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Results for “Translational repression”

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PubMed2006

Translational repression restricts expression of the C. elegans Nanos homolog NOS-2 to the embryonic germline.

Members of the nanos gene family are evolutionarily conserved regulators of germ cell development. In several organisms, Nanos protein expression is restricted to the primordial germ cells (PGCs) during early embryogenesis. Here, we investigate the regulation of the Caenorhabditis elegans nanos homolog nos-2. We find that the nos-2 RNA is translationally repressed. In the adult germline, translation of the nos-2 RNA is inhibited in growing oocytes, and this inhibition depends on a short stem loop in the nos-2 3'UTR. In embryos, nos-2 translation is repressed in early blastomeres, and this inhibition depends on a second region in the nos-2 3'UTR. nos-2 RNA is also degraded in somatic blastomeres by a process that is independent of translational repression and requires the CCCH finger proteins MEX-5 and MEX-6. Finally, the germ plasm component POS-1 activates nos-2 translation in the PGCs. A combination of translational repression, RNA degradation, and activation by germ plasm has also been implicated in the regulation of nanos homologs in Drosophila and zebrafish, suggesting the existence of conserved mechanisms to restrict Nanos expression to the germline.

3' Untranslated Regions↗

PubMed1996

Elements in the murine c-mos messenger RNA 5'-untranslated region repress translation of downstream coding sequences.

Murine c-mos transcripts isolated from testes have 5'-untranslated regions (5'UTRs) of approximately 300 nucleotides with a series of four overlapping open reading frames (ORFs) upstream of the AUG codon that initiates the Mos ORF. Ovarian c-mos transcripts have shorter 5'UTRs (70-80 nucleotides) and contain only 1-2 of the upstream ORFs (uORFs). To test whether these 5'UTRs affect translational efficiency, we have constructed plasmids for the expression of chimeric transcripts with a mos-derived 5'UTR fused to the Escherichia coli beta-galactosidase coding region. Translational efficiency has been evaluated by measuring beta-galactosidase activity NIH3T3 cells transiently transfected with these plasmids and with plasmids where various mutations have been introduced into the 5'UTR. We show that the 5'UTR characteristic of testis-specific c-mos mRNA strongly represses translation relative to the translation of transcripts that contain a 5'UTR derived from beta-globin mRNA, and this is mainly due to the four uORFs. Each of the four upstream AUG triplets can be recognized as a start site for translation, and no single uAUG dominates the repressive effect. The uORFs repress translation by a mechanism that is not affected by the amino acid sequence in the COOH-terminal region of the uORF-encoded peptides. The very short uORF (AUGUGA) present in ovary-specific transcripts does not repress translation. Staining of testis sections from transgenic mice carrying chimeric beta-galactosidase transgene constructs, which contain a mos 5'UTR with or without the uATGs, suggests that the uORFs can dramatically change the pattern of expression in spermatogenic cells.

Animals↗

PubMed2003

VgRBP71 stimulates cleavage at a polyadenylation signal in Vg1 mRNA, resulting in the removal of a cis-acting element that represses translation.

Translation of Vg1 mRNA is repressed in Xenopus oocytes until it is localized to the vegetal cortex. Localization and translational repression are mediated by separate elements in the 3'UTR of the mRNA. VgRBP71 binds to the 3' end of the localization element and stimulates cleavage at an adjacent polyadenylation signal. The protein has an RNA strand-separation activity that likely underlies this event. Polyadenylation occurs at this site in Vg1 mRNA with the consequence of removing the downstream translational repressor element. Ectopic expression of VgRBP71 in stage II oocytes results in cleavage of the mRNA and premature expression of Vg1 protein. These results support a model in which VgRBP71 activates translation of Vg1 mRNA by promoting the removal of a cis-acting repressor element.

3' Untranslated Regions↗

PubMed2006

Hypothesis: a role for fragile X mental retardation protein in mediating and relieving microRNA-guided translational repression?

MicroRNA (miRNA)-guided messenger RNA (mRNA) translational repression is believed to be mediated by effector miRNA-containing ribonucleoprotein (miRNP) complexes harboring fragile X mental retardation protein (FMRP). Recent studies documented the nucleic acid chaperone properties of FMRP and characterized its role and importance in RNA silencing in mammalian cells. We propose a model in which FMRP could facilitate miRNA assembly on target mRNAs in a process involving recognition of G quartet structures. Functioning within a duplex miRNP, FMRP may also mediate mRNA targeting through a strand exchange mechanism, in which the miRNA* of the duplex is swapped for the mRNA. Furthermore, FMRP may contribute to the relief of miRNA-guided mRNA repression through a reverse strand exchange reaction, possibly initiated by a specific cellular signal, that would liberate the mRNA for translation. Suboptimal utilization of miRNAs may thus account for some of themolecular defects in patients with the fragile X syndrome.

