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At least 505 records · Page 28Linked to original sources
PubMed1992

Analysis of promoter-specific repression by triple-helical DNA complexes in a eukaryotic cell-free transcription system.

A site-specific triple-helical DNA complex has previously been shown to inhibit DNA binding by eukaryotic transcription factor Sp1. To examine the functional consequences of such inhibition, homopurine target sequences for oligonucleotide-directed triple-helix formation were inserted in various configurations relative to Sp1 transcription activator binding sites, upstream of the TATA element of recombinant eukaryotic promoters. The resulting promoters were tested for activity in the presence or absence of recombinant human Sp1 in a Drosophila in vitro transcription system lacking endogenous Sp1. When triple-helical complexes were assembled on the promoters by incubation with specific oligodeoxyribonucleotides, promoter-specific repression of basal transcription was observed in the absence of Sp1. Transcriptional repression required the preassembly of triple-helical complexes before addition of nuclear extract. The degree of basal repression was a function of the number and proximity of triple-helical complexes relative to the basal promoter complex. Repression did not result from triple-helix-induced template degradation. Addition of recombinant Sp1 did not cause derepression. These results suggest that triple-helical complexes can repress transcription primarily by blocking promoter DNA assembly into initiation complexes rather than by occluding Sp1 binding. One of several plausible mechanisms for triple-helix-induced repression involves changes in DNA flexibility. Evidence in favor of this model is provided by a permutation-dependent gel mobility assay in which formation of site-specific triple-helical complexes is shown to stiffen double-helical DNA.

Animals↗
PubMed2001

Evidence that Myc isoforms transcriptionally repress caveolin-1 gene expression via an INR-dependent mechanism.

The c-Myc oncoprotein contributes to oncogenesis by activating and repressing a repertoire of genes involved in cellular proliferation, metabolism, and apoptosis. Increasing evidence suggests that the repressor function of c-Myc is critical for transformation. Therefore, identifying and characterizing Myc-repressed genes is imperative to understanding the mechanisms of Myc-induced tumorigenesis. Here, we employ NIH 3T3 cell lines harboring c-Myc-ER or N-Myc-ER to dissect the relationship between Myc activation and caveolin-1 expression. In this well-established inducible system, treatment with estrogen like molecules, such as tamoxifen, leads to activation of Myc, but in a tightly controlled fashion. Using this approach, we show that Myc activation induces the repression of caveolin-1 expression at the transcriptional level. We also provide two independent lines of evidence suggesting that caveolin-1 is a direct target of Myc: (i) the effect of Myc activation on caveolin-1 expression is independent of new protein synthesis, as revealed through the use of cycloheximide; and (ii) Myc-mediated repression of the caveolin-1 promoter is dependent on an intact INR sequence. Moreover, we show that expression of caveolin-1, via an adenoviral vector approach, can suppress cell transformation that is mediated by Myc activation. In support of these observations, treatment with an adenoviral vector harboring anti-sense caveolin-1 specifically potentiates transformation induced by Myc activation. Taken together, our results indicate that caveolin-1 is a direct target of Myc repression, and they also provide evidence for an additional mechanism by which Myc repression can elicit a malignant phenotype.

3T3 Cells↗
PubMedDate not supplied

Mathematical model of the lac operon: inducer exclusion, catabolite repression, and diauxic growth on glucose and lactose.

