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At least 991 records · Page 55Linked to original sources
PubMed1994

Engrailed-mediated repression of Ultrabithorax is necessary for the parasegment 6 identity in Drosophila.

The homeotic genes of Drosophila are expressed in overlapping domains along the anterior-to-posterior axis and specify the distinct morphological patterns of each parasegment. Within single parasegments, the levels of homeotic gene expression are often modulated, in part because of cross-regulation by other homeotic gene products. However, the functional significance of different levels of homeotic gene expression is unclear. Here modulations in Ultrabithorax (Ubx) expression within parasegment 6 are examined. Specifically, Ubx is shown to be down-regulated in the posterior compartment of this parasegment by engrailed (en). The significance of Ubx repression by en was demonstrated by characterizing the expression of the Ubx target gene, Distal-less (Dll). In the posterior compartment of parasegment 6, Dll is normally expressed in a small cluster of cells. If Ubx is expressed uniformly via a heat-shock promoter, Dll is inappropriately repressed in these posterior compartment cells. In the anterior compartment of parasegment 6, Dll is normally repressed by high levels of Ubx. However, if en is expressed uniformly via a heat-shock promoter, Ubx is repressed and Dll is derepressed. Because Dll is required for the development of larval sensory structures, these results demonstrate that en-mediated repression of Ubx in the posterior compartment is necessary for the morphology of parasegment 6. Thus, different levels of homeotic gene expression can be important for their segmental patterning functions.

Animals↗
PubMed2001

Groucho mediates a Ci-independent mechanism of hedgehog repression in the anterior wing pouch.

Groucho (Gro) is the founding member of a family of transcriptional co-repressors that are recruited by a number of different transcription factors. Drosophila has a single gro gene, whose loss of function affects processes ranging from sex determination to embryonic patterning and neuroblast specification. We have characterized a function of Gro in imaginal development, namely the repression of hedgehog (hh) in anterior wing pouch cells. hh encodes a secreted morphogen with potent patterning activities. In Drosophila thoracic appendages (legs, wings, halteres), hh is expressed in posterior compartments and induces the anteroposterior (AP) pattern organizer in the cells across the AP boundary. hh is repressed in anterior compartments at least partly via Ci[rep], a form of the multifunctional transcription factor Cubitus interruptus (Ci). We show that cells in the wing primordium close to the AP boundary need gro activity to maintain repression of hh transcription, whereas in more anterior cells gro is dispensable. This repressive function of Gro does not appear to be mediated by Ci[rep]. Analysis of mutant gro transgenes has revealed that the Q and WD40 domains are both necessary for hh repression. Yet, deletion of the WD40 repeats does not always abolish Gro activity. Our findings provide new insights both into the mechanisms of AP patterning of the wing and into the function of Gro.

Animals↗
PubMed2002

Anterior repression of a Drosophila stripe enhancer requires three position-specific mechanisms.

The striped expression pattern of the pair-rule gene even skipped (eve) is established by five stripe-specific enhancers, each of which responds in a unique way to gradients of positional information in the early Drosophila embryo. The enhancer for eve stripe 2 (eve 2) is directly activated by the morphogens Bicoid (Bcd) and Hunchback (Hb). As these proteins are distributed throughout the anterior half of the embryo, formation of a single stripe requires that enhancer activation is prevented in all nuclei anterior to the stripe 2 position. The gap gene giant (gt) is involved in a repression mechanism that sets the anterior stripe border, but genetic removal of gt (or deletion of Gt-binding sites) causes stripe expansion only in the anterior subregion that lies adjacent to the stripe border. We identify a well-conserved sequence repeat, (GTTT)(4), which is required for repression in a more anterior subregion. This site is bound specifically by Sloppy-paired 1 (Slp1), which is expressed in a gap gene-like anterior domain. Ectopic Slp1 activity is sufficient for repression of stripe 2 of the endogenous eve gene, but is not required, suggesting that it is redundant with other anterior factors. Further genetic analysis suggests that the (GTTT)(4)-mediated mechanism is independent of the Gt-mediated mechanism that sets the anterior stripe border, and suggests that a third mechanism, downregulation of Bcd activity by Torso, prevents activation near the anterior tip. Thus, three distinct mechanisms are required for anterior repression of a single eve enhancer, each in a specific position. Ectopic Slp1 also represses eve stripes 1 and 3 to varying degrees, and the eve 1 and eve 3+7 enhancers each contain GTTT repeats similar to the site in the eve 2 enhancer. These results suggest a common mechanism for preventing anterior activation of three different eve enhancers.

