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Results for “Translational repression”

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PubMed2003

Translational repression of a C. elegans Notch mRNA by the STAR/KH domain protein GLD-1.

In C. elegans, the Notch receptor GLP-1 is localized within the germline and early embryo by translational control of glp-1 mRNA. RNA elements in the glp-1 3'untranslated region (3' UTR) are necessary for repression of glp-1 translation in germ cells, and for localization of translation to anterior cells of the early embryo. The direct regulators of glp-1 mRNA are not known. Here, we show that a 34 nucleotide region of the glp-1 3' UTR contains two regulatory elements, an element that represses translation in germ cells and posterior cells of the early embryo, and an element that inhibits repressor activity to promote translation in the embryo. Furthermore, we show that the STAR/KH domain protein GLD-1 binds directly and specifically to the repressor element. Depletion of GLD-1 activity by RNA interference causes loss of endogenous glp-1 mRNA repression in early meiotic germ cells, and in posterior cells of the early embryo. Therefore, GLD-1 is a direct repressor of glp-1 translation at two developmental stages. These results suggest a new function for GLD-1 in regulating early embryonic asymmetry. Furthermore, these observations indicate that precise control of GLD-1 activity by other regulatory factors is important to localize this Notch receptor, and contributes to the spatial organization of Notch signaling.

Animals↗

PubMed1970

Translational repression in the arginine system of Escherichia coli.

Translation of bacterial mRNA, divorced from transcription, has been obtained for enzymes of arginine synthesis; evidence has been acquired for repression by arginine at the level of translation. mRNAs for acetylornithinase and ornithine transcarbamylase were accumulated by arginine starvation of argR(+) and argR(-) arginine auxotrophs derived from Escherichia coli K12. Further transcription was inhibited with rifampicin or miracil D, and enzyme formation was measured in the presence of either an excess of, or a restricted supply of, arginine. For the argR(+) strain 961, little mRNA was found without starvation; for the argR(-) strain 977, a considerable amount of mRNA was demonstrated even without starvation. There was relatively little translation for the argR(+) strain, but not for the argR(-) strain, in the presence of excess arginine, apparently due to an accelerated degradation of mRNA in the argR(+) strain under repressive conditions.

Amidohydrolases↗

PubMed1993

Allosteric mechanism for translational repression in the Escherichia coli alpha operon.

The ribosomal protein S4 is a translational repressor that binds to a complex mRNA pseudoknot structure containing the ribosome binding site for the first gene of the alpha operon. Either 30S subunits or S4 protein bound to the mRNA causes Moloney murine leukemia virus reverse transcriptase to pause near the 3' terminus of the pseudoknot. There is no competition between subunits and S4 for mRNA binding. The kinetics of forming S4-30S-mRNA complexes are biphasic, and the fraction of mRNA molecules reacting more rapidly decreases as the temperature is increased from 30 degrees C to 40 degrees C. The complex cannot be detected with mRNA mutants that cannot be repressed. We have previously shown similar kinetic behavior for the formation of tRNA(fMet) initiation complexes with tRNA(fMet), 30S subunits, and mRNA, except that the fraction reacting rapidly increases when the temperature is increased over the same 30-40 degrees C range. Thus the two sets of experiments show that there are two forms of 30S-mRNA complexes that differ in their abilities to bind S4 and tRNA(fMet). The results support an allosteric model for translational repression in which S4 traps the mRNA in a conformation able to bind 30S subunits but unable to form an initiation complex with tRNA(fMet).

Allosteric Regulation↗

PubMed1996

Programmed cell death in bacteria: translational repression by mRNA end-pairing.

The hok/sok and pnd systems of plasmids R1 and R483 mediate plasmid maintenance by killing plasmid-free cells. Translation of the exceptionally stable hok and pnd mRNAs is repressed by unstable antisense RNAs. The different stabilities of the killer mRNAs and their cognate repressors explain the onset of translation in plasmid-free cells. The full-length hok and pnd mRNAs are inert with respect to translation and antisense RNA binding. We have previously shown that the mRNAs contain two negative translational control elements. Thus, the mRNAs contain upstream anti-Shine-Dalgarno elements that repress translation by shielding the Shine-Dalgarno elements. The mRNAs also contain fold-back-inhibition elements (fbi) at their 3' ends that are required to maintain the inert mRNA configuration. Using genetic complementation, we show that the 3' fbi elements pair with the very 5' ends of the mRNAs. This pairing sets the low rate of 3' exonucleolytical processing, which is required for the accumulation of an activatable pool of mRNA. Unexpectedly, the hok and pnd mRNAs were found to contain translational activators at their 5' ends (termed tac). Thus, the fbi elements inhibit translation of the full-length mRNAs by sequestration of the tac elements. The fbi elements are removed by 3' exonucleolytical processing. Mutational analyses indicate that the 3' processing triggers refolding of the mRNA 5' ends into translatable configurations in which the 5' tac elements base pair with the anti-Shine-Dalgarno sequences.

