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At least 181 records · Page 10Linked to original sources
PubMed2004

Identification of alternative splicing regulators by RNA interference in Drosophila.

Alternative splicing is thought to be regulated by nonspliceosomal RNA binding proteins that modulate the association of core components of the spliceosome with the pre-mRNA. Although the majority of metazoan genes encode pre-mRNAs that are alternatively spliced, remarkably few splicing regulators are currently known. Here, we used RNA interference to examine the role of >70% of the Drosophila RNA-binding proteins in regulating alternative splicing. We identified 47 proteins as splicing regulators, 26 of which have not previously been implicated in alternative splicing. Many of the regulators we identified are nonspliceosomal RNA-binding proteins. However, our screen unexpectedly revealed that altering the concentration of certain core components of the spliceosome specifically modulates alternative splicing. These results significantly expand the number of known splicing regulators and reveal an extraordinary richness in the mechanisms that regulate alternative splicing.

Alternative Splicing↗
PubMed1998

Regulation of RNA polymerase I-dependent promoters by the hepatitis B virus X protein via activated Ras and TATA-binding protein.

The hepatitis B virus (HBV) X protein is essential for viral infectivity, and evidence indicates that it is a strong contributor to HBV-mediated oncogenesis. X has been shown to transactivate a wide variety of RNA polymerase (Pol) II-dependent, as well as RNA Pol III-dependent, promoters. In this study, we have investigated the possibility that X modulates RNA Pol I-dependent rRNA transcription. In both human hepatoma Huh7 and Drosophila Schneider S2 cell lines, X expression stimulated rRNA promoter activity. Extracts prepared from X-expressing cells stably transfected with an X gene also exhibited an increased ability to transcribe the rRNA promoter. The mechanism for X transactivation was examined by determining whether this regulatory event was dependent on Ras activation and increased TATA-binding protein (TBP) levels. Our previous studies have demonstrated that X, and the activation of Ras, produces an increase in the cellular levels of TBP (H.-D. Wang, A. Trivedi, and D. L. Johnson, Mol. Cell. Biol. 17:6838-6846, 1997). Expression of a dominant negative form of Ras blocked the X-mediated induction of the rRNA promoters, whereas expression of a constitutively activated form of Ras mimicked the enhancing effect of X on rRNA promoter activity. When TBP was overexpressed in either Huh7 or S2 cells, a dose-dependent increase in rRNA promoter activity was observed. To analyze whether the increase in TBP was modulating rRNA promoter activity indirectly, by increasing activity of RNA Pol II-dependent promoters, a Drosophila TBP cDNA was constructed with a mutation that eliminated its ability to stimulate RNA Pol II-dependent promoters. Transient expression of wild-type TBP in S2 cells increased the activities of specific RNA Pol I- and Pol II-dependent promoters. Expression of the mutant TBP protein failed to enhance the activity of the RNA Pol II-dependent promoters, yet the protein completely retained its ability to stimulate the rRNA promoter. Furthermore, the addition of recombinant TBP to S2 extracts stimulated rRNA promoter activity in vitro. Together, these results demonstrate that the HBV X protein up-regulates RNA Pol I-dependent promoters via a Ras-activated pathway in two distinct cell lines. The enhanced promoter activity can, at least in part, be attributed to the X- and Ras-mediated increase in cellular TBP, a limiting transcription component.

Animals↗
PubMed2005

6S RNA is a widespread regulator of eubacterial RNA polymerase that resembles an open promoter.

6S RNA is an abundant noncoding RNA in Escherichia coli that binds to sigma70 RNA polymerase holoenzyme to globally regulate gene expression in response to the shift from exponential growth to stationary phase. We have computationally identified >100 new 6S RNA homologs in diverse eubacterial lineages. Two abundant Bacillus subtilis RNAs of unknown function (BsrA and BsrB) and cyanobacterial 6Sa RNAs are now recognized as 6S homologs. Structural probing of E. coli 6S RNA and a B. subtilis homolog supports a common secondary structure derived from comparative sequence analysis. The conserved features of 6S RNA suggest that it binds RNA polymerase by mimicking the structure of DNA template in an open promoter complex. Interestingly, the two B. subtilis 6S RNAs are discoordinately expressed during growth, and many proteobacterial 6S RNAs could be cotranscribed with downstream homologs of the E. coli ygfA gene encoding a putative methenyltetrahydrofolate synthetase. The prevalence and robust expression of 6S RNAs emphasize their critical role in bacterial adaptation.

