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At least 757 records · Page 42Linked to original sources
PubMed2006

Growth factor signaling regulates elongation of RNA polymerase I transcription in mammals via UBF phosphorylation and r-chromatin remodeling.

Synthesis of the 45S rRNA by RNA polymerase I limits cell growth. Knowledge of the mechanism of its regulation is therefore key to understanding growth control. rRNA transcription is believed to be regulated solely at initiation/promoter release. However, we found that stimulation of endogenous 45S rRNA synthesis by epidermal growth factor (EGF) and serum failed to induce an increase in RNA polymerase I engagement on the rRNA genes, despite robust enhancement of 45S rRNA synthesis. Further, endogenous transcription elongation rates were measured and found to be directly proportional to 45S rRNA synthesis. Thus, elongation is a rate-limiting step for rRNA synthesis in vivo. ERK phosphorylation of the HMG boxes of UBF, an RNA polymerase I factor essential for transcription enhancement, was shown to directly regulate elongation by inducing the remodeling of ribosomal gene chromatin. The data suggest a mechanism for coordinating the cotranscriptional assembly of preribosomal particles.

Animals↗
PubMed2001

Cytochrome oxidase subunit VI of Trypanosoma brucei is imported without a cleaved presequence and is developmentally regulated at both RNA and protein levels.

Mitochondrial respiration in the African trypanosome undergoes dramatic developmental stage regulation. This requires co-ordinated control of components encoded by both the nuclear genome and the kinetoplast, the unusual mitochondrial genome of these parasites. As a model for understanding the co-ordination of these genomes, we have examined the regulation and mitochondrial import of a nuclear-encoded component of the cytochrome oxidase complex, cytochrome oxidase subunit VI (COXVI). By generating transgenic trypanosomes expressing intact or mutant forms of this protein, we demonstrate that COXVI is not imported using a conventional cleaved presequence and show that sequences at the N-terminus of the protein are necessary for correct mitochondrial sorting. Analyses of endogenous and transgenic COXVI mRNA and protein expression in parasites undergoing developmental stage differentiation demonstrates a temporal order of control involving regulation in the abundance of, first, mRNA and then protein. This represents the first dissection of the regulation and import of a nuclear-encoded protein into the cytochrome oxidase complex in these organisms, which were among the earliest eukaryotes to possess a mitochondrion.

Amino Acid Sequence↗
PubMed1990

Regulation of mdr RNA levels in response to cytotoxic drugs in rodent cells.

The mdr gene, which encodes an energy-dependent multidrug efflux pump termed P-glycoprotein, is expressed in some normal human and rodent tissues, including the adrenal gland, kidney, liver, colon, small intestine, and brain and testis capillary endothelial cells. Because of the important role played by the multidrug transporter in determining sensitivity of normal tissues and resistance of cancers to chemotherapeutic drugs, we and others have been determining the environmental factors which regulate expression of the mdr gene. In previous studies, expression of the human MDR1 gene has been shown to be regulated by heat shock, arsenite, and cadmium in a kidney carcinoma cell line, and mdr RNA is dramatically elevated in rat liver after partial hepatectomy or treatment of the animals with cytotoxic agents. We have now investigated the genetic response of the mdr gene to acute cytotoxic insults in rodent and human tissue culture cells. Following exposure to several drugs, most of which are known to be substrates for the multidrug transporter, mdr RNA levels were found to increase substantially in the rodent cells, but not the human cells. Furthermore, RNA levels for topoisomerase II, an intracellular target for these drugs, decreased in the rodent cells. These results suggest a complex pattern of regulation of mdr RNA levels, depending on animal species and cell type, and possible coordinate regulation with topoisomerase II RNA levels.

Animals↗
PubMed2002

The transcriptional regulator RfaH stimulates RNA chain synthesis after recruitment to elongation complexes by the exposed nontemplate DNA strand.

The transcriptional regulatory protein RfaH controls expression of several operons that encode extracytoplasmic components in bacteria. Regulation by RfaH occurs during transcript elongation and depends on a 5'-proximal, transcribed nucleic acid sequence called ops that induces transcriptional pausing in vitro and in vivo. We report that RfaH recognizes RNA polymerase transcribing RfaH-regulated operons by interacting with the ops sequence in the exposed nontemplate DNA strand of ops-paused transcription complexes. Although RfaH delays escape from the ops pause, once escape occurs, RfaH enhances elongation by suppressing pausing and rho-dependent termination without apparent involvement of other accessory proteins. This activity predicts a cumulative antitermination model for RfaH's regulation of ops-containing operons in vivo.

