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At least 1,171 records · Page 65Linked to original sources
PubMed1999

Amino acid regulation of gene expression.

In mammals, the plasma concentration of amino acids is affected by nutritional or pathological conditions. For example, an amino acid profile alteration has been reported as a result of a deficiency of any one of the essential amino acids, a dietary imbalance of amino acids or an insufficient intake of protein. Amino acid availability regulates the expression of several genes involved in the regulation of growth, cellular function or amino acid metabolism. A limitation of several amino acids strongly increases the expression of insulin-like growth factor binding protein CHOP and asparagine synthetase genes. Elevated messenger RNA levels result from both an increase in the rate of transcription and an increase in messenger RNA stability. DNA amino acid response elements have been characterized in the promoter of CHOP and asparagine synthetase genes. The underlying mechanisms of gene regulation by amino acid limitation are not yet completely understood. The results discussed in this review demonstrate that amino acids by themselves can play, in concert with hormones, an important role in the control of gene expression.

Amino Acids↗
PubMed2001

Recent advances on molecular mechanisms involved in amino acid control of gene expression.

In mammals, the impact of nutrients on gene expression has become an important area of research. Because amino acids have multiple and important functions, their homeostasis has to be finely maintained. However, amino acidaemia can be affected by certain nutritional conditions or various forms of aggression. It follows that mammals have to adjust several of their physiological functions involved in the adaptation to amino acid availability by regulating the expression of numerous genes. It has been shown that amino acids by themselves can modify the expression of target genes. However, the current understanding of amino acid-dependent control of gene expression has just started to emerge. This review focuses on the recent advances on mechanisms involved in the amino acids control of gene expression. Several examples discussed in this paper demonstrate that amino acids regulate gene expression at the level of transcription, messenger RNA stability and translation.

Amino Acids↗
PubMed2003

Molecular mechanisms of lung cell activation induced by cyclic stretch.

OBJECTIVE: To review molecular mechanisms of lung cell activation by stretch. DATA SOURCES: Published original and review articles. DATA SUMMARY: Positive-pressure mechanical ventilation is associated with both beneficial and harmful effects. Data indicate that mechanical ventilation can induce, or increase, lung inflammation. This effect is clearly linked to the degree of lung cell stretching. By modeling cyclic stretch in cultured cells, it has been possible to investigate the cellular pathways activated by this mechanical strain. Integrin receptors, proteins of the focal adhesion plaque, and the cytoskeleton itself participate in the multiple molecular complex that senses cyclic stretch, transforming a mechanical signal into a biological response. Several intracellular signaling pathways then are activated and eventually result in increased transcription of genes harboring "stretch-response elements" in their promoters. Among these pathways, the mitogen-activated protein kinase signaling cascade appears to be central in mediating the effects of cell stretching. Other posttranscriptional mechanisms, such as messenger RNA stabilization and the secretion of preformed mediators, also may account for the secretion of inflammatory mediators after cyclic stretch. CONCLUSION: Identification of the relevant molecular mechanisms will help in the development of novel ventilatory and pharmacologic therapeutic strategies aimed at preventing the deleterious effects of mechanical ventilation.

Animals↗
PubMed1988

The structure and function of the integrated polyoma virus DNA in 82-rat and 53-rat transformed cells.

Integrated viral sequences and adjacent cellular sequences from the polyoma virus (Py)-transformed 53-Rat and 82-Rat cell lines which contain two and three partial early regions respectively, each in a single viral insert, have been molecularly cloned. Each of the cloned partial early regions have been subcloned and assessed with regard to their transcription, translation products (T antigens, T Ags) and biological activity including their transforming ability. The 53-Rat 5.3 kb EcoRI fragment is an intact Py EcoRI linear genome (derived from within the tandem duplicated sequences) which transforms rat cells with high efficiency and produces infectious virus when circularized and transfected into mouse cells. The 82-Rat cell line expresses three novel T Ag species of 63K, 40K and 32K in addition to the Py middle and small T Ags. The 63K protein was found to be a truncated form of large T Ag produced as the result of an addition/deletion in early region B sequences unique to large T Ag. The 40K and 32K proteins are hybrid viral-cellular middle and large T Ags respectively, which are expressed from early region A that has been truncated by recombination with rat cellular DNA. Differences in the nuclear and cytoplasmic location of the different 82-Rat early region RNAs are due to RNA stability and/or transport from the nucleus to the cytoplasm most likely as a result of different cellular sequences at their 3' ends. Finally no common structural feature or sequence specificity was observed at the virus-host DNA joins of the two cell lines.