A mathematical model of the lactose (lac) operon was developed to study diauxic growth on glucose and lactose. The model includes catabolite repression, inducer exclusion, lactose hydrolysis to glucose and galactose, and synthesis and degradation of allolactose. Two models for catabolite repression were tested: (i) cyclic AMP (cAMP) synthesis inversely correlated with the external glucose concentration and (ii) synthesis inversely correlated with the glucose transport rate. No significant differences in the two models were observed. In addition to synthesis, degradation and secretion of cAMP were also included in the model. Two models for the phosphorylation of the glucose produced from lactose hydrolysis were also tested: (i) phosphorylation by intracellular hexokinase and (ii) secretion of glucose and subsequent phosphorylation upon transport back into the cell. The latter model resulted in weak catabolite repression when the glucose produced from lactose was transported out of the cell, whereas the former model showed no catabolite repression during growth on lactose. Parameter sensitivity analysis indicates the importance of key parameters to lac operon expression and cell growth: the lactose and allolactose transformation rates by beta-galactosidase and the glucose concentrations that affect catabolite repression and inducer exclusion. Large values of the allolactose hydrolysis rate resulted in low concentrations of allolactose, low-level expression of the lac operon, and slow growth due to limited import and metabolism of lactose; small values resulted in a high concentration of allolactose, high-level expression of the lac operon, and slow growth due to a limiting concentration of glucose 6-phosphate formed from allolactose. Changes in the rates of all beta-galactosidase-catalyzed reactions showed similar behavior, but had more drastic effects on the growth rate. Changes in the glucose concentration that inhibited lactose transport could extend or contract the diauxic growth period during growth in the presence of glucose and lactose. Moreover, changes in the glucose concentration that affected catabolite repression affected the cAMP levels and lac operon expression, but had a lesser effect on the growth rate.

Biological Transport↗
PubMed2003

RNA-binding protein-mediated translational repression of transgene expression in plants.

We have demonstrated that RNA-binding proteins from coliphages and yeast can function as translational repressors in plants. RNA sequences called translational operators were inserted at a cap-proximal position in the 5'-UTR of mRNAs of two reporter genes, gus or aroA:CP4. Translation of the reporter mRNAs was efficiently repressed when the RNA binding protein that specifically binds to its cognate operator was co-expressed. The efficiency of translational repression by RNA-binding protein positively correlated with the amount of binding protein in transformed plant cells. Detailed studies on coliphage MS2 coat protein-mediated translational repression also suggested that the efficiency of translational repression was position-dependent. A translational operator situated at the cap-proximal position was more efficient in conferring repression than one that was placed cap-distal. Translational repression can be an efficient means for regulation of transgene expression, thereby broadening current approaches for transgene regulation in plants.

3-Phosphoshikimate 1-Carboxyvinyltransferase↗
PubMed1998

Transcriptional repression by the methyl-CpG-binding protein MeCP2 involves a histone deacetylase complex.

Cytosine residues in the sequence 5'CpG (cytosine-guanine) are often postsynthetically methylated in animal genomes. CpG methylation is involved in long-term silencing of certain genes during mammalian development and in repression of viral genomes. The methyl-CpG-binding proteins MeCP1 and MeCP2 interact specifically with methylated DNA and mediate transcriptional repression. Here we study the mechanism of repression by MeCP2, an abundant nuclear protein that is essential for mouse embryogenesis. MeCP2 binds tightly to chromosomes in a methylation-dependent manner. It contains a transcriptional-repression domain (TRD) that can function at a distance in vitro and in vivo. We show that a region of MeCP2 that localizes with the TRD associates with a corepressor complex containing the transcriptional repressor mSin3A and histone deacetylases. Transcriptional repression in vivo is relieved by the deacetylase inhibitor trichostatin A, indicating that deacetylation of histones (and/or of other proteins) is an essential component of this repression mechanism. The data suggest that two global mechanisms of gene regulation, DNA methylation and histone deacetylation, can be linked by MeCP2.

Acetylation↗
PubMedDate not supplied

Negative control at a distance mediates catabolite repression in yeast.

In prokaryotic organisms, the control of gene expression is mediated by regulatory proteins that activate or repress transcription. However, the molecular mechanisms of positive and negative control are different. In terms of negative control, repressor proteins bind to sites located within the promoter region and as a consequence sterically interfere with functional binding by RNA polymerase. Here, I examine the properties of a regulatory sequence that specifies catabolite (glucose) repression in the yeast Saccharomyces cerevisiae. Specifically, a DNA segment containing this regulatory site was fused upstream of the intact his3 promoter region and structural gene at several locations. Normally, his3 expression in these derivatives occurs at a basal level which can be induced by conditions of amino-acid starvation. However, in glucose medium, the catabolite regulatory sequence overrides the normal his3 promoter elements and reduces transcription both in normal and starvation conditions. The implication from these results is that in contrast to catabolite repression in Escherichia coli, which is mediated by catabolite-activating protein (CAP), catabolite repression in yeast occurs by a negative control mechanism involving a putative repressor protein. The observation that this regulatory site exerts its repressing effects even when located upstream of an intact promoter region suggests that repression in yeast is not mediated by steric interference between regulatory proteins and the transcriptional apparatus.

