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At least 973 records · Page 54Linked to original sources
PubMed1997

Mapping of adenovirus 5 E1A domains responsible for suppression of neu-mediated transformation via transcriptional repression of neu.

Overexpression of neu (also known as c-erbB-2 or HER-2) commonly occurs in human cancer and is also known to enchance tumor metastasis and chemoresistance. Our earlier reports showed that the adenovirus 5 E1A can suppresss the neu-mediated transformation by repression of neu. Thus, E1A has the potential to be used as a therapeutic agent against the neu-overexpressing human cancers. However, a serious concern to this approach is that E1A is also capable of immortalizing primary culture cells and can co-operate with ras or E1B oncogenes to transform them. The E1A CR2 domain (amino acid residues 120 to 140) necessary for binding to RB is believed to be required for this oncogenic function. Here, we report that deletion of CR2 region did not affect E1A's capability to repress neu. Interestingly, deletion of the amino acid residues 4 to 25 or 40 to 80 completely disrupted E1A-mediated neu repression. By deleting the amino acid residues from 81 to 185, we have successfully generated a mini-E1A mutant that was sufficient to inhibit neu promoter activity and suppress neu-mediated transformation. The mini-E1A mutant does not contain the CR2 domain that is crucial for RB binding and immortalization, and hence, may serve as a more selective tumor suppressor, and a safer therapeutic agent. It may also be a useful tool to further investigate the molecular mechanism(s) of neu overexpression and E1A-mediated transcriptional repression in cancer cells.

3T3 Cells↗
PubMed1995

The monomer-binding orphan receptor Rev-Erb represses transcription as a dimer on a novel direct repeat.

Rev-Erb is an orphan nuclear receptor which binds as a monomer to the thyroid/retinoic acid receptor half-site AGGTCA flanked 5' by an A/T-rich sequence, referred to here as a Rev monomer site. Fusion of Rev-Erb to the DNA binding domain of yeast GAL4 strongly repressed basal transcription of a GAL4-luciferase reporter gene as a result of the presence of a C-terminal domain containing both the hinge and heptad repeat regions. Nevertheless, wild-type Rev-Erb did not repress basal transcription from the Rev monomer binding site. Therefore, a DNA binding site selection strategy was devised to test the hypothesis that Rev-Erb may function on a different site as a dimer. This approach identified sequences containing two Rev monomer sites arranged as direct repeats with the AGGTCA motifs separated by 2 bp (Rev-DR2). Remarkably, Rev-Erb bound as a homodimer to Rev-DR2 but not to other direct repeats or to a standard DR2 sequence. The DNA binding domain contained all of the determinants for Rev-DR2-specific homodimerization. Rev-Erb bound cooperatively as a homodimer to Rev-DR2, and this interaction was 5 to 10 times more stable than Rev-Erb monomer binding to the Rev monomer site. Functionally, Rev-Erb markedly repressed the basal activity of a variety of promoters with a strong Rev-DR2 specificity. The C terminus was required for this repression, consistent with the GAL4 results. However, the Rev-DR2 specificity did not require the C terminus in vivo, since fusion of C-terminally truncated Rev-Erb to a heterologous transactivation domain created a transcriptional activator specific for Rev-DR2. In addition to idealized Rev-DR2 sites, Rev-Erb also repressed basal as well as retinoic acid-induced transcription from a naturally occurring Rev-DR2 in the CRBPI gene. Thus, although Rev-Erb is distinguished from other thyroid/steroid receptor superfamily members by its ability to bind DNA as a monomer, it functions as a homodimer to repress transcription of genes containing a novel DR2 element.

Base Sequence↗
PubMed1992

Repressive coping and verbal-autonomic response dissociation: the influence of social context.

This study examined whether verbal-autonomic response dissociation in repressive copers is potentiated by conditions that enhance social evaluative concerns. Women classified as repressive, low-anxious, or high-anxious gave a self-disclosing speech in either a private condition (a single researcher observed) or a public condition (3 researchers ostensibly observed). Repressors exhibited heart rate elevations that were greater in magnitude than their self-reports of negative affect, but only in the public condition. High-anxious Ss in both conditions showed an opposite pattern of verbal-autonomic dissociation in which self-reported negative affect exceeded cardiac response. Low-anxious Ss in both conditions showed little responsivity in either channel. Results are interpreted within a self-regulatory framework in which differences in self-concept in the domain of emotionality predispose repressive and high-anxious individuals to engage in contrasting, emotion-focused coping styles.

