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At least 1,225 records · Page 68Linked to original sources
PubMed1999

Allosteric regulation of even-skipped repression activity by phosphorylation.

The Drosophila homeodomain protein Even-skipped (Eve) is a well characterized transcriptional repressor. Here, we show that Eve's ability to function in vitro is negatively regulated by phosphorylation. DNA-binding activity was unaffected by phosphorylation, but phosphorylated Eve was unable to interact with the TATA-binding protein (TBP), a known target for repression. Unexpectedly, phosphorylation of the Eve N terminus, which is dispensable for repression and TBP binding, was necessary and sufficient to inactivate Eve. LiCl, which specifically inhibits glycogen synthase kinase-3 (GSK-3), reduced Eve phosphorylation in nuclear extract and blocked inhibition of repression. In addition, Eve was phosphorylated and inactivated by purified GSK-3 beta plus casein kinase II. Our results suggest a novel mechanism of transcriptional control involving phosphorylation-induced allosteric interference with a repressive protein-protein interaction.

Allosteric Regulation↗
PubMed1999

SMRTER, a Drosophila nuclear receptor coregulator, reveals that EcR-mediated repression is critical for development.

The Drosophila ecdysone receptor (EcR)/ultraspiracle (USP) heterodimer is a key regulator in molting and metamorphoric processes, activating and repressing transcription in a sequence-specific manner. Here, we report the isolation of an EcR-interacting protein, SMRTER, which is structurally divergent but functionally similar to the vertebrate nuclear corepressors SMRT and N-CoR. SMRTER mediates repression by interacting with Sin3A, a repressor known to form a complex with the histone deacetylase Rpd3/HDAC. Importantly, we identify an EcR mutant allele that fails to bind SMRTER and is characterized by developmental defects and lethality. Together, these results reveal a novel nuclear receptor cofactor that exhibits evolutionary conservation in the mechanism to achieve repression and demonstrate the essential role of repression in hormone signaling.

Amino Acid Sequence↗
PubMed2002

Anticancer effect of retinoic acid via AP-1 activity repression is mediated by retinoic acid receptor alpha and beta in gastric cancer cells.

To uncover the mechanisms relating to the anticancer effect of retinoic acids in gastric cancer cells, the mediation of activator protein-1 (AP-1) activity repression by retinoic acid receptors (RARs) was investigated. All-trans retinoic acid (ATRA) inhibited AP-1 activity in BGC-823 cells (RARalpha(+), RARbeta(+)), but not in MKN-45 cells (RARalpha(lo), RARbeta(-)). Transient transfection of RARbeta expression vector into MKN-45 cells significantly resulted in direct repression of AP-1 activity in a receptor concentration-dependent manner, and this could be strengthened by ATRA. Stable transfection of RARbeta into MKN-45 cells directly inhibited cell growth and colony formation, and ATRA also enhanced these effects. Transient transfection of RARalpha into MKN-45 cells however, displayed receptor concentration-dependent AP-1 activity inhibition only in the presence of ATRA. Stable transfection of RARalpha into MKN-45 cells resulted in ATRA-dependent inhibition of cell growth and colony formation. For AP-1 binding activity induced by TPA, the repressive effect of ATRA was only observed in BGC-823 and RARalpha and RARbeta stably transfected MKN-45 cells, but not in intact MKN-45 cells. This indicates the necessity for sufficient cellular RARalpha and/or RARbeta in order for AP-1 activity repression to occur. Deletion of DNA binding domain (DBD) of RARbeta, but not ligand binding domain (LBD), eliminated the anti-AP-1 function of RARbeta. It is therefore concluded that both RARalpha and RARbeta are mediators in the anticancer function of ATRA via AP-1 activity inhibition, and that RARbeta, not RARalpha, can inhibit AP-1 activity to a certain extent directly by itself. Thus DBD, not LBD, is critical for anti-AP-1 activity.

Antineoplastic Agents↗
PubMed1998

Control of mRNA turnover as a mechanism of glucose repression in Saccharomyces cerevisiae.

