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Query: UNIPROT:P06889 (Mol)
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Rolling circle-replicating plasmids constitute a group of small, promiscuous multicopy replicons spread among eubacteria. Until recently, rolling circle replication seemed to be limited to small plasmids from Gram-positive hosts and to single-stranded bacteriophages from Gram-negative bacteria. However, characterization of two small plasmids from Gram-negative hosts has shown that this replication mechanism is general among eubacteria. This review focuses on a family of highly related promiscuous plasmids that replicate by the rolling circle mechanism, and that have been isolated from various Gram-positive bacteria and from the Gram-negative bacterium Helicobacter. They all share homologies at the leading-strand origins and at the initiator of replication proteins. The plasmids of this family have directly repeated sequences at their plus origin of replication, which is located 5' from the start point of the mRNA for the initiation of replication protein. Replication is controlled by an antisense RNA and by a transcriptional repressor protein. The features and regulatory circuits of replication of this plasmid family seem to be unique among rolling circle-replicating plasmids. Members of this family replicate autonomously in Gram-positive and -negative hosts.
Mol Microbiol 1993 May
PMID:Rolling circle-replicating plasmids from gram-positive and gram-negative bacteria: a wall falls. 835 6

The products of the HIR1 and HIR2 genes have been defined genetically as repressors of histone gene transcription in S. cerevisiae. A mutation in either gene affects cell cycle regulation of three of the four histone gene loci; transcription of these loci occurs throughout the cell cycle and is no longer repressed in response to the inhibition of DNA replication. The same mutations also eliminate autogenous regulation of the HTA1-HTB1 locus by histones H2A and H2B. The HIR1 and HIR2 genes have been isolated, and their roles in the transcriptional regulation of the HTA1-HTB1 locus have been characterized. Neither gene encodes an essential protein, and null alleles derepress HTA1-HTB1 transcription. Both HIR genes are expressed constitutively under conditions that lead to repression or derepression of the HTA1 gene, and neither gene regulates the expression of the other. The sequence of the HIR1 gene predicts an 88-kDa protein with three repeats of a motif found in the G beta subunit of retinal transducin and in a yeast transcriptional repressor, Tup1. The sequence of the HIR2 gene predicts a protein of 98 kDa. Both gene products contain nuclear targeting signals, and the Hir2 protein is localized in the nucleus.
Mol Cell Biol 1993 Jan
PMID:Characterization of HIR1 and HIR2, two genes required for regulation of histone gene transcription in Saccharomyces cerevisiae. 841 31

The expression of numerous Escherichia coli cellular proteins was previously demonstrated to be greatly enhanced in a hns deletion background, relative to the levels in wild-type cells. In this study, a subset of such proteins, expression of which is affected by H-NS, was partially purified, and the genes coding for some of the proteins were identified and characterized. Two of the proteins thus characterized, 19K and 17K, were found to be encoded by previously predicted genes that are located adjacent to, and downstream of, the trpABCDE operon (27.6 min on the E. coli genetic map). The genes coding for the other two proteins, 10K-L and 10K-S, are located at 77.5 min on the genetic map. Their nucleotide sequences were determined and revealed that they may constitute an operon. To characterize the putative promoters for these genes, a set of promoter-lacZ transcriptional fusion genes was constructed on the E. coli chromosome. The results of such promoter-probe analyses indicated that H-NS represses the expression of these genes at the transcriptional level. Furthermore, H-NS appeared to exhibit relatively strong affinity for the putative promoter sequences in vitro. These results are compatible with the hypothesis that H-NS functions as a transcriptional repressor.
Mol Gen Genet 1993 Feb
PMID:Function of the Escherichia coli nucleoid protein, H-NS: molecular analysis of a subset of proteins whose expression is enhanced in a hns deletion mutant. 845 49

We have shown previously that the immunoglobulin heavy-chain enhancer acts as a repressor of gene transcription in hybrids between immunoglobulin-producing myelomas and a T-lymphoma line. We have now mapped this repressive activity to a 51-bp enhancer subfragment which contains the octamer and mu E4 protein-binding motifs. Even a single copy of this subfragment will repress gene expression in hybrid cells. Mutational analyses of the repressor fragment suggest that in non-B cells, a strong transcriptional repressor(s) functions through the same motifs important for gene activation in B cells. Changes in chromatin structure that accompany reporter gene repression suggest a general mechanism for prohibiting immunoglobulin heavy-chain locus activation in inappropriate cell types.
Mol Cell Biol 1993 Jun
PMID:The octamer/mu E4 region of the immunoglobulin heavy-chain enhancer mediates gene repression in myeloma x T-lymphoma hybrids. 849 68

