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Results for “Translational control”

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PubMed2001

Repression of Manduca sexta ferritin synthesis by IRP1/IRE interaction.

Mammalian ferritin subunit synthesis is controlled at the translational level by the iron regulatory protein 1 (IRP1)/iron responsive element (IRE) interaction. Insect haemolymph ferritin subunit messages have an IRE in the 5'-untranslated region (UTR). We have shown that recombinant M. sexta IRP1 represses the in vitro translation of both the heavy and light chain ferritin subunits from this species without altering transcription. Deletion of either the 5'-UTR or the IRE from the mRNA abolishes IRP1 repression. Our studies indicated that the translational control of ferritin synthesis by IRP/IRE interaction could occur in insects in a manner similar to that of mammals. To our knowledge, this is the first report of the control of insect ferritin synthesis by IRP1/IRE interaction. Furthermore, this is the first indication that the synthesis of a secreted ferritin subunit can also be controlled in this manner.

Amino Acid Sequence↗

PubMed2000

ATLN elements, LINEs from Arabidopsis thaliana: identification and characterization.

Non-LTR retrotransposons (LINEs) are ubiquitous elements in the plant kingdom. Two hundred and nineteen LINE homologues (named ATLN) were identified in the A. thaliana genome, about 90% of which have been sequenced by a computer-aided homology search. Of these, the structures of 62 were analyzed in detail. Most, including those truncated for the 5' regions, were flanked by direct repeats of a sequence of 7-21 bp long, the target site sequence duplicated upon retrotransposition of each member. Thirty ATLN members had two consecutive open reading frames, corresponding to orf1 and orf2 essential for retrotransposition. The phylogenetic tree constructed from the amino acid sequences of the endonuclease domains of the Orf2 proteins showed that the ATLN members were grouped in two families (I and II) and that the members of each family could be further divided into several subfamilies. The members of each subfamily had several unique structural features in common in the intergenic region between orf1 and orf2 as well as in the downstream regions of orf2. Interestingly, orf2 in almost all the ATLN members is located in the -1 frame relative to orf1, indicative of the existence of such translational control mechanisms as translational coupling or frameshifting to produce an amount of Orf2 protein appropriate to that of Orf1. Moreover, the most proximal sequences in the 5' untranslated regions were non-homologous, even in members with the highest homology, unlike the LINEs in animals. The non-homologous sequences in the 5' untranslated regions might be acquired at or after transcription during retrotransposition of the ATLN elements.

5' Untranslated Regions↗

PubMed2002

Poly(A)-binding protein acts in translation termination via eukaryotic release factor 3 interaction and does not influence [PSI(+)] propagation.

Recent studies of translational control suggest that translation termination may not be simply the end of synthesizing a protein but rather be involved in modulating both the translation efficiency and stability of a given transcript. Using recombinant eukaryotic release factor 3 (eRF3) and cellular extracts, we have shown for Saccharomyces cerevisiae that yeast eRF3 and Pab1p can interact. This interaction, mediated by the N+M domain of eRF3 and amino acids 473 to 577 of Pab1p, was demonstrated to be direct by the two-hybrid approach. We confirmed that a genetic interaction exists between eRF3 and Pab1p and showed that Pab1p overexpression enhances the efficiency of termination in SUP35 (eRF3) mutant and [PSI(+)] cells. This effect requires the interaction of Pab1p with eRF3. These data further strengthen the possibility that Pab1p has a role in coupling translation termination events with initiation of translation. Several lines of evidence indicate that Pab1p does not influence [PSI(+)] propagation. First, "[PSI(+)]-no-more" mutations do not affect eRF3-Pab1p two-hybrid interaction. Second, overexpression of PAB1 does not cure the [PSI(+)] phenotype or solubilize detectable amounts of eRF3. Third, prion-curing properties of overexpressed HSP104p, which is required for formation and maintenance of [PSI(+)], were not modified by excess Pab1p.