DNA, Recombinant↗
PubMed2002

Distinct in vivo requirements for establishment versus maintenance of transcriptional repression.

Low-level ectopic expression of the Runt transcription factor blocks activation of the Drosophila melanogaster segmentation gene engrailed (en) in odd-numbered parasegments and is associated with a lethal phenotype. Here we show, by using a genetic screen for maternal factors that contribute in a dose-dependent fashion to Runt-mediated repression, that there are two distinct steps in the repression of en by Runt. The initial establishment of repression is sensitive to the dosage of the zinc-finger transcription factor Tramtrack. By contrast, the co-repressor proteins Groucho and dCtBP, and the histone deacetylase Rpd3, do not affect establishment but instead maintain repression after the blastoderm stage. The distinction between establishment and maintenance is confirmed by experiments with Runt derivatives that are impaired specifically for either co-repressor interaction or DNA binding. Other transcription factors can also establish repression in Rpd3-deficient embryos, which indicates that the distinction between establishment and maintenance may be a general feature of eukaryotic transcriptional repression.

Animals↗
PubMed2005

PU.1 inhibits the erythroid program by binding to GATA-1 on DNA and creating a repressive chromatin structure.

Transcriptional repression mechanisms are important during differentiation of multipotential hematopoietic progenitors, where they are thought to regulate lineage commitment and to extinguish alternative differentiation programs. PU.1 and GATA-1 are two critical hematopoietic transcription factors that physically interact and mutually antagonize each other's transcriptional activity and ability to promote myeloid and erythroid differentiation, respectively. We find that PU.1 inhibits the erythroid program by binding to GATA-1 on its target genes and organizing a complex of proteins that creates a repressive chromatin structure containing lysine-9 methylated H3 histones and heterochromatin protein 1. Although these features are thought to be stable aspects of repressed chromatin, we find that silencing of PU.1 expression leads to removal of the repression complex, loss of the repressive chromatin marks and reactivation of the erythroid program. This process involves incorporation of the replacement histone variant H3.3 into nucleosomes. Repression of one transcription factor bound to DNA by another transcription factor not on the DNA represents a new mechanism for downregulating an alternative gene expression program during lineage commitment of multipotential hematopoietic progenitors.

Animals↗
PubMed2006

The N-CoR complex enables chromatin remodeler SNF2H to enhance repression by thyroid hormone receptor.

Unliganded thyroid hormone receptor (TR) actively represses transcription via the nuclear receptor corepressor (N-CoR)/histone deacetylase 3 (HDAC3) complex. Although transcriptional activation by liganded receptors involves chromatin remodeling, the role of ATP-dependent remodeling in receptor-mediated repression is unknown. Here we report that SNF2H, the mammalian ISWI chromatin remodeling ATPase, is critical for repression of a genomically integrated, TR-regulated reporter gene. N-CoR and HDAC3 are both required for recruitment of SNF2H to the repressed gene. SNF2H does not interact directly with the N-CoR/HDAC3 complex, but binds to unacetylated histone H4 tails, suggesting that deacetylase activity of the corepressor complex is critical to SNF2H function. Indeed, HDAC3 as well as SNF2H are required for nucleosomal organization on the TR target gene. Consistent with these findings, reduction of SNF2H induces expression of an endogenous TR-regulated gene, dio1, in liver cells. Thus, although not apparent from studies of transiently transfected reporter genes, gene repression by TR involves the targeting of chromatin remodeling factors to repressed genes by the HDAC activity of nuclear receptor corepressors.

Adenosine Triphosphatases↗
PubMed2006

Repression of polymerase I-mediated gene expression at Trypanosoma brucei telomeres.