Bacillus subtilis↗
PubMed2006

Developmentally regulated, combinatorial RNA processing modulates AMPA receptor biogenesis.

The subunit composition determines AMPA receptor (AMPA-R) function and trafficking. Mechanisms underlying channel assembly are thus central to the efficacy and plasticity of glutamatergic synapses. We previously showed that RNA editing at the Q/R site of the GluR2 subunit contributes to the assembly of AMPA-R heteromers by attenuating formation of GluR2 homotetramers. Here we report that this function of the Q/R site depends on subunit contacts between adjacent ligand binding domains (LBDs). Changes of LBD interface contacts alter GluR2 assembly properties, forward traffic, and expression at synapses. Interestingly, developmentally regulated RNA editing within the LBD (at the R/G site) produces analogous effects. Our data reveal that editing to glycine reduces the self-assembly competence of this critical subunit and slows GluR2 maturation in the endoplasmic reticulum (ER). Therefore, RNA editing sites, located at strategic subunit interfaces, shape AMPA-R assembly and trafficking in a developmentally regulated manner.

Amino Acid Sequence↗
PubMed1976

[Transport RNA in early embryogenesis of fish. 3. Certain problems of regulation of RNA synthesis at the early stages of development of the loach (Misgurnus fossilis (1)].

tRNA synthesis in the early loach embryos of different ploidy and factors of the activation of synthesis and the maturation of tRNA molecules at the mid-blastula stage have been studied. tRNA synthesis is activated at the early- and mid-blastula and in the beginning of gastrulation. The normal activation of synthesis and maturation of tRNA molecules require the embryo to be maintained in the contact with the yolk at the earlier developmental stages. The methionine starvation may be one of the factors limiting the rate of tRNA maturation. The activity of tRNA synthesis during blastulation was shown to depend on gene dosage. At this stage the paternal and maternal tRNA genes are transcribed independently. In the beginning of gastrulation, the type of tRNA synthesis control markedly changes and the effect of gene dose compensation manifests itself, that is typical for the control of rRNA synthesis as well. The data obtained are discussed with respect to the state of protein synthesizing system at the moment of activation of specific protein syntheses with the onset of morphogenesis.

Animals↗
PubMed1983

Regulation of RNA polymerase I by phosphorylation and production of anti-RNA polymerase I antibodies in rheumatic autoimmune diseases.

Relative to resting liver, Morris hepatomas with different growth rates (3924A, 5123D, 7800, and 7777) all had higher (two to eightfold) levels (activity/gm tissue) of RNA polymerase I. Only the most rapidly growing tumor (hepatoma 3924A) showed a substantial increase (fivefold) in RNA polymerase III activity. RNA polymerase II activity/gm tissue in the hepatomas was similar to that in resting liver. The elevation in the hepatoma RNA polymerase I activity resulted from both an increase in the number of transcriptionally active enzyme molecules and an increase in the specific activity of the enzyme as a result of phosphorylation. Phosphorylation of RNA polymerase I from Morris hepatoma 3924A could be catalyzed either by an endogenous protein kinase or by a highly purified preparation of NII protein kinase from the same tumor. Three out of eight polypeptides (Mr 120,000, 65,000, and 25,000) or RNA polymerase I were phosphorylated. Phosphorylation resulted in enhanced RNA synthesis at the level of chain elongation. Another nuclear protein kinase, NI, had no significant effect on RNA polymerase I. The activity and/or amount of the NII protein kinase was significantly reduced in resting liver, which correlated with decreased specific activity of the liver RNA polymerase I. Anti-RNA polymerase I antibodies were found in the sera of patients with rheumatic autoimmune diseases such as systemic lupus erythematosus (SLE), mixed connective tissue disease (MCTD), and rheumatoid arthritis (RA). Sera from these patients were capable of specifically inhibiting RNA polymerase I activity in vitro. Antibodies were produced predominantly against three of the polypeptides--S3 (Mr 65,000), S4 (Mr 42,000), and S5 (Mr 25,000) of RNA polymerase I. The spectrum and proportion of the antibodies against these three subunits differ with each patient and with the type of the autoimmune disease. These observations indicate that (1) the NII kinase can regulate RNA polymerase I activity, (2) protein kinase NII is associated with the polymerase I enzyme complex, and (3) certain polypeptides of this enzyme complex may be the target antigens in rheumatic autoimmune disease.