Carrier Proteins↗

PubMed1988

The positive regulatory function of the 5'-proximal open reading frames in GCN4 mRNA can be mimicked by heterologous, short coding sequences.

Translational control of GCN4 expression in the yeast Saccharomyces cerevisiae is mediated by multiple AUG codons present in the leader of GCN4 mRNA, each of which initiates a short open reading frame of only two or three codons. Upstream AUG codons 3 and 4 are required to repress GCN4 expression in normal growth conditions; AUG codons 1 and 2 are needed to overcome this repression in amino acid starvation conditions. We show that the regulatory function of AUG codons 1 and 2 can be qualitatively mimicked by the AUG codons of two heterologous upstream open reading frames (URFs) containing the initiation regions of the yeast genes PGK and TRP1. These AUG codons inhibit GCN4 expression when present singly in the mRNA leader; however, they stimulate GCN4 expression in derepressing conditions when inserted upstream from AUG codons 3 and 4. This finding supports the idea that AUG codons 1 and 2 function in the control mechanism as translation initiation sites and further suggests that suppression of the inhibitory effects of AUG codons 3 and 4 is a general consequence of the translation of URF 1 and 2 sequences upstream. Several observations suggest that AUG codons 3 and 4 are efficient initiation sites; however, these sequences do not act as positive regulatory elements when placed upstream from URF 1. This result suggests that efficient translation is only one of the important properties of the 5' proximal URFs in GCN4 mRNA. We propose that a second property is the ability to permit reinitiation following termination of translation and that URF 1 is optimized for this regulatory function.

Base Sequence↗

PubMed2003

Genome-wide analysis of mRNA translation profiles in Saccharomyces cerevisiae.

We have analyzed the translational status of each mRNA in rapidly growing Saccharomyces cerevisiae. mRNAs were separated by velocity sedimentation on a sucrose gradient, and 14 fractions across the gradient were analyzed by quantitative microarray analysis, providing a profile of ribosome association with mRNAs for thousands of genes. For most genes, the majority of mRNA molecules were associated with ribosomes and presumably engaged in translation. This systematic approach enabled us to recognize genes with unusual behavior. For 43 genes, most mRNA molecules were not associated with ribosomes, suggesting that they may be translationally controlled. For 53 genes, including GCN4, CPA1, and ICY2, three genes for which translational control is known to play a key role in regulation, most mRNA molecules were associated with a single ribosome. The number of ribosomes associated with mRNAs increased with increasing length of the putative protein-coding sequence, consistent with longer transit times for ribosomes translating longer coding sequences. The density at which ribosomes were distributed on each mRNA (i.e., the number of ribosomes per unit ORF length) was well below the maximum packing density for nearly all mRNAs, consistent with initiation as the rate-limiting step in translation. Global analysis revealed an unexpected correlation: Ribosome density decreases with increasing ORF length. Models to account for this surprising observation are discussed.

Genome, Fungal↗

PubMed2026

Genes associated with translation and oxidative phosphorylation as components of the translational response in nodulated and water-restricted soybean.

BACKGROUND: Soybean primarily acquires nitrogen through symbiosis with nitrogen-fixing bacteria. Water deficit (WD) is a major stress limiting crop yield. Nodulation may enhance drought tolerance in legumes by modulating nitrogen and hormone metabolism, osmotic adjustment, and antioxidant defenses; however, the molecular basis underlying the differential WD responses between N-fix and N-fed plants remain unclear. Translational control of gene expression is a key regulatory mechanism during stress. RESULTS: We compared the transcriptome and translatome of soybean roots from N-fix and N-fed plants exposed to WD across four combined treatments. N-fix plants under WD exhibited more complex responses in terms of total differentially expressed genes (DEGs) compared to N-fed plants. This increased complexity was also evident among translationally regulated DEGs and differentially expressed transcription factors, whose involvement in WD responses of N-fix plants is novel. Co-expression network analysis identified modules associated with core biological processes encompassing nodulation, WD, and notably, their interplay was particularly prominent in Module 1, which was enriched in genes related to ribosomal protein synthesis and oxidative phosphorylation (OXPHOS). Guilt-by-Association analysis enabled the prediction of novel functions for differentially expressed, uncharacterized hub genes related to stress and/or nodulation responses. CONCLUSIONS: Translational regulation of genes involved in OXPHOS and translation initiation emerged as a central response in N-fix plants under WD. These findings reveal distinct molecular adaptations in N-fix soybean roots facing WD and highlight translational control as a key regulatory layer. We also identified promising candidate genes-including transcription factors and uncharacterized hub genes under translational regulation-that represent potential targets for improving drought tolerance in legumes once validated functionally.