Animals↗
PubMed2004

pRb, Myc and p53 are critically involved in SV40 large T antigen repression of PDGF beta-receptor transcription.

The expression of the PDGF beta-receptor is tightly regulated during a normal cell cycle. c-Myc and p73alpha repress transcription of the receptor through interaction with NF-Y. In ST15A cells which stably express the temperature-sensitive SV40 large T antigen (LT) the receptor expression and ligand binding decreased under the permissive condition. Transient expression of the LT, but not small t, decreased the endogenous receptor expression at mRNA and protein levels in NIH3T3 cells but not in the myc-null HO15.19 cells. The wild-type LT, but not the various pRb or p53 binding defective LT mutants, represses the PDGF beta-receptor promoter activity. Moreover, the inability of the LT-mediated repression in the myc-null cells, the Rb-null 3T3 cells, and the Saos-2 cells lacking pRb and p53, indicates that Myc, pRb and p53 are all necessary elements. PDGF beta-receptor promoter-luciferase assays revealed that the CCAAT motif is important for the repression. Furthermore, p53 was found to increase the promoter activity mainly via the upstream Sp1 binding sites together with the CCAAT motif in the NIH 3T3 cells. This was confirmed by Schneider's Drosophila line (SL2) cells deficient in both endogenous NF-Y and Sp1. Chromatin immunoprecipitation using ST15A cells revealed that both LT and p53 bound the PDGF beta-receptor promoter and the binding of p53 diminished when LT was expressed in the permissive condition. However, LT binds the promoter in the absence of pRb and p53 in Saos-2 cells stably expressing LT. These results suggest that LT binds the promoter and interferes with NF-Y and Sp1 to repress it in the presence of Myc, pRb and p53.

Amino Acid Motifs↗
PubMed2001

Mechanism for the transcriptional repression by c-Myc on PDGF beta-receptor.

c-Myc plays a key role in the cell cycle dependent control of the PDGF beta-receptor mRNA. The mouse platelet-derived growth factor (PDGF) beta-receptor promoter contains a CCAAT motif, and NF-Y plays an essential role in its transcription. Coexpression of c-Myc represses PDGF beta-receptor luciferase reporter activity, and the CCAAT motif in the promoter is indispensable for this repression. Here we show that c-Myc binds NF-Y subunits, YB and YC, by immunoprecipitation from cotransfected COS-1 cells. The in vitro-translated c-Myc also binds the glutathione S-transferase (GST)-NF-YB fusion protein and GST-NF-YC, but not GST-NF-YA. The most C-terminal region of HAP domains of NF-YB and NF-YC, and the Myc homology boxes, but not the C-terminal bHLHZip domain, are indispensable for the coimmunoprecipitation, and also for the repression of PDGF beta-receptor. c-Myc binds NF-Y complex without affecting the efficiency of NF-Y binding to DNA. However, the expression of Myc represses the transcriptional activation of NF-YC when fused to the GAL4 DNA binding domain. Furthermore, this repression was seen only when Myc homology boxes are present, and NF-YC contains the c-Myc binding region.

3T3 Cells↗
PubMed2007

Wingless directly represses DPP morphogen expression via an armadillo/TCF/Brinker complex.

BACKGROUND: Spatially restricted morphogen expression drives many patterning and regeneration processes, but how is the pattern of morphogen expression established and maintained? Patterning of Drosophila leg imaginal discs requires expression of the DPP morphogen dorsally and the wingless (WG) morphogen ventrally. We have shown that these mutually exclusive patterns of expression are controlled by a self-organizing system of feedback loops that involve WG and DPP, but whether the feedback is direct or indirect is not known. METHODS/FINDINGS: By analyzing expression patterns of regulatory DNA driving reporter genes in different genetic backgrounds, we identify a key component of this system by showing that WG directly represses transcription of the dpp gene in the ventral leg disc. Repression of dpp requires a tri-partite complex of the WG mediators armadillo (ARM) and dTCF, and the co-repressor Brinker, (BRK), wherein ARM.dTCF and BRK bind to independent sites within the dpp locus. CONCLUSIONS/SIGNIFICANCE: Many examples of dTCF repression in the absence of WNT signaling have been described, but few examples of signal-driven repression requiring both ARM and dTCF binding have been reported. Thus, our findings represent a new mode of WG mediated repression and demonstrate that direct regulation between morphogen signaling pathways can contribute to a robust self-organizing system capable of dynamically maintaining territories of morphogen expression.

