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Results for “Translational control”

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PubMed1993

An upstream open reading frame represses expression of Lc, a member of the R/B family of maize transcriptional activators.

The R/B genes of maize encode a family of basic helix-loop-helix proteins that determine where and when the anthocyanin-pigment pathway will be expressed in the plant. Previous studies showed that allelic diversity among family members reflects differences in gene expression, specifically in transcription initiation. We present evidence that the R gene Lc is under translational control. We demonstrate that the 235-nt transcript leader of Lc represses expression 25- to 30-fold in an in vivo assay. Repression is mediated by the presence in cis of a 38-codon upstream open reading frame. Furthermore, the coding capacity of the upstream open reading frame influences the magnitude of repression. It is proposed that translational control does not contribute to tissue specificity but prevents overexpression of the Lc protein. The diversity of promoter and 5' untranslated leader sequences among the R/B genes provides an opportunity to study the coevolution of transcriptional and translational mechanisms of gene regulation.

Amino Acid Sequence↗

PubMed1992

Bacteriophage and spliceosomal proteins function as position-dependent cis/trans repressors of mRNA translation in vitro.

The translational regulation of ferritin expression currently represents the only well characterized example for eukaryotic translational control by high affinity interactions between a specific cytoplasmic protein, iron regulatory factor [IRF], and an mRNA-binding site, the iron-responsive element [IRE], located in the 5' untranslated region [UTR] of ferritin mRNAs. To elucidate whether IRE/IRF may represent the first physiological example of a more general mechanism for mRNA-specific translational control, high affinity RNA-binding sites for the bacteriophage MS2 coat protein or the spliceosomal protein U1A were introduced into the 5' UTR of capped chloramphenicol acetyltransferase [CAT] transcripts. In the absence of these RNA-binding proteins, CAT mRNA was efficiently translated. Addition of purified MS2 coat protein or U1A caused a specific, dose-dependent repression of CAT biosynthesis in rabbit reticulocyte and wheat germ in vitro translation systems. The translational blockage imposed by the RNA/protein complex was reversible and did not alter the stability of the repressed mRNAs. Translational repression caused by binding of U1A or MS2 proteins to their target mRNAs is shown to be position-dependent in vitro. Thus, mRNA/protein complexes without an a priori role in eukaryotic mRNA translation function as translational effectors with characteristics resembling those of IRE/IRF.

Bacteriophages↗

PubMed2005

Regulation of endothelial derived nitric oxide in health and disease.

Endothelial nitric oxide synthase (eNOS) is the primary physiological source of nitric oxide (NO) that regulates cardiovascular homeostasis. Historically eNOS has been thought to be a constitutively expressed enzyme regulated by calcium and calmodulin. However, in the last five years it is clear that eNOS activity and NO release can be regulated by post-translational control mechanisms (fatty acid modification and phosphorylation) and protein-protein interactions (with caveolin-1 and heat shock protein 90) that direct impinge upon the duration and magnitude of NO release. This review will summarize this information and apply the post-translational control mechanisms to disease states.

Animals↗

PubMed1994

Positions 13 and 914 in Escherichia coli 16S ribosomal RNA are involved in the control of translational accuracy.

Using a conditional expression system with the temperature-inducible lambda PL promoter, we previously showed that the single mutations 13U-->A and 914A-->U, and the double mutation 13U-->A and 914A-->U in Escherichia coli 16S ribosomal RNA impair the binding of streptomycin (Pinard et al., The FASEB Journal, 1993, 7, 173-176). In this study, we found that the two single mutations and the double mutation increase translational fidelity, reducing in vivo readthrough of nonsense codons and frameshifting, and decreasing in vitro misincorporation in a poly(U)-directed system. Using oligodeoxyribonucleotide probes which hybridize to the 530 loop and to the 1400 region of 16S rRNA, two regions involved in the control of tRNA binding to the A site, we observed that the mutations in rRNA increase the binding of the probe to the 530 loop but not to the 1400 region. We suggest that the mutations at positions 13 and 914 of 16S rRNA induce a conformational rearrangement in the 530 loop, which contributes to the increased accuracy of the ribosome.

Base Sequence↗

PubMed2005

Global gene expression profiling reveals widespread yet distinctive translational responses to different eukaryotic translation initiation factor 2B-targeting stress pathways.

