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PubMed2003

Perspective: repression of competition and the evolution of cooperation.

Repression of competition within groups joins kin selection as the second major force in the history of life shaping the evolution of cooperation. When opportunities for competition against neighbors are limited within groups, individuals can increase their own success only by enhancing the efficiency and productivity of their group. Thus, characters that repress competition within groups promote cooperation and enhance group success. Leigh first expressed this idea in the context of fair meiosis, in which each chromosome has an equal chance of transmission via gametes. Randomized success means that each part of the genome can increase its own success only by enhancing the total number of progeny and thus increasing the success of the group. Alexander used this insight about repression of competition in fair meiosis to develop his theories for the evolution of human sociality. Alexander argued that human social structures spread when they repress competition within groups and promote successful group-against-group competition. Buss introduced a new example with his suggestion that metazoan success depended on repression of competition between cellular lineages. Maynard Smith synthesized different lines of thought on repression of competition. In this paper, I develop simple mathematical models to illustrate the main processes by which repression of competition evolves. With the concepts made clear, I then explain the history of the idea. I finish by summarizing many new developments in this subject and the most promising lines for future study.

Animals↗
PubMed2004

Translation repression by an RNA polymerase elongation complex.

Bacteriophage lambda N and bacterial Nus proteins together with a unique site NUT in the leader of the early viral N gene transcript bind RNA polymerase (RNAP) and form a highly processive antitermination complex; N bound at NUT also represses N translation. In this study, we investigate whether N and NUT cause N translation repression as part of the antitermination complex by testing conditions that inhibit the formation of the N-modified transcription complex for their effect on N-mediated translation repression. We show that nus and nut mutations that in combination destabilize multiple interactions in the antitermination complex prevent N-mediated translation repression. Likewise, transcription of the nut-N region by T7 RNAP, which does not lead to the assembly of an effective antitermination complex when N is supplied, eliminates translation repression. We also demonstrate that a unique mutant beta subunit of RNAP reduces N-mediated translation repression, and that overexpression of transcription factor NusA suppresses this defect. We conclude that the N-modified RNAP transcription complex is necessary to repress N translation.

Base Sequence↗
PubMed2005

Integration of three signals at the Escherichia coli nrf promoter: a role for Fis protein in catabolite repression.

Expression from the Escherichia coli nrf operon promoter is activated by the anaerobically triggered transcription factor, FNR, and by the nitrate/nitrite ion-controlled response regulators, NarL or NarP, but is repressed by the IHF and Fis proteins. Here, we present in vitro studies on the nrf promoter, using permanganate footprinting to measure open complex formation, and DNase I footprinting to monitor binding of the different regulators and the interactions between them. Our results show that open complex formation is completely dependent on FNR and is enhanced by NarL, but is repressed by IHF or Fis. NarL counteracts repression by IHF but is unable to alter repression by Fis. These results suggest mechanisms by which nrf promoter activity is modulated by the different factors. Expression from the nrf promoter is known to be repressed in rich media, especially in the presence of glucose, but the molecular basis of this is not understood. Here, we show that this catabolite repression is relieved by mutations that weaken the DNA site for Fis, improve the DNA site for FNR or improve the promoter -10 or -35 elements. Hence, Fis protein is a major factor responsible for catabolite repression at the nrf promoter, and Fis can override activation by FNR and NarL or NarP.

Base Sequence↗
PubMed1991

Characterization of Hex2 protein, a negative regulatory element necessary for glucose repression in yeast.

The regulatory HEX2 gene plays an important role in glucose repression in the yeast Saccharomyces cerevisiae. The hex2 mutants have pleiotropic defects in the regulation of glucose-repressible enzymes, hexokinase PII synthesis and maltose uptake [Entian, K.-D. & Zimmermann, F.K. (1980) Mol. Gen. Genet. 177, 345-350]. The HEX2 gene encodes a protein of 114137 Da, deduced from its DNA sequence. There were no strong similarities to previously known genes. HEX2-lacZ fusions revealed a largely constitutive expression when repressing and non-repressing growth conditions were compared. Cellular fractionation studies indicated a nuclear localization of the Hex2 protein. The hex2 mutation was shown to be allelic to reg1, which releases galactose pathway enzymes from glucose repression [Matsumoto, K., Yoshimatsu, T. & Oshima, Y. (1983) J. Bacteriol. 153, 1405-1414]. Overexpression of HEX2 resulted in a 70% reduction of GAL1 expression under induced growth conditions. Our studies support the view that protein Hex2 is a negative regulatory element in glucose repression which may directly influence transcription, possibly by interaction with transcriptional factors. Deletion experiments identified a central core of Hex2, spanning only 492 out of 1026 amino acid residues, as mainly important for glucose repression. There are two strongly acidic regions within this part of the protein, their possible importance is discussed.