The phenomenon of glucose repression in yeast is concerned with the repression of a large number of genes when glucose is an abundant carbon source and almost all of the energy requirements of the cell can be satisfied from glycolysis. Prominent among the repressed genes are those encoding mitochondrial proteins required for respiration and oxidative phosphorylation. Past studies have characterized a pathway by which a signal generated from extracellular glucose is transmitted to the nucleus. The ultimate outcome is the repression of transcription of numerous genes, but also the induction of a limited number of others. The emphasis has been almost exclusively on transcriptional control mechanisms. A discovery made originally with the transcript of the SDH2 gene prompted an investigation of post-transcriptional mechanisms, and more specifically a study of the turnover rate of this mRNA in the absence and presence of glucose. SDH2 mRNA has a very short half-life in medium with glucose (YPD) and a significantly longer half-life in medium with glycerol (YPG). Experimental evidence and recent progress in understanding of (1) mRNA turnover in yeast and (2) initiation of translation on the 5' untranslated region of mRNAs, lead to a working hypothesis with the following major features: the carbon source, via a signaling pathway involving kinase/phosphatase activities, controls the rate of initiation, and thus influences a competition between eukaryotic initiation factors (prominently eIF4E, eIF4G, eIF3) binding to the capped mRNA and a decapping activity (DCP1) which is one of the rate limiting activities in the turnover of such mRNAs.

Carbohydrate Dehydrogenases↗
PubMed2001

Mechanisms of transcriptional repression.

Transcriptional repressors are usually viewed as proteins that bind to promoters in a way that impedes subsequent binding of RNA polymerase. Although this repression mechanism is found at several promoters, there is a growing list of repressors that inhibit transcription initiation in other ways. For example, several repressors allow the simultaneous binding of RNA polymerase to the promoter, but interfere with subsequent events of the initiation process, eventually inhibiting transcription initiation. The recent increase in the number of repressors for which the repression mechanism has been characterized in detail has shown an amazing variety of strategies to repress transcription initiation. It is not surprising to find that the repression mechanism used is usually exquisitely adapted to the characteristics of the promoter and of the repressor involved.

Archaeal Proteins↗
PubMed2002

Specificity of Distalless repression and limb primordia development by abdominal Hox proteins.

In Drosophila, differences between segments, such as the presence or absence of appendages, are controlled by Hox transcription factors. The Hox protein Ultrabithorax (Ubx) suppresses limb formation in the abdomen by repressing the leg selector gene Distalless, whereas Antennapedia (Antp), a thoracic Hox protein, does not repress Distalless. We show that the Hox cofactors Extradenticle and Homothorax selectively enhance Ubx, but not Antp, binding to a Distalless regulatory sequence. A C-terminal peptide in Ubx stimulates binding to this site. However, DNA binding is not sufficient for Distalless repression. Instead, an additional alternatively spliced domain in Ubx is required for Distalless repression but not DNA binding. Thus, the functional specificities of Hox proteins depend on both DNA binding-dependent and -independent mechanisms.

Amino Acid Sequence↗
PubMed2003

Ras modulates Myc activity to repress thrombospondin-1 expression and increase tumor angiogenesis.

Tumor angiogenesis is postulated to be regulated by the balance between pro- and anti-angiogenic factors. We demonstrate that the critical step in establishing the angiogenic capability of human cells is the repression of the critical anti-angiogenic factor, thrombospondin-1 (Tsp-1). This repression is essential for tumor formation by mammary epithelial cells and kidney cells engineered to express SV40 early region proteins, hTERT, and H-RasV12. We have uncovered the signaling pathway leading from Ras to Tsp-1 repression. Ras induces the sequential activation of PI3 kinase, Rho, and ROCK, leading to activation of Myc through phosphorylation; phosphorylation of Myc via this mechanism enables it to repress Tsp-1 expression. We thus describe a novel mechanism by which the cooperative activity of the oncogenes, ras and myc, leads directly to angiogenesis and tumor formation.

Cell Line↗
PubMed1999

Smaug, a novel and conserved protein, contributes to repression of nanos mRNA translation in vitro.

Proper deployment of Nanos protein at the posterior of the Drosophila embryo, where it directs posterior development, requires a combination of RNA localization and translational controls. These controls ensure that only the posteriorly-localized nanos mRNA is translated, whereas unlocalized nanos mRNA is translationally repressed. Here we describe cloning of the gene encoding Smaug, an RNA-binding protein that interacts with the sequences, SREs, in the nanos mRNA that mediate translational repression. Using an in vitro translation assay, we demonstrate that SRE-dependent repression occurs in extracts from early stage embryos. Immunodepletion of Smaug from the extracts eliminates repression, consistent with the notion that Smaug is involved. Smaug is a novel gene and the existence of potential mammalian Smaug homologs raises the possibility that Smaug represents a new class of conserved translational repressor.

Amino Acid Sequence↗
PubMed1998

Transactivation of the ApoCIII promoter by ATF-2 and repression by members of the Jun family.