The African trypanosome, Trypanosoma brucei, is a flagellated pathogenic protozoan that branched early from the eukaryotic lineage. Unusually, it uses RNA polymerase I (Pol I) for mono-telomeric expression of variant surface glycoprotein (VSG) genes in bloodstream-form cells. Many other subtelomeric VSG genes are reversibly repressed, but no repressive DNA sequence has been identified in any trypanosomatid. Here, we show that artificially seeded de novo telomeres repress Pol I-dependent gene expression in mammalian bloodstream and insect life-cycle stages of T. brucei. In a telomeric VSG expression site, repression spreads further along the chromosome and this effect is specific to the bloodstream stage. We also show that de novo telomere extension is telomerase dependent and that the rate of extension correlates with the expression level of the adjacent gene. Our results show constitutive telomeric repression in T. brucei and indicate that an enhanced, developmental stage-specific repression mechanism controls antigenic variation.

Animals↗
PubMed1999

The Wilms' tumor gene product represses the transcription of thrombospondin 1 in response to overexpression of c-Jun.

Thrombospondin 1 (TSP1) is known for its significant anti-angiogenic properties. In a previous study, we have shown that transient or stable overexpression of the transcription factor c-Jun, in rat fibroblasts, leads to repression of TSP1. We now demonstrate that the c-Jun-induced repression of TSP1 does not occur directly and does not require binding of c-Jun to the TSP1 promoter. Instead, repression involves a factor secreted by c-Jun-overexpressing cells. This secreted factor triggers a signal transduction pathway from the membrane to the nucleus, and these signals lead to the binding of the product of the Wilms' tumor suppressor gene, WT1, to the -210 region of the TSP1 promoter. This region binds WT1 and SP1, but not EGR1, although its sequence fits the consensus binding site for this transcription factor. WT1 overexpression in transfected cells inhibits endogenous TSP1 gene expression and TSP1 transcription in experiments using TSP1 promoter-reporter constructs. The WT1 - KTS isoform is more active in repressing TSP1 transcription than WT1 + KTS, while EGR1 is inactive. Enhancement of WT1 binding to DNA in response to c-Jun does not require de novo protein synthesis. The above mechanism for TSP1 repression could apply to other genes, thus coordinating their regulation in the vicinity of a c-Jun-overexpressing cell. We conclude that WT1, which was discovered as a result of its tumor suppressor properties, may also possess oncogenic characteristics in the c-Jun transformation process, and thus repress the anti-angiogenic protein, TSP1.

Animals↗
PubMed2001

Repression of transcription of the p27(Kip1) cyclin-dependent kinase inhibitor gene by c-Myc.

Upon engagement of the B Cell Receptor (BCR) of WEHI 231 immature B cells, a drop in c-Myc expression is followed by activation of the cyclin-dependent kinase inhibitor (CKI) p27(Kip1), which induces growth arrest and apoptosis. Here, we report inverse patterns of p27 and c-Myc protein expression follow BCR engagement. We present evidence demonstrating, for the first time, that the p27(Kip1) gene is a target of transcriptional repression by c-Myc. Specifically, the changes in p27 protein levels correlated with changes in p27 mRNA levels, and gene transcription. Induction of p27 promoter activity followed BCR engagement of WEHI 231 cells, and this induction could be repressed upon co-transfection of a c-Myc expression vector. Inhibition of the TATA-less p27 promoter by c-Myc was also observed in Jurkat T cells, vascular smooth muscle, and Hs578T breast cancer cells, extending the observation beyond immune cells. Consistent with a putative Inr element CCAGACC (where +1 is underlined) at the start site of transcription in the p27 promoter, deletion of Myc homology box II reduced the extent of repression. Furthermore, enhanced repression was observed upon transfection of the c-Myc 'super-repressor', with mutation of Phe115 to Leu. The sequences mediating transcriptional activity and c-Myc repression were mapped to bp -20 to +20 of the p27 gene. Finally, binding of Max was shown to facilitate c-Myc binding and repression of p27 promoter activity. Overall, these studies identify the p27 CKI gene as a new target whereby c-Myc can control cell proliferation, survival and neoplastic transformation.

Animals↗
PubMed2001

In vivo complex formation of PU.1 with HDAC1 associated with PU.1-mediated transcriptional repression.

