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PubMed1991

Adenovirus inhibition of cellular protein synthesis involves inactivation of cap-binding protein.

Adenovirus (Ad) infection results in a marked inhibition of cellular protein synthesis that initiates during the late phase of the viral infectious cycle. We show that the mechanism used for suppression of cellular protein synthesis during cell cycle progression is exploited by Ad to repress host and enhance late viral mRNA translation. Discrimination between cellular and late Ad mRNAs and inhibition of host protein synthesis are shown to involve viral-mediated underphosphorylation of cap-binding protein (CBP) and subsequent inactivation of CBP complex, a large enzymatic complex required for cap-dependent mRNA translation. Late Ad mRNAs, like those of poliovirus, possess the unique ability to translate independent of a normal cap recognition process and do not require the activity of CBP complex. Inhibition of cellular translation by these two viruses is quite similar, except that whereas CBP complex is proteolytically degraded by poliovirus, it is functionally inactivated by Ad.

Adenoviruses, Human↗
PubMed1998

Maximal induction of p69 2', 5'-oligoadenylate synthetase in Daudi cells requires cooperation between an ISRE and two IRF-1-like elements.

The human 2', 5'-oligoadenylate (2-5A) synthetases are members of a family interferon (IFN)-inducible anti-viral proteins. Three size classes of these enzymes: small (p40, p46), intermediate (p69, p71) and large (p100), are encoded by three genes that exhibit differential constitutive and IFN-inducible expression. Since the 5'-regulatory region of the 69 kDa isoform contains multiple putative control elements, deletion analysis and site directed mutagenesis were done to identify key regulatory motifs. The region located between bp -972 and -452 from the translational start site contains elements that slightly repress constitutive and IFN-inducible transcription. The region from bp -366 to -117 contains two positive regulatory elements that differ slightly from consensus IFN-regulated factor 1 (IRF-1) binding sites. In mobility shift assays, the proximal IRF-1 site weakly binds a novel factor found in both control and IFN-treated cells. The region from bp -117 to -10 contains a functional interferon stimulated response element (ISRE) that contributes to constitutive expression and confers IFN-inducibility on a heterologous promoter. The ISRE specifically binds an IFN-inducible factor that contains signal transducer activator of transcription (STAT) 1alpha. The ISRE and the two IRF-1-like sites cooperatively interact to control transcription. These three elements are sufficient for constitutive and IFN-inducible expression, since expression from reporter constructs containing mutations in all three elements is low in both control and IFN-treated cells.

2',5'-Oligoadenylate Synthetase↗
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↗
PubMed2000

In vitro selection of an RNA sequence that interacts with high affinity with thymidylate synthase.

Previous studies have shown that the repressive effect of thymidylate synthase (TS) mRNA translation is mediated by direct binding of TS itself to two cis-acting elements on its cognate mRNA. To identify the optimal RNA nucleotides that interact with TS, we in vitro synthesized a completely degenerate, linear RNA pool of 25 nt and employed in vitro selection to isolate high affinity RNA ligands that bind human TS protein. After 10 rounds of selection and amplification, a single RNA molecule was selected that bound TS protein with nearly 20-fold greater affinity than native, wild-type TS RNA sequences. Secondary structure analysis of this RNA sequence predicted it to possess a stem-loop structure. Deletion and/or modification of the UGU loop element within the RNA sequence decreased binding to TS by up to 1000-fold. In vivo transfection experiments revealed that the presence of the selected RNA sequence resulted in a significant increase in the expression of a heterologous luciferase reporter construct in human colon cancer H630 and TS-overexpressing HCT-C:His-TS+ cells, but not in HCT-C18 cells expressing a functionally inactive TS. In addition, the presence of this element in H630 cells leads to induced expression of TS protein. An immunoprecipitation method using RT-PCR confirmed a direct interaction between human TS protein and the selected RNA sequence in transfected human cancer H630 cells. This study identified a novel RNA sequence from a degenerate RNA library that specifically interacts with TS.

