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At least 1,279 records · Page 71Linked to original sources
PubMed1987

The accumulation of mature RNA for the Xenopus laevis ribosomal protein L1 is controlled at the level of splicing and turnover of the precursor RNA.

A specific control regulates, at the level of RNA splicing, the expression of the L1 ribosomal protein gene in Xenopus laevis. Under particular conditions, which can be summarized as an excess of free L1 protein, a precursor RNA which still contains two of the nine introns of the L1 gene accumulates. In addition to the splicing block the two intron regions undergo specific endonucleolytic cleavages which produce abortive truncated molecules. The accumulation of mature L1 RNA therefore results from the regulation of the nuclear stability of its precursor RNA. We propose that a block to splicing can permit the attack of specific intron regions by nucleases which destabilize the pre-mRNA in the nucleus. Therefore the efficiency of splicing could indirectly control the stability of the pre-mRNA.

Animals↗
PubMed1999

Circadian clock-regulated expression of an RNA-binding protein in Arabidopsis: characterisation of a minimal promoter element.

The Atgrp7 transcript encodes a clock-regulated, glycine-rich, RNA-binding protein in Arabidopsis thaliana and shows a circadian variation in steady-state abundance. Constitutive overexpression of its product, AtGRP7, in transgenic Arabidopsis plants depresses the oscillations of the endogenous Atgrp7 transcript, indicating that both the transcript and the protein are part of a clock-regulated negative feedback circuit. Here we characterise the upstream region of the Atgrp7 gene in order to begin to dissect the molecular basis of this oscillating autoregulatory feedback loop. Fusion of a 1.5-kb promoter fragment to the beta-glucuronidase (gus) reporter gene leads to circadian oscillations in the level of the gus transcript in transgenic Arabidopsis plants, with highest levels in the evening, indicating that transcription of the Atgrp7 gene is rhythmically activated by the endogenous circadian clock. A 265-bp fragment upstream of the transcription start site is necessary for high-amplitude Atgrp7 cycling. Within this region, a 56-bp clock-responsive element that confers a low-amplitude circadian oscillation (approximately threefold) with peak abundance in the early evening maps between positions -112 and -57. Another element necessary for augmenting the amplitude of the oscillation lies between -178 and -264. Genetic crosses between a line bearing a promoter-gus fusion and plants that overexpress AtGRP7 show that the promoter by itself does not mediate the negative feedback of AtGRP7 on the oscillations of its own transcript.

Arabidopsis↗
PubMed2004

Dissecting the ribosomal inhibition mechanisms of edeine and pactamycin: the universally conserved residues G693 and C795 regulate P-site RNA binding.

The crystal structures of the universal translation-initiation inhibitors edeine and pactamycin bound to ribosomal 30S subunit have revealed that edeine induces base pairing of G693:C795, residues that constitute the pactamycin binding site. Here, we show that base pair formation by addition of edeine inhibits tRNA binding to the P site by preventing codon-anticodon interaction and that addition of pactamycin, which rebreaks the base pair, can relieve this inhibition. In addition, edeine induces translational misreading in the A site, at levels comparable to those induced by the classic misreading antibiotic streptomycin. Binding of pactamycin between residues G693 and C795 strongly inhibits translocation with a surprising tRNA specificity but has no effect on translation initiation, suggesting that reclassification of this antibiotic is necessary. Collectively, these results suggest that the universally conserved G693:C795 residues regulate tRNA binding at the P site of the ribosome and influence translocation efficiency.

Anticodon↗
PubMed1984

Rapid action of insulin and cyclic AMP in the regulation of functional messenger RNA coding for glucokinase in rat liver.