Journal Article↗

PubMed1999

Sequence interval within the PEST motif of Bicoid is important for translational repression of caudal mRNA in the anterior region of the Drosophila embryo.

The Drosophila body organizer Bicoid (Bcd) is a maternal homeodomain protein. It forms a concentration gradient along the longitudinal axis of the preblastoderm embryo and activates early zygotic segmentation genes in a threshold-dependent fashion. In addition, Bcd acts as a translational repressor of maternal caudal (cad) mRNA in the anterior region of the embryo. This process involves a distinct Bcd-binding region (BBR) in the 3' untranslated region (UTR) of cad mRNA. Using cotransfection assays, we found that Bcd represses translation in a cap-dependent manner. Bcd-dependent translational repression involves a portion of the PEST motif of Bcd, a conserved protein motif best known for its function in protein degradation. Rescue experiments with Bcd-deficient embryos expressing transgene-derived Bcd mutants indicate that amino acid replacements within the C-terminal portion of the PEST motif prevent translational repression of cad mRNA but allow for Bcd-dependent transcriptional activation. Thus, Bcd contains separable protein domains for transcriptional and translational regulation of target genes. Maternally-derived cad protein in the anterior region of embryos interferes with head morphogenesis, showing that cad mRNA suppression by Bcd is an important control event during early Drosophila embryogenesis.

Amino Acid Sequence↗

PubMed1997

Binding of eukaryotic translation initiation factor 4E (eIF4E) to eIF4G represses translation of uncapped mRNA.

mRNA translation in crude extracts from the yeast Saccharomyces cerevisiae is stimulated by the cap structure and the poly(A) tail through the binding of the cap-binding protein eukaryotic translation initiation factor 4E (eIF4E) and the poly(A) tail-binding protein Pab1p. These proteins also bind to the translation initiation factor eIF4G and thereby link the mRNA to the general translational apparatus. In contrast, uncapped, poly(A)-deficient mRNA is translated poorly in yeast extracts, in part because of the absence of eIF4E and Pab1p binding sites on the mRNA. Here, we report that uncapped-mRNA translation is also repressed in yeast extracts due to the binding of eIF4E to eIF4G. Specifically, we find that mutations which weaken the eIF4E binding site on the yeast eIF4G proteins Tif4631p and Tif4632p lead to temperature-sensitive growth in vivo and the stimulation of uncapped-mRNA translation in vitro. A mutation in eIF4E which disturbs its ability to interact with eIF4G also leads to a stimulation of uncapped-mRNA translation in vitro. Finally, overexpression of eIF4E in vivo or the addition of excess eIF4E in vitro reverses these effects of the mutations. These data support the hypothesis that the eIF4G protein can efficiently stimulate translation of exogenous uncapped mRNA in extracts but is prevented from doing so as a result of its association with eIF4E. They also suggest that some mRNAs may be translationally regulated in vivo in response to the amount of free eIF4G in the cell.

Amino Acid Sequence↗

PubMed2003

Stress-induced gene expression requires programmed recovery from translational repression.

Active repression of protein synthesis protects cells against protein malfolding during endoplasmic reticulum stress, nutrient deprivation and oxidative stress. However, long-term adaptation to these conditions requires synthesis of new stress-induced proteins. Phosphorylation of the alpha-subunit of translation initiation factor 2 (eIF2alpha) represses translation in diverse stressful conditions. GADD34 is a stress-inducible regulatory subunit of a holophosphatase complex that dephosphorylates eIF2alpha, and has been hypothesized to play a role in translational recovery. Here, we report that GADD34 expression correlated temporally with eIF2alpha dephosphorylation late in the stress response. Inactivation of both alleles of GADD34 prevented eIF2alpha dephosphorylation and blocked the recovery of protein synthesis, normally observed late in the stress response. Furthermore, defective recovery of protein synthesis markedly impaired translation of stress-induced proteins and interfered with programmed activation of stress-induced genes in the GADD34 mutant cells. These observations indicate that GADD34 controls a programmed shift from translational repression to stress-induced gene expression, and reconciles the apparent contradiction between the translational and transcriptional arms of cellular stress responses.

