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PubMed2006

Human Daxx-mediated repression of human cytomegalovirus gene expression correlates with a repressive chromatin structure around the major immediate early promoter.

Upon herpesvirus infection, viral DNA becomes associated with nuclear structures known as nuclear domain 10 (ND10). The role of ND10 during herpesvirus infection has long been contentious; data arguing for a role for ND10 in repression of infection have been countered by other data showing little effect of ND10 on virus infection. Here we show that knockdown of human Daxx (hDaxx) expression, an important component of ND10, prior to infection with human cytomegalovirus resulted in increased levels of viral immediate early RNA and protein expression and that this correlated with an increased association of the major immediate early promoter with markers of transcriptionally active chromatin. Conversely, we also show that stable overexpression of hDaxx renders cells refractory to cytomegalovirus immediate early gene expression. Intriguingly, this hDaxx-mediated repression appears to be restricted to cells stably overexpressing hDaxx and is not recapitulated in transient transfection assays. Finally, hDaxx-mediated repression of cytomegalovirus major immediate early gene expression was overcome by infecting at higher virus titers, suggesting that an incoming viral structural protein or viral DNA is responsible for overcoming the repression of viral gene expression in hDaxx superexpressing cells. These data suggest that hDaxx in ND10 functions at the site of cytomegalovirus genome deposition to repress transcription of incoming viral genomes and that this repression is mediated by a direct and immediate effect of hDaxx on chromatin modification around the viral major immediate early promoter.

Adaptor Proteins, Signal Transducing↗

PubMed1990

Determination of the cis sequence involved in catabolite repression of the Bacillus subtilis gnt operon; implication of a consensus sequence in catabolite repression in the genus Bacillus.

The mechanism underlying catabolite repression in Bacillus species remains unsolved. The gluconate (gnt) operon of Bacillus subtilis is one of the catabolic operons which is under catabolite repression. To identify the cis sequence involved in catabolite repression of the gnt operon, we performed deletion analysis of a DNA fragment carrying the gnt promoter and the gntR gene, which had been cloned into the promoter probe vector, pWP19. Deletion of the region upstream of the gnt promoter did not affect catabolite repression. Further deletion analysis of the gnt promoter and gntR coding region was carried out after restoration of promoter activity through the insertion of internal constitutive promoters of the gnt operon before the gntR gene (P2 and P3). These deletions revealed that the cis sequence involved in catabolite repression of the gnt operon is located between nucleotide positions +137 and +148. This DNA segment contains a sequence, ATTGAAAG, which may be implicated as a consensus sequence involved in catabolite repression in the genus Bacillus.

Bacillus subtilis↗

PubMed1993

Transcriptional repression by the Drosophila even-skipped protein: definition of a minimal repression domain.

We have used a transient expression assay employing Drosophila tissue culture cells to study the transcriptional repression activity of the homeo domain protein Even-skipped (Eve). Eve was found to repress all promoters that contained Eve-binding sites, including both TATA-containing and TATA-lacking minimal promoters, as well as promoters activated by several different classes of activator proteins. These findings suggest that the general transcription machinery can be a target of Eve. By analyzing properties of a variety of Eve mutants and chimeric fusion proteins, we have identified several features important for efficient repression. In addition to the DNA-binding domain, a potent repressor requires a repression domain, which can be as small as 27 residues. The minimal 57-residue Eve repression domain, as well as several others studied here, were all found to be proline rich and to contain a high percentage of hydrophobic residues. An intriguing feature of the strong repressors was that their DNA-binding activities, measured by gel retention assays with nuclear extracts, were significantly less than those of derivatives inactive in repression.

Amino Acid Sequence↗

PubMed2004

Identification of endogenous glucocorticoid repressed genes differentially regulated by a glucocorticoid receptor mutant able to separate between nuclear factor-kappaB and activator protein-1 repression.