Glycine max↗

PubMed1991

Control of gene expression in adult skeletal muscle by changes in the inherent level of contractile activity.

The evidence presented here supports the concept that multiple, complex controls of gene regulation underlie the adaptive changes in protein quantity associated with alterations of the inherent amount of contractile activity in adult skeletal muscle. Investigations of increased contractile activity by running and resistance exercise, as well by recovery from the reduced contractile activity of limb immobilization suggest that control of the alterations of gene expression are initially (one day) at the level of translation. Likewise, experimental models which do not closely mimic human physical training (i.e. electrical stimulation and chronic overload) produce early alterations in the translational control of gene expression. More prolonged changes in contractile activity, brought about by either physical training or experimental models, produce altered gene expression via changes in pre-, post- and translational control.

Animals↗

PubMed2006

Glutamate-dependent translational regulation in cultured Bergmann glia cells: involvement of p70S6K.

Glutamate, the main excitatory amino acid transmitter in the vertebrate brain is involved in the dynamic changes in protein repertoire that underlie synaptic plasticity. Activity-dependent differential expression patterns occur not only in neurons but also in glial cells. In fact, a membrane to nuclei signaling has been described after ionotropic glutamate receptor stimulation in cultured chick cerebellar Bergmann glia cells. In order to characterize other levels of protein expression regulation, we explored the effect of glutamate treatment in [35S]-methionine incorporation into newly synthesized polypeptides. A time-dependent modification in protein synthesis was found. An important component of translational control is the ribosomal S6 protein kinase. Threonine phosphorylation renders the kinase active increasing translation initiation. Glutamate exposure results in ribosomal S6 protein kinase Thr389 phosphorylation in a dose and time-dependent manner that matches perfectly with the overall protein synthesis profile detected upon the excitatory amino acid. Pharmacological characterization of the receptors involved suggests the participation of both ionotropic as well as metabotropic glutamate receptors. The non-receptor tyrosine kinase Src, phosphatidylinositol 3-kinase, protein kinase B and the mammalian target of rapamycin are mediators of the glutamate effect. These results not only demonstrate that glutamate receptors activation is critically involved in translational control in glial cells adjacent to synaptic processes like cerebellar Bergmann glia cells, but also further strengthen the notion of an active participation of glial cells in synaptic transmission.

Analysis of Variance↗

PubMed1970

Translation-level control of amylase and protein synthesis by epinephrine.

The synthesis of RNA, protein, and amylase has been studied in normal and epinephrine-treated slices of rat parotid gland. Epinephrine stimulates synthesis of total cell protein and specifically of amylase, but amylase synthesis is preferentially increased. There is no change in either the specific radioactivity or pattern of labeling of total RNA. In the presence of actinomycin D, epinephrine stimulates secretion of amylase, as well as protein and amylase synthesis. RNA synthesis under these conditions is reduced to 10 per cent of control values. Slices obtained from animals treated with actinomycin D nine and a half hours prior to study show responses to epinephrine comparable to those from control animals, with RNA synthesis inhibited by 70 per cent. Since amylase synthesis is stimulated by epinephrine in the absence of RNA synthesis, control of the production of this enzyme is probably exerted at the level of translation.