3T3 Cells↗

PubMed2004

Lithium can relieve translational repression of TOP mRNAs elicited by various blocks along the cell cycle in a glycogen synthase kinase-3- and S6-kinase-independent manner.

TOP mRNAs are translationally controlled by mitogenic, growth, and nutritional stimuli through a 5'-terminal oligopyrimidine tract. Here we show that LiCl can alleviate the translational repression of these mRNAs when progression through the cell cycle is blocked at G(0), G(1)/S, or G(2)/M phases in different cell lines and by various physiological and chemical means. This derepressive effect of LiCl does not involve resumption of cell division. Unlike its efficient derepressive effect in mitotically arrested cells, LiCl alleviates inefficiently the repression of TOP mRNAs in amino acid-deprived cells and has no effect in lymphoblastoids whose TOP mRNAs are constitutively repressed even when they are proliferating. LiCl is widely used as a relatively selective inhibitor of glycogen synthase kinase-3. However, inhibition per se of this enzyme by more specific drugs failed to derepress the translation of TOP mRNAs, implying that relief of the translational repression of TOP mRNAs by LiCl is carried out in a glycogen synthase kinase-3-independent manner. Moreover, this effect is apparent, at least in some cell lines, in the absence of S6-kinase 1 activation and ribosomal protein S6 phosphorylation, thus further supporting the notion that translational control of TOP mRNAs does not rely on either of these variables.

Amino Acids↗

PubMed1998

A translational repression assay procedure (TRAP) for RNA-protein interactions in vivo.

RNA-protein interactions are central to many aspects of cellular metabolism, cell differentiation, and development as well as the replication of infectious pathogens. We have devised a versatile, broadly applicable in vivo system for the analysis of RNA-protein interactions in yeast. TRAP (translational repression assay procedure) is based on the translational repression of a reporter mRNA encoding green fluorescent protein by an RNA-binding protein for which a cognate binding site has been introduced into the 5' untranslated region. Because protein binding to the 5' untranslated region can sterically inhibit ribosome association, expression of the cognate binding protein causes significant reduction in the levels of green fluorescent protein fluorescence. By using RNA-protein interactions with affinities in the micromolar to nanomolar range, we demonstrate the specificity of TRAP as well as its ability to recover the cDNA encoding a specific RNA-binding protein, which has been diluted 500,000-fold with unrelated cDNAs, by using fluorescence-activated cell sorting. We suggest that TRAP offers a strategy to clone RNA-binding proteins for which little else than the binding site is known, to delineate RNA sequence requirements for protein binding as well as the protein domains required for RNA binding, and to study effectors of RNA-protein interactions in vivo.

Base Sequence↗

PubMed1986

Changes in the half-life of ribosomal protein messenger RNA caused by translational repression.

The half-life of ribosomal protein operon L11 mRNA in vivo was measured during exponential growth by following the kinetics of incorporation of radioactive precursors into L11 mRNA transcribed from multi-copy plasmids. The degree of translational feedback regulation by L1, the L11 operon-specific translational repressor protein, was changed by altering the site on the "L11 mRNA" where L1 interacts. The half-life of the overproduced L11 mRNA increased by about fivefold when translational repression was abolished, while the half-life of mRNA from the spc ribosomal protein operon, which is not translationally regulated by L1, stayed constant. Furthermore, the half-life of L11 operon mRNA carrying an additional mutation in the ribosome binding site that abolishes translation remains short. This indicates that the change in half-life observed during increased gene dosage is due to translational repression by L1 and is probably a consequence of L1 blocking translation of L11 mRNA and not due to some nucleolytic activity mediated by L1.

Base Sequence↗

PubMed1984

Failure of translational repression in the phage f2 op3 mutant is not due to an altered coat protein-RNA interaction.

A secondary phenotype of the op3 mutant of RNA bacteriophage f2 is the absence of translational repression of the phage replicase gene by the phage coat protein. We have synthesized RNA fragments corresponding to the site of translational repression for both the wild type and the op3 mutant. Using a quantitative assay, we show that the affinity of the closely related R17 coat protein for the mutant and wild type RNA fragments is the same. In addition, we find that the op3 and R17 coat proteins bind to the wild type RNA fragment with essentially identical dissociation constants. Thus, the altered regulation of replicase protein synthesis in the op3 mutant does not appear to be due simply to a reduced affinity of the translational repressor for its target site.