Glucocorticoids are commonly used in the clinic, but long-term treatment is often associated with severe side effects. One way to reduce unwanted effects is to restrict glucocorticoid receptor (GR) signaling through defined pathways. In this study, we examine endogenous target genes regulated by a GR mutant that in contrast to the wild-type GR is unable to repress stimulated nuclear factor-kappaB (NF-kappaB) activity, whereas repression of activator protein-1 (AP-1) activity is maintained. This GR mutant (GRR488Q) harbors a point mutation in the second zinc finger of the DNA binding domain. Its ability to distinguish between NF-kappaB and AP-1 repression is defined using reporter genes regulated by both simple and natural promoters. The inability of GRR488Q to repress NF-kappaB was not related to its inability to activate target genes through a glucocorticoid response element. Furthermore, the discriminating property was observed in three different cell lines, suggesting that this is not a cell-specific effect. These results show that different receptor surfaces or mechanisms are involved in repression of NF-kappaB and AP-1, respectively. It is interesting that the GRR488Q still interacted physically with NF-kappaB. Gene expression profiling of human embryonic kidney 293 cells, which express the wild-type GR and the GRR488Q mutant allowed identification of endogenous genes preferentially repressed by GR interference with NF-kappaB activity. The genes differentially regulated by GRR488Q mutant versus the wild-type GR after 2 h of treatment seem mainly to be involved in control of transcription and cell growth. At 8 h, no such distinction could be seen.

Animals↗

PubMed1996

The human cut homeodomain protein can repress gene expression by two distinct mechanisms: active repression and competition for binding site occupancy.

By analogy with other homeodomain proteins conserved in evolution, mammalian Cut proteins are believed, as in Drosophila melanogaster, to play an important role in determining cell type specificity in several tissues. At the molecular level, Cut proteins appear to serve as transcriptional repressors. In this study, we have examined the mechanism by which the human Cut (hCut) protein down-regulates gene expression. The homeodomain and the three regions called Cut repeats are evolutionarily conserved and were previously shown to function as DNA binding domains. The carboxy-terminal region, although it does not show amino acid sequence homology per se, in all cases is enriched in alanine and proline residues, a distinctive feature of some transcriptional repression domains. Our results reveal two distinct modes of repression: competition for binding site occupancy and active repression. On one hand, the composite DNA binding domain formed by Cut repeat 3 and the Cut homeodomain was shown to bind to CCAAT and Sp1 sites within the tk gene promoter and to reduce gene expression, presumably by preventing activation by the corresponding transcription factors. On the other hand, the carboxy-terminal region of mammalian Cut proteins was found to function as an active repression domain in a distance-independent manner. We have further narrowed this activity to two subdomains that can independently repress activated transcription. Finally, we present a model to illustrate the two mechanisms by which Cut proteins repress gene expression.

Amino Acid Sequence↗

PubMed2000

HES-1 repression of differentiation and proliferation in PC12 cells: role for the helix 3-helix 4 domain in transcription repression.

HES-1 is a Hairy-related basic helix-loop-helix protein with three evolutionarily conserved regions known to define its function as a transcription repressor. The basic region, helix-loop-helix domain, and WRPW motif have been characterized for their molecular function in DNA binding, dimer formation, and corepressor recruitment, respectively. In contrast, the function conferred by a fourth conserved region, the helix 3-helix 4 (H-3/4) domain, is not known. To better understand H-3/4 domain function, we expressed HES-1 variants under tetracycline-inducible control in PC12 cells. As expected, the induced expression of moderate levels of wild-type HES-1 in PC12 cells strongly inhibited nerve growth factor-induced differentiation. This repression was dependent on the H-3/4 domain. Unexpectedly, expression of HES-1 also arrested cell growth, an effect that could be reversed upon down regulation of HES-1. Concomitant with growth arrest, there was a strong reduction in bromodeoxyuridine incorporation and PCNA protein levels, although not in cyclin D1 expression. Expression of a HES-1 protein carrying the H-3/4 domain, but not the WRPW domain, still partially inhibited both proliferation and differentiation. Transcription assays in PC12 cells directly demonstrated that the H-3/4 domain can mediate DNA-binding-dependent transcription repression, even in the absence of corepressor recruitment by the WRPW motif. HES-1 expression strongly repressed transcription of the p21(cip1) promoter, a cyclin-cyclin-dependent kinase inhibitor up regulated during NGF-induced differentiation, and the H-3/4 domain is necessary for this repression. Thus, the H-3/4 domain of HES-1 contributes to transcription repression independently of WRPW function, inhibits neurite formation, and facilitates two distinct and previously uncharacterized roles for HES-1: the inhibition of cell proliferation and the direct transcriptional repression of the NGF-induced gene, p21.