Bacteria↗
PubMed2004

Lipopolysaccharide and double-stranded RNA up-regulate toll-like receptor 2 independently of myeloid differentiation factor 88.

Toll-like receptor 2 (TLR2) is a signaling receptor for a variety of microbial products, including bacterial lipoproteins and peptidoglycan, and is central in initiating immune responses toward Gram-positive bacteria, spirochetes, and mycobacteria. The mechanisms behind regulation of TLR2 protein expression are still not well understood. By using a newly developed monoclonal antibody against mouse TLR2, we detected TLR2 protein expression on macrophages, neutrophils, and dendritic cells. Endogenous macrophage TLR2 localized mostly to the cell membrane, with particular accumulation around phagosomes containing zymosan. Treatment of macrophages with the TLR2 antibody diminished cellular response to lipoproteins and down-regulated membrane TLR2. Marked up-regulation of surface TLR2 was observed on macrophages in response to whole bacteria, lipoproteins, lipopolysaccharide, poly(I-C) (double-stranded RNA), R848, and CpG DNA, and this up-regulation appeared to be a very sensitive marker for the presence of microbial products. Up-regulation of TLR2 in response to stimuli correlated with an increased response to secondary lipoprotein exposure following a low concentration of primary lipoprotein challenge. By comparison, exposure to a larger primary challenge induced a hyporeactive state. Most interestingly, lipopolysaccharide- and double-stranded RNA-induced up-regulation of surface TLR2 in macrophages was found to be MyD88-independent, whereas the up-regulation in response to lipoproteins, R848, and CpG DNA was absent in MyD88-deficient cells. We conclude that complex mechanisms regulate expression and signaling via TLR2. Up-regulation of TLR2 in the presence of low, yet clinically relevant amounts of microbial products may be an important mechanism by which the immune system boosts its response to a beginning infection.

Adaptor Proteins, Signal Transducing↗
PubMed1984

A decrease of RNA synthesis during macrophage activation with lipopolysaccharide--an association with novel regulating factors.

RNA synthesis during macrophage activation with lipopolysaccharide (LPS) was analyzed in mice. The RNA synthesis of macrophages was considerably increased early after LPS stimulation, but drastically decreased at a later period. The decrease of RNA synthesis was observed in mouse strains responding to LPS such as BALB/c, ATL and ddY, but not in nonresponder strain, C3H/HeJ. Furthermore, the decrease of RNA synthesis occurred in both alpha-amanitin resistant and sensitive RNA polymerase reactions. However, RNA polymerases in nuclei were not changed significantly in LPS-treated macrophages, but the factors affecting RNA polymerase reactions were drastically changed. Amongst these factors, the stimulating factors were decreased and a novel repressing factor was remarkably increased. The factors were partially characterized and their significance in macrophage activation is discussed.

Animals↗
PubMed2006

Regulation of RNA-polymerase-II-dependent transcription by N-WASP and its nuclear-binding partners.

The presence of actin in the nucleus has been well established, and several studies have implicated nuclear actin in transcriptional regulation. Neuronal Wiskott-Aldrich syndrome protein (N-WASP) is a member of the WASP family of proteins; these proteins function in the cytoplasm as key regulators of cortical actin filament. Interestingly, N-WASP has also been observed in the nucleus. However, a potential nuclear function for N-WASP has not been established. Here, we report the identification of nuclear N-WASP within a large nuclear-protein complex containing PSF-NonO (polypyrimidine-tract-binding-protein-associated splicing factor-non-Pou-domain octamer-binding protein/p54(nrb)), nuclear actin and RNA polymerase II. The PSF-NonO complex is involved in the regulation of many cellular processes, such as transcription, RNA processing, DNA unwinding and repair. We demonstrate that the interaction of N-WASP with the PSF-NonO complex can couple N-WASP with RNA polymerase II to regulate transcription. We also provide evidence that the potential function of N-WASP in promoting polymerization of nuclear actins has an important role in this process. Based on these results, we propose a nuclear function for N-WASP in transcriptional regulation.