The mRNA activity coding for rat liver glucokinase was measured in vivo under different hormonal and nutritional conditions. Starvation resulted in minimal levels of glucokinase mRNA activity. Glucose refeeding caused a 4-fold induction of glucokinase mRNA within 48 h, which followed similar alterations in enzyme activity. Minimal values for glucokinase mRNA were also measured in diabetic animals fed glucose and were significantly elevated by insulin injection within 1.5 h. Administration of dibutyryl cyclic AMP to glucose-fed rats caused a rapid loss of the specific mRNA. The half-life of glucokinase mRNA, determined after the administration of cordycepin to glucose-fed animals, was approximately 40 min. This half-life was unaffected by the administration of dibutyryl cyclic AMP. Glucokinase mRNA was reduced 60% in glucose-fed adrenalectomized or thyroidectomized rats. The activity of the glucokinase mRNA agreed well with the measured rates of enzyme synthesis. These data indicate that insulin regulates hepatic glucokinase synthesis in vivo by increasing glucokinase mRNA; its effect is reduced by the absence of glucocorticoids or thyroid hormones and is rapidly antagonized by cyclic AMP.

Animals↗
PubMed2002

Protein kinase R regulates double-stranded RNA induction of TNF-alpha but not IL-1 beta mRNA in human epithelial cells.

Epithelial cells represent the initial site of respiratory viral entry and the first line of defense against such infections. This early antiviral response is characterized by an increase in the production of proinflammatory cytokines such as TNF-alpha and IL-1 beta. dsRNA, which is a common factor present during the life cycle of both DNA and RNA viruses, is known to induce TNF-alpha and IL-1 beta in a variety of cells. In this work we provide data showing that dsRNA treatment induces TNF-alpha and IL-1 beta in human lung epithelial cells via two different mechanisms. Our data show that dsRNA activation of dsRNA-activated protein kinase (PKR) is associated with induction of TNF-alpha but not IL-1 beta expression. An inhibitor of PKR activation blocked the dsRNA-induced elevations in TNF-alpha but not IL-1 beta mRNA in epithelial cells. Data obtained from infection of epithelial cells with a vaccinia virus lacking the PKR inhibitory polypeptide, E3L, revealed that PKR activation was essential for TNF-alpha but not for IL-1 beta expression. In this report, we provide experimental support for the differential regulation of proinflammatory cytokine expression by dsRNA and viral infections in human airway epithelial cells.

Cell Line↗
PubMed1999

Regulation of alternative splicing by RNA editing.

The enzyme ADAR2 is a double-stranded RNA-specific adenosine deaminase which is involved in the editing of mammalian messenger RNAs by the site-specific conversion of adenosine to inosine. Here we identify several rat ADAR2 mRNAs produced as a result of two distinct alternative splicing events. One such splicing event uses a proximal 3' acceptor site, adding 47 nucleotides to the ADAR2 coding region, changing the predicted reading frame of the mature ADAR2 transcript. Nucleotide-sequence analysis of ADAR2 genomic DNA revealed the presence of adenosine-adenosine (AA) and adenosine-guanosine (AG) dinucleotides at these proximal and distal alternative 3' acceptor sites, respectively. Use of the proximal 3' acceptor depends upon the ability of ADAR2 to edit its own pre-mRNA, converting the intronic AA to an adenosine-inosine (AI) dinucleotide which effectively mimics the highly conserved AG sequence normally found at 3' splice junctions. Our observations indicate that RNA editing can serve as a mechanism for regulating alternative splicing and they suggest a novel strategy by which ADAR2 can modulate its own expression.

Adenosine↗
PubMed1992

Responsiveness of RNA degradation to amino acids in cultured rat hepatocytes: comparison with isolated rat hepatocytes.

The role of amino acids in the regulation of RNA degradation was investigated in cultured hepatocytes from fed rats previously labeled in vivo with [6-14C]orotic acid. Rates of RNA degradation were determined between 42 and 48 h of culture from the release of radioactive cytidine in the presence of 0.5 mM unlabeled cytidine. The fractional rate was about 4.4 +/- 0.4%/h in the absence of amino acids (0x). The catabolism of RNA was decreased to basal level (1.5 +/- 0.3%/h) by the addition of amino acids at 10 times normal plasma concentration (10x). The inhibition of RNA degradation, expressed as percentage of maximal deprivation-induced response (0x minus 10x), averaged 60% at normal plasma levels of amino acids. The degree of responsiveness was greatly improved as compared to freshly isolated hepatocytes (20%) and was similar to the sensitivity previously observed with perfused livers. In cultured hepatocytes, the sensitivity of RNA degradation to amino acids was not affected by varying the volume of medium from 1 to 4 ml per dish. In freshly isolated hepatocytes, the inhibitory effect of amino acids was not modified by changing the cell density from 0.5 to 5 x 10(6) cells per ml. In the range of normal plasma concentration of amino acids, the low sensitivity of RNA degradation in isolated hepatocytes persisted with inhibition ranging from 10 to 20%. These findings suggest that the control of RNA degradation in both cultured and isolated hepatocytes is not affected by the total quantity of amino acids available in the medium, but their concentration is crucial. Electron microscopy observations and the inhibitory effect of 3-methyl-adenine in cultured rat hepatocytes partially confirmed the role of the lysosomal system in the increase of RNA degradation and its regulation by amino acids.