Adaptation, Psychological↗
PubMed1993

Interferon-beta promoters contain a DNA element that acts as a position-independent silencer on the NF-kappa B site.

The human interferon-beta (IFN-beta) promoter contains several functional domains that contribute to its virus-inducible regulation. One of them, PRDII, and NF-kappa B-binding sequence, can function as a constitutively activating element. Due to the presence of a negative regulatory domain that mediates a constitutive repression the natural IFN-beta promoter is silent in the non-induced state. Within this domain we have delimited an 11 bp element that acts as a negative regulatory element (NRE) of PRDII. Although the NRE is physically overlapping with PRDII in the IFN-beta promoter, it acts as a position-independent silencer of PRDII. Virus infection, which leads to the transcriptional activation of the IFN-beta promoter, does not alter the negative activity of the NRE on an isolated PRDII. It is the cooperative effect of PRDI and PRDII that is able to overcome the NRE function after virus infection. By UV cross-linking analysis using uninduced and virus-induced nuclear extracts, we show that two factors with molecular masses of approximately 95 and 100 kDa bind to the NRE.

Base Sequence↗
PubMed2006

Estrogen-occupied estrogen receptor represses cyclin G2 gene expression and recruits a repressor complex at the cyclin G2 promoter.

Estrogens, acting through their nuclear receptors have a broad impact on target cells, eliciting a transcriptional response program that involves gene repression as well as gene stimulation. While much is known about the mechanisms by which the estrogen-occupied estrogen receptor (ER) stimulates gene expression, the molecular events that lead to gene repression by the hormone-ER complex are largely unknown. Because estradiol represses expression of the cyclin G2 gene, which encodes a negative regulator of the cell cycle, our aim was to understand the mechanism by which cyclin G2 is repressed by estrogen. We show that cyclin G2 is a primary ER target gene in MCF-7 breast cancer cells that is rapidly and robustly down-regulated by estrogen. Promoter analysis reveals a responsive region containing a half-estrogen response element and GC-rich region that interact with ER and Sp1 proteins. Mutation of the half-ERE abrogates hormone-mediated repression. Mutational mapping of receptor reveals a requirement for its N-terminal region and DNA binding domain to support cyclin G2 repression. Following estradiol treatment of cells, chromatin immunoprecipitation analyses reveal recruitment of ER to the cyclin G2 regulatory region, dismissal of RNA polymerase II, and recruitment of a complex containing N-CoR and histone deacetylases, leading to a hypoacetylated chromatin state. Our study provides evidence for a mechanism by which the estrogen-occupied ER is able to actively repress gene expression in vivo and indicates a role for nuclear receptor corepressors and associated histone deacetylase activity in mediating negative gene regulation by this hormone-occupied nuclear receptor.

Cell Line, Tumor↗
PubMed1998

RP58 associates with condensed chromatin and mediates a sequence-specific transcriptional repression.

An approximately 120-amino acid domain present generally at the NH2 termini, termed the POZ domain, is highly conserved in various proteins with zinc finger DNA binding motifs. We have isolated a novel protein sharing homology with the POZ domain of a number of zinc finger proteins, including the human BCL-6 protein. By using a binding site selection technique (CAST), a high affinity binding site of the protein was determined to be (A/C)ACATCTG(G/T)(A/C), containing the E box core sequence motif. The protein was shown to repress transcription from a promoter linked to its target sequences and was hence named RP58 (Repressor Protein with a predicted molecular mass of 58 kDa). Immunogold electron microscopic study revealed that almost all RP58 is localized in condensed chromatin regions. These observations demonstrate for the first time that a protein mediating a sequence-specific transcriptional repression associates with highly condensed chromatin. We suggest that RP58 may be involved in a molecular link between sequence-specific transcriptional repression and the organization of chromosomes in the nucleus.

Amino Acid Sequence↗
PubMed2006

Ectopic expression of Tollo/Toll-8 antagonizes Dpp signaling and induces cell sorting in the Drosophila wing.