Animals↗
PubMed2006

tRNA-dependent cleavage of the ColE1 plasmid-encoded RNA I.

Effects of tRNA(Ala)(UGC) and its derivative devoid of the 3'-ACCA motif [tRNA(Ala)(UGC)DeltaACCA] on the cleavage of the ColE1-like plasmid-derived RNA I were analysed in vivo and in vitro. In an amino-acid-starved relA mutant, in which uncharged tRNAs occur in large amounts, three products of specific cleavage of RNA I were observed, in contrast to an otherwise isogenic relA(+) host. Overexpression of tRNA(Ala)(UGC), which under such conditions occurs in Escherichia coli mostly in an uncharged form, induced RNA I cleavage and resulted in an increase in ColE1-like plasmid DNA copy number. Such effects were not observed during overexpression of the 3'-ACCA-truncated tRNA(Ala)(UGC). Moreover, tRNA(Ala)(UGC), but not tRNA(Ala)(UGC)DeltaACCA, caused RNA I cleavage in vitro in the presence of MgCl(2). These results strongly suggest that tRNA-dependent RNA I cleavage occurs in ColE1-like plasmid-bearing E. coli, and demonstrate that tRNA(Ala)(UGC) participates in specific degradation of RNA I in vivo and in vitro. This reaction is dependent on the presence of the 3'-ACCA motif of tRNA(Ala)(UGC).

Bacteriocin Plasmids↗
PubMed2003

Coupled degradation of a small regulatory RNA and its mRNA targets in Escherichia coli.

RyhB is a small antisense regulatory RNA that is repressed by the Fur repressor and negatively regulates at least six mRNAs encoding Fe-binding or Fe-storage proteins in Escherichia coli. When Fe is limiting, RyhB levels rise, and target mRNAs are rapidly degraded. RyhB is very stable when measured after treatment of cells with the transcription inhibitor rifampicin, but is unstable when overall mRNA transcription continues. We propose that RyhB turnover is coupled to and dependent on pairing with the target mRNAs. Degradation of both mRNA targets and RyhB is dependent on RNase E and is slowed in degradosome mutants. RyhB requires the RNA chaperone Hfq. In the absence of Hfq, RyhB is unstable, even when general transcription is inhibited; degradation is dependent upon RNase E. Hfq and RNase E bind similar sites on the RNA; pairing may allow loss of Hfq and access by RNase E. Two other Hfq-dependent small RNAs, DsrA and OxyS, are also stable when overall transcription is off, and unstable when it is not, suggesting that they, too, are degraded when their target mRNAs are available for pairing. Thus, this large class of regulatory RNAs share an unexpected intrinsic mechanism for shutting off their action.

Arabinose↗
PubMed2004

Genome-wide mRNA surveillance is coupled to mRNA export.

Nuclear export of mRNA is a central step in gene expression that shows extensive coupling to transcription and transcript processing. However, little is known about the fate of mRNA and its export under conditions that damage the DNA template and RNA itself. Here we report the discovery of four new factors required for mRNA export through a screen of all annotated nonessential Saccharomyces cerevisiae genes. Two of these factors, mRNA surveillance factor Rrp6 and DNA repair protein Lrp1, are nuclear exosome components that physically interact with one another. We find that Lrp1 mediates specific mRNA degradation upon DNA-damaging UV irradiation as well as general mRNA degradation. Lrp1 requires Rrp6 for genomic localization to genes encoding its mRNA targets, and Rrp6 genomic localization in turn correlates with transcription. Further, Rrp6 and Lrp1 are both required for repair of UV-induced DNA damage. These results demonstrate coupling of mRNA surveillance to mRNA export and suggest specificity of the RNA surveillance machinery for different transcript populations. Broadly, these findings link DNA and RNA surveillance to mRNA export.

DNA Damage↗
PubMed2005

Perspective: machines for RNAi.