Actin Cytoskeleton↗
PubMed1998

Polyadenylation of oop RNA in the regulation of bacteriophage lambda development.

We have shown that Escherichia coli pcnB mutants are lysogenized by bacteriophage lambda with lower efficiency as compared to the pcnB+ strains. Our genetic analysis revealed that expression of the lambda cII gene is decreased in the pcnB mutants. However, using various lacZ fusions we demonstrated that neither activities of pL and pR promoters nor transcription termination at tR1 were significantly impaired in the pcnB- host. On the other hand, we found that oop RNA, an antisense RNA for cII expression, is involved in this regulation. Primer protection experiments revealed that oop RNA was polyadenylated and that this polyadenylation was impaired in the pcnB mutant. We found that the oop RNA was more abundant in the pcnB mutant than in the pcnB+ strain. Furthermore, we showed that activity of the pO promoter was not stimulated in the pcnB mutant. Such findings indicated that degradation of oop RNA in the pcnB strain was slower because of inefficient polyadenylation, which could lead to more effective inhibition of cII expression by the antisense oop RNA, resulting in less efficient lysogenization of the host. The oop RNA was found previously to play a role in phage lambda development only under conditions of overproduction of this transcript. Here we demonstrate for the first time, the physiological function of oop RNA in lambda development, confirming that this short transcript plays an important role in the negative regulation of cII gene expression during lambda infection. Moreover, polyadenylation of oop RNA is one of very few known examples of specific RNA polyadenylation by PAP I in prokaryotic cells and its role in gene expression regulation.

Bacterial Proteins↗
PubMed2006

rRNA promoter regulation by nonoptimal binding of sigma region 1.2: an additional recognition element for RNA polymerase.

Regulation of transcription initiation is generally attributable to activator/repressor proteins that bind to specific DNA sequences. However, regulators can also achieve specificity by binding directly to RNA polymerase (RNAP) and exploiting the kinetic variation intrinsic to different RNAP-promoter complexes. We report here a previously unknown interaction with Escherichia coli RNAP that defines an additional recognition element in bacterial promoters. The strength of this sequence-specific interaction varies at different promoters and affects the lifetime of the complex with RNAP. Selection of rRNA promoter mutants forming long-lived complexes, kinetic analyses of duplex and bubble templates, dimethylsulfate footprinting, and zero-Angstrom crosslinking demonstrated that sigma subunit region 1.2 directly contacts the nontemplate strand base two positions downstream of the -10 element (within the "discriminator" region). By making a nonoptimal sigma1.2-discriminator interaction, rRNA promoters create the short-lived complex required for specific responses to the RNAP binding factors ppGpp and DksA, ultimately accounting for regulation of ribosome synthesis.

Base Sequence↗
PubMed2005

Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids.

Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. Our laboratory has previously demonstrated that high-level HCV replication during acute infection of chimpanzees is associated with the modulation of multiple genes involved in lipid metabolism, and that drugs that regulate cholesterol and fatty acid biosynthesis regulate the replication of the subgenomic HCV replicon in Huh-7 cells. In this article, we demonstrate that Huh-7 cells harboring replicating, full-length HCV RNAs express elevated levels of ATP citrate lyase and acetyl-CoA synthetase genes, both of which are involved in cholesterol and fatty acid biosynthesis. Further, we confirm that the cholesterol-biosynthetic pathway controls HCV RNA replication by regulating the cellular levels of geranylgeranyl pyrophosphate, we demonstrate that the impact of geranylgeranylation depends on the fatty acid content of the cell, and we show that fatty acids can either stimulate or inhibit HCV replication, depending on their degree of saturation. These results illustrate a complex cellular-regulatory network that controls HCV RNA replication, presumably by modulating the trafficking and association of cellular and/or viral proteins with cellular membranes, suggesting that pharmacologic manipulation of these pathways may have a therapeutic effect in chronic HCV infection.

ATP Citrate (pro-S)-Lyase↗
PubMed2006

The S(MK) box is a new SAM-binding RNA for translational regulation of SAM synthetase.