Alleles↗
PubMed2004

Differential effects of RU486 reveal distinct mechanisms for glucocorticoid repression of prostaglandin E release.

In A549 pulmonary cells, the dexamethasone- and budesonide-dependent repression of interleukin-1beta-induced prostaglandin E2 release was mimicked by the steroid antagonist, RU486. Conversely, whereas dexamethasone and budesonide were highly effective inhibitors of interleukin-1beta-induced cyclooxygenase (COX)/prostaglandin E synthase (PGES) activity and COX-2 expression, RU486 (<1 microm) was a poor inhibitor, but was able to efficiently antagonize the effects of dexamethasone and budesonide. In addition, both dexamethasone and RU486 repressed [3H]arachidonate release, which is consistent with an effect at the level of phospholipase A2 activity. By contrast, glucocorticoid response element-dependent transcription was unaffected by RU486 but induced by dexamethasone and budesonide, whilst dexamethasone- and budesonide-dependent repression of nuclear factor-kappaB-dependent transcription was maximally 30-40% and RU486 (<1 microm) was without significant effect. Thus, two pharmacologically distinct mechanisms of glucocorticoid-dependent repression of prostaglandin E2 release are revealed. First, glucocorticoid-dependent repression of arachidonic acid is mimicked by RU486 and, second, repression of COX/PGES is antagonized by RU486. Finally, whilst all compounds induced glucocorticoid receptor translocation, no role for glucocorticoid response element-dependent transcription is supported in these inhibitory processes and only a limited role for glucocorticoid-dependent inhibition of nuclear factor-kappaB in the repression of COX-2 is indicated.

Arachidonic Acid↗
PubMed1998

CcpB, a novel transcription factor implicated in catabolite repression in Bacillus subtilis.

Recent work has shown that in Bacillus subtilis catabolite repression of several operons is mediated by a mechanism dependent on DNA-binding protein CcpA complexed to a seryl-phosphorylated derivative of HPr [HPr(Ser-P)], the small phosphocarrier protein of the phosphoenolpyruvate-sugar phosphotransferase system. In this study, it was found that a transposon insertional mutation resulted in the partial loss of gluconate (gnt) and xylose (xyl) operon catabolite repression by glucose, mannitol, and sucrose. The transposon insertion was localized to a gene, designated ccpB, encoding a protein 30% identical to CcpA, and relief from catabolite repression was shown to be due to the absence of CcpB rather than to the absence of a protein encoded by a downstream gene within the same operon. The relative intensities of CcpA- and CcpB-mediated catabolite repression depended on growth conditions. On solid media, and when cells were grown in liquid media with little agitation, CcpB and CcpA both proved to function in catabolite repression. However, when cells were grown in liquid media with much agitation, CcpA alone mediated catabolite repression. Like CcpA, CcpB appears to exert its catabolite-repressing effect by a mechanism dependent on the presence of HPr(Ser-P).

Amino Acid Sequence↗
PubMed1999

The bvr locus of Listeria monocytogenes mediates virulence gene repression by beta-glucosides.

