of nonadjacent F4 thiolates. These findings are discussed in the context of existing models for metalloregulation by MTF-1.
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PMID:Ratiometric pulsed alkylation/mass spectrometry of the cysteine pairs in individual zinc fingers of MRE-binding transcription factor-1 (MTF-1) as a probe of zinc chelate stability. 1173 99

The Gal4p family of yeast zinc cluster proteins comprises over 50 members that are putative transcriptional regulators. For example, Pdr1p and Pdr3p activate multidrug resistance genes by binding to pleiotropic drug response elements (PDREs) found in promoters of target genes such as PDR5, encoding a drug efflux pump involved in resistance to cycloheximide. However, the role of many zinc cluster proteins is unknown. We tested a panel of strains carrying deletions of zinc cluster genes in the presence of various drugs. One deletion strain (Deltardr1) was resistant to cycloheximide, whereas eight strains showed sensitivity to the antifungal ketoconazole or cycloheximide. Unnamed zinc cluster genes identified in our screen were called RDS for regulators of drug sensitivity. RNA levels of multidrug resistance genes such as PDR16, SNQ2, and PDR5 were decreased in many deletion strains. For example, cycloheximide sensitivity of a Deltastb5 strain was correlated with decreased RNA levels and promoter activity of the PDR5 gene. We tested if activation of PDR5 is mediated via a PDRE by inserting this DNA element in front of a minimal promoter linked to the lacZ gene. Strikingly, activity of the reporter was decreased in a Deltastb5 strain. The purified DNA binding domain of Stb5p bound to a PDRE in vitro. Mutations in the PDRE known to affect binding of Pdr1p/Pdr3p showed similar effects when assayed with Stb5p. These results strongly suggest that Stb5p is a transcriptional activator of multidrug resistance genes. Thus, we have identified new regulators of drug sensitivity in the family of zinc cluster proteins.
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PMID:New regulators of drug sensitivity in the family of yeast zinc cluster proteins. 1194 86

Acquisition of metals such as iron, copper, and zinc by the yeast Saccharomyces cerevisiae is tightly regulated. High affinity uptake systems are induced under metal-limiting conditions to maintain an adequate supply of these essential nutrients. Low affinity uptake systems function when their substrates are in greater supply. The FET4 gene encodes a low affinity iron and copper uptake transporter. FET4 expression is regulated by several environmental factors. In this report, we describe the molecular mechanisms underlying this regulation. First, we found that FET4 expression is induced in iron-limited cells by the Aft1 iron-responsive transcriptional activator. Second, FET4 is regulated by zinc status via the Zap1 transcription factor. We present evidence that FET4 is a physiologically relevant zinc transporter and this provides a rationale for its regulation by Zap1. Finally, FET4 expression is regulated in response to oxygen by the Rox1 repressor. Rox1 attenuates activation by Aft1 and Zap1 in aerobic cells. Derepression of FET4 may allow the Fet4 transporter to play an even greater role in metal acquisition under anaerobic conditions. Thus, Fet4 is a multisubstrate metal ion transporter under combinatorial control by iron, zinc, and oxygen.
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PMID:Combinatorial control of yeast FET4 gene expression by iron, zinc, and oxygen. 1209 98

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

Transgenic mouse models have provided evidence that activation of the zinc-finger transcription factor GLI1 by Hedgehog (Hh)-signalling is a key step in the initiation of the tumorigenic programme leading to Basal Cell Carcinoma (BCC). However, the downstream events underlying Hh/GLI-induced BCC development are still obscure. Using in vitro model systems to analyse the effect of Hh/GLI-signalling in human keratinocytes, we identified a positive feedback mechanism involving the zinc finger transcription factors GLI1 and GLI2. Expression of GLI1 in human keratinocytes induced the transcriptional activator isoforms GLI2alpha and GLI2beta. Both isoforms were also shown to be expressed at elevated levels in 21 BCCs compared to normal skin. Detailed time course experiments monitoring the transcriptional response of keratinocytes either to GLI1 or to GLI2 suggest that GLI1 is a direct target of GLI2, while activation of GLI2 by GLI1 is likely to be indirect. Furthermore, expression of either GLI2 or GLI1 led to an increase in DNA-synthesis in confluent human keratinocytes. Taken together, these results suggest an important role of the positive GLI1-GLI2 feedback loop in Hh-mediated epidermal cell proliferation.
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PMID:Human GLI2 and GLI1 are part of a positive feedback mechanism in Basal Cell Carcinoma. 1216 51

WT1 encodes a zinc finger transcription factor implicated in normal development and tumorigenesis. Germline mutation or deletion of WT1 results in a spectrum of abnormal kidney development, male-to-female intersex disorders, and predisposition to pediatric nephroblastoma, Wilms tumor. Initially thought to encode a transcriptional repressor, WT1-dependent functions are now more clearly linked to its property as a transcriptional activator of genes involved in renal development and sex determination. WT1 is expressed in 4 isoforms as a result of 2 alternative messenger RNA splicing events, the more significant of which encodes the 3 amino acids lysine, threonine, and serine (KTS) between zinc fingers 3 and 4. Although WT1 isoforms lacking KTS act as sequence-specific DNA binding factors, a large body of evidence now implicates the KTS-containing isoforms in RNA processing. In keeping with distinct biochemical mechanisms for these isoforms, genetic data from humans and mice point to separate but partially overlapping roles for WT1 (+KTS) and (-KTS) during genitourinary development. Recently, a hematopoietic model system has been used to study functional properties of WT1 in vitro. WT1 expression in primary hematopoietic cells leads to stage-specific effects that may be relevant to WT1-mediated tumor suppression.
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PMID:Regulation of gene expression by WT1 in development and tumorigenesis. 1221 8

In Streptomyces griseus, A-factor (2-isocapryloyl-3R-hydroxymethyl-gamma-butyrolactone) switches on aerial mycelium formation and secondary metabolite biosynthesis. An A-factor-dependent transcriptional activator, AdpA, activates multiple genes required for morphological development and secondary metabolism in a programmed manner. A region upstream of a zinc-containing metalloendopeptidase gene (sgmA) was found among the DNA fragments that had been isolated as AdpA-binding sites. The primary product of sgmA consisted of N-terminal pre, N-terminal pro, mature, and C-terminal pro regions. sgmA was transcribed in an AdpA-dependent manner, and its transcription was markedly enhanced at the timing of aerial mycelium formation. AdpA bound two sites in the region upstream of the sgmA promoter; one was at about nucleotide position -60 (A site) with respect to the transcriptional start point of sgmA, and the other was at about position -260 (B site), as determined by DNase I footprinting. Transcriptional analysis with mutated promoters showed that the A site was essential for the switching on of sgmA transcription and that the B site was necessary for the marked enhancement of transcription at the timing of aerial mycelium formation. Disruption of the chromosomal sgmA gene resulted in a delay in aerial hypha formation by half a day. SgmA is therefore suggested to be associated with the programmed morphological development of Streptomyces, in which this peptidase, perhaps together with other hydrolytic enzymes, plays a role in the degradation of proteins in substrate hyphae for reuse in aerial hypha formation.
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PMID:Control by A-factor of a metalloendopeptidase gene involved in aerial mycelium formation in Streptomyces griseus. 1237 36


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