Global inhibition of protein synthesis is a hallmark of many cellular stress conditions. Even though specific mRNAs defy this (e.g., yeast GCN4 and mammalian ATF4), the extent and variation of such resistance remain uncertain. In this study, we have identified yeast mRNAs that are translationally maintained following either amino acid depletion or fusel alcohol addition. Both stresses inhibit eukaryotic translation initiation factor 2B, but via different mechanisms. Using microarray analysis of polysome and monosome mRNA pools, we demonstrate that these stress conditions elicit widespread yet distinct translational reprogramming, identifying a fundamental role for translational control in the adaptation to environmental stress. These studies also highlight the complex interplay that exists between different stages in the gene expression pathway to allow specific preordained programs of proteome remodeling. For example, many ribosome biogenesis genes are coregulated at the transcriptional and translational levels following amino acid starvation. The transcriptional regulation of these genes has recently been connected to the regulation of cellular proliferation, and on the basis of our results, the translational control of these mRNAs should be factored into this equation.

Amino Acids↗

PubMed2001

Cell adhesion regulates gene expression at translational checkpoints in human myeloid leukocytes.

Engagement of adhesion molecules on monocytes and other myeloid leukocytes, which are effector cells of the innate immune system, not only tethers the leukocytes in place but also transmits outside-in signals that induce functional changes and alter gene expression. We found that a subset of mRNAs that are induced or amplified by adhesion of human monocytes to P-selectin via its surface ligand, P-selectin glycoprotein 1, have characteristics that suggest specialized translational control. One of these codes for urokinase plasminogen activator receptor (UPAR), a critical surface protease receptor and regulator of cell adhesion and migration. Although UPAR transcripts are induced by adhesion, rapid synthesis of the protein uses constitutive mRNA without a requirement for new transcription and is regulated by mammalian target of rapamycin, demonstrating new biologic roles for the signal-dependent translation pathway controlled by this intracellular kinase. The synthesis of UPAR in monocytic cells is also regulated by eukaryotic translation initiation factor 4E, a second key translational checkpoint, and phosphorylation of eukaryotic translation initiation factor 4E is induced by adhesion of monocytes to P-selectin. Translationally controlled display of UPAR by monocytes confers recognition of the matrix protein, vitronectin. Adhesion-dependent signaling from the plasma membrane to translational checkpoints represents a previously unrecognized mechanism for regulating surface phenotype that may be particularly important for myeloid leukocytes and other cells that are specialized for rapid inflammatory and vascular responses.

Cell Adhesion↗

PubMed2002

Quality control of translation through the kinetic discrimination of tRNAs in the network of aminoacyl-tRNA synthetases.

It is known that each aminoacyl-tRNA synthetase (aaRS) specifically recognizes its cognate tRNAs to ensure the correct translation of the genetic information. However, we had previously demonstrated that mammalian mitochondrial seryl-tRNA synthetase (mt SerRS) can markedly misacylate mitochondrial (mt) tRNA(Gln). To investigate extensively misacylation reactions in mammalian mitochondrion, we purified overall twenty-two mt tRNAs from bovine liver, and determined their misacylation activities using mt SerRS. In addition to tRNA(Gln), tRNA(Ala) and tRNA(Asn) showed weak but significant serylation activities, which raises the possibility that each mammalian mt aaRS can misacylate several non-cognate mt tRNAs in varying degrees, but translational fidelity might be maintained by kinetic discrimination of tRNAs in the network of aaRSs.

Amino Acyl-tRNA Synthetases↗

PubMed2003

A novel hypoxia-inducible factor-independent hypoxic response regulating mammalian target of rapamycin and its targets.