Adenine↗
PubMed2005

Down-regulation of CT120A by RNA interference suppresses lung cancer cells growth and sensitizes to ultraviolet-induced apoptosis.

CT120A gene was isolated from chromosome 17p13.3 by using positional cloning and RACE by our laboratory. Here, we reported the evidence that CT120A protein was a potential molecular target for treatment of lung cancers. CT120A was overexpressed in 15 cases of the 16 primary lung cancer specimens. Knockdown of CT120A by small hairpin RNA in the human lung adenocarcinoma cell line SPC-A-1 cells resulted in a reduced cell growth rate in vitro and decrease of the capacity for anchorage-independent growth and tumorigenicity in nude mice. The suppression of CT120A expression also sensitized cells to ultraviolet-induced apoptosis. Atlas cDNA expression array revealed that the expressions of several apoptosis- and growth-associated genes were altered underlying the molecular mechanisms of these cell biological behaviors. These results suggested that CT120A was a novel lung cancer-related gene and CT120A might be a potential target for therapeutic anti-cancer drugs.

Adenocarcinoma↗
PubMed1977

Action of cyclic nucleotides on protein and RNA synthesis in the thyroid.

Thyrotrophin (TSH) regulates the biosynthesis of thyroid protein and RNA. This action is mediated by adenylate cyclase and cycl AMP. In the present study the action of cyclic GMP and cyclic CMP was investigated in beef slices. Both cyclic AMP and cyclic GMP significantly increased the incorporation of [3H]uridine into RNA. These effects were blocked by actinomycin D, suggesting that their action is located at a preor at a transcriptional step. The PCA soluble fraction radioactivity followed in parallel with tha variations observed in the RNA fraction, supporting the view that cyclic nucleotides may regulate RNA by modulating the nucleotide precursors pool. Cyclic CMP in concentrations between 0.35 to 1.5 mM progressively decreased the RNA labelling, and the values of the PCA soluble radioactivity again followed those of RNA. Furthermore, cyclic CMP also blocked the in vitro stimulatory action of cyclic AMP on the incorporation of [3H]leucine into protein, and of [3H]uridine into RNA. The present results provide the first information on the action of cyclic AMP on RNA synthesis and suggest that negative signals may also play a part in the regulation of thyroid function.

Adenosine Monophosphate↗
PubMed1993

Regulation of maternal messenger RNA translation during oogenesis and embryogenesis in Urechis caupo.

We have tested the hypothesis that the selective translation of mRNAs in oocytes and embryos is controlled by when during oogenesis individual maternal mRNAs are synthesized. In an earlier paper we described the isolation of cDNA probes to 21 maternal mRNAs which accumulate with different patterns during oogenesis in Urechis caupo (E. T. Rosenthal and F. H. Wilt, 1986, Dev. Biol. 117, 55-62). Many of these probes have now been used to analyze the translation of the maternal mRNAs in growing oocytes, full-grown oocytes, and embryos. The translation of all of the mRNAs studied changes dramatically when full-grown Urechis oocytes are fertilized. Our data do not support the idea that the translation of the different maternal mRNAs depends on when they were synthesized during oogenesis. This strongly suggests that, at some level, the ability of the cell's translational machinery to distinguish between different maternal mRNAs must reside directly, or indirectly, in the mRNA sequences. We have also found that in Urechis, as in Xenopus, the selective translation of maternal mRNAs is correlated with their selective adenylation. Consequently, we have sequenced the 3' ends of 16 translationally controlled maternal mRNAs in an effort to detect consensus sequences that might regulate adenylation. No such consensus sequences have been found, suggesting that the mRNA characteristics involved in the regulation of polyadenylation may reside in a wide variety of sequences or in more subtle features, such as secondary structure.