Apoptosis↗

PubMed2000

Regulation of SOCS-1 expression by translational repression.

Accumulating evidence demonstrates that cytokine receptor signaling is negatively regulated by a family of Src homology 2 domain-containing adaptor molecules termed SOCS (suppressor of cytokine signaling). Previous studies have indicated that the expression of SOCS-related molecules is tightly controlled at the level of transcription. Furthermore, it has been reported that SOCS polypeptides are relatively unstable in cells, unless they are associated with elongins B and C. Herein, we document the existence of a third mechanism of regulation of SOCS function. Our data showed that expression of SOCS-1, a member of the SOCS family, is strongly repressed at the level of translation initiation. Structure-function analyses indicated that this effect is mediated by the 5' untranslated region of socs-1 and that it relates to the presence of two upstream AUGs in this region. Further studies revealed that socs-1 translation is cap-dependent and that it is modulated by eIF4E-binding proteins. In combination, these results uncover a novel level of regulation of SOCS-related molecules. Moreover, coupled with previous findings, they suggest that SOCS expression is tightly regulated through multiple mechanisms, in order to avoid inappropriate interference with cytokine-mediated effects.

Animals↗

PubMed1988

Translational repression in eukaryotes: partial purification and characterization of a repressor of ferritin mRNA translation.

Mouse and rabbit ferritin mRNAs translate very poorly in rabbit reticulocyte lysates relative to most other mRNAs. This translational deficiency is not seen in wheat germ lysates, suggesting the presence of an inhibitor in reticulocyte lysate that is specific for ferritin mRNA. A specific repressor of ferritin mRNA translation has been partially purified from rabbit reticulocytes by differential ultracentrifugation, ammonium sulfate fractionation, and chromatography on phosphocellulose, DEAE-cellulose, and Sephacryl S-300. The elution profile from the latter suggests an aggregate molecular mass of approximately 180 kDa for the repressor. The inhibitory activity of this repressor against native ferritin mRNA can be relieved by adding in vitro transcripts of ferritin light-chain RNAs that contain the first 92 nucleotides of the 5' untranslated region. No other sequences appear to be necessary for this effect.

Animals↗

PubMed1998

Identification of GCD14 and GCD15, novel genes required for translational repression of GCN4 mRNA in Saccharomyces cerevisiae.

In Saccharomyces cerevisiae, expression of the transcriptional activator GCN4 increases at the translational level in response to starvation for an amino acid. The products of multiple GCD genes are required for efficient repression of GCN4 mRNA translation under nonstarvation conditions. The majority of the known GCD genes encode subunits of the general translation initiation factor eIF-2 or eIF-2B. To identify additional initiation factors in yeast, we characterized 65 spontaneously arising Gcd- mutants. In addition to the mutations that were complemented by known GCD genes or by GCN3, we isolated mutant alleles of two new genes named GCD14 and GCD15. Recessive mutations in these two genes led to highly unregulated GCN4 expression and to derepressed transcription of genes in the histidine biosynthetic pathway under GCN4 control. The derepression of GCN4 expression in gcd14 and gcd15 mutants occurred with little or no increase in GCN4 mRNA levels, and it was dependent on upstream open reading frames (uORFs) in GCN4 mRNA that regulate its translation. We conclude that GCD14 and GCD15 are required for repression of GCN4 mRNA translation by the uORFs under conditions of amino acid sufficiency. The gcd14 and gcd15 mutations confer a slow-growth phenotype on nutrient-rich medium, and gcd15 mutations are lethal when combined with a mutation in gcd13. Like other known GCD genes, GCD14 and GCD15 are therefore probably required for general translation initiation in addition to their roles in GCN4-specific translational control.