The beta-glucoside cellobiose has been reported to specifically repress the PrfA-dependent virulence genes hly and plcA in Listeria monocytogenes NCTC 7973. This led to the hypothesis that beta-glucosides, sugars of plant origin, may act as signal molecules, preventing the expression of virulence genes if L. monocytogenes is living in its natural habitat (soil). In three other laboratory strains (EGD, L028, and 10403S), however, the effect of cellobiose was not unique, and all fermentable carbohydrates repressed hly. This suggested that the downregulation of virulence genes by beta-glucosides is not a specific phenomenon but, rather, an aspect of a global regulatory mechanism of catabolite repression (CR). We assessed the effect of carbohydrates on virulence gene expression in a panel of wild-type isolates of L. monocytogenes by using the PrfA-dependent phospholipase C gene plcB as a reporter. Utilization of any fermentable sugar caused plcB repression in wild-type L. monocytogenes. However, an EGD variant was identified in which, as in NCTC 7973, plcB was only repressed by beta-glucosides. Thus, the regulation of L. monocytogenes virulence genes by sugars appears to be mediated by two separate mechanisms, one presumably involving a CR pathway and another specifically responding to beta-glucosides. We have identified in L. monocytogenes a 4-kb operon, bvrABC, encoding an antiterminator of the BglG family (bvrA), a beta-glucoside-specific enzyme II permease component of the phosphoenolpyruvate-sugar phosphotransferase system (bvrB), and a putative ADP-ribosylglycohydrolase (bvrC). Low-stringency Southern blots showed that this locus is absent from other Listeria spp. Transcription of bvrB was induced by cellobiose and salicin but not by arbutin. Disruption of the bvr operon by replacing part of bvrAB with an interposon abolished the repression by cellobiose and salicin but not that by arbutin. Our data indicate that the bvr locus encodes a beta-glucoside-specific sensor that mediates virulence gene repression upon detection of cellobiose and salicin. Bvr is the first sensory system found in L. monocytogenes that is involved in environmental regulation of virulence genes.

Bacterial Proteins↗
PubMed2000

Catabolite repression and induction of the Mg(2+)-citrate transporter CitM of Bacillus subtilis.

In Bacillus subtilis the citM gene encodes the Mg(2+)-citrate transporter. A target site for carbon catabolite repression (cre site) is located upstream of citM. Fusions of the citM promoter region, including the cre sequence, to the beta-galactosidase reporter gene were constructed and integrated into the amyE site of B. subtilis to study catabolic effects on citM expression. In parallel with beta-galactosidase activity, the uptake of Ni(2+)-citrate in whole cells was measured to correlate citM promoter activity with the enzymatic activity of the CitM protein. In minimal media, CitM was only expressed when citrate was present. The presence of glucose in the medium completely repressed citM expression; repression was also observed in media containing glycerol, inositol, or succinate-glutamate. Studies with B. subtilis mutants defective in the catabolite repression components HPr, Crh, and CcpA showed that the repression exerted by all these medium components was mediated via the carbon catabolite repression system. During growth on inositol and succinate, the presence of glutamate strongly potentiated the repression of citM expression by glucose. A reasonable correlation between citM promoter activity and CitM transport activity was observed in this study, indicating that the Mg(2+)-citrate uptake activity of B. subtilis is mainly regulated at the transcriptional level.

ATP-Binding Cassette Transporters↗
PubMed2002

Inactivation of cytochrome o ubiquinol oxidase relieves catabolic repression of the Pseudomonas putida GPo1 alkane degradation pathway.

Expression of the alkane degradation pathway encoded by the OCT plasmid of Pseudomonas putida GPo1 is regulated by two control systems. One relies on the transcriptional regulator AlkS, which activates expression of the pathway in the presence of alkanes. The other, which is a dominant global regulation control, represses the expression of the pathway genes when a preferred carbon source is present in the growth medium in addition to alkanes. This catabolite repression control occurs through a poorly characterized mechanism that ultimately regulates transcription from the two AlkS-activated promoters of the pathway. To identify the factors involved, a screening method was developed to isolate mutants without this control. Several isolates were obtained, all of which contained mutations that mapped to genes encoding cytochrome o ubiquinol oxidase, the main terminal oxidase of the electron transport chain under highly aerobic conditions. Elimination of this terminal oxidase led to a decrease in the catabolic repression observed both in rich Luria-Bertani medium and in a defined medium containing lactate or succinate as the carbon source. This suggests that catabolic repression could monitor the physiological or metabolic status by using information from the electron transport chain or from the redox state of the cell. Since inactivation of the crc gene also reduces catabolic repression in rich medium (although not that observed in a defined medium), a strain was generated lacking both the Crc function and the cytochrome o terminal oxidase. The two mutations had an additive effect in relieving catabolic repression in rich medium. This suggests that crc and cyo belong to different regulation pathways, both contributing to catabolic repression.