Base Sequence↗
PubMed1999

Messenger RNA-binding properties of nonpolysomal ribonucleoproteins from heat-stressed tomato cells

Most cells experiencing heat stress reprogram their translational machinery to favor the synthesis of heat-stress proteins. Translation of other transcripts is almost completely repressed, but most untranslated messengers are not degraded. In contrast to yeast, Drosophila melanogaster, and HeLa cells, plant cells store repressed messengers in cytoplasmic nonpolysomal ribonucleoproteins (RNPs). To follow the fate of untranslated transcripts, we studied protein composition, mRNA content, and RNA-binding properties of nonpolysomal RNPs from heat-stressed tomato (Lycopersicon peruvianum) cells. Contrary to the selective interaction in vivo, RNPs isolated from tomato cells bound both stress-induced and repressed messengers, suggesting that the selection mechanism resides elsewhere. This binding was independent of a cap or a poly(A) tail. The possible role of proteasomes and heat-stress granules (HSGs) in mRNA storage is a topic of debate. We found in vitro messenger-RNA-binding activity in messenger RNP fractions free of C2-subunit-containing proteasomes and HSGs. In addition, mRNAs introduced into tobacco (Nicotiana plumbaginifolia) protoplasts were found in the cytoplasm but were not associated with HSGs.

Journal Article↗
PubMed1995

Characterization of cis elements that regulate the expression of glnA in Synechococcus sp. strain PCC 7942.

The upstream noncoding region of the Synechococcus sp. strain PCC 7942 (hereafter referred to as Synechococcus 7942) glnA gene was fused to the cat gene in order to study the expression of glnA both in Synechococcus 7942 and in Escherichia coli. The lack of cat expression in E. coli indicated that the glnA promoter was not recognized by E. coli RNA polymerase. The fused construct was integrated into the Synechococcus 7942 chromosome at a neutral site. Expression of the cat reporter gene was regulated under various nitrogen conditions in a way similar to that of the glnA gene. A deletion introduced at the binding site of the NtcA regulatory protein abolished derepression of the glnA promoter during growth in nitrate and under nitrogen starvation. Deletion of the sequence between the transcription and translation start sites of glnA prevented the repression observed during growth in ammonium. These results indicate that the glnA promoter is subject to complex regulation that involves sequences upstream and downstream from the transcription start site.

Base Sequence↗
PubMed1994

The effect of time of day on levels of hypothalamic proopiomelanocortin primary transcript, processing intermediate and messenger ribonucleic acid in proestrous and estrous rats.

Several lines of evidence from different laboratories suggest that hypothalamic beta-endorphinergic activity decreases around the time of initiation of the LH surge and may increase on estrus to extinguish the expression of the daily neuronal signal for the surge. In several hormone systems, factors that stimulate or suppress hormone release also stimulate or repress transcription of the hormone gene and translation of the messenger RNA encoding the hormone. Therefore, information about neurohormone activity may be inferred from data on changes in the levels of RNA species encoding these neurohormones. We used a solution hybridization/RNase protection assay to test the hypotheses that 1) the abundance of primary transcript of the hypothalamic POMC gene decreases at the time of initiation of the proestrous LH surge and 2) levels of POMC primary transcript (and by inference, levels of beta-endorphin neuronal activity and secretion) increase on estrus. 96 rats exhibiting at least two consecutive 4-day estrous cycles were killed at either 0600 or 1300 h on proestrus and estrus. Dissections of the medial basal hypothalamus were pooled into 4 samples at each time-point (6 rats per sample) and RNA was extracted from nuclear and cytoplasmic fractions separately. We measured levels of POMC primary transcript, processing intermediate and fully spliced mRNA in the nuclear fractions and POMC mRNA in cytoplasmic fractions. Compared to 0600 h, levels of POMC primary transcript decreased significantly during the afternoons of both proestrus and estrus (P < 0.05). Levels of nuclear processing intermediate RNA and cytoplasmic mRNA followed the same trend but the afternoon declines did not reach statistical significance. We conclude from these data that the afternoon decline in POMC gene expression is not unique to the day of proestrus and we speculate that an afternoon decline in beta-endorphinergic neuronal activity may instead be a component of the daily signal for the LH surge.

Animals↗
PubMed2006

Posttranscriptional regulation by the upstream open reading frame of the phosphoethanolamine N-methyltransferase gene.