Animals↗
PubMed1997

PKR--a protein kinase regulated by double-stranded RNA.

The RNA-regulated protein kinase, (PKR) is an interferon-inducible enzyme of widespread occurrence in eukaryotic organisms. This serine/threonine-specific protein kinase is activated by double-stranded RNA by a mechanism involving autophosphorylation. Once activated, the enzyme phosphorylates the alpha subunit of protein synthesis initiation factor eIF2, thereby inhibiting translation. Recent evidence suggests that there may be additional substrates, and that signal transduction and gene transcription pathways also may be regulated by the protein kinase. As well as being important in mediating the antiviral effects of interferons, PKR is implicated in regulating cell proliferation in uninfected cells and may have a tumour suppressor function under normal conditions. Studies using cell lines expressing inactive mutants of PKR and mice with homozygous disruptions of the PKR gene are leading to greater insights into the biological significance of this enzyme.

Amino Acid Sequence↗
PubMed1984

Studies on the regulation of RNA labeling and on the biochemical constituents of normal and abnormal human thyroid.

The present studies were performed in order to analyze the incorporation of 3H-uridine into RNA and its hormonal regulation as well as the content of total iodine, T3, T4, RNA, DNA and protein in normal and abnormal human thyroid obtained at surgery. The content of protein, RNA and DNA is not significantly changed in follicular adenoma and in adenomatous goiter, RNA labeling from 3H-uridine showed similar values in slices from normal and abnormal glands. TSH and cyclic AMP increased the labeling of RNA in normal tissue but had no effect in the follicular adenoma and adenomatous goiter. A significant decrease in total iodine, T3 and T4 concentration was found in the pathological samples when compared to normals. The present results would suggest that in these patients the biochemical abnormalities lie at a step distal to the TSH receptor and the adenylate cyclase.

Adenoma↗
PubMed1985

Regulation of RNA Synthesis by DNA-Dependent RNA Polymerases and RNases during Cold Acclimation in Winter and Spring Wheat.

Chromatin DNA-dependent RNA polymerases and RNases activities were measured in winter and spring varieties to understand the overall regulation of RNA synthesis during cold acclimation. We found that total RNA polymerase activities were significantly higher in chromatin isolated from winter wheat compared to the spring wheat during the acclimation period. This increase was parallel to the increase in protein and RNA contents during hardening. The ratio of RNA polymerase I to RNA polymerase II activity was higher than 2 in winter wheat after 30 days of hardening compared, to a ratio of 0.90 under the nonhardening conditions. The increase in activity and the ratio of polymerase I to polymerase II was maintained after the separation of the enzymes from the template, suggesting that RNA synthesis is regulated in part at the enzyme level. On the other hand, the chromatin associated RNase activity decreased in both varieties during acclimation, indicating a nonspecific inhibition caused by low temperature rather than a selective genetic response associated with cold acclimation.

Journal Article↗
PubMed1995

P62 association with RNA is regulated by tyrosine phosphorylation.

The ras-GAP associated protein, p62, is a major tyrosine phosphoprotein in transformed and growth factor treated cells. Although its exact function is not known, it can bind directly to src-family tyrosine kinases and has been implicated as a linker protein bridging activated src family tyrosine kinases with downstream effectors. One novel feature of p62, revealed by its predicted amino acid sequence, is the presence of an RNA-binding region, the KH domain. As p62 becomes tyrosine phosphorylated when src-kinases become activated, we compared the RNA binding ability of p62 in both its phosphorylated and unphosphorylated state. The ability of p62 to bind RNA was severely impaired when p62 was tyrosine phosphorylated. This suggests that the ability of p62 to bind RNA is regulated by tyrosine phosphorylation and implicates the regulation of RNA as a component of tyrosine kinase signaling pathways.

Base Sequence↗
PubMed1984

In vitro evidence that eukaryotic ribosomal RNA transcription is regulated by modification of RNA polymerase I.

We have utilized a cell-free transcription system from Acanthamoeba castellanii to test the functional activity of RNA polymerase I and transcription initiation factor I (TIF-I) during developmental down regulation of rRNA transcription. The results strongly suggest that rRNA transcription is regulated by modification, probably covalent, of RNA polymerase I: (1) The level of activity of TIF-I in extracts from transcriptionally active and inactive cells is constant. (2) The number of RNA polymerase I molecules in transcriptionally active and inactive cells is also constant. (3) In contrast, though the specific activity of polymerase I on damaged templates remains constant, both crude and purified polymerase I from inactive cells have lost the ability to participate in faithful initiation of rRNA transcription. (4) Polymerase I purified from transcriptionally active cells has the same subunit architecture as enzyme from inactive cells. However, the latter is heat denatured 5 times faster than the active polymerase.