Alkanes↗
PubMed2003

pH-Dependent modulation of cyclic AMP levels and GadW-dependent repression of RpoS affect synthesis of the GadX regulator and Escherichia coli acid resistance.

Extreme acid resistance is a remarkable property of virulent and avirulent Escherichia coli. The ability to resist environments in which the pH is 2.5 and below is predicted to contribute significantly to the survival of E. coli during passage through the gastric acid barrier. One acid resistance system imports glutamate from acidic environments and uses it as a proton sink during an intracellular decarboxylation reaction. Transcription of the genes encoding the glutamate decarboxylases and the substrate-product antiporter required for this system is induced under a variety of conditions, including the stationary phase and a low pH. Acid induction during log-phase growth in minimal medium appears to occur through multiple pathways. We recently demonstrated that GadE, the essential activator of the genes, was itself acid induced. In this report we present evidence that there is a regulatory loop involving cross-repression of two AraC-like regulators, GadX and GadW, that can either assist or interfere with GadE activation of the gad decarboxylase and antiporter genes, depending on the culture conditions. Balancing cross-repression appears to be dependent on cAMP and the cAMP regulator protein (CRP). The control loop involves the GadX protein repressing the expression of gadW and the GadW protein repressing or inhibiting RpoS, which is the alternative sigma factor that drives transcription of gadX. CRP and cAMP appear to influence GadX-GadW cross-repression from outside the loop by inhibiting production of RpoS. We found that GadW represses the decarboxylase genes in minimal medium and that growth under acidic conditions lowers the intracellular cAMP levels. These results indicate that CRP and cAMP can mediate pH control over gadX expression and, indirectly, expression of the decarboxylase genes. Mutational or physiological lowering of cAMP levels increases the level of RpoS and thereby increases the production of GadX. Higher GadX levels, in turn, repress gadW and contribute to induction of the gad decarboxylase genes. The presence of multiple pH control pathways governing expression of this acid resistance system is thought to reflect different environmental routes to a low pH.

AraC Transcription Factor↗
PubMed2005

Importance of tetramer formation by the nitrogen assimilation control protein for strong repression of glutamate dehydrogenase formation in Klebsiella pneumoniae.

The nitrogen assimilation control protein (NAC) from Klebsiella pneumoniae is a very versatile regulatory protein. NAC activates transcription of operons such as hut (histidine utilization) and ure (urea utilization), whose products generate ammonia. NAC also represses the transcription of genes such as gdhA, whose products use ammonia. NAC exerts a weak repression at gdhA by competing with the binding of a lysine-sensitive activator. NAC also strongly represses transcription of gdhA (about 20-fold) by binding to two separated sites, suggesting a model involving DNA looping. We have identified negative control mutants that are unable to exert this strong repression of gdhA expression but still activate hut and ure expression normally. Some of these negative control mutants (e.g., NAC(86ter) and NAC(132ter)) delete the C-terminal domain, thought to be required for tetramerization. Other negative control mutants (e.g., NAC(L111K) and NAC(L125R)) alter single amino acids involved in tetramerization. In this work we used gel filtration to show that NAC(86ter) and NAC(L111K) are dimers in solution, even at high concentration (NAC(WT) is a tetramer). Moreover, using a combination of DNase I footprints and gel mobility shifts assays, we showed that when NAC(WT) binds to two adjacent sites on a DNA fragment, NAC(WT) binds as a tetramer that bends the DNA fragment significantly. NAC(L111K) binds to such a fragment as two independent dimers without inducing the strong bend. Thus, NAC(L111K) is a dimer in solution or when bound to DNA. NAC(L111K) (typical of the negative control mutants) is wild type for every other property tested: (i) it activates transcription at hut and ure; (ii) it competes with the lysine-sensitive activator for binding at gdhA; (iii) it binds to the same sites at the hut, ure, nac, and gdhA promoters as NAC(WT); (iv) the relative affinity of NAC(L111K) for these sites follows the same order as NAC(WT) (ure > gdhA > nac > hut); (v) it induces the same slight bend as dimers of NAC(WT); and (vi) its DNase I footprints at these sites are indistinguishable from those of NAC(WT) (except for features ascribed to tetramer formation). The only two phenotypes we know for negative control mutants of NAC are their inability to tetramerize and their inability to cause the strong repression of gdhA. Thus, we propose that in order for NAC(WT) to exert the strong repression, it must form a tetramer that bridges the two sites at gdhA (similar to other DNA looping models) and that the negative control mutants of NAC, which fail to tetramerize, cannot form this loop and thus fail to exert the strong repression at gdhA.