Animals↗
PubMed1995

Physiological regulation of peptide messenger RNA colocalization in rat hypothalamic paraventricular medial parvicellular neurons.

In the present study, we used subcutaneous polyethylene glycol injections to show that a physiologically relevant stimulus, hypovolemia, will selectively increase the expression of neuropeptide genes in a restricted population of parvicellular corticotropin-releasing hormone-containing neurons in the hypothalamic paraventricular nucleus. Our results show that a large reduction in extracellular fluid maintained over approximately 20 hours is associated with a significant increase in the level of corticotropin-releasing hormone mRNA in the medial parvicellular division of the paraventricular nucleus. Additionally, there are concomitant increases in cellular levels of both neurotensin/neuromedin N and proenkephalin mRNAs. Our colocalization results show that the increases in neurotensin/neuromedin N and proenkephalin mRNAs after polyethylene glycol injection occur to a significant degree in cells that also contain corticotropin-releasing hormone mRNA. Furthermore, significant numbers of cells containing proenkephalin mRNA also contain neurotensin/neuromedin N mRNA, raising the possibility that some neurons have increased levels of all three mRNAs. Finally, in the medial parvicellular division of the paraventricular nucleus, the number of identified corticotropin-releasing hormone neurons also containing vasopressin mRNA is very low in control animals and is not increased by polyethylene glycol injections, suggesting that, within this period, activation of the vasopressin gene may not be a critical event in the neuroendocrine response of corticotropin-releasing hormone neurosecretory neurons to extracellular dehydration. Considered together with the effects of adrenalectomy on peptide colocalization, our results suggest the existence of several phenotypically distinct sets of neurons within the medial parvicellular division of the paraventricular nucleus, each characterized by its ability to regulate the expression of neuropeptide genes in a stimulus-specific manner.

Animals↗
PubMed1992

Transient down-regulation of PKC-zeta RNA following crosslinking of membrane IgM on WEHI-231 B lymphoma cells.

Regulation of protein kinase C (PKC) isoform mRNAs has been studied in the immature, murine B lymphoma WEHI-231 by the MAPPing protocol and by slot blot analysis of unamplified mRNA. This membrane IgM (mIgM)-positive cell line has been previously used as a model to study signal transduction by mIgM in immature B lymphocytes and the role of those signals in the induction of immune tolerance in the B cell compartment. Stimulation of the cells by anti-mu antibodies, phorbol ester, or Ca2+ ionophore caused growth arrest and death of the cells. IL 4 and IL 5 slowed the growth of the cells. Of these stimuli, only anti-mu stimulation affected PKC mRNA levels. Anti-mu treatment caused a transient decrease in the amount of PKC-zeta isoform mRNA within 3 hr. Within 24 hr levels returned toward normal. Anti-mu had little or no effect on the expression of mRNA for the alpha, beta, delta, or epsilon isoforms of PKC. WEHI-231 cells do not express PKC-gamma. Although anti-mu treatment blocked progression of the cells from the G0/G1 stage into the S phase of cell cycle, viable sort selected cells in either the G0/G1 or the S/G2/M phases showed no clear difference in the expression of PKC-zeta message. Thus, there is not preferential regulation of expression of PKC-zeta during stages of the cell cycle. The results show that mIgM on WEHI-231 cells can transduce a signal that is not mediated by PKC or Ca2+ mobilization alone. The signal causes transient, selective down-regulation of mRNA encoding the zeta PKC isoform.

Animals↗
PubMed1981

Differential regulation of the messenger RNA for three major senescence marker proteins in male rat liver.