Animals↗
PubMed2025

Widespread release of translational repression across Plasmodium's host-to-vector transmission event.

Malaria parasites must respond quickly to environmental changes, including during their transmission between mammalian and mosquito hosts. Therefore, female gametocytes proactively produce and translationally repress mRNAs that encode essential proteins that the zygote requires to establish a new infection. While the release of translational repression of individual mRNAs has been documented, the details of the global release of translational repression have not. Moreover, changes in the spatial arrangement and composition of the DOZI/CITH/ALBA complex that contribute to translational control are also not known. Therefore, we have conducted the first quantitative, comparative transcriptomics and DIA-MS proteomics of Plasmodium parasites across the host-to-vector transmission event to document the global release of translational repression. Using female gametocytes and zygotes of P. yoelii, we found that ~200 transcripts are released for translation soon after fertilization, including those encoding essential functions. Moreover, we identified that many transcripts remain repressed beyond this point. TurboID-based proximity proteomics of the DOZI/CITH/ALBA regulatory complex revealed substantial spatial and/or compositional changes across this transmission event, which are consistent with recent, paradigm-shifting models of translational control. Together, these data provide a model for the essential translational control mechanisms that promote Plasmodium's efficient transmission from mammalian host to mosquito vector.

Animals↗
PubMed2004

Repression of the melanocyte-specific promoter of the microphthalmia-associated transcription factor by the adenoviral E1A 12S oncoprotein.

Melanocytes express MITF, which is crucial for the development of the melanocyte lineage and is overexpressed in malignant melanomas. Adenoviral E1A protein-expressing melanocytes are unpigmented, with the expression of MITF being silenced. We tested here a direct repression of the melanocyte-specific MITF promoter by E1A and its mutants. We found that the extreme N-terminus and conserved region 1 are required for repression. In contrast, the motif in conserved region 2 (a.a. 122-126), as well as amino acids 26-35 at the N-terminus, are not necessary. As these two later motifs mediate E1A binding to the retinoblastoma protein or to the transcriptional co-activator TRRAP, respectively, and are important for transformation by E1A in cooperation with other oncogenes, the results suggest that the transformation-defective E1A can still efficiently repress the MITF promoter. The CREB binding motif-mutated promoter had lower activity, but was also repressed by the same E1A mutants in human melanoma cells. The E1A protein is known to also exert an antitumour activity, which is associated with its transcription repression function and the ability to induce apoptosis, and is a potential antimelanoma agent. Since recent data suggest that MITF may be a survival factor for melanoma cells, the E1A mutants described here might constitute a good targeting agent for antimelanoma therapy.

Adenovirus E1A Proteins↗
PubMed2006

Transcription factor FOXM1c is repressed by RB and activated by cyclin D1/Cdk4.

The proliferation-stimulating transactivator FOXM1c (MPP2) is repressed by RB and activated by cyclin D1/Cdk4 and therefore behaves like E2F. Despite its strong transactivation domain, FOXM1c is kept almost inactive by two different inhibitory domains, the N-terminus and the central domain. The tumor suppressor RB binds directly to the central domain of FOXM1c and thereby indirectly represses the transactivation domain, so that the central domain of FOXM1c functions as an RB-recruiting negative-regulatory domain. Cyclin D1/Cdk4 releases FOXM1c from this repression by RB and from the repression by its own inhibitory N-terminus, thereby strongly activating FOXM1c. However, cyclin D1/Cdk4 does not directly affect the transactivation domain or the DNA-binding domain. By phosphorylation of RB, but not FOXM1c, cyclin D1/Cdk4 interrupts their direct interaction and thus abrogates the repression of FOXM1c by RB. Cyclin D1/Cdk4 also eliminates the inhibition of the transactivation domain by the N-terminus of FOXM1c, probably by interruption of their direct interaction. Consequently, the G1-phase proliferation signal cyclin D1/Cdk4 converts FOXM1c from an almost inactive form into a strong transactivator in G1-phase, i.e., just at the time point at which the transcriptional activity of FOXM1 is required for stimulation of the G1/S-transition.