Amino Acid Substitution↗
PubMed2006

CcpA causes repression of the phoPR promoter through a novel transcription start site, P(A6).

The Bacillus subtilis PhoPR two-component system is directly responsible for activation or repression of Pho regulon genes in response to phosphate deprivation. The response regulator, PhoP, and the histidine kinase, PhoR, are encoded in a single operon with a complex promoter region that contains five known transcription start sites, which respond to at least two regulatory proteins. We report here the identification of another direct regulator of phoPR transcription, carbon catabolite protein A, CcpA. This regulator functions in the presence of glucose or other readily metabolized carbon sources. The maximum derepression of phoPR expression in a ccpA mutant compared to a wild-type stain was observed under excess phosphate conditions with glucose either throughout growth in a high-phosphate defined medium or in a low-phosphate defined medium during exponential growth, a growth condition when phoPR transcription is low in a wild-type strain due to the absence of autoinduction. Either HPr or Crh were sufficient to cause CcpA dependent repression of the phoPR promoter in vivo. A ptsH1 (Hpr) crh double mutant completely relieves phoPR repression during phosphate starvation but not during phosphate replete growth. In vivo and in vitro studies showed that CcpA repressed phoPR transcription by binding directly to the cre consensus sequence present in the promoter. Primer extension and in vitro transcription studies revealed that the CcpA regulation of phoPR transcription was due to repression of P(A6), a previously unidentified promoter positioned immediately upstream of the cre box. Esigma(A) was sufficient for transcription of P(A6), which was repressed by CcpA in vitro. These studies showed direct repression by CcpA of a newly discovered Esigma(A)-responsive phoPR promoter that required either Hpr or Crh in vivo for direct binding to the putative consensus cre sequence located between P(A6) and the five downstream promoters characterized previously.

Bacillus subtilis↗
PubMed2006

Human papillomavirus E7 repression in cervical carcinoma cells initiates a transcriptional cascade driven by the retinoblastoma family, resulting in senescence.

This work demonstrates a central role for the retinoblastoma (Rb) family in driving the transcriptional program of induced and replicative senescence. HeLa cervical carcinoma cells rapidly undergo senescence when the human papillomavirus (HPV) type 18 E7 gene in these cells is repressed by the bovine papillomavirus (BPV) E2 protein. This senescence response requires the endogenous Rb pathway but not the p53 pathway. Microarray analysis 6 days after BPV E2 introduction into HeLa cells identified 224 cellular genes induced by E7 repression and 354 repressed genes. Many repressed genes were involved in cell cycle progression, and numerous induced genes encoded lysosomal proteins. These gene expression changes were blocked by constitutive expression of the wild-type HPV16 E7 or adenovirus E1A gene, but not by E7 or E1A mutants defective for Rb binding. Short hairpin RNAs targeting the Rb family also inhibited these gene expression changes and blocked senescence. Therefore, surprisingly, the transcriptional response to BPV E2 expression was entirely dependent on E7 repression and activation of the Rb family, and the BPV E2 protein did not directly affect the expression of cellular genes. Activation of the Rb family repressed E2F-responsive genes and stimulated transcriptional activators, thereby mobilizing multiple signals, such as repression of B-MYB and DEK, that were independently sufficient to induce senescence. There was extensive overlap between the transcriptional profiles of senescent, late-passage primary human fibroblasts and senescent cervical carcinoma cells, suggesting that this Rb family-mediated transcriptional cascade also plays a central role in replicative senescence.