It was shown previously that cytokines such as tumor necrosis factor-alpha that stimulate signal transduction pathways involving transcription factors ATF-2 and Jun repress apoCIII promoter activity in HepG2 cells. In the present study, DNase I footprinting analysis established that ATF-2 protected three regions in the apoCIII promoter. One region (-747/-726) present in the apoCIII enhancer is within the previously identified footprint I and has overlapping boundaries with the binding sites of Sp1 (-764/-742) and HNF-4 (-736/-714). The other two regions represent new footprints and have been designated D/E (-219/-199) and B/C (-102/-75). The B/C region overlaps with the previously identified footprint B which contains an HNF-4 binding site (-87/-63). Cotransfection experiments in HepG2 cells showed that ATF-2 transactivated the -890/+24 apoCIII promoter 1.6-fold. In addition, mutations in the proximal D/E (-219/-199) and distal I (-747/-726) ATF-2-binding sites reduced the apoCIII promoter strength to 33 and 9% of control, respectively, indicating that ATF-2 is a positive regulator of apoCIII gene transcription. Cotransfections with ATF-2 and HNF-4 expression plasmids resulted in additive transactivation of the apoCIII promoter. Furthermore, apoCIII promoter constructs bearing mutations in the D/E and I ATF-2 binding sites were efficiently transactivated by HNF-4, suggesting that these two factors contribute independently to the apoCIII promoter strength. Members of the Jun family (c-Jun, JunB, and JunD) caused a dose-dependent inhibition of the -890/+24 apoCIII promoter activity. A synthetic promoter containing the apoCIII enhancer in front of the minimal AdML promoter was also repressed by Jun. In contrast, apoCIII promoter segments lacking the enhancer region were transactivated by Jun. The findings suggest that homodimers of Jun or heterodimers of Jun with other AP-1 subunits could be responsible for the observed repression by interfering with the function(s) of the apoCIII enhancer. Repression by Jun could be reversed in the presence of ATF-2 and HNF-4, suggesting that ATF2 and possibly Jun/ATF-2 heterodimers exert a positive effect on apoCIII gene transcription, as opposed to Jun homodimers or heterodimers with other AP-1 members. These findings suggest a role for members of the Jun family and ATF-2 that participate in signal transduction pathways in basal or induced apoCIII promoter activity in cells of hepatic origin.

Activating Transcription Factor 2↗
PubMed2000

Glucose repression of alpha-amylase in barley embryos is independent of GAMYB transcription.

The induction of alpha-amylase triggered by gibberellic acid in barley embryos is repressed by sugars. We investigated the effects of glucose on the gibberellin signal transduction pathway to localize the site of interaction of the sugar/hormone signalling pathways. Our results indicate that glucose represses gibberellin signalling late along this hormone transduction pathway, downstream of transcription of the gibberellin-modulated transcriptional activator (GAMYB) needed for alpha-amylase induction. This result suggests either that glucose repression is transduced by a pathway independent of gibberellin signalling or that repression occurs at the level of GAMYB translation.

Gene Expression Regulation, Enzymologic↗
PubMed2002

Cloning by pathway activation in yeast: identification of an Arabidopsis thaliana F-box protein that can turn on glucose repression.

We describe a method for identifying signal transducing proteins from other organisms by their ability to turn on a signalling pathway when they are expressed at high level in yeast. The method was tested on a cDNA library from Arabidopsis thaliana, which was screened for clones that can activate glucose repression in the absence of glucose. Six clones were characterized. One of them codes for AtGRH1, a new F-box protein that shows similarity to GRR1, a yeast protein involved in glucose repression. The ability of AtGRHI to activate glucose repression is dependent on the MIG1 repressor. Two-hybrid experiments revealed that AtGRH1 can interact with AtSKP1a and AtSKP1b, two recently identified SKP1 homologues in Arabidopsis. Other clones identified in the screen encode the transcription factor AtEBP, the 14-3-3 protein AtGF14 and two new proteins: AtMYR1 and AtPOZ1. None of these proteins turn on glucose repression. Instead, they illustrate various other ways by which foreign proteins can interfere with expression of a yeast gene. We conclude that our method worked as expected in at least one case, and that it could be applied to other signalling pathways that are conserved between yeast and higher eukaryotes.

Amino Acid Sequence↗
PubMed2002

Experimental evidence that the maize Activator (ac) transposase can act on a non-transposable element promoter to repress reporter gene expression in transient plant assays.