Animals↗
PubMed2004

Redundant roles for histone H3 N-terminal lysine residues in subtelomeric gene repression in Saccharomyces cerevisiae.

The transcription of genes located in subtelomeric regions of yeast chromosomes is repressed relative to the rest of the genome. This repression requires wild-type nucleosome levels but not the telomere silencing factors Sir2, Sir3, Sir4, and Rap1. Subtelomeric heterochromatin is characterized by the absence of acetylation or methylation of histone H3 lysine residues, but it is not known whether histone H3 hypoacetylation or hypomethylation is a prerequisite for the establishment of subtelomeric heterochromatin. We have systematically mutated the N-terminal tails of histone H3 and H4 in Saccharomyces cerevisiae and characterized the effects each mutant has on genome-wide expression. Our results show that subtelomeric transcriptional repression is dependent on the histone H3 N-terminal domain, but not the histone H4 N-terminal domain. Mutating lysine-4, lysine-9, lysine-14, lysine-18, lysine-23, and lysine-27 to glycine in histone H3 is also sufficient to significantly reduce subtelomeric gene repression. Individual histone H3 lysine mutations, however, have little effect on subtelomeric gene repression or genome-wide expression, indicating that these six lysine residues have redundant functions. We propose that acetylation and methylation of histone H3 N-terminal lysine residues act as redundant mechanisms to demarcate regions of euchromatin from heterochromatin.

Acetylation↗
PubMed2005

YY-1 and c-Jun transcription factors participate in the repression of the human involucrin promoter.

The human involucrin gene, which encodes a precursor of the keratinocyte cornified layer, is strongly expressed in response to differentiation stimuli. Earlier studies suggested that YY1 and components of the AP-1 family might participate in the silencing of involucrin in proliferating keratinocytes. This study shows that overexpression of either YY1 or c-Jun represses transcription of the human involucrin gene in multiplying keratinocytes. Transient overexpression and site-directed mutagenesis experiments of the involucrin 5'-non-coding region (5'-NCR) confirmed that YY1 and c-Jun repress involucrin transcription. This repression involves the distal zinc fingers of YY1 protein and the DNA binding and leucine zipper domains of c-Jun. The results with protein pull-down experiments are consistent with the hypothesis that interaction of YY1 with c-Jun is an important mechanism for involucrin repression. Cotransfection of YY1 modified the stimulatory function of mutant c-Jun proteins independently of their DNA binding capacity suggesting that interactions may be more complex in vivo. Additionally, c-Jun protein levels are affected by differentiation stimuli indicating the importance of c-Jun in the YY1 repression pathway. Thus YY1 and c-Jun have an important role in epidermal differentiation by negatively regulating the human involucrin gene.

5' Untranslated Regions↗
PubMed2000

Repression of IL-2 promoter activity by the novel basic leucine zipper p21SNFT protein.

IL-2 is the major autocrine and paracrine growth factor produced by T cells upon T cell stimulation. The inducible expression of IL-2 is highly regulated by multiple transcription factors, particularly AP-1, which coordinately activate the promoter. Described here is the ability of the novel basic leucine zipper protein p21SNFT to repress AP-1 activity and IL-2 transcription. A detailed analysis of the repression by p21SNFT repression on the IL-2 promoter distal NF-AT/AP-1 site demonstrates that it can bind DNA with NF-AT and Jun, strongly suggesting that it represses NF-AT/AP-1 activity by competing with Fos proteins for Jun dimerization. The importance of this repression is that p21SNFT inhibits the trans-activation potential of protein complexes that contain Jun, thereby demonstrating an additional level of control for the highly regulated, ubiquitous AP-1 transcription factor and the IL-2 gene.

Basic-Leucine Zipper Transcription Factors↗
PubMed2004

Localization of the domains in Runx transcription factors required for the repression of CD4 in thymocytes.