Diminished expression of major histocompatibility complex class I antigens on the surface of adenovirus type 12 (Ad12)-transformed cells contributes to their high tumorigenic potential by enabling them to escape immune recognition by cytotoxic T lymphocytes. This low class I antigen expression is due to a block in class I transcription, which is mediated by Ad12 E1A. Genetic analysis has shown that the class I enhancer is the target for transcriptional down-regulation. In this study, we show that the ability of the R1 element of the class I enhancer to stimulate transcription is greatly reduced in Ad12-transformed cells. The loss of functional activity by the R1 element was attributed to loss of binding by the NF-kappa B p50-p65 heterodimer. NF-kappa B binding appears to be blocked within the nucleus rather than at the level of nuclear translocation. Significantly, NF-kappa B binding activity could be recovered from the nuclear extracts of Ad12-transformed cells following detergent treatment, suggesting that the block is mediated through a nuclear inhibitor present in the Ad12-transformed cells. These results, taken together with the fact that the R2 element of the class I enhancer exhibits strong binding to the transcriptional repressor COUP-TF, suggest that the class I enhancer is globally down-regulated in Ad12-transformed cells.
Mol Cell Biol 1996 Jan
PMID:Evidence for the involvement of a nuclear NF-kappa B inhibitor in global down-regulation of the major histocompatibility complex class I enhancer in adenovirus type 12-transformed cells. 852 21

The cAMP response element modulator (CREM) gene encodes multiple activators and repressors of cAMP-responsive transcription. Differential splicing generates a developmental switch in CREM function during spermatogenesis, while the use of an alternative promoter is responsible for the production of a cAMP-inducible transcriptional repressor, ICER (inducible cAMP early repressor). The ICER promoter is strongly inducible by cAMP because of the presence of four tandemly repeated cAMP response elements. Furthermore, ICER negatively autoregulates the ICER promoter activity, thus generating a feedback loop. CREM constitutes an early response gene of the cAMP pathway in several neuroendocrine cells. We have previously shown that CREM is highly expressed in the adult rat pineal gland at nighttime. Here, we show that the only additional site of rhythmic ICER expression within the photoneuroendocrine system is the lamina intercalaris. Ontogenetically, the ICER day-night switch and cAMP inducibility mature in the pineal gland at the end of the first postnatal week. Importantly, this correlates with the onset of melatonin synthesis and the establishment of functional adrenergic innervation. At this developmental phase we document a significant increase in protein kinase A levels, thus suggesting that ICER inducibility reflects a complete maturation of the cAMP-dependent signaling pathway at the nuclear level.
Mol Endocrinol 1995 Jun
PMID:Developmental maturation of pineal gland function: synchronized CREM inducibility and adrenergic stimulation. 859 16

The actinomycete Amycolatopsis methanolica contains a 13.3 kb plasmid (pMEA300), capable of enhancing the spontaneous mutation frequency of its host. Depending on the growth medium pMEA300 is not only maintained as an integrated element but can additionally be present as a multicopy, autonomously replicating plasmid. The minimal replicon of pMEA300 was identified. Two unlinked DNA fragments of 2.6 kb and 0.8 kb were required for pMEA300 maintenance. Sequence analysis of the 2.6 kb fragment revealed at least two open reading frames, orfA and orfB, encoding putative proteins of 170 amino acids (18,373 Da) and 416 amino acids (45,260 Da), respectively. No clear similarities were found between the deduced amino acid sequences of the putative orfA and orfB products of pMEA300 and replication proteins identified for various Streptomyces plasmids. The pMEA300 proteins of A. methanolica thus may represent unfamiliar types. The 0.8 kb fragment contained a single complete open reading frame (korA), encoding a protein of 118 amino acids (12,917 Da). The putative KorA protein of pMEA300 shows sequence similarity with various other Streptomyces plasmid-encoded Kor proteins which may belong to the GntR family of transcriptional repressor proteins. The data provide preliminary evidence for the possible involvement of a kilkor system in autonomous replication of pMEA300.
Mol Microbiol 1995 Oct
PMID:Identification of the minimal replicon of plasmid pMEA300 of the methylotrophic actinomycete Amycolatopsis methanolica. 859 58

The Notch/Lin-12/Glp-1 receptor family participates in cell-cell signaling events that influence cell fate decisions. Although several Notch homologs and receptor ligands have been identified, the nuclear events involved in this pathway remain incompletely understood. A truncated form of Notch, consisting only of the intracellular domain (NotchIC), localizes to the nucleus and functions as an activated receptor. Using both an in vitro binding assay and a cotransfection assay based on the two-hybrid principle, we show that mammalian NotchIC interacts with the transcriptional repressor CBF1, which is the human homolog of Drosophila Suppressor of Hairless. Cotransfection assays using segments of mouse NotchIC and CBF1 demonstrated that the N-terminal 114-amino-acid region of mouse NotchIC contains the CBF1 interactive domain and that the cdc10/ankyrin repeats are not essential for this interaction. This result was confirmed in immunoprecipation assays in which the N-terminal 114-amino-acid segment of NotchIC, but not the ankyrin repeat region, coprecipitated with CBF1. Mouse NotchIC itself is targeted to the transcriptional repression domain (aa179 to 361) of CBF1. Furthermore, transfection assays in which mouse NotchIC was targeted through Gal4-CBF1 or through endogenous cellular CBF1 indicated that NotchIC transactivates gene expression via CBF1 tethering to DNA. Transactivation by NotchIC occurs partially through abolition of CBF1-mediated repession. This same mechanism is used by Epstein-Barr virus EBNA2. Thus, mimicry of Notch signal transduction is involved in Epstein-Barr virus-driven immortalization.
Mol Cell Biol 1996 Mar
PMID:Truncated mammalian Notch1 activates CBF1/RBPJk-repressed genes by a mechanism resembling that of Epstein-Barr virus EBNA2. 862 98