Bacteriophages↗

PubMed2002

RNA-binding properties and translation repression in vitro by germ cell-specific MSY2 protein.

The large amount of MSY2 protein, a mouse germ cell-specific Y-box protein, in oocytes and its degradation by the late two-cell stage suggest that MSY2 may stabilize and/or regulate the translation of maternal mRNAs. We report here the ability of bacterially expressed recombinant MSY2 protein to bind to mRNA and repress translation in vitro. Although MSY2 displays some sequence specificity in binding to short RNA sequences derived from the 3' untranslated region (UTR) of the protamine 1 (Prm1) mRNA, as determined by both gel shift and filter binding assays, essentially no sequence specificity is observed when full-length Prm1 mRNA is used. The binding of MSY2 is approximately 10-fold greater to the full-length Prm1 mRNA than to a 37-nucleotide sequence derived from the 3' UTR, and gel shift assays indicate that multiple MSY2 molecules bind to a single Prm1 mRNA. MSY2 binding to luciferase mRNA at ratios of protein to mRNA that are likely to exist in the oocyte also leads to a moderate inhibition of protein synthesis in vitro. Given the abundance of MSY2 in mouse oocytes (2% of total oocyte protein), these data suggest that MSY2 packages mRNAs in vivo with relatively little sequence specificity, which may lead to both stabilization and translation repression of maternal mRNAs.

3' Untranslated Regions↗

PubMed2006

Translational repression is sufficient for gene silencing by bacterial small noncoding RNAs in the absence of mRNA destruction.

Stress-induced Hfq-binding small RNAs of Escherichia coli, SgrS and RyhB, down-regulate the expression of target mRNAs through base-pairing. These small RNAs form ribonucleoprotein complexes with Hfq and RNase E. The regulatory outcomes of the RNase E/Hfq/small RNA-containing ribonucleoprotein complex (sRNP) are rapid degradation of target mRNAs and translational inhibition. Here, we ask to what extent the sRNP-mediated mRNA destabilization contributes to the overall silencing of target genes by using strains in which the rapid degradation of mRNA no longer occurs. We demonstrate that translational repression occurs in the absence of sRNP-mediated mRNA destabilization. We conclude that translational repression is sufficient for gene silencing by sRNP. One possible physiological role of mRNA degradation mediated by sRNP is to rid the cell of translationally inactive mRNAs, making gene silencing irreversible.

Biological Transport↗

PubMed2001

A highly conserved sequence essential for translational repression of the protamine 1 messenger rna in murine spermatids.

Translational regulation of the protamine 1 mRNA is mediated by sequences in its 3' untranslated region. In this study, we demonstrate that a highly conserved sequence, the translational control element, is solely responsible for protamine 1 translational regulation. Mutation of the conserved sequence causes premature translation of a transgene containing a fusion between the human growth hormone coding sequence and the protamine 1 3' untranslated region. Temporal expression of the transgene was monitored in prepubertal animals by Northern and Western blotting and in adult animals by immunocytochemistry. Messenger RNAs lacking the translational control element sediment in the messenger ribonucleoprotein particle and ribosomal fractions of polysome gradients, suggesting that the translational control element is required for translational repression but not for incorporation of mRNAs into ribonucleoprotein particles.

Acrosome↗

PubMed1994

Vertebrate mRNAs with a 5'-terminal pyrimidine tract are candidates for translational repression in quiescent cells: characterization of the translational cis-regulatory element.

The translation of mammalian ribosomal protein (rp) mRNAs is selectively repressed in nongrowing cells. This response is mediated through a regulatory element residing in the 5' untranslated region of these mRNAs and includes a 5' terminal oligopyrimidine tract (5' TOP). To further characterize the translational cis-regulatory element, we monitored the translational behavior of various endogenous and heterologous mRNAs or hybrid transcripts derived from transfected chimeric genes. The translational efficiency of these mRNAs was assessed in cells that either were growing normally or were growth arrested under various physiological conditions. Our experiments have yielded the following results: (i) the translation of mammalian rp mRNAs is properly regulated in amphibian cells, and likewise, amphibian rp mRNA is regulated in mammalian cells, indicating that all of the elements required for translation control of rp mRNAs are conserved among vertebrate classes; (ii) selective translational control is not confined to rp mRNAs, as mRNAs encoding the naturally occurring ubiquitin-rp fusion protein and elongation factor 1 alpha, which contain a 5' TOP, also conform this mode of regulation; (iii) rat rpP2 mRNA contains only five pyrimidines in its 5' TOP, yet this mRNA is translationally controlled in the same fashion as other rp mRNAs with a 5' TOP of eight or more pyrimidines; (iv) full manifestation of this mode of regulation seems to require both the 5' TOP and sequences immediately downstream; and (v) an intact translational regulatory element from rpL32 mRNA fails to exert its regulatory properties even when preceded by a single A residue.