The runt family transcription factors Runx1 and Runx3 are expressed in developing murine thymocytes. We show that enforced expression of full-length Runx1 in CD4(-)CD8(-) thymocytes results in a profound suppression of immature CD4/CD8 double-positive thymocytes and mature CD4 single-positive thymocytes compared with controls. This effect arises from Runx1- or Runx3-mediated repression of CD4 expression, and is independent of positively selecting signals. Runx1 is able to repress CD4 in CD4/CD8 double-positive thymocytes, but not in mature splenic T cells. Runx-mediated CD4 repression is independent of association with the corepressors Groucho/TLE or Sin3. Two domains are required for complete Runx-mediated CD4 repression. These are contained within Runx1 aa 212-262 and 263-360. The latter region contains the nuclear matrix targeting sequence, which is highly conserved among runt family transcription factors across species. The presence of the nuclear matrix targeting sequence is required for Runx-mediated CD4 repression, suggesting that Runx transcription factors are stabilized on the CD4 silencer via association with the nuclear matrix.

Amino Acid Sequence↗
PubMed1999

Structure-function studies of the BTB/POZ transcriptional repression domain from the promyelocytic leukemia zinc finger oncoprotein.

The evolutionarily conserved BTB/POZ domain from the promyelocytic leukemia zinc finger (PLZF) oncoprotein mediates transcriptional repression through the recruitment of corepressor proteins containing histone deacetylases in acute promyelocytic leukemia. We have determined the 2.0 A crystal structure of the BTB/POZ domain from PLZF (PLZF-BTB/POZ), and have carried out biochemical analysis of PLZF-BTB/POZ harboring site-directed mutations to probe structure-function relationships. The structure reveals a novel alpha/beta homodimeric fold in which dimer interactions occur along two surfaces of the protein subunits. The conservation of BTB/POZ domain residues at the core of the protomers and at the dimer interface implies an analogous fold and dimerization mode for BTB/POZ domains from otherwise functionally unrelated proteins. Unexpectedly, the BTB/POZ domain forms dimer-dimer interactions in the crystals, suggesting a mode for higher-order protein oligomerization for BTB/POZ-mediated transcriptional repression. Biochemical characterization of PLZF-BTB/POZ harboring mutations in conserved residues involved in protein dimerization reveals that the integrity of the dimer interface is exquisitely sensitive to mutation and that dimer formation is required for wild-type levels of transcriptional repression. Interestingly, similar mutational analysis of residues within a pronounced protein cleft along the dimer interface, which had been implicated previously for interaction with corepressors, has negligible effects on dimerization or transcriptional repression. Together, these studies form a structure-function framework for understanding BTB/POZ-mediated oligomerization and transcriptional repression properties.

Amino Acid Sequence↗
PubMed2000

Sp1 and chromatin environment are important contributors to the formation of repressive chromatin structures on the transfected human adenine nucleotide translocase-2 promoter.

The influence of chromatin on the human adenine nucleotide translocase isoform 2 (ANT2) promoter was investigated in transfected cells treated with the deacetylase inhibitors butyrate and trichostatin A (TSA). Both inhibitors activated the expression of reporter plasmids transfected into HeLa cells, indicating that the promoter was suppressed by hypoacetylated chromatin and activated by hyperacetylation. Inhibitor-dependent activation was traced to the two Sp1-activation elements within the proximal promoter region, indicating that the Sp1 elements are repressed by chromatin structure. Repressive chromatin structures were also formed on the promoter integrated into a stable chromatin environment, as shown by the effects of TSA and butyrate on 14 single-cell-derived NIH3T3 clones bearing the stable integrated ANT2 promoter. Both the basal expression of the luciferase reporter gene and the response to TSA and butyrate varied widely between clones. The range of basal expression (4000-fold) was due partially to variation in the formation of repressive chromatin, since clones with low basal expression were induced by TSA, but those with high basal expression were less effected. These data indicate that chromatin environment surrounding the integrated DNA exerts a strong influence on chromatin-dependent repression of the ANT2 promoter, and that the ability of Sp1 to activate ANT2 expression is compromised in the repressed state.

3T3 Cells↗
PubMed2003

Involvement of hydrogen peroxide in repression of catalase in TMV-infected resistant tobacco.