Animals↗
PubMed1995

Repression in vitro, by human adenovirus E1A protein domains, of basal or Tat-activated transcription of the human immunodeficiency virus type 1 long terminal repeat.

Human adenovirus E1A proteins can repress the expression of several viral and cellular genes. By using a cell-free transcription system, we demonstrated that the gene product of the E1A 12S mRNA, the 243-residue protein E1A243R, inhibits basal transcription from the human immunodeficiency virus type 1 (HIV-1) long terminal repeat (LTR). The HIV-1 transactivator protein Tat greatly stimulates transcription from the viral promoter in vitro. However, E1A243R can repress Tat-activated transcription in vitro. Strong repression of both basal and Tat-activated transcriptions requires only E1A N-terminal amino acid residues 1 to 80. Deletion analysis showed that E1A N-terminal amino acids 4 to 25 are essential for repression, whereas amino acid residues 30 to 49 and 70 to 80 are dispensable. Transcriptional repression by E1A in the cell-free transcription system is promoter specific, since under identical conditions, transcription of the adenovirus major late promoter and the Rous sarcoma virus LTR promoter was unaffected. The repression of transcription by small E1A peptides in vitro provides an assay for investigation of molecular mechanisms governing E1A-mediated repression of both basal and Tat-activated transcriptions of the HIV-1 LTR promoter.

Adenovirus E1A Proteins↗
PubMed1995

Transcriptional repression of the c-fos gene by YY1 is mediated by a direct interaction with ATF/CREB.

Transcriptional activation of the mouse c-fos gene by the adenovirus 243-amino-acid E1A protein requires a binding site for transcription factor YY1 located at -54 of the c-fos promoter. YY1 normally represses transcription of c-fos, and this repression depends on the presence of a cyclic AMP (cAMP) response element located immediately upstream of the -54 YY1 DNA-binding site. This finding suggested that the mechanism of transcriptional repression by YY1 might involve a direct interaction with members of the ATF/CREB family of transcription factors. In vitro and in vivo binding assays were used to demonstrate that YY1 can interact with ATF/CREB proteins, including CREB, ATF-2, ATFa1, ATFa2, and ATFa3. Structure-function analyses of YY1 and ATFa2 revealed that the C-terminal zinc finger domain of YY1 is necessary and sufficient for binding to ATFa2 and that the basic-leucine zipper region of ATFa2 is necessary and sufficient for binding to YY1. Overexpression of YY1 in HeLa cells resulted in repression of a mutant c-fos chloramphenicol acetyltransferase reporter that lacked binding sites for YY1, suggesting that repression can be triggered through protein-protein interactions with ATF/CREB family members. Consistent with this finding, repression was relieved upon removal of the upstream cAMP response element. These data support a model in which YY1 binds simultaneously to its own DNA-binding site in the c-fos promoter and also to adjacent DNA-bound ATF/CREB proteins in order to effect repression. They further suggest that the ATF/CREB-YY1 complex serves as a target for the adenovirus 243-amino-acid E1A protein.

Activating Transcription Factor 2↗
PubMed1995

Relationship between TATA-binding protein and herpes simplex virus type 1 ICP4 DNA-binding sites in complex formation and repression of transcription.

The herpes simplex virus (HSV) regulatory protein, infected-cell polypeptide 4 (ICP4), represses the transcription of promoters that have binding sites for ICP4 located near the transcription start site. It also been shown that ICP4 binds such promoter DNA cooperatively with the TATA-binding protein (TBP) and TFIIB to form a tripartite protein-DNA complex (C. Smith, P. Bates, R. Rivera-Gonzales, B. Gu, and N. A. DeLuca, J. Virol. 67:4676-4687, 1993). In this study, we analyzed the effects of position and orientation of the ICP4-binding site relative to the TATA box in the ICP4 promoter on transcriptional repression by ICP4 and on the ability of ICP4 to form tripartite complexes with TBP and TFIIB. The results of theis parallel study provide a strong correlation between tripartite complex formation and repression. Both tripartite-complex formation and transcriptional repression were efficient when the ICP4-binding site was downstream of the TATA box, within a short distance and in proper orientation. In addition, both tripartite-complex formation and repression were partially sensitive to the stereoaxial positioning of the ICP4-binding site relative to the TATA box. As a preliminary characterization of the tripartite complex, circular permutation analysis was performed to assess the distortion of the proximal promoter region in the tripartite complex. As previously reported, both TBP and ICP4 independently could bend DNA and the relative magnitude by which each of these proteins bent DNA in the tripartite complex was preserved. The results of this study suggest that the formation of tripartite complexes on a promoter is part of the mechanism of repression and that simple blocking as a sole result of ICP4 binding is not sufficient for full repression.