We have identified the S(MK) box as a conserved RNA motif in the 5' untranslated leader region of metK (SAM synthetase) genes in lactic acid bacteria, including Enterococcus, Streptococcus and Lactococcus species. This RNA element bound SAM in vitro, and binding of SAM caused an RNA structural rearrangement that resulted in sequestration of the Shine-Dalgarno (SD) sequence. Mutations that disrupted pairing between the SD region and a sequence complementary to the SD blocked SAM binding, whereas compensatory mutations that restored pairing restored SAM binding. The Enterococcus faecalis S(MK) box conferred translational repression of a lacZ reporter when cells were grown under conditions where SAM pools are elevated, and mutations that blocked SAM binding resulted in loss of repression, demonstrating that the S(MK) box is functional in vivo. The S(MK) box therefore represents a new SAM-binding riboswitch distinct from the previously identified S box RNAs.

5' Untranslated Regions↗
PubMed1988

Insertion of Mu into the Shrunken 1 gene of maize affects transcriptional and post-transcriptional regulation of Sh1 RNA.

Insertion of a Mu transposable element at the Shrunken 1 (Sh1) locus of maize has resulted in kernels with the typical collapsed appearance of sh mutants. Molecular analysis of the mutant gene has revealed the presence of a 1.4 kb insertion immediately upstream from the normal transcriptional start site. Mu insertion has brought about a series of changes in gene expression: the mRNA cap site has been shifted downstream so that it now lies inside the Mu element; transcription is reduced approximately sixfold, and the sh mRNA steady-state level is less than 4% of that found in the nonmutant. This disparity reflects a mutational defect in post-transcriptional regulation which is manifested as a decrease in Sh RNA abundance.

Base Sequence↗
PubMed2004

Antisense RNA down-regulation of bcl-2 expression in DU145 prostate cancer cells does not diminish the cytostatic effects of G3139 (Oblimersen).

PURPOSE: Inhibition of the function of the bcl-2 protein has been postulated to sensitize cells to cytotoxic chemotherapy, and thus provides an attractive target for investigative therapies. G3139, a phosphorothioate antisense oligonucleotide targeted to the initiation codon region of the bcl-2 mRNA, is currently being evaluated in several Phase II and Phase III clinical trials. However, the mechanism of action of this molecule appears to depend on a combination of antisense plus nonantisense events. Indeed, the very idea that bcl-2 is a critical target is, at least in part, an extrapolation from experiments in which intracellular bcl-2 protein concentrations have been dramatically increased, yielding chemoresistant cells. EXPERIMENTAL DESIGN: In this work, we down-regulated the expression of bcl-2 protein by 80-90% by two different antisense RNA strategies (antisense RNA and small interfering RNA) in DU145 prostate cancer cells. RESULTS: Even after down-regulation of bcl-2 protein expression by either one of these strategies, the cellular phenotype induced by subsequent G3139 treatment (inhibition of cellular growth and the generation of reactive oxygen species) was essentially identical to that induced in mock-infected or wild-type DU145 cells in which bcl-2 protein expression had not been down-regulated previously. CONCLUSIONS: These results strongly suggest that bcl-2 expression in DU145 cells is not strongly associated with the prolife phenotype and that the mechanism by which G3139 produces its cytostatic effects in this cell line is bcl-2 independent.

Apoptosis↗
PubMed1983

Transcriptional regulation of three double-stranded RNA segments of bacteriophage phi 6 in vitro.

Three double-stranded RNA segments of bacteriophage phi 6 (L, M, and S) were transcribed in vitro by a virion-associated RNA polymerase. Regulation of L transcription was distinct from regulation of M and S transcription. Transcription of the L segment, which codes for early proteins, required manganous ion and high concentrations of all four ribonucleoside triphosphates and was inhibited by polyamines such as spermine. Transcription of the M and S segments, which code for late proteins, required manganous or magnesium ion and relatively low concentrations of all ribonucleoside triphosphates except GTP and was enhanced by polyamines. Optimal conditions for L transcription were more stringent than those for M and S transcription. These two apparently different patterns produced in in vitro transcription presumably reflect the two distinct in vivo transcription patterns; i.e., (i) similar amounts of three single-stranded RNA species were transcribed from the three corresponding segments of double-stranded RNA (early pattern) and (ii) a much larger amount of single-stranded RNA species was transcribed from M and S segments than from the L segment (late pattern). The early transcription pattern may be changed into the late pattern by a change of environment, such as substrate concentration. This suggests that the different enzymatic properties under the different environmental conditions of the virion-associated transcriptase are responsible for the transcriptional regulation throughout the infection cycle of bacteriophage phi 6.

Cations, Divalent↗