We previously reported that overexpression of PU.1, a member of the Ets family of transcription factors, induces differentiation inhibition and apoptosis associated with c-Myc down-regulation in murine erythroleukemia (MEL) cells. To understand the molecular mechanism by which c-Myc is down-regulated due to overexpression of PU.1, we performed luciferase reporter assays using the mouse c-myc promoter. PU.1 repressed the activities of not only the c-myc promoter but also several other promoters. Experiments with deletion mutants of PU.1 revealed that the C-terminal region spanning amino acids (aa) 123-272 including the PEST and ETS domains but not the activation domain was sufficient for this transcriptional repression. It was unlikely that the repression was due to sequestration of a limited amount of CBP/p300 nor pCAF, because overexpression of these co-activators did not relieve PU.1-mediated transcriptional repression. Instead, it was found that the C-terminal aa 101-272 of PU.1 formed a complex with mSin3A and HDAC1 in vivo, which was speculated to be associated with the repression. The C-terminal region of PU.1 also formed a complex with the basic transcription factor TBP in vitro and in vivo. Our results suggest that overexpression of PU.1 induces transcriptional repression in several gene promoters including the c-myc promoter which may be mediated by its complex formation with HDACs.

Cell Line↗
PubMed2004

HDAC4 mediates transcriptional repression by the acute promyelocytic leukaemia-associated protein PLZF.

PLZF, the promyelocytic leukaemia zinc-finger protein, is a transcriptional repressor essential to development. In some acute leukaemias, a chromosomal translocation fusing the PLZF gene to that encoding the retinoic acid receptor RARalpha gives rise to a fusion protein, PLZF-RARalpha, thought to be responsible for constitutive repression of differentiation-associated genes in these cells. Repression by both PLZF and PLZF-RARalpha is sensitive to the histone deacetylase inhibitor TSA, and PLZF was previously shown to interact physically with HDAC1, a class I histone deacetylase. We here asked whether class II histone deacetylases, known to be generally involved in differentiation processes, participate in the repression mediated by PLZF and PLZF-RARalpha, and found that PLZF interacts with HDAC4 in both GST-pull-down and co-immunoprecipitation assays. Furthermore, HDAC4 is indeed involved in PLZF and PLZF-RARalpha-mediated repression, since an enzymatically dead mutant of HDAC4 released the repression, as did an siRNA that blocks HDAC4 expression. Taken together, our data indicate that recruitment of HDAC4 is necessary for PLZF-mediated repression in both normal and leukaemic cells.

Animals↗
PubMed2000

Transcriptional repression of the 5-HT1A receptor promoter by corticosterone via mineralocorticoid receptors depends on the cellular context.

The diverse effects of the corticosteroid hormones are mediated in large measure by the mineralocorticoid and glucocorticoid receptors, two closely related members of the nuclear receptor superfamily. In the brain, corticosteroids regulate neuronal excitability and responses to neurotransmitters in a cell type-specific manner. The 5-HT1A receptor, for example, is highly expressed in the hippocampus and raphe but transcription is repressed by corticosterone (the principal glucocorticoid in rodents) only in hippocampus. We have used transient transfection of cultured cells to study the transcriptional regulation of the 5-HT1A receptor promoter by activators and repression by glucocorticoids. We find that transcription factors Sp1 and NF-kB subunit p65, both of which are coexpressed in hippocampus with the 5-HT1A receptor in vivo, synergistically activate a reporter driven by receptor 5'-flanking region. Primer extension data suggest that the multiple transcription initiation sites used in reporter gene transcription correlate with those used in transcription of the endogenous gene which has a TATA-less promoter. Repression of transcription by corticosteroids was found to be mediated by both mineralocorticoid and glucocorticoid receptors, but not identically. While glucocorticoid receptors potently inhibited both p65- and p65/Sp1-stimulated transcription, repression via mineralocorticoid receptors (MR) depended on the transcriptional activators that were present: p65-stimulated reporter activity was not repressed via MR, whereas a similar level of transcription resulting from synergistic activation by p65/Sp1-stimulation was repressed via MR. The context-dependence of these MR-mediated effects provides a model for the cell-type and state-dependent actions of corticosterone in the brain.

Animals↗
PubMed1999

Lrp binds to two regions in the dadAX promoter region of Escherichia coli to repress and activate transcription directly.