Hypoxia triggers a reversible inhibition of protein synthesis thought to be important for energy conservation in O2-deficient environments. The mammalian target of rapamycin (mTOR) pathway integrates multiple environmental cues to regulate translation in response to nutrient availability and stress, suggesting it as a candidate for O2 regulation. We show here that hypoxia rapidly and reversibly triggers hypophosphorylation of mTOR and its effectors 4E-BP1, p70S6K, rpS6, and eukaryotic initiation factor 4G. Hypoxic regulation of these translational control proteins is dominant to activation via multiple distinct signaling pathways such as insulin, amino acids, phorbol esters, and serum and is independent of Akt/protein kinase B and AMP-activated protein kinase phosphorylation, ATP levels, ATP:ADP ratios, and hypoxia-inducible factor-1 (HIF-1). Finally, hypoxia appears to repress phosphorylation of translational control proteins in a manner analogous to rapamycin and independent of phosphatase 2A (PP2A) activity. These data demonstrate a new mode of regulation of the mTOR pathway and position this pathway as a powerful point of control by O2 of cellular metabolism and energetics.

Adaptor Proteins, Signal Transducing↗

PubMed1994

Translation through an uncDC mRNA secondary structure governs the level of uncC expression in Escherichia coli.

Escherichia coli expresses the beta and epsilon subunits of F1F0-ATP synthase at relative levels consistent with the 3:1 (beta/epsilon) stoichiometry in the holoenzyme. The mechanism of translational control of expression of the uncC gene (epsilon subunit) relative to the immediately 5' uncD gene (beta subunit) was examined. Previous expression studies and a computer analysis suggested the presence of an RNA secondary structure including the 3' end of uncD, the uncDC intergenic region, and the uncC Shine-Dalgarno sequence (S. D. Dunn and H. G. Dallmann, J. Bacteriol. 172:2782-2784, 1990). Analysis of in vitro-transcribed RNA by cleavage with RNases T1, V1, and CL3 and by chemical modification with dimethyl sulfate and diethyl pyrocarbonate confirmed a predicted structure. Introduction of premature uncD stop codons inserted 5' of the secondary structure strongly reduced epsilon expression, whereas stop codons inserted at positions within the secondary structure showed smaller effects, indicating that translational control of epsilon synthesis involves partial coupling to beta synthesis. Possible mechanisms by which the RNA secondary structure and the unfolding of this structure by translation of uncD may govern the level of uncC expression are discussed.

Base Sequence↗

PubMed2000

In vivo regulation of protein synthesis by phosphorylation of the alpha subunit of wheat eukaryotic initiation factor 2.

The regulation of protein synthesis is a critical component in the maintenance of cellular homeostasis. A major mechanism of translational control in response to diverse abiotic and biotic stress signals involves the phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha). The pathway has been demonstrated in all eukaryotes except plants, although components of a putative plant pathway have been characterized. To evaluate the in vivo capability of plant eIF2alpha to participate in the translation pathway, we have used vaccinia virus recombinants that constitutively express wheat eIF2alpha and inducibly express the eIF2alpha dsRNA-stimulated protein kinase, PKR, in BSC-40 cells. Activation of PKR in cells expressing wild-type wheat eIF2alpha resulted in an inhibition of cellular and viral protein synthesis and an induction of cellular apoptosis correlating with phosphorylation of eIF2alpha on serine 51. Expression of a nonphosphorylatable mutant (51A) of plant eIF2alpha reversed the PKR-mediated translational block as well as the PKR-induced apoptosis. A direct interaction of the plant proteins with the mammalian translational initiation apparatus is supported by coimmunoprecipitation of wild-type plant eIF2alpha and the 51A mutant with mammalian eIF2gamma and the localization of the plant proteins in ribosome fractions. These findings suggest that plant eIF2alpha is capable of interacting with the guanine nucleotide exchange factor eIF2B within the context of the eIF2 holoenzyme and provide direct evidence for its ability to participate in phosphorylation-mediated translational control in vivo.

Amino Acid Sequence↗

PubMed2000

Synthesis of the translational apparatus is regulated at the translational level.

The synthesis of many mammalian proteins associated with the translational apparatus is selectively regulated by mitogenic and nutritional stimuli, at the translational level. The apparent advantages of the regulation of gene expression at the translational level are the speed and the readily reversible nature of the response to altering physiological conditions. These two features enable cells to rapidly repress the biosynthesis of the translational machinery upon shortage of amino acids or growth arrest, thus rapidly blocking unnecessary energy wastage. Likewise, when amino acids are replenished or mitogenic stimulation is applied, then cells can rapidly respond in resuming the costly biosynthesis of the translational apparatus. A structural hallmark, common to mRNAs encoding many components of the translational machinery, is the presence of a 5' terminal oligopyrimidine tract (5'TOP), referred to as TOP mRNAs. This structural motif comprises the core of the translational cis-regulatory element of these mRNAs. The present review focuses on the mechanism underlying the translational control of TOP mRNAs upon growth and nutritional stimuli. A special emphasis is put on the pivotal role played by ribosomal protein S6 kinase (S6K) in this mode of regulation, and the upstream regulatory pathways, which might be engaged in transducing external signals into activation of S6K. Finally, the possible involvement of pyrimidine-binding proteins in the translational control of TOP mRNAs is discussed.