Changes in the mRNAs coding for specific hepatic proteins in male rats during aging were examined by in vitro translation of the liver mRNA in the rabbit reticulocyte lysate. Characterization of the [35S]methionine-labeled translation products by sodium dodecyl sulfate-polyacrylamide slab gel electrophoresis followed by autoradiography showed major age-dependent changes in the hepatic concentrations of three mRNA species. The translation products of these three mRNAs were found to have Mr = 28,500, 26,300, and 19,500 and are called senescence marker proteins (SMP) 1, 2, 3, respectively. On the basis of its immunochemical reactivity, SMP-3 (Mr = 19,500) is identified as alpha 2u-globulin while the mRNAs for SMP-1 (Mr = 28,500) and SMP-2 (Mr = 26,300) code for two yet uncharacterized proteins. The liver of the prepubertal male rats was found to contain the mRNA for SMP-2 and showed almost complete absence of the mRNAs for SMP-1 and SMP-3. However, the mRNAs for both SMP-1 and SMP-3 were present in the postpubertal young adults while the mRNA for SMP-2 was absent. Finally, when the animals reached senescence, the mRNAs for SMP-1 and SMP-3 disappeared from the liver with the reappearance of the SMP-2 mRNA. Age-dependent regulation of the mRNAs for these three senescence marker proteins can serve as an important model for the study of differential gene expression during aging.

Aging↗
PubMed2006

Physiological analysis of the stringent response elicited in an extreme thermophilic bacterium, Thermus thermophilus.

Guanosine tetraphosphate (ppGpp) is a key mediator of stringent control, an adaptive response of bacteria to amino acid starvation, and has thus been termed a bacterial alarmone. Previous X-ray crystallographic analysis has provided a structural basis for the transcriptional regulation of RNA polymerase activity by ppGpp in the thermophilic bacterium Thermus thermophilus. Here we investigated the physiological basis of the stringent response by comparing the changes in intracellular ppGpp levels and the rate of RNA synthesis in stringent (rel(+); wild type) and relaxed (relA and relC; mutant) strains of T. thermophilus. We found that in wild-type T. thermophilus, as in other bacteria, serine hydroxamate, an amino acid analogue that inhibits tRNA(Ser) aminoacylation, elicited a stringent response characterized in part by intracellular accumulation of ppGpp and that this response was completely blocked in a relA-null mutant and partially blocked in a relC mutant harboring a mutation in the ribosomal protein L11. Subsequent in vitro assays using ribosomes isolated from wild-type and relA and relC mutant strains confirmed that (p)ppGpp is synthesized by ribosomes and that mutation of RelA or L11 blocks that activity. This conclusion was further confirmed in vitro by demonstrating that thiostrepton or tetracycline inhibits (p)ppGpp synthesis. In an in vitro system, (p)ppGpp acted by inhibiting RNA polymerase-catalyzed 23S/5S rRNA gene transcription but at a concentration much higher than that of the observed intracellular ppGpp pool size. On the other hand, changes in the rRNA gene promoter activity tightly correlated with changes in the GTP but not ATP concentration. Also, (p)ppGpp exerted a potent inhibitory effect on IMP dehydrogenase activity. The present data thus complement the earlier structural analysis by providing physiological evidence that T. thermophilus does produce ppGpp in response to amino acid starvation in a ribosome-dependent (i.e., RelA-dependent) manner. However, it appears that in T. thermophilus, rRNA promoter activity is controlled directly by the GTP pool size, which is modulated by ppGpp via inhibition of IMP dehydrogenase activity. Thus, unlike the case of Escherichia coli, ppGpp may not inhibit T. thermophilus RNA polymerase activity directly in vivo, as recently proposed for Bacillus subtilis rRNA transcription (L. Krasny and R. L. Gourse, EMBO J. 23:4473-4483, 2004).

Adaptation, Physiological↗
PubMed2006

A germline-specific class of small RNAs binds mammalian Piwi proteins.