The wing imaginal disc of Drosophila consists of the primordia for the adult wing and the body wall. The zinc-finger transcription factor Teashirt (Tsh) is expressed in the region proximal to the wing primordium and regulates the formation of the wing-body wall boundary. Here, we report that Tollo/Toll-8, a member of Toll family transmembrane proteins, is also expressed proximal to the wing domain. Ectopic expression of Decapentaplegic (Dpp), a morphogen for wing development, represses tollo expression in the proximal domain. Likewise, misexpression of Tollo in the presumptive wing strongly antagonizes the effects of Dpp signaling. The extracellular domain of Tollo containing the Leucine-Rich Repeats (LRR) is required for the inhibition of Dpp signaling in the wing. Furthermore, clones of cells with Tollo overexpression are sorted out from the surrounding wild-type cells, resulting in the formation of epithelial folds around the clone boundaries. Tsh is ectopically induced at the border of Tollo-expressing clones. Despite the strong effects of Tollo overexpression on Dpp signaling and cell sorting, loss-of-function tollo mutants are viable with normal external morphology. Our data suggest that Tollo function might be redundant but is sufficient to antagonize Dpp signaling and induce sorting of Tollo expressing cells from the wing cells to develop proximal cell fate.

Animals↗
PubMed1998

Drosophila Goosecoid requires a conserved heptapeptide for repression of paired-class homeoprotein activators.

Goosecoid (Gsc) is a homeodomain protein expressed in the organizer region of vertebrate embryos. Its Drosophila homologue, D-Gsc, has been implicated in the formation of the Stomatogastric Nervous System. Although there are no apparent similarities between the phenotypes of mutations in the gsc gene in flies and mice, all known Gsc proteins can rescue dorsoanterior structures in ventralized Xenopus embryos. We describe how D-Gsc behaves as a transcriptional repressor in Drosophila cells, acting through specific palindromic HD binding sites (P3K). D-Gsc is a 'passive repressor' of activator homeoproteins binding to the same sites and an 'active repressor' of activators binding to distinct sites. In addition, D-Gsc is able to strongly repress transcription activated by Paired-class homeoproteins through P3K, via specific protein-protein interactions in what we define as 'interactive repression'. This form of repression requires the short conserved GEH/eh-1 domain, also present in the Engrailed repressor. Although the GEH/eh-1 domain is necessary for rescue of UV-ventralized Xenopus embryos, it is dispensable for ectopic induction of Xlim-1 expression, demonstrating that this domain is not required for all Gsc functions in vivo. Interactive repression may represent specific interactions among Prd-class homeoproteins, several of which act early during development of invertebrate and vertebrate embryos.

Amino Acid Sequence↗
PubMed1994

The hormone binding domain of the mineralocorticoid receptor can regulate heterologous activities in cis.

Steroid receptors are maintained inactive in the absence of cognate ligand partly because of repression by their hormone binding domain (HBD). Proteins complexed with the unliganded HBD of vertebrate steroid receptors, including the heat-shock protein 90, have been implicated as components of a molecular switch. As such, the HBDs of both the glucocorticoid and estrogen receptors have been shown to be autonomous regulatory cassettes which can subject heterologous activities resident on the same polypeptide to hormonal control. We show that the HBD of the mineralocorticoid receptor (MR) carries a similar "protein inactivation" function. Thus, the MR HBD can be used as a movable regulatory domain, a powerful tool for aldosterone regulation of chimeric proteins.

Aldosterone↗
PubMed2000

Groucho/TLE family proteins and transcriptional repression.