Animals↗

PubMed1969

Carabolite repression of the lac operon. Repression of translation.

1. Experiments were devised to show whether catabolite repression of beta-galactosidase synthesis operates at the level of transcription or of translation. Escherichia coli K12 was induced for a short period in non-repressing medium (glycerol-minimal medium), and transcription of the lac operon was terminated by either of two methods; glucose was then added as a source of the catabolite repressor during the subsequent translation of the accumulated beta-galactosidase messenger RNA. 2. When induced bacteria in glycerol medium were infected with T6 phage, which is known to halt transcription, the addition of glucose up to 3min. later diminished the yield of beta-galactosidase. 3. When induced bacteria in glycerol medium were removed from the inducer and resuspended in fresh medium (a process that is also known to halt transcription), the yield of enzyme was again diminished by the presence of glucose in the resuspension medium. 4. It is concluded that repression of beta-galactosidase synthesis can be brought about by the presence of glucose during the translation phase only. 5. In E. coli strain 300U the effect on translation was sufficient to account for almost all the catabolite repression of beta-galactosidase synthesis observed during exponential growth of the organism in glucose-minimal medium. In E. coli strain 200P, however, much more severe repression occurred during exponential growth, and an additional effect of glucose is postulated.

Coliphages↗

PubMedDate not supplied

The relationship between repressive and defensive coping styles and monocyte, eosinophile, and serum glucose levels: support for the opioid peptide hypothesis of repression.

The opioid peptide hypothesis of repression (1) predicts that repressive coping is associated with increased functional endorphin levels in the brain, which can result in decreased immunocompetence and hyperglycemia. In a random sample of 312 patients seen at a Yale Medical School outpatient clinic, significant main effects of coping style were found for monocyte and eosinophile counts, serum glucose levels, and self-reports of medication allergies. Specifically, repressive and defensive high-anxious patients demonstrated significantly decreased monocyte counts. In addition, repressive coping was associated with elevated eosinophile counts, serum glucose levels, and self-reported reactions to medications. This behavioral, immunologic, and endocrine profile is consistent with the opioid peptide hypothesis, which provides an integrative framework for relating the attenuated emotional experience of pain and distress characteristic of repressive coping with reduced resistance to infectious and neoplastic disease.

Adaptation, Psychological↗

PubMed1969

Repression of the histidine operon: effect of the first enzyme on the kinetics of repression.

Kinetic studies on repression of the enzymes for histidine biosynthesis in Salmonella typhimurium showed that, upon addition of histidine to a derepressed culture, the enzymes became repressed in a temporal sequence which corresponds with the positional sequence of the genes in the histidine operon. This serial pattern of repression occurred under conditions in which the feedback site of the first enzyme for histidine biosynthesis is intact. When this site was rendered nonfunctional the pattern of repression was changed so that all of the enzymes became repressed concomitantly. These results suggest that the first enzyme for histidine biosynthesis plays a hitherto unrecognized role in control of the histidine system.

Enzyme Repression↗

PubMed1991

Transcriptional repression by YY1, a human GLI-Krüppel-related protein, and relief of repression by adenovirus E1A protein.

A sequence within the transcription control region of the adeno-associated virus P5 promoter has been shown to mediate transcriptional activation by the adenovirus E1A protein. We report here that this same element mediates transcriptional repression in the absence of E1A. Two cellular proteins have been found to bind to overlapping regions within this sequence element. One of these proteins, YY1, is responsible for the repression. E1A relieves repression exerted by YY1 and further activates transcription through its binding site. A YY1-specific cDNA has been isolated. Its sequence reveals YY1 to be a zinc finger protein that belongs to the GLI-Krüppel gene family. The product of the cDNA binds to YY1 sites. When fused to the GAL4 DNA-binding domain, it is capable of repressing transcription directed by a promoter that contains GAL4-binding sites, and E1A proteins can relieve the repression and activate transcription through the fusion protein.

Adenoviridae↗

PubMed2001

A dominant repression domain in Tbx3 mediates transcriptional repression and cell immortalization: relevance to mutations in Tbx3 that cause ulnar-mammary syndrome.