Small RNAs associate with Argonaute proteins and serve as sequence-specific guides to regulate messenger RNA stability, protein synthesis, chromatin organization and genome structure. In animals, Argonaute proteins segregate into two subfamilies. The Argonaute subfamily acts in RNA interference and in microRNA-mediated gene regulation using 21-22-nucleotide RNAs as guides. The Piwi subfamily is involved in germline-specific events such as germline stem cell maintenance and meiosis. However, neither the biochemical function of Piwi proteins nor the nature of their small RNA guides is known. Here we show that MIWI, a murine Piwi protein, binds a previously uncharacterized class of approximately 29-30-nucleotide RNAs that are highly abundant in testes. We have therefore named these Piwi-interacting RNAs (piRNAs). piRNAs show distinctive localization patterns in the genome, being predominantly grouped into 20-90-kilobase clusters, wherein long stretches of small RNAs are derived from only one strand. Similar piRNAs are also found in human and rat, with major clusters occurring in syntenic locations. Although their function must still be resolved, the abundance of piRNAs in germline cells and the male sterility of Miwi mutants suggest a role in gametogenesis.

Animals↗
PubMed2002

RNA-protein interactions that regulate pre-mRNA splicing.

Splicing of nuclear precursor messenger RNAs is an important and ubiquitous type of gene regulation in metazoans. Splicing joins the coding sequences called exons by removing the intervening noncoding sequences, introns, from primary transcripts. Alternative splicing generates an enormous repertoire of functional diversity by producing multiple RNAs and proteins from a single gene. In fact, recent genome sequences from several organisms suggest that splicing regulation is likely to provide an important source of functional diversity in more complex organisms. Because splice sites are short sequences at the ends of introns, the functional splice sites have to be distinguished from an excessively large number of sequences in the primary transcripts that resemble a splice site. Furthermore, alternative splice sites have to be correctly chosen at appropriate times. Thus, selection of proper splice sites remains a daunting biological problem. This review focuses on a few examples in which the molecular and biochemical basis for splice site selection is better understood.

Alternative Splicing↗
PubMed2003

A vertebrate RNA-binding protein Fox-1 regulates tissue-specific splicing via the pentanucleotide GCAUG.

Alternative splicing is one of the central mechanisms that regulate eukaryotic gene expression. Here we report a tissue-specific RNA-binding protein, Fox-1, which regulates alternative splicing in vertebrates. Fox-1 bound specifically to a pentanucleotide GCAUG in vitro. In zebrafish and mouse, fox-1 is expressed in heart and skeletal muscles. As candidates for muscle-specific targets of Fox-1, we considered two genes, the human mitochondrial ATP synthase gamma-subunit gene (F1gamma) and the rat alpha-actinin gene, because their primary transcripts contain several copies of GCAUG. In transfection experiments, Fox-1 induced muscle-specific exon skipping of the F1gamma gene via binding to GCAUG sequences upstream of the regulated exon. Fox-1 also regulated mutually exclusive splicing of the alpha-actinin gene, antagonizing the repressive effect of polypyrimidine tract-binding protein (PTB). It has been reported that GCAUG is essential for the alternative splicing regulation of several genes including fibronectin. We found that Fox-1 promoted inclusion of the fibronectin EIIIB exon. Thus, we conclude that Fox-1 plays key roles in both positive and negative regulation of tissue-specific splicing via GCAUG.

Actinin↗
PubMed1988

Regulation of Rous sarcoma virus RNA splicing and stability.

Only a fraction of retroviral primary transcripts are spliced to subgenomic mRNAs; the unspliced transcripts are transported to the cytoplasm for packaging into virions and for translation of the gag and pol genes. We identified cis-acting sequences within the gag gene of Rous sarcoma virus (RSV) which negatively regulate splicing in vivo. Mutations were generated downstream of the splice donor (base 397) in the intron of a proviral clone of RSV. Deletion of bases 708 to 800 or 874 to 987 resulted in a large increase in the level of spliced RSV RNA relative to unspliced RSV RNA. This negative regulator of splicing (nrs) also inhibited splicing of a heterologous splice donor and acceptor pair when inserted into the intron. The nrs element did not affect the level of spliced RNA by increasing the rate of transport of the unspliced RNA to the cytoplasm but interfered more directly with splicing. To investigate the possible role of gag proteins in splicing, we studied constructs carrying frameshift mutations in the gag gene. While these mutations, which caused premature termination of gag translation, did not affect the level of spliced RSV RNA, they resulted in a large decrease in the accumulation of unspliced RNA in the cytoplasm.

Avian Sarcoma Viruses↗