The Drosophila Groucho (Gro) protein is the prototype for a large family of corepressors, examples of which are found in most metazoans. This family includes the human transducin-like Enhancer of split (TLE) proteins. As corepressors, Gro/TLE family proteins do not bind to DNA directly, but rather are recruited to the template by DNA-bound repressor proteins. Gro/TLE family proteins are required for many developmental processes, including lateral inhibition, segmentation, sex determination, dorsal/ventral pattern formation, terminal pattern formation, and eye development. These proteins are characterized by a conserved N-terminal glutamine-rich domain and a conserved C-terminal WD-repeat domain. The primary role of the glutamine-rich domain is apparently to mediate tetramerization, while the WD-repeat domain may mediate interactions with DNA-bound repressors. The glutamine rich and WD-repeat domains are separated by a less conserved region containing domains that have been implicated in transcriptional repression and nuclear localization. In addition to encoding full-length Gro/TLE family proteins, most metazoan genomes encode truncated family members that contain the N-terminal oligomerization domain, but lack the C-terminal WD-repeat domain. These truncated proteins may negatively regulate full-length Gro/TLE proteins, perhaps by sequestering them in non-productive complexes. Gro/TLE family proteins probably repress transcription by multiple mechanisms. For example, a glycine/proline-rich domain in the central variable region functions to recruit the histone deacetylase Rpd3 to the template. This histone deacetylase then presumably silences transcription by altering local chromatin structure. Other repression domains in Gro may function in a histone deacetylase-independent manner. Many aspects of Gro/TLE protein function remain to be explored, including the possible post-translational regulation of Gro/TLE activity as well as the mechanisms by which Gro/TLE proteins direct repression at a distance.

Animals↗
PubMed1999

p53 represses CAAT enhancer-binding protein (C/EBP)-dependent transcription of the albumin gene. A molecular mechanism involved in viral liver infection with implications for hepatocarcinogenesis.

p53 is a transcription factor that is activated by genotoxic stress and mediates cell cycle arrest and apoptosis. Here we demonstrate that infection of mouse liver with recombinant E1/E3-deleted adenovirus leads to p53 activation and simultaneously to the down-regulation of albumin gene expression. In vitro transcription assays indicate that transcriptional mechanisms mediated through the albumin promoter are responsible for reduced albumin mRNA levels during viral infection. Albumin expression is maintained in the liver by a combination of liver-enriched transcription factors such as CAAT enhancer-binding protein (C/EBP)alpha and C/EBPbeta. We show that p53 wild type and tumor-derived p53 mutations repress C/EBP-mediated transactivation of the albumin promoter. The binding of C/EBPalpha or -beta to its cognate sequence in the albumin promoter is not inhibited by p53 expression. Deletion analysis and domain swapping experiments show that repression of C/EBPbeta-mediated transactivation is dependent on the N-terminal domain of p53 and the transactivation domain, leucine zipper domain, and the inhibitory domain II (amino acids 163-191) of C/EBPbeta. Our results provide a molecular explanation for the p53-mediated down-regulation of liver-specific gene expression after viral infection. Additionally, as overexpression of p53 mutants is frequently found in undifferentiated hepatocellular carcinomas, the same mechanisms may contribute to the lack of liver-specific gene transcription in these tumors.

Albumins↗
PubMed1997

Gene silencing by chicken ovalbumin upstream promoter-transcription factor I (COUP-TFI) is mediated by transcriptional corepressors, nuclear receptor-corepressor (N-CoR) and silencing mediator for retinoic acid receptor and thyroid hormone receptor (SMRT).

Chicken ovalbumin upstream promoter-transcription factors (COUP-TFs) are orphan receptors that belong to the steroid/thyroid hormone receptor (TR) superfamily and can repress the transcriptional activity of several target genes; however, the precise mechanism of this repression is unknown. Transfection of a Gal4 DNA-binding domain fused to the putative ligand-binding domain of COUP-TFI (Gal4-COUP-TFI) significantly represses the basal transcriptional activity of a reporter gene containing Gal4-binding sites. Cotransfection of COUP-TFI can relieve the Gal4-COUP-TFI repression in a dose-dependent manner. In contrast, COUP-TFI delta35, which lacks the repressor domain (the C-terminal 35 amino acids), fails to relieve this repression. This finding suggests that the repressor domain of COUP-TFI may squelch a limiting amount of corepressor in HeLa cells. In addition, increasing concentrations of TRbeta also can relieve the COUP-TFI repression in a hormone-sensitive manner. Similarly, overexpression of increasing concentration of COUP-TFI, but not COUP-TFI delta35, can squelch the silencing activity of the unliganded TRbeta. Collectively, these results indicate that COUP-TFI and TRbeta share a common corepressor(s) for their silencing activity. To determine which corepressor is involved in the COUP-TF-silencing activity, we used a yeast two-hybrid and in vitro GST pull-down assays to demonstrate that COUP-TFI can interact with the fragment of N-CoR (nuclear receptor-corepressor) encoding amino acids 921-2453 and the fragments of SMRT (silencing mediator for retinoic acid receptor and TR) encoding amino acids 29-564 and 565-1289, respectively. Interestingly, the fragment of SMRT encoding amino acids 1192-1495, which strongly interacts with TRbeta, interacts very weakly with COUP-TFI. Furthermore, overexpression of N-CoR or SMRT potentiates the silencing activity of COUP-TFI and can relieve the COUP-TFI-mediated squelching of Gal4-COUP-TFI activity. Therefore, our studies indicate that N-CoR and SMRT act as corepressors for the COUP-TFI silencing activity.