Alcohol Oxidoreductases↗

PubMed2003

Cup is an eIF4E binding protein required for both the translational repression of oskar and the recruitment of Barentsz.

In Drosophila oocytes, precise localization of the posterior determinant, Oskar, is required for posterior patterning. This precision is accomplished by a localization-dependent translational control mechanism that ensures translation of only correctly localized oskar transcripts. Although progress has been made in identifying localization factors and translational repressors of oskar, none of the known components of the oskar complex is required for both processes. Here, we report the identification of Cup as a novel component of the oskar RNP complex. cup is required for oskar mRNA localization and is necessary to recruit the plus end-directed microtubule transport factor Barentsz to the complex. Surprisingly, Cup is also required to repress the translation of oskar. Furthermore, eukaryotic initiation factor 4E (eIF4E) is localized within the oocyte in a cup-dependent manner and binds directly to Cup in vitro. Thus, Cup is a translational repressor of oskar that is required to assemble the oskar mRNA localization machinery. We propose that Cup coordinates localization with translation.

Animals↗

PubMed2001

Translational repression determines a neuronal potential in Drosophila asymmetric cell division.

Asymmetric cell division is a fundamental strategy for generating cellular diversity during animal development. Daughter cells manifest asymmetry in their differential gene expression. Transcriptional regulation of this process has been the focus of many studies, whereas cell-type-specific 'translational' regulation has been considered to have a more minor role. During sensory organ development in Drosophila, Notch signalling directs the asymmetry between neuronal and non-neuronal lineages, and a zinc-finger transcriptional repressor Tramtrack69 (TTK69) acts downstream of Notch as a determinant of non-neuronal identity. Here we show that repression of TTK69 protein expression in the neuronal lineage occurs translationally rather than transcriptionally. This translational repression is achieved by a direct interaction between cis-acting sequences in the 3' untranslated region of ttk69 messenger RNA and its trans-acting repressor, the RNA-binding protein Musashi (MSI). Although msi can act downstream of Notch, Notch signalling does not affect MSI expression. Thus, Notch signalling is likely to regulate MSI activity rather than its expression. Our results define cell-type-specific translational control of ttk69 by MSI as a downstream event of Notch signalling in asymmetric cell division.

3' Untranslated Regions↗

PubMed2000

The lymphocytic choriomeningitis virus RING protein Z associates with eukaryotic initiation factor 4E and selectively represses translation in a RING-dependent manner.

Only a few host cell proteins that associate with arenaviruses have been identified. To date, the arenavirus Z protein associates with the promyelocytic leukemia protein PML and the ribosomal P proteins. The majority of PML is present in nuclear bodies which are translocated to the cytoplasm by infection with the arenavirus, lymphocytic choriomeningitis virus (LCMV). The Z protein is a small zinc-binding RING protein with an unknown function which is required for the viral life cycle. Here, we demonstrate an association between Z and the host cell translation factor, eukaryotic initiation factor 4E (eIF-4E) in infected and transfected cells. Z's association with both ribosomal proteins and this translation factor led us to investigate whether Z could modulate host cell translation. In cell culture, Z selectively represses protein production in an eIF-4E-dependent manner. Specifically, we see reduction in cyclin D1 protein production with no effect on glyceraldehyde-3-phosphate dehydrogenase (GAPDH) in cells transfected with Z. Previous reports indicate that cyclin D1 is sensitive to eIF-4E levels, whereas GAPDH is not. Consistent with this, we observe preferential downregulation of cyclin D1 during infection and no effect on GAPDH. Further, no changes in RNA levels were observed for cyclin D1 or GAPDH transcripts. The interaction between eIF-4E and Z may provide a mechanism for slower growth observed in infected cells and a viral strategy for establishing chronic infection.

3T3 Cells↗

PubMed1989

Requirements for the translational repression of ferritin transcripts in wheat germ extracts by a 90-kDa protein from rabbit liver.