The dadAX operon is expressed by multiple promoters that are repressed by leucine-responsive regulatory protein (Lrp) and activated by cyclic AMP-CRP. In previous work, we found that alanine or leucine acted as inducers to antagonize Lrp repression of the three major promoters directly. Here, we identify 11 Lrp binding sites located within 350 bp of dad DNA. A mutational analysis, coupled with in vivo and in vitro transcription experiments, indicated that Lrp sites that overlap the dad promoters were involved in repression. In contrast, sites upstream of the promoters did not appear to be necessary for repression, but were required for activation by Lrp plus alanine or leucine of one of the major dad promoters, P2. This activation by alanine or leucine was not simply relief of repression, as P2 transcription from a constitutive template was increased fivefold compared with the basal level of transcription found in the absence of Lrp and the co-activator cyclic AMP-CRP. Alanine or leucine decreased the affinity of Lrp to repressor sites, while having little or no effect on the binding of Lrp to activator sites. This differential effect of alanine and leucine on Lrp binding helps to explain how these modifiers influence both repression and activation of the dad operon.

Alanine↗
PubMed2003

Coordinate repression of regulators of embryonic identity by PICKLE during germination in Arabidopsis.

In angiosperms, germination represents an important developmental transition during which embryonic identity is repressed and vegetative identity emerges. PICKLE (PKL) encodes a CHD3-chromatin-remodeling factor necessary for the repression of expression of LEAFY COTYLEDON1 (LEC1), a central regulator of embryogenesis. A candidate gene approach and microarray analysis identified nine additional genes that exhibit PKL-dependent repression of expression during germination. Transcripts for all three LEAFY COTYLEDON genes, LEC1, LEC2, and FUS3, exhibit PKL-dependent repression, and all three transcripts are elevated more than 100-fold in pkl primary roots that inappropriately express embryonic traits (pickle roots). Three other genes that exhibit PKL-dependent regulation have expression patterns correlated with zygotic or somatic embryogenesis, and one gene encodes a putative Lin-11, Isl-1, MEC-3 (LIM) domain transcriptional regulator that is preferentially expressed in siliques. Genes that exhibit PKL-dependent repression during germination are not necessarily regulated by PKL at other points in development. Our data suggest that PKL selectively regulates a suite of genes during germination to repress embryonic identity. In particular, we propose that PKL acts as a master regulator of the LEAFY COTYLEDON genes, and that joint derepression of these genes is likely to contribute substantially to expression of embryonic identity in pkl seedlings.

Arabidopsis↗
PubMed1999

Abundant secretory lipocalins displaying male and lactation-specific expression in adult hamster submandibular gland. cDNA cloning and sex hormone-regulated repression.

We have previously identified massively expressed 24- and 20.5-kDa male-specific proteins in submandibular salivary glands (SMG) of adult hamsters. Here we report the cloning of the cDNA encoding the 24-kDa protein which we have now found to be a heterogenously N-glycosylated form of the 20.5-kDa protein. The deduced amino acid sequence indicated that the protein is a member of the lipocalin family, the two most related lipocalins being rat odorant-binding protein of nasal mucosa and aphrodisin, a pheromonal protein present in vaginal discharge and saliva of female hamsters. Northern blot analysis showed that cognate mRNA is expressed in hamster SMG and lacrimal gland (LG) displaying marked sex-hormonal repression. The sex-hormonal repression patterns showed similarities and dissimilarities between SMG and LG but they were, respectively, similar to the sex-hormonal repression pattern noted for the SMG 24/20.5-kDa male-specific proteins and for an abundant female-specific 20-kDa LG secretory protein. These SMG and LG proteins were found to be immunologically similar and secretion of the SMG proteins in saliva and their excretion in urine was detected. The male-specific and abundant expression of the SMG proteins were seen at and after sexual maturity but was not dependent on androgens. Surprisingly, a temporary male-like expression of these SMG proteins was seen in lactating females which was obliterated by oestrogen administration. Our results show that despite differences in their repression by sex hormones, the gene for SMG 24/20.5-kDa proteins is similar or identical to that of LG 20-kDa protein and their marked repression by both androgens and oestrogens might be at the transcriptional level. Moreover, they might be excellent models with which to study sex hormone repression of gene expression at the molecular level. The results of homology search and the male- and lactation-specific pressure of the SMG proteins in adult saliva and urine suggests a possibility of their involvement in olfaction-mediated chemical communication between hamsters.

Age Factors↗