Phosphoethanolamine N-methyltransferase (PEAMT) is involved in choline biosynthesis in plants. The 5' untranslated region (UTR) of several PEAMT genes was found to contain an upstream open reading frame (uORF). We generated transgenic Arabidopsis calli that expressed a chimeric gene constructed by fusing the 5' UTR of the Arabidopsis PEAMT gene (AtNMT1) upstream of the beta-glucuronidase gene. The AtNMT1 uORF was found to be involved in declining levels of the chimeric gene mRNA and repression of downstream beta-glucuronidase gene translation in the calli when the cells were treated with choline. Further, we discuss the role of the uORF.

5' Untranslated Regions↗
PubMed2026

Phage-encoded sRNA counteracts xenogeneic silencing in pathogenic E. coli.

Horizontal gene transfer introduces foreign DNA that can disrupt cellular processes and is therefore subject to xenogeneic silencing by nucleoid-associated proteins such as H-NS and Hha. In Enterohaemorrhagic Escherichia coli (EHEC), prophages make up a large fraction of the accessory genome and encode many virulence factors, yet their expression must overcome this silencing. We identify a prophage-encoded small RNA (sRNA), HnrS, that functions as an anti-silencing factor by targeting the H-NS paralogue Hha. HnrS is a short (66-nt) sRNA that is enriched in the locus of enterocyte effacement (LEE&#x207a;) E. coli strains and present in up to nine copies in EHEC and Enteropathogenic Escherichia coli (EPEC) genomes. HnrS base-pairs with the hha ribosome-binding site to inhibit translation, thereby modulating Hha-H-NS repression of virulence loci including the LEE type III secretion system. Loss of HnrS alters motility, T3SS expression, and a subset of Hha-regulated genes. These findings reveal an RNA-based counter-silencing strategy encoded by prophage to relieve xenogenic silencing.

Escherichia coli Proteins↗
PubMedDate not supplied

Adenosine receptors: protein and gene structure.

Adenosine produces a wide variety of effects throughout the body via activation of cell surface adenosine receptors. Adenosine receptors belong to the family of seven transmembrane domain G protein-coupled receptors and four subtypes have been cloned from a variety of species: the A1AR, A2aAR, A2bAR and A3AR. With a knowledge of both the protein sequence of adenosine receptors and the structure of the A1AR gene, the function and regulation of these receptors can be further explored. Site-directed mutagenesis of the A1AR has resulted in the identification of amino acid residues in transmembrane domains 6 and 7 that are critical in both agonist and antagonist binding. The construction and analysis of A1/A3 chimeric receptors has also revealed regions of adenosine receptors important in ligand binding. These include the distal region of the second extracellular loop of adenosine receptors, which has a role in the binding of both agonist and antagonist ligands. A segment of the exofacial portion of the transmembrane domain 5 of adenosine receptors appears to be involved in the selective recognition of agonist ligands containing a substitution at the 5'-position of the ribose moiety. Isolation of the genomic sequence of the human A1AR, in combination with analysis of the transcript distribution in several tissues, indicates that alternative splicing of the human A1AR occurs in the 5'-untranslated region of the gene. Two distinct transcripts, containing either exons 3, 5 and 6 or exons 4, 5 and 6, exist with exons 3 and 4 apparently mutually exclusive. The exon 4, 5 and 6 transcript has been detected in all tissues that express the A1AR, while the exon 3, 5 and 6 mRNA is found in tissues that display a relatively high A1AR expression. Findings suggest that the presence of two ATG codons in exon 4, upstream of the translation start site, is involved in the repression of the A1AR expression in those tissues containing the exon 4, 5 and 6 transcript.

Animals↗
PubMed1998

Cyclin D expression is controlled post-transcriptionally via a phosphatidylinositol 3-kinase/Akt-dependent pathway.