RNA silencing pathways convert the sequence information in long RNA, typically double-stranded RNA, into approximately 21-nt RNA signaling molecules such as small interfering RNAs (siRNAs) and microRNAs (miRNAs). siRNAs and miRNAs provide specificity to protein effector complexes that repress mRNA transcription or translation, or catalyze mRNA destruction. Here, we review our current understanding of how small RNAs are produced, how they are loaded into protein complexes, and how they repress gene expression.

Animals↗
PubMed2005

RNase E-based ribonucleoprotein complexes: mechanical basis of mRNA destabilization mediated by bacterial noncoding RNAs.

Hfq-binding antisense small RNAs of Escherichia coli, SgrS and RyhB, mediate the destabilization of target mRNAs in an RNase E-dependent manner. SgrS, whose expression is induced in response to phosphosugar stress, act on the ptsG mRNA encoding a major glucose transporter, while RyhB, whose expression is induced in response to Fe depletion, acts on several mRNAs encoding Fe-binding proteins. In this report, we addressed the question of how SgrS and RyhB RNAs cooperate with RNase E to destabilize the target mRNAs. We demonstrate that Hfq along with SgrS and RyhB copurified with RNase E but not with truncated RNase E. In addition, we show that RNase E but not other degradosome components copurified with Hfq. Taken together, we conclude that RNase E forms variable ribonucleoprotein complexes with Hfq/small RNAs through its C-terminal scaffold region. These complexes, distinct from the RNA degradosome, may act as specialized RNA decay machines that initiate the degradation of mRNAs targeted by each small RNA. The present finding has uncovered the mechanical basis of mRNA destabilization mediated by bacterial small RNAs. The formation of ribonucleoprotein complexes containing RNases could be a general way by which small RNAs destabilize target mRNAs in both prokaryotes and eukaryotes.

Endoribonucleases↗
PubMed2005

Lost in translation: the influence of ribosomes on bacterial mRNA decay.

The lifetimes of bacterial mRNAs are strongly affected by their association with ribosomes. Events occurring at any stage during translation, including ribosome binding, polypeptide elongation, or translation termination, can influence the susceptibility of mRNA to ribonuclease attack. Ribosomes usually act as protective barriers that impede mRNA cleavage, but in some instances they can instead trigger the decay of the mRNA to which they are bound or send a signal that leads to widespread mRNA destabilization within a cell. The influence of translation on mRNA decay provides a quality-control mechanism for minimizing the use of poorly or improperly translated mRNAs as templates for the production of abnormal proteins that might be toxic to bacteria.

Bacteria↗
PubMed2006

Quantitative microarray profiling provides evidence against widespread coupling of alternative splicing with nonsense-mediated mRNA decay to control gene expression.

Sequence-based analyses have predicted that approximately 35% of mammalian alternative splicing (AS) events produce premature termination codon (PTC)-containing splice variants that are targeted by the process of nonsense-mediated mRNA decay (NMD). This led to speculation that AS may often regulate gene expression by activating NMD. Using AS microarrays, we show that PTC-containing splice variants are generally produced at uniformly low levels across diverse mammalian cells and tissues, independently of the action of NMD. Our results suggest that most PTC-introducing AS events are not under positive selection pressure and therefore may not contribute important functional roles.

Alternative Splicing↗
PubMed2006

Endotoxic shock in AUF1 knockout mice mediated by failure to degrade proinflammatory cytokine mRNAs.

Excessive production of proinflammatory cytokines, particularly tumor necrosis factor-alpha (TNFalpha) and interleukin-1beta (IL-1beta), plays a critical role in septic shock induced by bacterial endotoxin (endotoxemia). Precise control of cytokine expression depends on rapid degradation of cytokine mRNAs, mediated by an AU-rich element (ARE) in the 3' noncoding region and by interacting ARE-binding proteins, which control the systemic inflammatory response. To understand the function of the ARE-binding protein AUF1, we developed an AUF1 knockout mouse. We show that AUF1 normally functions to protect against the lethal progression of endotoxemia. Upon endotoxin challenge, AUF1 knockout mice display symptoms of severe endotoxic shock, including vascular hemorrhage, intravascular coagulation, and high mortality, resulting from overproduction of TNFalpha and IL-1beta. Overexpression of these two cytokines is specific, and shown to result from an inability to rapidly degrade these mRNAs in macrophages following induction. Neutralizing antibodies to TNFalpha and IL-1beta protect AUF1 knockout mice against lethal endotoxic shock. These and other data describe a novel post-transcriptional mechanism whereby AUF1 acts as a crucial attenuator of the inflammatory response, promoting the rapid decay of selective proinflammatory cytokine mRNAs following endotoxin activation. Defects in the AUF1 post-transcriptionally controlled pathway may be involved in human inflammatory disease.