Catalases are ubiquitous, and play a role in plant defense against pathogens. We have reported that catalase mRNA and enzyme activity are repressed in the vicinity of hypersensitive tobacco lesions following TMV infection. We wished to identify the signals involved in this repression. Inoculation with TMV reduced catalase levels 26 to 28 h following infection, coincident with the known timing of endogenous salicylic acid (SA) accumulation. Application of SA caused a transient reduction in Ngcat1 mRNA level and catalase activity 4 to 6 h after treatment. However, repression was also observed in transgenic plants harboring the salicylate hydroxylase gene (NahG) and in TMV susceptible plants, which do not accumulate SA following TMV infection. In the same blots there was no induction of PR-1 or enhanced expression of H2O2-inducible glutathione-S-transferase and found that exposure to H2O2 also repressed Ngcat1 mRNA. Our findings suggest that repression of catalase transcription may be caused by the accumulation of H2O2 rather than of SA.

Catalase↗
PubMed2003

Characterization of a strong repression domain in the hinge region of orphan nuclear receptor hB1F/hLRH-1.

Human hepatitis B virus enhancer II B1 binding factor (hB1F also known as NR5A2, LRH-1, FTF or CPF) is an orphan nuclear receptor and belongs to the fushi tarazu factor I (FTZ-F1) subfamily. It plays important roles in the transcriptional regulation of a number of genes involved in bile acid biosynthesis pathway, hepatitis B virus (HBV) replication and liver specific regulatory network. Like other nuclear receptors, hB1F is composed of modular functional domains. We characterized a domain in its hinge region that imposes a strong repression on the transcriptional activity of hB1F, which is important for the function of hB1F on regulating the activity of HBV enhancer II/core promoter. Mutations of the core residues in this domain abrogate the repression. Bioinformatic analysis reveals that the amino acid sequence of this region is highly conserved only among members of the FTZ-F1 subfamily. The repression is observed in five cell lines tested, while the degree of the repression varies greatly, which does not parallel with the expression level of the DEAD box protein of 130 kD (DP103), a potential interacting protein of a homologous domain in the steroidogenic factor 1 (SF-1). Moreover, the repression is not affected by the silencing mediator for retinoic acid receptor and thyroid hormone receptor (SMRT) and steroid receptor coactivator 1 (SRC-1). Collectively, these data suggest a novel regulatory mechanism for the transcriptional activity of hB1F.

Amino Acid Sequence↗
PubMed2005

Cisplatin represses transcriptional activity from the minimal promoter of the O6-methylguanine methyltransferase gene and increases sensitivity of human gallbladder cancer cells to 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-2-chloroethyl)-3-nitrosourea.

O(6)-methylguanine methyltransferase (MGMT) repairs O(6)-alkylguanine in cellular DNA introduced by the clinically used alkylating drug 1-(4-amino-2-methyl-5-pyrimidinyl) methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU). Thus, cancer cells with MGMT expression are resistant to ACNU treatment. Cisplatin has been reported to suppress MGMT expression; however, the molecular mechanism by which cisplatin reduces MGMT expression remains to be elucidated. Using gallbladder cancer cells (KMG-C) expressing MGMT, we analyzed whether a low dose of cisplatin suppresses MGMT expression, followed by an enhanced drug effect of ACNU in vitro and in vivo. We also investigated the promoter region critical for the transcriptional repression of MGMT gene by cisplatin using 5 deletion mutants in reporter promoter assays. In RT-PCR analysis, the expression of MGMT mRNA in KMG-C cells was dose- and time-dependently repressed. Drug sensitivity to ACNU was increased 2-fold by pretreatment with cisplatin, compared with only ACNU treatment, in MTT assays as well as tumor-bearing nude mice. Although the 5'-flanking region is deleted as far as -69 bp upstream of the transcription start site, cisplatin dose dependently inhibited luciferase activity. However, cisplatin did not cause such repression when 59 bp region from -69 to -10 bp was deleted. We confirmed that cisplatin enhanced sensitivity to ACNU in KMG-C cells expressing MGMT both in vitro and in vivo. Furthermore, a low dose of cisplatin repressed the transcription of the MGMT promoter. The 59 bp region in the MGMT promoter was crucial for repression by cisplatin. These results might form the basis of a chemotherapeutic strategy involving alkylating agents via prior cisplatin-induced biochemical modulation.

Antineoplastic Agents↗