Amino Acids↗

PubMed1996

The Nanos gradient in Drosophila embryos is generated by translational regulation.

Abdominal segmentation in the Drosophila embryo is governed by a gradient of Nanos (Nos) emanating from the posterior pole. This gradient is derived from translation of the nos mRNA that is localized in the pole plasm; in contrast, unlocalized nos mRNA is translationally repressed. Here we define the essential signals in the 3' untranslated region (UTR) of nos mRNA. Deletion of a 184-nucleotide translational control element (TCE) from the 3' UTR leads to the derepression of nos mRNA in the bulk cytoplasm and the development of lethal anterior defects. Furthermore, a minimal mRNA containing essentially only the TCE in its 3' UTR rescues nos- embryos to adulthood. The TCE is also sufficient to confer on maternal torso mRNA all three aspects of nos mRNA regulation: translational repression in the bulk cytoplasm, localization to the pole plasm, and translational activation at the posterior pole. These three phenomena are coupled intimately, as mutations in a pair of CUGGC pentamers within the TCE simultaneously abrogate all three regulatory events. This coupling suggests a model in which the polarized distribution of nos protein is generated primarily by translational control and that nos mRNA localization is a byproduct of this regulation, at least in part.

Animals↗

PubMed1995

mRNA localisation during development.

Although there are many differences, mRNA localisations in the Xenopus oocyte show some tantalizing similarities to those occurring in Drosophila development. As in Drosophila, transcripts localise to opposite poles of the oocyte, this localisation is hierarchical and occurs in a multistep process in which localisation is followed by anchoring at the cortex. This distinction between initial transport and long-term maintenance reflects the dynamic nature of the cytoskeleton: the microtubule tracks form and reform according to the needs of the cell so that stable localisation must be mediated by a more constant structure--the cortex. A possible exception is the localisation of gurken mRNA where it is unknown whether there are separate mechanisms for transport to and maintenance at the oocyte nucleus. However, gurken is responsible for the transmission of a transitory signal; once this has been received, and the fate of the recipient follicle cells determined, there is no further need for localisation. It is possible that the time scale over which the localisation machinery is stable is sufficient for transmission of this signal without the need for a separate maintenance phase. The existence of a nanos homologue, Xcat-2 (Mosquera et al., 1993), associated with the Xenopus germ plasm is particularly interesting because of the morphological and functional similarities between Drosophila polar granules, Caenorhabditis P-granules, and Xenopus germ plasm. These electron-dense protein-RNA complexes are maternally supplied and in each case segregate with the germ line. These granules may represent a fundamental conserved pathway to germ-cell specification and it is now at least a possibility that they are also involved in establishing the embryonic axis through translational repression. In the case of Drosophila, this occurs through localised nanos acting (via Pumilio) on nanos response elements in hunchback mRNA. No such regulatory pair has yet been demonstrated in C. elegans or X. laevis, but each contains a candidate for one half of the interaction: glp-1 could be a target for an unidentified nanos-like protein; Xcat-2 may control translation of an unknown NRE-containing mRNA. Another common feature of mRNA localisation is that in every case where the targeting signal has been determined, it has been mapped to a region of the 3' UTR capable of forming an extensive secondary structure (e.g., David and Ish-Horowicz, 1991; Dalby and Glover, 1992; Gavis and Lehmann, 1992; Kim-Ha et al., 1993; Kislauskis et al., 1993, 1994; Lantz and Schedl, 1994). In several cases, translational control and transcript stability signals have also been mapped to these regions (Jackson and Standart, 1990; Standart et al., 1990; Standart and Hunt, 1990; Davis and Ish-Horowicz, 1991; Wharton and Struhl, 1991; Dalby and Glover, 1993; Evans et al., 1994; Kim-Ha et al., 1995). The large secondary structures may provide a means for stably exposing sequence-specific regions of RNA to proteins. Due to the ease with which RNA forms base pairs, it is likely that rather than remaining single-stranded, RNA within the cell forms some sort of secondary structure. The geometry of purely double-stranded RNA does not permit sequence specific interactions between proteins and the bases because the major groove is inaccessible to amino acid side chains (Weeks and Crothers, 1993). However, the distortions to the dsRNA helix provided by bulges, pseudoknots, and the single-strand loop regions in stem-loop structures do present sequence information that can be "read" by proteins. The extensive 3'UTRs may produce a stable secondary structure which ensures that regulatory elements remain exposed in such regions rather than hidden in double-stranded stems. (ABSTRACT TRUNCATED)