Animals↗
PubMed2005

Hfq-dependent regulation of OmpA synthesis is mediated by an antisense RNA.

This paper shows that the small RNA MicA (previously SraD) is an antisense regulator of ompA in Escherichia coli. MicA accumulates upon entry into stationary phase and down-regulates the level of ompA mRNA. Regulation of ompA (outer membrane protein A), previously attributed to Hfq/mRNA binding, is lost upon deletion of the micA gene, whereas overexpression of MicA inhibits the synthesis of OmpA. In vitro, MicA binds to the ompA mRNA leader. Enzymatic and chemical probing was used to map the structures of MicA, the ompA mRNA leader, and the complex formed upon binding. MicA binding generates a footprint across the ompA Shine-Dalgarno sequence, consistent with a 12 + 4 base-pair interaction, which is additionally supported by the effect of mutations in vivo and by bioinformatics analysis of enterobacterial micA/ompA homolog sequences. MicA is conserved in many enterobacteria, as is its ompA target site. In vitro toeprinting confirmed that binding of MicA specifically interferes with ribosome binding. We propose that MicA, when present at high levels, blocks ribosome binding at the ompA translation start site, which-in line with previous work-secondarily facilitates RNase E cleavage and subsequent mRNA decay. MicA requires the presence of the Hfq protein, although the mechanistic basis for this remains unclear.

Bacterial Outer Membrane Proteins↗
PubMed2003

Extensive exon reshuffling over evolutionary time coupled to trans-splicing in Drosophila.

The relative position of exons in genes can be altered only after large structural mutations. These mutations are frequently deleterious, impairing transcription, splicing, RNA stability, or protein function, as well as imposing strong inflexibility to protein evolution. Alternative cis- or trans-splicing may overcome the need for genomic structural stability, allowing genes to encode new proteins without the need to maintain a specific exon order. Trans-splicing in the Drosophila melanogaster modifier of mdg4 (mod[mdg4]) gene is the best documented example in which this process plays a major role in the maturation of mRNAs. Comparison of the genomic organization of this locus among several insect species suggests that the divergence between the lineages of the mosquito Anopheles gambiae and D. melanogaster involved an extensive exon rearrangement, requiring >11 breakpoints within the mod(mdg4) gene. The massive reorganization of the locus also included the deletion or addition of a new function as well as exon duplications. Whereas both DNA strands are sense strands in the Drosophila gene, the coding region in mosquito lays in a single strand, suggesting that trans-splicing may have originated in the Drosophila lineage and might have been the triggering factor for such a dramatic reorganization.

Amino Acid Sequence↗
PubMed2002

Overexpression of the clpP 5'-untranslated region in a chimeric context causes a mutant phenotype, suggesting competition for a clpP-specific RNA maturation factor in tobacco chloroplasts.

The plastid ribosomal RNA (rrn) operon promoter was fused with DNA segments encoding the leader sequence (5'-untranslated region [UTR]) of plastid mRNAs to compare their efficiency in mediating translation of a bacterial protein neomycin phosphotransferase (NPTII) in tobacco (Nicotiana tabacum) chloroplasts. In young leaves, NPTII accumulated at 0.26% and 0.8% of the total soluble leaf protein from genes with the clpP and atpB 5'-UTR, respectively. Interestingly, expression of NPTII from the promoter with the clpP 5'-UTR (0.26% NPTII) caused a mutant (chlorotic) phenotype, whereas plants accumulating approximately 0.8% NPTII from the atpB 5'-UTR were normal green, indicating that the mutant phenotype was independent of NPTII accumulation. Low levels of monocistronic clpP mRNA and accumulation of intron-containing clpP transcripts in the chlorotic leaves suggest competition between the clpP 5'-UTR in the chimeric transcript and the native clpP pre-mRNA (ratio 16:1) for an mRNA maturation factor. Because maturation of 11 other intron-containing mRNAs was unaffected in the chlorotic leaves, it appears that the factor is clpP specific. The mutant phenotype is correlated with reduced levels (approximately 2 times) of the ClpP1 protease subunit, supporting an important role for ClpP1 in chloroplast development.