Cyclin D expression is regulated by growth factors and is necessary for the induction of mitogenesis. Herbimycin A, a drug that binds to Hsp90, induces the destruction of tyrosine kinases and causes the down-regulation of cyclin D and an Rb-dependent growth arrest in the G1 phase of the cell cycle. We find that the induction of D-cyclin expression by serum and its repression by herbimycin A are regulated at the level of mRNA translation. Induction of cyclin D by serum occurs prior to the induction of its mRNA and does not require transcription. Herbimycin A repression is characterized by a decrease in the synthetic rate of D-cyclins prior to changes in mRNA expression and in the absence of changes in the half-life of the protein. This effect on D-cyclin translation is mediated via a phosphatidylinositol 3-kinase (PI 3-kinase)-dependent pathway. PI 3-kinase inhibitors such as wortmannin and LY294002, and rapamycin, an inhibitor of FRAP/TOR, cause a decline in the level of D-cyclins, whereas inhibitors of mitogen-activated protein kinase kinase and farnesyltransferase do not. Cells expressing the activated, myristoylated form of Akt kinase, a target of PI 3-kinase, are refractory to the effects of herbimycin A or serum starvation on D-cyclin expression. These data suggest that serum induction of cyclin D expression results from enhanced translation of its mRNA and that this results from activation of a pathway that is dependent upon PI 3-kinase and Akt kinase.

Benzoquinones↗
PubMed1992

Synergism between the Trp repressor and Tyr repressor in repression of the aroL promoter of Escherichia coli K-12.

Computer analysis identified a potential Trp repressor operator 56 nucleotides downstream of the transcriptional start point of aroL, the gene that encodes shikimate kinase II. Tryptophan-dependent interaction of Trp repressor with this operator was demonstrated in vitro by means of a restriction endonuclease protection assay. Regulation of expression from the aroL promoter was evaluated with several genetically marked Escherichia coli strains by using a single-copy aroL-lacZ transcriptional-translational reporter system. The expression of aroL was repressed 6.9-fold by the Tyr repressor alone and 29-fold when both Tyr and Trp repressors were present. The Trp repressor had no effect on expression from the aroL promoter in the absence of the Tyr repressor. Possible mechanisms for Trp repressor-mediated repression, including cooperative interactions with the Tyr repressor, are discussed.

Bacteriophage lambda↗
PubMed1977

Development of Escherichia coli virus T1: repression of host gene expression.

Host protein synthesis, measured either as amino acid incorporation into proteins or as enzyme synthesis, is inhibited rapidly after infection Escherichia coli with T1. Analysis of this inhibition, using a technique which distinguishes between translation and transcription, revealed that translation of host mRNA is specifically blocked. Comparison of the time course of T1-induced host repression with inhibition by the drugs rifampicin, nitrofurantoin and chloramphenicol showed that T1 affects the initiation step of host translation. Intact membranes are apparently essential for host repression, suggesting a membrane-mediated process. Concomitant viral protein synthesis is not required. The membrane-altering principle is a constituent of the viral particle.

Bacterial Proteins↗
PubMed2003

[Role of eukaryotic initiation factor-4E (eIF-4E) in regulation of expression of NF-kappaB and its subsequent influence on transcription and activity of heparanase in human colon adenocarcinoma cell line].

BACKGROUND & OBJECTIVE: Recent studies have revealed that some transcription factors may be translationally regulated by eukaryotic initiation factor-4E (eIF-4E) in human cancer. These modifications in the expression levels of the key transcription factors will alter the expression of some malignancy-related gene products at the transcriptional levels. The current study was designed to investigate the effect of eIF-4E on the expression and activity of NF-kappaB and observe how the activity level of NF-kappaB contributes, as a secondary effect, to the transcription of heparanase in human colon adenocarcinoma LS-174T cells. METHODS: In order to repress the expression of eIF-4E, a 20-mer antisense oligodeoxynucleotide (ASODN) targeted against the translation start site of eIF-4E mRNA was transfected into human colorectal cancer cell line LS-174T via liposome reagent, followed by assessment of the activity and the protein expression of NF-kappaB by an electrophoretic gel mobility shift assay (EMSA) and Western blot analysis respectively. The alterations of heparanase expression were examined by RT-PCR and Western blot analysis, and heparanase activity in LS-174T cells was measured by specific enzymatic activity test using radiolabeled heparan sulfate as the substrate and gel filtration chromatography for the analysis of the degradation product. RESULTS: The 20-mer ASODN against eIF-4E specifically and significantly inhibited eIF-4E expression at both transcriptional and translational levels, and the repression of eIF-4E gene expression was correlated with decreased expression levels and activity of NF-kappaB protein. Furthermore, this down regulation of the ubiquitous transcription factor NF-kappaB led to reduced transcription of the heparanase gene, and the transfected cells also showed a considerable decrease in heparanase protein and activity. CONCLUSION: These results suggest that eIF-4E play an important role in translational regulation of NF-kappaB expression in LS-174T cells.NF-kappaB is an essential factor in the regulatory mechanisms of heparanase gene transcription, and the suppressed NF-kappaB activity in LS-174T cells may significantly reduce the transcriptional expression of heparanase that consequently leads to decreased heparanase protein expression and enzymatic activity.