A specific repressor of ferritin mRNA translation originally detected in rabbit reticulocyte lysates has now been purified to homogeneity from rabbit liver, as described in a companion paper (Walden, W. E., Patino, M. M., and Gaffield, L. (1989) J. Biol. Chem. 264, 13765-13769). This repressor is a 90-kDa protein that binds to a sequence in the 5'-untranslated region of ferritin mRNA. In this communication we describe the molecular features of a ferritin light chain transcript that are required for the repression of its translation by this protein. Addition of small amounts of the 90-kDa ferritin repressor protein (FRP) completely inhibited translation of ferritin transcripts in a wheat germ system. This repression did not require mRNA sequences contained in the 3'-untranslated region or in the majority of the ferritin coding region. In contrast, the first 130 nucleotides of the 5'-untranslated region, which contains the 28-nucleotide "iron responsive element" (IRE), was required for the repressive effect. Moreover, repression of full length transcripts was relieved by addition of a molar excess of a 92-nucleotide transcript of the 5'-untranslated region which also contained the IRE. These results suggest that no sequence information other than a portion of the 5'-untranslated region containing the IRE sequence is required for action of the 90-kDa FRP. In addition, a quantitative comparison of the repression of transcript with that of poly(A+) RNAs indicates that no post-transcriptional modifications of the latter (other than cap addition) are involved in the action of the 90-kDa FRP.

Animals↗

PubMed2005

The RNA-binding protein Musashi-1 regulates neural development through the translational repression of p21WAF-1.

RNA-binding proteins regulate cell fate decisions during nervous system development. The Msi family of RNA-binding proteins is expressed in multipotential neural progenitors, and is required for maintaining cells in a proliferative state. We demonstrate that Msi-1's ability to regulate progenitor maintenance is through the translational inhibition of the cyclin-dependent kinase inhibitor p21WAF-1. Msi-1 ectopic expression increases the proliferation rate and the capacity to regulate p21WAF-1 protein expression, independent of p53. The 3' untranslated region (UTR) of the native p21(WAF-1) mRNA contains a Msi-1 consensus-binding site that permits Msi-1 to directly repress the translation of p21WAF-1 protein. Reduction of Msi-1 through antisense leads to aberrant p21WAF-1 expression, which significantly impairs neural differentiation. A double knockdown for p21WAF-1 and Msi-1 rescues the production of mature MAP+ neurons. Our results further elucidate the symbiotic relationship between cell cycle withdrawal and the onset of differentiation in the developing nervous system, as well as increasing the understanding of the influence that RNA-binding proteins serve in regulating these processes.

Cell Cycle↗

PubMed2005

Translational repression of C. elegans p53 by GLD-1 regulates DNA damage-induced apoptosis.

p53 is a tumor suppressor gene whose regulation is crucial to maintaining genome stability and for the apoptotic elimination of abnormal, potentially cancer-predisposing cells. C. elegans contains a primordial p53 gene, cep-1, that acts as a transcription factor necessary for DNA damage-induced apoptosis. In a genetic screen for negative regulators of CEP-1, we identified a mutation in GLD-1, a translational repressor implicated in multiple C. elegans germ cell fate decisions and related to mammalian Quaking proteins. CEP-1-dependent transcription of proapoptotic genes is upregulated in the gld-1(op236) mutant and an elevation of p53-mediated germ cell apoptosis in response to DNA damage is observed. Further, we demonstrate that GLD-1 mediates its repressive effect by directly binding to the 3'UTR of cep-1/p53 mRNA and repressing its translation. This study reveals that the regulation of cep-1/p53 translation influences DNA damage-induced apoptosis and demonstrates the physiological importance of this mechanism.

3' Untranslated Regions↗

PubMed2006

Drosophila UNR is required for translational repression of male-specific lethal 2 mRNA during regulation of X-chromosome dosage compensation.

The inhibition of male-specific lethal 2 (msl-2) mRNA translation by the RNA-binding protein sex-lethal (SXL) is an essential regulatory step for X-chromosome dosage compensation in Drosophila melanogaster. The mammalian upstream of N-ras (UNR) protein has been implicated in the regulation of mRNA stability and internal ribosome entry site (IRES)-dependent mRNA translation. Here we have identified the Drosophila homolog of mammalian UNR as a cofactor required for SXL-mediated repression of msl-2 translation. UNR interacts with SXL, a female-specific protein. Although UNR is present in both male and female flies, binding of SXL to uridine-rich sequences in the 3' untranslated region (UTR) of msl-2 mRNA recruits UNR to adjacent regulatory sequences, thereby conferring a sex-specific function to UNR. These data identify a novel regulator of dosage compensation in Drosophila that acts coordinately with SXL in translational control.