5' Untranslated Regions↗
PubMed1998

Characterization of two glutamate decarboxylase cDNA clones from Arabidopsis.

Two distinct cDNA clones encoding for the glutamate decarboxylase (GAD) isoenzymes GAD1 and GAD2 from Arabidopsis (L.) Heynh. were characterized. The open reading frames for GAD1 and GAD2 were expressed in Escherichia coli and the recombinant proteins were purified by affinity chromatography. Analysis of the recombinant proteins by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and immunoblot analysis suggest that GAD1 and GAD2 encode for 58- and 56-kD peptides, respectively. The enzymatic activities of the pure recombinant GAD1 and GAD2 proteins were stimulated 35- and 13-fold, respectively, by Ca2+/calmodulin but not by Ca2+ or calmodulin alone. Southern-blot analysis of genomic DNA suggests that there is only one copy of each gene in Arabidopsis. The GAD1 transcript and a corresponding 58-kD peptide were detected in roots only. Conversely, the GAD2 transcript and a corresponding 56-kD peptide were detected in all organs tested. The specific activity, GAD2 transcript, and 56-kD peptide increased in leaves of plants treated with 10 mM NH4Cl, 5 mM NH4NO3, 5 mM glutamic acid, or 5 mM glutamine as the sole nitrogen source compared with samples from plants treated with 10 mM KNO3. The results from these experiments suggest that in leaves GAD activity is partially controlled by gene expression or RNA stability. Results from preliminary analyses of different tissues imply that these tendencies were not the same in flower stalks and flowers, suggesting that other factors may control GAD activity in these organs. The results from this investigation demonstrate that GAD activity in leaves is altered by different nitrogen treatments, suggesting that GAD2 may play a unique role in nitrogen metabolism.

Amino Acid Sequence↗
PubMed2000

Conservation of matrix attachment region-binding filament-like protein 1 among higher plants.

The interaction of chromatin with the nuclear matrix via matrix attachment regions (MARs) on the DNA is considered to be of fundamental importance for higher-order chromatin organization and the regulation of gene expression. We have previously isolated a novel nuclear matrix-localized protein (MFP1) from tomato (Lycopersicon esculentum) that preferentially binds to MAR DNA. Tomato MFP1 has a predicted filament-protein-like structure and is associated with the nuclear envelope via an N-terminal targeting domain. Based on the antigenic relationship, we report here that MFP1 is conserved in a large number of dicot and monocot species. Several cDNAs were cloned from tobacco (Nicotiana tabacum) and shown to correspond to two tobacco MFP1 genes. Comparison of the primary and predicted secondary structures of MFP1 from tomato, tobacco, and Arabidopsis indicates a high degree of conservation of the N-terminal targeting domain, the overall putative coiled-coil structure of the protein, and the C-terminal DNA-binding domain. In addition, we show that tobacco MFP1 is regulated in an organ-specific and developmental fashion, and that this regulation occurs at the level of transcription or RNA stability.

Amino Acid Sequence↗
PubMed1989

cis-Acting Elements for Light Regulation of Pea Ferredoxin I Gene Expression Are Located within Transcribed Sequences.

An intact pea gene encoding ferredoxin I (Fed-1) and several chimeric constructs containing portions of Fed-1 were introduced into tobacco plants by Agrobacterium-mediated transformation. The intact gene was correctly transcribed and translated to produce a protein that was imported into the chloroplast and processed to its mature size. Fed-1 mRNA accumulation in these plants was strongly light-dependent, as it is in pea leaves. In chimeric constructs, the Fed-1 promoter was active but no light responses were seen, even when as much as 2 kilobases of 5[prime] -flanking sequence were included. We also failed to observe clear light responses with a construct containing 3[prime] -flanking sequences from Fed-1 attached to a [beta]-glucuronidase gene driven by the cauliflower mosaic virus 35S promoter. However, the transcribed portion of Fed-1 conveyed normal light responsiveness when driven by the 35S promoter. The results are discussed in terms of the hypothesis that light determines Fed-1 mRNA abundance by affecting RNA stability rather than by affecting transcription.

Journal Article↗