Animals↗

PubMed2004

Translation repression by GLD-1 protects its mRNA targets from nonsense-mediated mRNA decay in C. elegans.

Previously, we identified multiple in vivo mRNA targets of the maxi-KH/STAR domain protein GLD-1 by their ability to interact with GLD-1 in cytoplasmic extracts and, for all targets tested thus far, GLD-1 functions as a translational repressor. However, here we show that GLD-1 stabilizes the mRNAs of two targets, gna-2 (T23G11.2) and Y75B12B.1. gna-2 mRNA has two upstream open reading frames (uORF), resulting in two premature stop codons. We found that gna-2 mRNA is a naturally occurring mRNA target of nonsense-mediated mRNA decay (NMD) and that the binding of GLD-1 protects gna-2 mRNA from NMD, likely by repressing translation of the uORFs. Therefore, gna-2 mRNA comes under two posttranscriptional controls: (1) translation regulation by a specific translational repressor, GLD-1; and (2) uORF elicited regulation, mainly through NMD. As a result, these two posttranscriptional controls together provide precise temporal and spatial control of gene expression. Consistent with this novel mode of regulation, when GLD-1 mRNA targets acquire premature stop codon mutations, GLD-1 protects them from NMD. Analysis of several mRNA targets containing premature stop codons suggests that in translation repression, GLD-1 either represses ribosome assembly on the target mRNA, or subsequent ribosome elongation to the premature stop codon.

3' Untranslated Regions↗

PubMed1978

Evidence for translational repression of arginine biosynthetic enzymes in Escherichia coli: altered regulation in a streptomycin-resistant mutant.

The formation and repressibility of the arginine biosyntietic enzymes acetylornithine delta-aminotransferase (EC 2.6.1.11), acetylornithine deacetylase (EC 3.5.1.16), ornithine carbamoyltransferase (EC 2.1.3.3), and argininosuccinate lyase (EC 4.3.2.1) were studied in an Escherichia coli W derivative (strain 250-10) that carries (a) a mutant allele of the argR regulatory gene causing a diminished repression-derepression range and (b) a streptomycin resistance mutation. In comparison with the streptomycin-sensitive parent 250, all four enzymes (a) are formed as smaller proportions of the total protein (overall range, 12% to 71%), whether the conditions are repressive (arginine excess) or derepressive (arginine restriction), and (b) show increased repressibility ratios, the carbamoyltransferase giving the largest increase (from 5.7 to 25.0). These effects appear to depend on the concurrent expression of the regulatory-gene and streptomycin resistance mutations, as indicated by analogous experiments with canavanine-resistant mutants of 250-10 that have partial argR- character. The results provide evidence for translational repression in the arginine system, and are interpreted in terms of a functional interaction of a mutant arginine repressor with a mutant S12 ribosomal protein. The locale of translational repression may be near the site of S12, and this mode of regulation may involve initiational selectivity of groupwise recognizable arginine messenger RNA's.

Acetamides↗

PubMed2003

RNA-binding protein-mediated translational repression of transgene expression in plants.

We have demonstrated that RNA-binding proteins from coliphages and yeast can function as translational repressors in plants. RNA sequences called translational operators were inserted at a cap-proximal position in the 5'-UTR of mRNAs of two reporter genes, gus or aroA:CP4. Translation of the reporter mRNAs was efficiently repressed when the RNA binding protein that specifically binds to its cognate operator was co-expressed. The efficiency of translational repression by RNA-binding protein positively correlated with the amount of binding protein in transformed plant cells. Detailed studies on coliphage MS2 coat protein-mediated translational repression also suggested that the efficiency of translational repression was position-dependent. A translational operator situated at the cap-proximal position was more efficient in conferring repression than one that was placed cap-distal. Translational repression can be an efficient means for regulation of transgene expression, thereby broadening current approaches for transgene regulation in plants.

3-Phosphoshikimate 1-Carboxyvinyltransferase↗