The transposase (TPase) encoded by the maize Activator (Ac) transposable element (TE) has been shown to repress the Ac TPase gene promoter (a form of element 'self-repression'). However, there is a lack of current experimental evidence to suggest that the Ac TPase can repress or activate the expression of non-TE gene promoters. Despite certain attributes of the maize Ac element and its TPase that might argue against such a broader, 'second function', that is, in regulating non-TE genes, the hypothesis that Ac TPase regulates gene expression was nevertheless tested in an in vivo tobacco BY-2 cell system using three different (non-TE) CaMV 35S promoters each linked to a gusA reporter gene. Four experiments were conducted; in each, BY-2 cells were co-transfected with two types of constructs: a CaMV 35S-gusA promoter construct (reporter) and an Ac expression construct (effector). In transient assays, a significant reduction in the magnitude of GUS enzyme activity was observed in the presence of an Ac effector (TPase-encoding) construct, below that observed for the 'no effector construct' treatment. A similar effector versus no effector comparison was made by Fridlender et al., who studied Ac element 'self-repression'. This Ac-associated GUS enzyme activity reduction was observed herein specifically for the gusA promoter construct with the 700 bp native CaMV 35S promoter region (a non-TE promoter). This construct contains 34 putative Ac TPase binding site motifs, 71% of which overlap one another on either DNA strand, motifs which also fall into the class of 'CpG islands' in plants. It is suggested that the Ac TPase can bind to such Ac DNA motifs and CpG islands existing within non-TE promoter regions, and can function as a regulator of transcription. Such a transcriptional mode of regulation has not been shown explicitly herein. The implications of the findings are discussed and a genomic (whole genome) regulation model is presented.

Base Sequence↗
PubMed1998

Retinoblastoma protein recruits histone deacetylase to repress transcription.

The retinoblastoma protein (Rb) silences specific genes that are active in the S phase of the cell cycle and which are regulated by E2F transcription factors. Rb binds to the activation domain of E2F and then actively represses the promoter by a mechanism that is poorly understood. Here we show that Rb associates with a histone deacetylase, HDAC1, through the Rb 'pocket' domain. Association with the deacetylase is reduced by naturally occurring mutations in the pocket and by binding of the human papilloma virus oncoprotein E7. We find that Rb can recruit histone deacetylase to E2F and that Rb cooperates with HDAC1 to repress the E2F-regulated promoter of the gene encoding the cell-cycle protein cyclin E. Inhibition of histone deacetylase activity by trichostatin A (TSA) inhibits Rb-mediated repression of a chromosomally integrated E2F-regulated promoter. Our results indicate that histone deacetylases are important for regulating the cell cycle and that active transcriptional repression by Rb may involve the modification of chromatin structure.

Amino Acid Sequence↗
PubMed1993

Specific repression of TATA-mediated but not initiator-mediated transcription by wild-type p53.

The p53 protein is apparently central to the development of human cancers because both alleles are often found to be mutated in different tumour types. In addition, wild-type p53 can inhibit transformation by viral and cellular oncogenes in vitro, so p53 has been classified as a tumour suppressor. Investigations of the normal function of p53 have indicated that at least one of its functions could involve the activation of gene expression through the binding of specific DNA-regulatory sequences. Also, overexpression of p53 can mediate growth arrest and repress transcription from a variety of promoters. We demonstrate here both in vivo and in vitro that expression of wild-type p53 specifically represses the activity of promoters whose initiation is dependent on the presence of a TATA box. Promoters whose accurate transcription is directed by a pyrimidine-rich initiator element, however, are immune to the effects of p53. Furthermore, we observe that repression is mediated by an interaction of p53 with basal transcription factor(s). Thus, p53 appears to repress the activity of certain promoters through direct communication with TATA box-dependent basal transcription machinery.

3T3 Cells↗
PubMed1994

Transcriptional repression directed by the yeast alpha 2 protein in vitro.

The alpha 2 protein, a homeodomain protein involved in specifying cell type in the budding yeast Saccharomyces cerevisiae, is a transcriptional repressor. alpha 2 binds cooperatively with Mcm1, a serum response factor-related protein, to the a-specific gene operator. The alpha 2-Mcm1 complex in turn recruits Ssn6 and Tup1 to the operator, and we believe that these latter two proteins are responsible for the transcriptional repression. Placement of the a-specific gene operator in any of a variety of positions upstream of a test promoter leads to repression of that promoter in vivo. In this respect, the a-specific gene operator resembles a negatively acting enhancer. Here we describe the in vitro reconstitution of this example of negative control from a distance. We observe repression in vitro in the absence of exogenously added activator protein and on templates that lack binding sites for known activator proteins, and we infer that alpha 2-directed repression acts on the general transcription machinery.