Animals↗

PubMed1990

Regulation by a protein-free carbohydrate-rich diet of rat pancreatic mRNAs encoding trypsin and elastase isoenzymes.

The levels of mRNAs coding for trypsin and elastase isoenzymic forms were determined in the pancreatic tissue of rats fed a high-carbohydrate protein-free diet for a 0-5-day period. No change in the amounts of mRNAs coding for the two isoelastases was observed, although previous results showed that the biosynthesis of anionic elastase was markedly increased, whereas the biosynthesis of cationic elastase decreased, suggesting the existence of a translational-control mechanism in response to nutritional substrates. In contrast, the levels of mRNAs specific for the three isotrypsins were significantly enhanced, possibly as a result of transcriptional regulation and/or a change in messenger stability. In combination with earlier observations of an overall decrease in cationic trypsin biosynthesis during the same nutritional manipulation, these results suggest that formation of this enzyme is also subject to translational control.

Animals↗

PubMed1991

GCD2, a translational repressor of the GCN4 gene, has a general function in the initiation of protein synthesis in Saccharomyces cerevisiae.

The GCD2 protein is a translational repressor of GCN4, the transcriptional activator of multiple amino acid biosynthetic genes in Saccharomyces cerevisiae. We present evidence that GCD2 has a general function in the initiation of protein synthesis in addition to its gene-specific role in translational control of GCN4 expression. Two temperature-sensitive lethal gcd2 mutations result in sensitivity to inhibitors of protein synthesis at the permissive temperature, and the gcd2-503 mutation leads to reduced incorporation of labeled leucine into total protein following a shift to the restrictive temperature of 36 degrees C. The gcd2-503 mutation also results in polysome runoff, accumulation of inactive 80S ribosomal couples, and accumulation of at least one of the subunits of the general translation initiation factor 2 (eIF-2 alpha) in 43S-48S particles following a shift to the restrictive temperature. The gcd2-502 mutation causes accumulation of 40S subunits in polysomes, known as halfmers, that are indicative of reduced 40S-60S subunit joining at the initiation codon. These phenotypes suggest that GCD2 functions in the translation initiation pathway at a step following the binding of eIF-2.GTP.Met-tRNA(iMet) to 40S ribosomal subunits. consistent with this hypothesis, we found that inhibiting 40S-60S subunit joining by deleting one copy (RPL16B) of the duplicated gene encoding the 60S ribosomal protein L16 qualitatively mimics the phenotype of gcd2 mutations in causing derepression of GCN4 expression under nonstarvation conditions. However, deletion of RPL16B also prevents efficient derepression of GCN4 under starvation conditions, indicating that lowering the concentration of 60S subunits and reducing GCD2 function affect translation initiation at GCN4 in different ways. This distinction is in accord with a recently proposed model for GCN4 translational control in which ribosomal reinitiation at short upstream open reading frames in the leader of GCN4 mRNA is suppressed under amino acid starvation conditions to allow for increased reinitiation at the GCN4 start codon.

Amino Acids↗

PubMed2005

Trans-10,cis-12 CLA increases adipocyte lipolysis and alters lipid droplet-associated proteins: role of mTOR and ERK signaling.