Animals↗
PubMed2002

Estrogen receptor-mediated repression of human hepatic lipase gene transcription.

Estrogen replacement therapy in women decreases hepatic lipase (HL) activity, which may account for the associated increase in HDL cholesterol. To investigate whether estrogen decreases HL transcription, transient cotransfection assays with HL promoter and estrogen receptor-alpha (ERalpha) expression constructs were performed in HepG2 cells. 17beta-estradiol (E(2)) decreased transcription driven by the -1557/+41 human HL promoter by up to 50% at 10(-7) M. Mutation of ERalpha by deletion of its transactivation domains or ligand-binding domain eliminated E(2)-induced repression of the promoter, whereas deletion of the DNA-binding domain of ERalpha resulted in a 7-fold activation by E(2). The E(2)-induced repression was maintained after mutation of a potential estrogen-response element in the promoter. The region of estrogen responsiveness was localized to -1557/-1175 of the HL promoter by deletion analysis. Mutation of an AP-1 site at -1493 resulted in a partial loss of E(2)-induced repression, similar to that caused by deletion of nucleotides -1557 to -1366. Gel shift assays with nuclear extracts from E(2)-treated HepG2 cells stably expressing ERalpha demonstrated an increase in binding to an AP-1 consensus oligonucleotide. The AP-1 activator, phorbol 12-myristate 13-acetate, inhibited the HL promoter by greater than 50%. Collectively, the data suggest that estrogen represses the transcription of the HL gene, possibly through an AP-1 pathway.

5' Untranslated Regions↗
PubMed1990

Promoter-specific trans activation and repression by human cytomegalovirus immediate-early proteins involves common and unique protein domains.

trans activation of promoters by viral regulatory proteins provides a useful tool to study coordinate control of gene expression. Immediate-early (IE) regions 1 and 2 of human cytomegalovirus (CMV) code for a series of proteins that originate from differentially spliced mRNAs. These IE proteins are proposed to regulate the temporal expression of the viral genome. To examine the structure and function of the IE proteins, we used linker insertion mutagenesis of the IE gene region as well as cDNA expression vector cloning of the abundant IE mRNAs. We showed that IE1 and IE2 proteins of CMV exhibit promoter-specific differences in their modes of action by either trans activating early and IE promoters or repressing the major IE promoter (MIEP). Transient cotransfection experiments with permissive human cells revealed a synergistic interaction between the 72- and the 86-kilodalton (kDa) IE proteins in trans activating an early promoter. In addition, transfection studies revealed that the 72-kDa protein was capable of trans activating the MIEP. In contrast, the 86-kDa protein specifically repressed the MIEP and this repression was suppressed by the 72-kDa protein. Furthermore, observations based on the primary sequence structure revealed a modular arrangement of putative regulatory motifs that could either potentiate or repress gene expression. These modular domains are either shared or unique among the IE proteins. From these data, we propose a model for IE protein function in the coordinate control of CMV gene expression.

Base Sequence↗
PubMed1998

Retinoblastoma protein represses transcription by recruiting a histone deacetylase.

The retinoblastoma tumour-suppressor protein Rb inhibits cell proliferation by repressing a subset of genes that are controlled by the E2F family of transcription factors and which are involved in progression from the G1 to the S phase of the cell cycle. Rb, which is recruited to target promoters by E2F1, represses transcription by masking the E2F1 transactivation domain and by inhibiting surrounding enhancer elements, an active repression that could be crucial for the proper control of progression through the cell cycle. Some transcriptional regulators act by acetylating or deacetylating the tails protruding from the core histones, thereby modulating the local structure of chromatin: for example, some transcriptional repressors function through the recruitment of histone deacetylases. We show here that the histone deacetylase HDAC1 physically interacts and cooperates with Rb. In HDAC1, the sequence involved is an LXCXE motif, similar to that used by viral transforming proteins to contact Rb. Our results strongly suggest that the Rb/HDAC1 complex is a key element in the control of cell proliferation and differentiation and that it is a likely target for transforming viruses.