Mutations in Tbx3 are responsible for ulnar-mammary syndrome (UMS), an autosomal dominant disorder affecting limb, tooth, hair, apocrine gland and genital development. Tbx3 is a member of a family of transcription factors that share a highly conserved DNA-binding domain known as the T-domain. UMS-causing mutations in Tbx3 have been found at numerous sites within the TBX3 gene, with many occurring downstream from the N-terminally located T-domain. The occurrence of mutations downstream of the DNA-binding domain raises the possibility that there exist important functional domains in C-terminal portions of the Tbx3 protein that affect its behavior as a transcription factor. To determine if and how such C-terminal mutations affect transcription we have mapped regions that confer transcriptional activity and nuclear localization and characterized the DNA binding properties of Tbx3. We find that Tbx3 binds the canonical Brachyury binding site as a monomer and represses transcription. We show that a key repression domain (RD1) resides in the Tbx3 C-terminus that can function as a portable repression domain. Most UMS-associated C-terminal mutants lack the RD1 and exhibit decreased or loss of transcriptional repression activity. In addition, we identify a domain responsible for nuclear localization of Tbx3 and show that two C-terminal mutants of Tbx3 have increased rates of protein decay. Finally, we show that Tbx3 can immortalize primary embryo fibroblasts and that the RD1 repression domain is required for this activity. Our results identify critical functional domains within the Tbx3 protein and facilitate interpretation of the functional consequences of present and future UMS mutations.

3T3 Cells↗

PubMed1989

Parallel changes in catabolite repression of haem biosynthesis and cytochromes in repression-resistant mutants of Saccharomyces cerevisiae.

Effects of three mutant genes, CAT1-2d, cat2-1 and hex2-3, on catabolite repression of mitochondrial cytochromes and the first two enzymes of haem biosynthesis were compared. The CAT1-2d mutation gave no resistance to glucose, whereas cat2-1 endowed both cytochromes and 5-aminolaevulinate dehydratase with resistance, but did not alter the effect of glucose on 5-aminolaevulinate synthase. The hex2-3 mutation caused repression resistance of cytochromes and of the two haem biosynthetic enzymes. hex2-3 strains also accumulated intracellular 5-aminolaevulinate. Co-inheritance of the latter traits, sensitivity to maltose inhibition and ability to grow on raffinose in the presence of 2-deoxyglucose, demonstrated that the pleiotropic phenotype is a function of the single gene hex2-3. Revertants which grew on maltose regained sensitivity to deoxyglucose and exhibited normal sensitivity of cytochromes and haem biosynthesis enzymes to repression. Addition of the hex1-18 mutation, which renders cytochromes resistant to repression, to a cat2-1 strain did not produce the same effect on 5-aminolaevulinate synthase as hex2-3. It is concluded that repression patterns of haem and cytochrome biosynthesis are substantially affected by hex2-3 and cat2-1 but not by CAT1-2d.

5-Aminolevulinate Synthetase↗

PubMed1999

Transcription of the pcbAB, pcbC and penDE genes of Penicillium chrysogenum AS-P-78 is repressed by glucose and the repression is not reversed by alkaline pHs.

Glucose repressed transcription of the penicillin biosynthesis genes pcbAB, pcbC and penDE when added at inoculation time to cultures of Penicillium chrysogenum AS-P-78 but it had little repressive effect when added at 12 h and no effect when added at 24 or 36 h. A slight increase in the expression of pcbC and penDE (and to a smaller extent of pcbAB) was observed in glucose-grown cultures at pH 6.8, 7.4 and 8.0 as compared with pH 6.2, but alkaline pHs did not override the strong repression exerted by glucose. Transcription of the actin gene used as control was not significantly affected by glucose or alkaline pHs. Repression by glucose of the three penicillin biosynthetic genes was also observed using the lacZ reporter gene coupled to each of the three promoters in monocopy transformants with the constructions integrated at the pyrG locus. Glucose repression of the three genes encoding enzymes of penicillin biosynthesis therefore appears to be exerted by a regulatory mechanism independent from pH regulation.

Acyltransferases↗

PubMed1998

Repression of transcription initiation by Escherichia coli FNR protein: repression by FNR can be simple.