Lipid droplet-associated proteins play an important role in adipocyte triglyceride (TG) metabolism. Here, we show that trans-10,cis-12 conjugated linoleic acid (CLA), but not cis-9,trans-11 CLA, increased lipolysis and altered human adipocyte lipid droplet morphology. Before this change in morphology, there was a rapid trans-10,cis-12 CLA-induced increase in the accumulation of perilipin A in the cytosol, followed by the disappearance of perilipin A protein. In contrast, protein levels of adipose differentiation-related protein (ADRP) were increased in cultures treated with trans-10,cis-12 CLA. Immunostaining revealed that ADRP localized to the surface of small lipid droplets, displacing perilipin. Intriguingly, trans-10,cis-12 CLA increased ADRP protein expression to a much greater extent than ADRP mRNA without affecting stability, suggesting translational control of ADRP. To this end, we found that trans-10,cis-12 CLA increased activation of the mammalian target of rapamycin/p70 S6 ribosomal protein kinase/S6 ribosomal protein (mTOR/p70S6K/S6) pathway. Collectively, these data demonstrate that the trans-10,cis-12 CLA-mediated reduction of human adipocyte TG content is associated with the differential localization and expression of lipid droplet-associated proteins. This process involves both the translational control of ADRP through the activation of mTOR/p70S6K/S6 signaling and transcriptional control of perilipin A.

Adipocytes↗

PubMed1988

Translational attenuation control of ermSF, an inducible resistance determinant encoding rRNA N-methyltransferase from Streptomyces fradiae.

An inducible resistance determinant, ermSF, from the tylosin producer Streptomyces fradiae NRRL 2338 has been cloned, sequenced, and shown to confer inducible macrolide-lincosamide-streptogramin B resistance when transferred to Streptomyces griseofuscus NRRL 23916. From mapping studies with S1 nuclease to locate the site of transcription initiation, the ermSF message contains a 385-nucleotide 5' leader sequence upstream from the 960-nucleotide major open reading frame that encodes the resistance determinant. On the basis of the potential secondary structure that the ermSF leader can assume, a translational attenuation model similar to that for ermC is proposed. The model is supported by mutational analysis involving deletions in the proposed attenuator. By analysis with restriction endonucleases, ermSF is indistinguishable from the tlrA gene described by Birmingham et al. (V. A. Birmingham, K. L. Cox, J. L. Larson, S. E. Fishman, C. L. Hershberger, and E. T. Seno, Mol. Gen. Genet. 204:532-539, 1986) which comprises one of at least three genes from S. fradiae that can confer tylosin resistance when subcloned into S. griseofuscus. When tested for inducibility, ermSF appears to be strongly induced by erythromycin, but not by tylosin.

Amino Acid Sequence↗

PubMed2005

The role of X-linked genes in breast cancer.

While contribution of X chromosome in the susceptibility of prostate and ovarian cancer has been demonstrated, the role of X-linked genes in breast carcinogenesis is not clearly known. This study investigated and compared the X-linked gene expression profiles of MMTV-c-myc transgenic mammary tumor (MT) or MMTV-c-myc/MT-tgf-alpha double transgenic mouse mammary tumor (DT) to lactating mammary gland. cDNA microarray analysis using the Affymetrix system identified 1081 genes localized on the X chromosome with 174 and 194 genes at +/-2-fold change levels in MT and DT samples, respectively. Differentially expressed X-linked genes were predominantly related to chromatin structure/remodeling (e.g., Hdac8, Suv39h1, RbAp46 and Adr1), segregation (e.g., CENP-I and smc111) and, ribosomal biogenesis and translational control (e.g., Dkc1, Rpl44, Rpl39, Eif2s3x, Gspt2 and Rsk4). Confirmation of microarray data by semi-quantitative and quantitative RT-PCR in selected X-linked genes also showed similar pattern. In addition, the expression pattern of two chromosomal regions, XE3 and XF5, suggests that XE3 may have escaped from inactivation and XF5 subjected to inactivation. In conclusion, our data suggest that X-linked genes may play the key regulatory roles in the maintenance of chromatin structure, accurate chromosomal segregation and translational control; hence deregulation of X-linked genes may promote mammary gland tumorigenesis by promoting genetic instability and cell proliferation. Increased understanding of the role of X-linked genes and genetic pathways will provide the strategies to develop the molecular therapeutics to treat and prevent reproductive related cancers.

Animals↗