DNA-Binding Proteins↗
PubMed2004

The upstream sequence of Mycobacterium leprae 18-kDa gene confers transcription repression activity in orientation-independent manner.

In order to understand the role of the upstream region of the Mycobacterium leprae 18-kDa gene on the gene regulation, the region was divided into two at the -50 position from the first start codon of the gene and their effect on transcription was examined by using a LacZ transcriptional reporter gene assay. The presence of each of these two regions conferred transcription repression not only on its cognate M. lepraerae 18-kDa gene promoter, but also on a heterologous promoter such as the Mycobacterium bovis BCG hsp65 gene promoter. Moreover, it was found that these regions could confer transcription repression activity in both cases in an orientation-independent manner. Thus, these results indicate that the upstream region of the M. leprae 18-kDa gene harbors transcription repression responsive element(s) acting as an operator and can be further divided into two separately functional regions, suggesting a bipartite structure of the element(s). The identification of transcription repression activity of the upstream region in the M. leprae 18-kDa gene will contribute greatly for the understanding of the 18-kDa gene regulation mechanism, and provide also useful information for the manipulation of mycobacterium gene expression.

Bacterial Proteins↗
PubMed2005

LSD1 demethylates repressive histone marks to promote androgen-receptor-dependent transcription.

Gene regulation in eukaryotes requires the coordinate interaction of chromatin-modulating proteins with specific transcription factors such as the androgen receptor. Gene activation and repression is specifically regulated by histone methylation status at distinct lysine residues. Here we show that lysine-specific demethylase 1 (LSD1; also known as BHC110) co-localizes with the androgen receptor in normal human prostate and prostate tumour. LSD1 interacts with androgen receptor in vitro and in vivo, and stimulates androgen-receptor-dependent transcription. Conversely, knockdown of LSD1 protein levels abrogates androgen-induced transcriptional activation and cell proliferation. Chromatin immunoprecipitation analyses demonstrate that androgen receptor and LSD1 form chromatin-associated complexes in a ligand-dependent manner. LSD1 relieves repressive histone marks by demethylation of histone H3 at lysine 9 (H3-K9), thereby leading to de-repression of androgen receptor target genes. Furthermore, we identify pargyline as an inhibitor of LSD1. Pargyline blocks demethylation of H3-K9 by LSD1 and consequently androgen-receptor-dependent transcription. Thus, modulation of LSD1 activity offers a new strategy to regulate androgen receptor functions. Here, we link demethylation of a repressive histone mark with androgen-receptor-dependent gene activation, thus providing a mechanism by which demethylases control specific gene expression.

Androgens↗
PubMed2006

Oncogenic activity of Cdc6 through repression of the INK4/ARF locus.

The INK4/ARF locus encodes three tumour suppressors (p15(INK4b), ARF and p16(INK4a)) and is among the most frequently inactivated loci in human cancer. However, little is known about the mechanisms that govern the expression of this locus. Here we have identified a putative DNA replication origin at the INK4/ARF locus that assembles a multiprotein complex containing Cdc6, Orc2 and MCMs, and that coincides with a conserved noncoding DNA element (regulatory domain RD(INK4/ARF)). Targeted and localized RNA-interference-induced heterochromatinization of RD(INK4/ARF) results in transcriptional repression of the locus, revealing that RD(INK4/ARF) is a relevant transcriptional regulatory element. Cdc6 is overexpressed in human cancers, where it might have roles in addition to DNA replication. We have found that high levels of Cdc6 result in RD(INK4/ARF)-dependent transcriptional repression, recruitment of histone deacetylases and heterochromatinization of the INK4/ARF locus, and a concomitant decrease in the expression of the three tumour suppressors encoded by this locus. This mechanism is reminiscent of the silencing of the mating-type HM loci in yeast by replication factors. Consistent with its ability to repress the INK4/ARF locus, Cdc6 has cellular immortalization activity and neoplastic transformation capacity in cooperation with oncogenic Ras. Furthermore, human lung carcinomas with high levels of Cdc6 are associated with low levels of p16(INK4a). We conclude that aberrant expression of Cdc6 is oncogenic by directly repressing the INK4/ARF locus through the RD(INK4/ARF) element.

Animals↗