Naturally occurring promoters that are repressed by the Escherichia coli FNR protein are complex. In this work, we have constructed a simple semi-synthetic promoter that is repressed by FNR binding to a single site that overlaps the promoter -35 element. Our results show that a single site for FNR is sufficient for effective repression. This semi-synthetic promoter provides a simple tool for monitoring FNR binding to target sites in the absence of its activation function. We have exploited this to study FNR mutants that are defective in repressing the ndh promoter, a complex naturally occurring promoter that is repressed by FNR.

Bacterial Proteins↗

PubMed1990

Transcriptional activation and repression by Fos are independent functions: the C terminus represses immediate-early gene expression via CArG elements.

The Fos-Jun complex has been shown to activate transcription through the regulatory element known as the AP-1 binding site. We show that Fos down regulates several immediate-early genes (c-fos, Egr-1, and Egr-2) after mitogenic stimulation. Specifically, we demonstrate that the target for this repression is a sequence of the form CC(A/T)6GG, also known as a CArG box. Whereas Fos bound to the AP-1 site through a domain rich in basic amino acids and associated with Jun via a leucine zipper interaction, mutant Fos proteins lacking these structures were still capable of causing repression. Furthermore, Jun neither enhanced nor inhibited down regulation by Fos. Critical residues required for repression are located within the C-terminal 27 amino acids of c-Fos, since v-Fos and C-terminal truncations of c-Fos did not down regulate. In addition, transfer of 180 c-Fos C-terminal amino acids to Jun conferred upon it the ability to repress. Finally, Fra-1, a Fos-related protein which has striking similarity to Fos in its C-terminal 40 amino acids, also down regulated Egr-1 expression. Thus, Fos is a transcriptional regulator that can activate or repress gene expression by way of two separate functional domains that act on distinct regulatory elements.

Animals↗

PubMed1996

Molecular mechanisms of COUP-TF-mediated transcriptional repression: evidence for transrepression and active repression.

COUP-TF, an orphan member of the nuclear receptor superfamily, has been proposed to play a key role in regulating organogenesis, neurogenesis, and cellular differentiation during embryonic development. Since heterodimierization is a common theme within the nuclear receptor superfamily and has been demonstrated to modulate transcriptional properties of heterodimeric partners via allosteric interactions, we have devised a strategy to examine the silencing function of COUP-TF in a heterodimeric context. We find that the intrinsic active repression function of COUP-TF is not affected by heterodimerization. Moreover, COUP-TF can transrepress the ligand-dependent activation of its heterodimeric partners without its own DNA binding site. Using receptor deletion mutants in transfection assays, we show that the region necessary for COUP-TF silencing function is not sufficient for its transrepression activity. Furthermore, our studies indicate that in addition to its active repression function, COUP-TF can repress several different types of activator-dependent transactivation. However, this active repression function of COUP-TF may be differentially regulated by some other activator(s). These studies provide new insights into the molecular mechanism(s) of COUP-TF-mediated repression.

Allosteric Regulation↗

PubMed2000

Rox1 mediated repression. Oxygen dependent repression in yeast.

For a large number of oxygen-regulated genes in the facultative aerobe, Saccharomyces cerevisiae, the presence of oxygen is sensed through the ability to use oxygen for heme biosynthesis. Heme induces the transcription of oxygen-induced genes and represses the transcription of hypoxic genes. Repression is mediated by the Rox1 protein in conjunction with the Ssn6/Tup1 general repression complex. The differential repression of hypoxic genes results from a combination of the tightness of Rox1 binding to the regulatory region of specific hypoxic genes and the presence or absence of binding sites for Mot3 which enhances Rox1 repression.

Aerobiosis↗

PubMed1988

An asparaginase of Aspergillus nidulans is subject to oxygen repression in addition to nitrogen metabolite repression.

Of five amidohydrolase activities subject to nitrogen metabolite repression in Aspergillus nidulans, L-asparaginase shows clearest evidence of also being subject to repression by atmospheric oxygen. Such oxygen repressibility is only evident under nitrogen metabolite derepressed conditions. Asparaginase levels are also considerably elevated by areA300, an altered function allele of the positive acting wide domain regulatory gene areA mediating nitrogen metabolite repression and are drastically reduced by loss of function mutations in areA. A. nidulans has two L-asparaginase enzymes and it has been shown by the use of appropriate mutants that these regulatory effects are exerted on the expression of that specified by the ahrA gene but probably not that specified by the apnA gene.

Aerobiosis↗