Adenocarcinoma↗
PubMed1975

Derepression and repression of the histidine operon: role of the feedback site of the first enzyme.

Thiazolealanine, a false feedback inhibitor, causes transient repression of the his operon previously derepressed by a severe histidine limitation in strains with a wild-type or feedback-hypersensitive first enzyme but not in feedback-resistant mutants. Since experiments reported here clearly demonstrate that thiazolealanine is not transferred to tRNAHis, it is proposed that this "transient repression" is effected through the interaction of thiazolealanine with the feedback site of the enzyme. Experiments in the presence of rifampin indicate that this thiazolealanine-mediated effect is exerted at the level of translation. We conclude that histidine (free), in addition to forming co-repressor, also represses the operon at the level of translation through feedback interaction with the first enzyme of the pathway (adenosine 5'-triphosphate phosphoribosyltransferase). Rates of derepression in feedback-resistant strains are roughly half of those observed in controls, suggesting a positive role played by a first enzyme with a normal but unoccupied feedback site. Some feedback-resistant mutants, in contrast to the wild type, were unable to exhibit derepression under histidine limitation caused by aminotriazole.

ATP Phosphoribosyltransferase↗
PubMed2005

Pelota controls self-renewal of germline stem cells by repressing a Bam-independent differentiation pathway.

In the Drosophila ovary, germline stem cell (GSC) self-renewal is controlled by both extrinsic and intrinsic factors. The Bmp signal from niche cells controls GSC self-renewal by directly repressing a Bam-dependent differentiation pathway in GSCs. pelota (pelo), which has been previously shown to be required for Drosophila male meiosis, was identified in our genetic screen as a dominant suppressor of the dpp overexpression-induced GSC tumor phenotype. In this study, we reveal the unexpected new role of Pelo in controlling GSC self-renewal by repressing a Bam-independent differentiation pathway. In pelo mutant ovaries, GSCs are lost rapidly owing to differentiation. Results from genetic mosaic analysis and germ cell-specific rescue show that it functions as an intrinsic factor to control GSC self-renewal. In pelo mutant GSCs, Bmp signaling activity detected by Dad-lacZ expression is downregulated, but bam expression is still repressed. Furthermore, bam mutant germ cells are still able to differentiate into cystocytes without pelo function, indicating that Pelo is involved in repressing a Bam-independent differentiation pathway. Consistent with its homology to the eukaryotic translation release factor 1alpha, we show that Pelo is localized to the cytoplasm of the GSC. Therefore, Pelo controls GSC self-renewal by repressing a Bam-independent differentiation pathway possibly through regulating translation. As Pelo is highly conserved from Drosophila to mammals, it may also be involved in the regulation of adult stem cell self-renewal in mammals, including humans.

Animals↗
PubMed2002

Instruction of translating ribosome by nascent peptide.

Expression of the tryptophanase operon of Escherichia coli is regulated by catabolite repression and tryptophan-induced transcription antitermination. An induction site activated by l-tryptophan is created in the translating ribosome during synthesis of TnaC, the 24-residue leader peptide. Replacing the tnaC stop codon with a tryptophan codon allows tryptophan-charged tryptophan transfer RNA to substitute for tryptophan as inducer. This suggests that the ribosomal A site occupied by the tryptophanyl moiety of the charged transfer RNA is the site of induction. The location of tryptophan-12 of nascent TnaC in the peptide exit tunnel was crucial for induction. These results show that a nascent peptide sequence can influence translation continuation and termination within a translating ribosome.

Aminoglycosides↗