3' Untranslated Regions↗

PubMed1987

The leader peptide of yeast gene CPA1 is essential for the translational repression of its expression.

The expression of gene CPA1, encoding the glutaminase subunit of the arginine pathway carbamoyl-phosphate synthetase, is repressed by arginine at a posttranscriptional level. The 5' region of CPA1 mRNA contains a 25 codon upstream open reading frame. The importance of this feature for the repression of CPA1 expression has been analyzed by oligonucleotide-directed mutagenesis and by sequencing of constitutive cis-dominant mutations obtained in vivo. The results show that the leader peptide, the product of the upstream open reading frame, plays an essential, negative role in the specific repression of CPA1 by arginine. A model of translational regulation of CPA1 is proposed that takes into account the cis-dominance of the mutations affecting the leader peptide.

Arginine↗

PubMed1989

Translational repression of TEM beta-lactamase synthesis as a response of Escherichia coli to heat shock.

As a result of a temperature shift-up from 30 degrees C to 42 degrees C, beta-lactamase synthesis in Escherichia coli carrying pBR322 ceased transiently, even though the level of beta-lactamase mRNA was not altered. pBR328-directed pre-beta-lactamase synthesis in an in vitro transcription-translation coupled system was also repressed by incubation at the higher temperature. Translation of the lacZ sequence from the amp translation start signal, inserted into the open reading frame vector pORF1, was also repressed transiently upon the temperature shift-up. Pre-heating of the in vitro coupled system at 45 degrees C specifically reduced its capacity for pre-beta-lactamase synthesis. This capacity was restored by the addition of a 160,000 x g supernatant prepared from E. coli grown at 30 degrees C, but not by the supernatant from the cells incubated at 42 degrees C. These and other results indicate that (i) the 160,000 x g supernatant contains a heat-labile protein(s) that is required for efficient initiation of the translation of pre-beta-lactamase mRNA, and (ii) the heat shock-induced repression of beta-lactamase synthesis is due to inactivation of the protein(s) in the 160,000 x g supernatant.

Ampicillin↗

PubMed1986

Translational repression in vitro by the bacteriophage T4 regA protein.

The bacteriophage T4 translational repressor regA protein has been purified from an overproducing strain, and its activity has been studied in simple in vitro protein synthesis reactions. RegA protein was found to inhibit the translation of T4 genes 44, 45, and ORF45-1 in a concentration-dependent fashion. Expression of two other T4 genes which are insensitive to regA protein in vivo, genes 32 and 43, was unaffected by the presence of regA protein. Specific inhibition of synthesis of genes 44, 45, and ORF 45-1 proteins was achieved with 5-20 microM concentrations of regA protein, without the addition of any other T4 encoded proteins or cofactors. When in vitro protein synthesis was performed in two steps, uncoupling translation from transcription, regA protein had an inhibitory effect regardless of whether it was added at the initiation of transcription or only at the translation step. This indicates that regA protein functions during the translation step of protein synthesis in vitro in agreement with previous in vivo studies of regA protein.

Gene Expression Regulation↗

PubMed2004

Global mRNA stabilization preferentially linked to translational repression during the endoplasmic reticulum stress response.

The stability of mRNAs undergoing translation has long been a controversial question. Here, we systematically investigate links between mRNA turnover and translation during the endoplasmic reticulum (ER) stress response, a process during which protein synthesis is potently regulated. cDNA array-based approaches to assess the stability and translational status of each mRNA were devised. First, ER stress-triggered changes in mRNA stability were studied by comparing differences in steady-state mRNA levels with differences in gene transcription. Second, changes in translational status were monitored by studying ER stress-induced shifts in the relative distribution of each mRNA along sucrose gradients. Together, the array-derived data reveal complex links between mRNA stability and translation, with all regulatory groups represented: both stabilized and destabilized mRNAs were found among translationally induced as well as translationally suppressed mRNA collections. Remarkably, however, the subset of stabilized mRNAs was prominently enriched in translationally suppressed transcripts, suggesting that ER stress was capable of causing the stabilization of mRNAs associated with a global reduction in protein synthesis. The cDNA array-based approach described here can be applied to global analyses of mRNA turnover and translation and can serve to investigate subsets of mRNAs subject to joint posttranscriptional control.

Blotting, Northern↗