Amino Acid Sequence↗
PubMed1993

Negative regulation of the neu promoter by the SV40 large T antigen.

The neu gene is amplified and its protein product is overexpressed in certain human tumors. The adenovirus 5 E1a gene product and c-myc repress neu transcription. Moreover, expression of E1a in neu-transformed cells leads to decrease in transformation phenotype and metastatic potential. The simian virus 40 large T antigen (LT) shares structural and functional homology with E1a and c-myc, and all three proteins bind to the retinoblastoma gene product, Rb. We found that LT also represses neu expression at the transcriptional level. However, LT represses neu promoter by a different mechanism compared to E1a and c-myc, because the region of the neu promoter mediating repression by LT (-172 to -79) is downstream from the region responding to E1a and c-myc (-312 to -172). In addition, a LT mutant (K1) unable to complex Rb still represses neu promoter activity, indicating that the Rb binding domain of LT is not required for repression of neu. Since K1, unlike LT, does not transform Rat-1 cells but, like LT, represses the neu promoter, we tested whether K1 functions as a transformation suppressor of activated neu oncogene. Focus-forming assays showed that K1 indeed suppresses the strong cell-transforming activity of activated neu.

Animals↗
PubMed2003

Randomly inserted and targeted Hox/reporter fusions transcriptionally silenced in Polycomb mutants.

Polycomb-group (Pc-G) proteins ensure late maintenance of transcriptional repression outside the expression domain of target genes in flies and vertebrates. They act in complexes, presumably by modulating chromatin structure. In Drosophila, they have been found to be associated with transcriptionally inactive loci but seem to be present in association with actively transcribed promoters as well, a feature which is not yet understood. In the mouse, mutations in several Pc-G genes result in an often subtle, local derepression of only a subset of the Hox genes rostral to their expression domains. We report here that Hox/reporter fusion genes, either randomly integrated as transgenes or as insertions within endogenous loci, are transcriptionally silenced in two mouse Pc-G-null mutants, Mel18 and rae28. Transcriptional silencing of Hox/reporter transgenes in Pc-G mutants was accompanied by increased DNA methylation in the promoter region. Gene silencing was observed at early developmental stages, long before Pc-G and trithorax-group proteins exert their function in maintenance of the Hox patterns. Although all five Hox genes tested as Hox/reporter fusions were silenced in the Pc-G mutants, transcription of the endogenous loci was mildly decreased in a subset of these Hox genes, and Hoxb1 was the most strongly affected. We discuss the possibilities that the observed negative effect of Pc-G mutations on Hox and Hox/reporter expression may reflect a positive involvement of the Pc-G epigenetic repressors in initial Hox gene transcription and that this requirement is exacerbated by the reporter insertion.

Alkaline Phosphatase↗
PubMed2005

Regulation of iro3 expression in the zebrafish spinal cord.

Specification of spinal cord neurons is regulated by several different transcription factors. In this study, we analyze expression and regulation of the transcription factor iro3 in zebrafish spinal cord. In addition to its broad expression in the progenitor domain of intermediate spinal cord, iro3 is also expressed in postmitotic ventral neurons, starting at early somitogenesis stages. Initially, this expression is only in two primary motoneurons, CaP and VaP, but by 24 hr postfertilization, iro3 is expressed by all classes of zebrafish spinal motoneurons as well as by a ventral interneuron called VeLD. iro3 expression in the progenitor domain of intermediate spinal cord is regulated independently from its expression in ventral neurons. Hedgehog (Hh) signaling is unnecessary for iro3 expression in intermediate spinal cord, but it is required to repress iro3 expression in the progenitor domain of ventral spinal cord. We also show that the basic helix-loop-helix transcription factor Olig2 is required for repression of iro3 expression in the progenitor domain of ventral spinal cord. We discuss our findings in the context of previous studies, suggesting that iro3 represses formation of motoneurons and promotes formation of interneurons.

Alleles↗