Amoeba↗
PubMed1999

Mechanisms by which T7 lysozyme specifically regulates T7 RNA polymerase during different phases of transcription.

Bacteriophage T7 lysozyme binds to T7 RNA polymerase (RNAP) and regulates its transcription by differentially repressing initiation from different T7 promoters. This selective repression is due in part to a lysozyme-induced increase in the KNTP of the initiation complex (IC) and to intrinsically different NTP concentration requirements for efficient initiation from different T7 promoters. While lysozyme represses initiation, once the enzyme has left the promoter and formed an elongation complex (EC) it is generally resistant to the effects of lysozyme. The mechanism by which the inhibitory effects of lysozyme are largely restricted to the initiation phase of transcription is not well understood. We find that T7 lysozyme destabilizes initial transcription complexes (ITCs) and increases the rate of release of transcripts from these complexes but does not destabilize ECs. However, if the RNA:RNAP interaction proposed to be important for EC stability is disrupted by proteolysis of the RNA-binding domain or use of templates which interfere with establishment of this RNA:RNAP interaction, the EC becomes sensitive to lysozyme. Comparison of the X-ray structures of T7RNAP and of a T7RNAP:T7 lysozyme complex reveals that lysozyme causes the C terminus of the polymerase to flip out of the active site. Experiments in which carboxypeptidase A is used to probe the lysozyme-induced exposure of the C terminus reveal a large decrease in carboxypeptidase sensitivity following transcription initiation, suggesting that interactions with the 3'-end of the RNA help stabilize the active site in a functional (carboxypeptidase protected) conformation. Thus, the resistance of the EC to lysozyme appears to be due to the consecutive establishment of two sets of RNA:RNAP interactions. The first is made with the 3'-end of the RNA and helps stabilize a functional conformation of the active site, thereby suppressing the effects of lysozyme on KNTP. The second is made with a more upstream element of the RNA and keeps the EC from being destabilized by lysozyme binding.

Allosteric Regulation↗
PubMed1982

RNA processing regulation of neuroendorcrine gene expression.

Alternative RNA processing events account for biological polymorphism in the endocrine, immune, and other systems; these may have possible widespread significance in the regulation of eukaryotic gene expression. The selective use of alternative hormone-encoding exons can produce multiple mRNAs generating different protein products. The resultant "peptide switching" is a previously unrecognized mechanism allowing a single gene to encode different hormones in different tissues and thus increases the diversity of endocrine gene expression.

Animals↗
PubMed2000

Regulation of insulin-like growth factor binding protein-5 mRNA abundance in rat intestinal smooth muscle.

IGF-I increases abundance of IGFBP-5 mRNA in rat intestinal smooth muscle cells (RISM), and IGFBP-5 protein in RISM conditioned media. The translational blocker, cycloheximide, decreased the abundance of IGFBP-5 mRNA to undetectable levels, suggesting that IGFBP-5 mRNA integrity is linked to protein synthesis. We studied the mechanism of IGF-I's effect on IGFBP-5 mRNA, and the role of cytoplasmic proteins in modulating IGFBP-5 mRNA abundance. Anisomycin, emetine, and puromycin abolished IGFBP-5 mRNA as seen with cycloheximide. Cycloheximide had a dose- and time-dependent effect on IGFBP-5 mRNA. IGF-I increased IGFBP-5 nuclear transcripts by reverse transcription-polymerase chain reaction (RT-PCR), suggesting that IGF-I acts at least partially by increasing IGFBP-5 mRNA transcription. Protein synthesis inhibitors did not affect IGFBP-5 nuclear transcripts, therefore, they affect only mature mRNA. The IGFBP-5 mRNA 3' and 5' UTRs were cloned and their sequences searched for adenosine-uridine rich elements (AUREs), elements shown to regulate RNA stability. RNA mobility gel shift assay showed two protein activities that bind to nt 922 to 2076 of the 3' UTR, a region that contains an AURE. One protein activity (BA2) was decreased in cytoplasmic extracts from cycloheximide-treated RISM. These data demonstrate that IGFBP-5 mRNA integrity is dependent on protein synthesis. The 3' UTR of IGFBP-5 contains elements shown to bind proteins important for RNA stability regulation. This region binds RISM cytoplasmic proteins, and may mediate the dramatic effect of cycloheximide on IGFBP-5 abundance. RNA-protein interactions may be important to IGFBP-5 mRNA stability and ultimately, to IGFBP-5 actions.