Unliganded thyroid hormone receptor (TR) functions as a transcriptional repressor of genes bearing thyroid hormone response elements in their promoters. Binding of hormonal ligand to the receptor releases the transcriptional silencing and leads to gene activation. Previous studies showed that the silencing activity of TR is located within the C-terminal ligand-binding domain (LBD) of the receptor. To dissect the role of the LBD in receptor-mediated silencing, we used a cell-free transcription system containing HeLa nuclear extracts in which exogenously added unliganded TRbeta repressed the basal level of RNA polymerase II-driven transcription from a thyroid hormone response element-linked template. We designed competition experiments with a peptide fragment containing the entire LBD (positions 145 to 456) of TRbeta. This peptide, which lacks the DNA-binding domain, did not affect basal RNA synthesis from the thyroid hormone response element-linked promoter when added to a cell-free transcription reaction mixture. However, the addition of the LBD peptide to a reaction mixture containing TRbeta led to a complete reversal of receptor-mediated transcriptional silencing in the absence of thyroid hormone. An LBD peptide harboring point mutations, which severely impair receptor dimerization, also inhibited efficiently the silencing activity of TR, indicating that the relief of repression by the LBD was not due to the sequestration of TR or its heterodimeric partner retinoid X receptor into inactive homo- or heterodimers. We postulate that the LBD peptide competed with TR for a regulatory molecule, termed a corepressor, that exists in the HeLa nuclear extracts and is essential for efficient receptor-mediated gene repression. We have identified the region from positions 145 to 260 (the D domain) of the LBD as a potential binding site of the putative corepressor. We observed further that a peptide containing the LBD of retinoic acid receptor (RAR) competed for TR-mediated silencing, suggesting that the RAR LBD may bind to the same corepressor activity as the TR LBD. Interestingly, the RAR LBD complexed with its cognate ligand, all-trans retinoic acid, failed to compete for transcriptional silencing by TRbeta, indicating that the association of the LBD with the corepressor is ligand dependent. Finally, we provide strong biochemical evidence supporting the existence of the corepressor activity in the HeLa nuclear extracts. Our studies demonstrated that the silencing activity of TR was greatly reduced in the nuclear extracts preincubated with immobilized, hormone-free glutathione S-transferase-LBD fusion proteins, indicating that the corepressor activity was depleted from these extracts through protein-protein interactions with the LBD. Similar treatment with immobilized, hormone-bound glutathione S-transferase-LBD, on the other hand, failed to deplete the corepressor activity from the nuclear extracts, indicating that ligand binding to the LBD disrupts its interaction with the corepressor. From these results, we propose that a corepressor binds to the LBD of unliganded TR and critically influences the interaction of the receptor with the basal transcription machinery to promote silencing. Ligand binding to TR results in the release of the corepressor from the LBD and triggers the reversal of silencing by allowing the events leading to gene activation to proceed.
Mol Cell Biol 1996 May
PMID:Transcriptional silencing by unliganded thyroid hormone receptor beta requires a soluble corepressor that interacts with the ligand-binding domain of the receptor. 862 57

The mouse mammary tumor virus (MMTV) promoter is transcriptionally silent prior to hormonal induction, partly because its organization into phased nucleosomes precludes access of transcription factors to their cognate sites. A T47D-derived cell line carrying a single integrated copy of the MMTV promoter exhibited a positioned nucleosome, which prevented binding of nuclear factor I (NFI). To study the molecular mechanisms controlling promoter accessibility we have made use of a strong chimeric transactivator, NFI-VP16, composed of NFI linked to the transactivation function of VP16. T47D cells transiently transfected with an MMTV-CAT reporter show little transcription even after cotransfection of an expression vector for NFI-VP16. However, a truncated MMTV promoter, lacking the hormone regulatory region (HRR) was transactivated by cotransfected NFI-VP16. The repressive effect of the HRR was not due to binding of a sequence-specific transcriptional repressor, and was evident with the DEAE-Dextran transfection procedure but not with the calcium phosphate technique. A similar behavior was observed in Saccharomyces cerevisiae carrying wild type or truncated MMTV-lacZ reporters and expressing NFI-VP16. Reconstitution experiments suggest that the promoter lacking the HHR generates less stable nucleosomes, a fraction of which contain a more accessible NFI site. Recombinant NFI binds to nucleosomes assembled on this truncated promoter but not to nucleosomes encompassing the HRR. These results are compatible with the notion that transiently transfected MMTV promoters behave like their stably integrated counterparts, in that the HRR drives positioning of a nucleosome and mediates transcriptional repression by preventing access of NFI to its cognate site.
J Steroid Biochem Mol Biol 1996 Jan
PMID:The hormone responsive region of mouse mammary tumor virus positions a nucleosome and precludes access of nuclear factor I to the promoter. 864 14


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