Base Sequence↗
PubMed1996

Repression of the alpha0 gene by ICP4 during a productive herpes simplex virus infection.

During a productive infection by herpes simplex virus type 1 (HSV-1), ICP4, the major regulatory protein encoded by the alpha4 gene, binds to its transcription initiation site and represses the accumulation of alpha4 RNA. Evidence suggests that the degree of repression by ICP4 is a function of the absolute distance of an ICP4 binding site 3' from a TATA box. However, repression of HSV-1 gene expression by ICP4 through binding sites located 5' of TATA boxes, as in the case of the alpha0 gene, has not been adequately addressed. To this end, recombinant alpha0 promoters with various arrays of ICP4 binding sites flanking the alpha0 TATA box were constructed and recombined into the HSV-1 genome. Our results demonstrate the following. (i) Destruction of the endogenous alphaO ICP4 binding site, located 5' of the TATA box, results in derepression of alpha0 protein and RNA accumulation in infected Vero cells. (ii) The degree of alpha0 derepression is equivalent to that reported for the alpha4 gene following destruction of the ICP4 binding site at the alpha4 mRNA cap site in HSV-1. (iii) Introduction of an ICP4 binding site at the alpha0 mRNA cap site represses the accumulation of alpha0 RNA greater than threefold relative to the wild type. (iv) Changes in the abundance of alpha0 protein and RNA in infected cells do not affect replication or growth of HSV-1 in tissue culture. Our findings are consistent with the conclusion that alpha0 transcription is repressed by ICP4. These results demonstrate that repression by ICP4 can occur through binding sites located 5' of virus gene TATA boxes in HSV-1. Thus, models addressing repression of HSV-1 gene expression by ICP4 should incorporate the role of binding sites located 5', as well as 3', of virus gene TATA boxes.

Animals↗
PubMed1997

Epstein-Barr virus EBNA3C represses Cp, the major promoter for EBNA expression, but has no effect on the promoter of the cell gene CD21.

EBNA3C is a potent repressor of transcription when bound to DNA as a fusion with the DNA binding domain (DBD) of GALA. A survey of promoters has revealed that the wild-type, unfused EBNA3C can specifically repress expression from reporter plasmids containing the Epstein-Barr virus Cp latency-associated promoter. Repression of Cp activity required amino acids 207 to 368, which encompasses a region resembling a basic DBD adjacent to a leucine zipper DNA binding motif and a site which binds to the cellular factor CBF1/RBP-Jkappa. However, amino acids 207 to 368 are dispensable when the protein is bound to DNA as a fusion with the GAL4 DBD, thus implicating this region in DNA binding. Mutation of the CBF1/RBP-Jkappa binding site in EBNA3C abrogated repression, strongly suggesting that CBF1/RBP-Jkappa is necessary for targeting the viral protein to Cp. Consistent with this result, mutation of the EBNA2 response element (a CBF1/RBP-Jkappa binding site) in Cp also prevented significant repression. In addition, amino acids 346 to 543, which were previously defined as important for the repressor activity of the GAL4-EBNA3C fusion proteins, also appear to be necessary for the repression of Cp. Since repression by these fusions was not observed in all cell types, it seems likely that EBNA3C either depends on a corepressor which may interact with amino acids 346 to 543 or is modified in a cell-specific manner in order to repress. These data are consistent with EBNA3C contributing to the regulation of EBNA expression in latently infected B cells through CBF1/RBP-Jkappa and another factor, but this need not directly involve EBNA2. Finally, although it has been reported that EBNA3C can upregulate CD21 in some B cells, we were unable to demonstrate any effect of EBNA3C on reporter plasmids which contain the CD21 promoter.

B-Lymphocytes↗