3' Untranslated Regions↗
PubMed2026

Quantitative RNA modification mapping by mass spectrometry with isobaric tags and nucleobase fragment analysis.

RNA modifications regulate RNA stability, translation, stress responses, and disease processes, yet their function remains poorly understood due to technical limitations in sequence analysis. Here, we present an RNA-specific isobaric tandem mass tagging (RMT) platform for omic-scale quantitative mapping of RNA modifications. The platform combines RNA-specific tags adapted from proteomics with an end-to-end workflow spanning sample preparation through data processing. Validation using synthetic oligonucleotides and total tRNA from Pseudomonas aeruginosa yielded reproducible quantification, with coefficients of variation below 5%. Together with nucleobase fragment analysis, we identified and quantified 24 RNA modifications in PA14 tRNAs, including previously undescribed m2A38 and Gm/Cm39, and assigned their corresponding writer enzymes. Further analyses of tRNAs from writer knockout strains and stressed cells revealed dynamic modification patterns, modification interdependencies, and their potential roles in stress adaptation. This method provides a robust, cost-effective platform for quantitative RNA modification mapping, enabling deeper biological insights.

RNA, Transfer↗
PubMed1997

RNA-protein interactions in the regulation of coronavirus RNA replication and transcription.

Coronavirus, with a 31-kb RNA genome, replicates its own RNA and transcribes subgenomic mRNAs by complex mechanisms. Viral RNA synthesis is regulated by multiple RNA regions, which appear to interact either directly or indirectly. Multiple cellular proteins bind to these regions and may undergo additional protein-protein interactions. These findings suggest that coronavirus RNA synthesis is carried out on a ribonucleoprotein via a mechanism that involves both viral and cellular proteins associated with viral RNA, similar to DNA-dependent RNA transcription. This mode of RNA synthesis may be applicable to most RNA viruses.

Animals↗
PubMed1999

A novel gonadotropin-regulated testicular RNA helicase. A new member of the dead-box family.

A gonadotropin-regulated testicular RNA helicase (GRTH) was identified and characterized. GRTH cloned from rat Leydig cell, mouse testis, and human testis cDNA libraries is a novel member of the DEAD-box protein family. GRTH is transcriptionally up-regulated by chorionic gonadotropin via cyclic AMP-induced androgen formation in the Leydig cell. It has ATPase and RNA helicase activities and increases translation in vitro. This helicase is highly expressed in rat, mouse, and human testes and weakly expressed in the pituitary and hypothalamus. GRTH is produced in both somatic (Leydig cells) and germinal (meiotic spermatocytes and round haploid spermatids) cells and is developmentally regulated. GRTH predominantly localized in the cytoplasm may function as a translational activator. This novel helicase could be relevant to the control of steroidogenesis and the paracrine regulation of androgen-dependent spermatogenesis in the testis.

Amino Acid Sequence↗
PubMed2002

The amino-terminal half of Sendai virus C protein is not responsible for either counteracting the antiviral action of interferons or down-regulating viral RNA synthesis.

The Sendai virus C proteins, C', C, Y1, and Y2, are a nested set of independently initiated carboxy-coterminal proteins translated from a reading frame overlapping the P frame on the P mRNA. The C proteins are extremely versatile and have been shown to counteract the antiviral action of interferons (IFNs), to down-regulate viral RNA synthesis, and to promote virus assembly. Using the stable cell lines expressing the C, Y1, Y2, or truncated C protein, we investigated the region responsible for anti-IFN action and for down-regulating viral RNA synthesis. Truncation from the amino terminus to the middle of the C protein maintained the inhibition of the signal transduction of IFNs, the formation of IFN-stimulated gene factor 3 (ISGF3) complex, the generation of the anti-vesicular stomatitis virus state, and the synthesis of viral RNA, but further truncation resulted in the simultaneous loss of all of these inhibitory activities. A relatively small truncation from the carboxy terminus also abolished all of these inhibitory activities. These data indicated that the activities of the C protein to counteract the antiviral action of IFNs and to down-regulate viral RNA synthesis were not encoded within a region of at least 98 amino acids in its amino-terminal half.

Animals↗