Amylases↗

PubMed1989

Regulated polyadenylation controls mRNA translation during meiotic maturation of mouse oocytes.

The translational activation of dormant tissue-type plasminogen activator mRNA during meiotic maturation of mouse oocytes is accompanied by elongation of its 3'-poly(A) tract. Injected RNA fragments that correspond to part of the 3'-untranslated region (3'UTR) of this mRNA are also subject to regulated polyadenylation. Chimeric mRNAs containing part of this 3'UTR are polyadenylated and translated following resumption of meiosis. Polyadenylation and translation of chimeric mRNAs require both specific sequences in the 3'UTR and the canonical 3'-processing signal AAUAAA. Injection of 3'-blocked mRNAs and in vitro polyadenylated mRNAs shows that the presence of a long poly(A) tract is necessary and sufficient for translation. These results establish a role for regulated polyadenylation in the post-transcriptional control of gene expression.

Animals↗

PubMed2000

A GG nucleotide sequence of the 3' untranslated region of amyloid precursor protein mRNA plays a key role in the regulation of translation and the binding of proteins.

The alternative polyadenylation of the mRNA encoding the amyloid precursor protein (APP) involved in Alzheimer's disease generates two molecules, with the first of these containing 258 additional nucleotides in the 3' untranslated region (3'UTR). We have previously shown that these 258 nucleotides increase the translation of APP mRNA injected in Xenopus oocytes (5). Here, we demonstrate that this mechanism occurs in CHO cells as well. We also present evidence that the 3'UTR containing 8 nucleotides more than the short 3'UTR allows the recovery of an efficiency of translation similar to that of the long 3'UTR. Moreover, the two guanine residues located at the 3' ends of these 8 nucleotides play a key role in the translational control. Using gel retardation mobility shift assay, we show that proteins from Xenopus oocytes, CHO cells, and human brain specifically bind to the short 3'UTR but not to the long one. The two guanine residues involved in the translational control inhibit this specific binding by 65%. These results indicate that there is a correlation between the binding of proteins to the 3'UTR of APP mRNA and the efficiency of mRNA translation, and that a GG motif controls both binding of proteins and translation.

3' Untranslated Regions↗

PubMed1991

New mechanisms for effects of anti-inflammatory glucocorticoids.

Suppression of inflammatory prostaglandins (PGs) is a major factor in the anti-inflammatory action of the glucocorticoids. The molecular mechanisms whereby this inhibition occurs are complex, but considerable progress has been made in recent years towards their understanding. A principal mechanism in glucocorticoid sensitive cells studied in tissue culture is a new type of translational control of the messenger RNA for the PG synthase enzyme. In common with other examples of translational control this may involve interaction of glucocorticoid-induced or glucocorticoid-activated proteins with a highly conserved 3' untranslated region in the PG synthase mRNA, converting it into a non-translated cryptic form. The glucocorticoid-linked lipocortin/annexin family of proteins may be involved in the process. In many cell types, translation of the cryptic form of PG synthase mRNA is activated by epidermal growth factor (EGF). This is accompanied by phosphorylation of endogenous lipocortin by the tyrosine kinase activity of the EGF receptor. The possibility that glucocorticoids induce specific protein phosphatases needs further exploration. A second mechanism by which glucocorticoids suppress PG synthesis is to inhibit release of arachidonic acid substrate by phospholipase A2 (PLA2). The long-held belief that this is due to a direct inhibitory action of lipocortin on PLA2 has recently been disproved. Instead glucocorticoids may inhibit PLA2 in some cells directly by inducing dephosphorylation of the active form of the enzyme. In vascular muscle cells, glucocorticoids inhibit expression of the PLA2 enzyme both at the transcriptional and translational levels by mechanisms that remain to be determined.

Animals↗

PubMed1981

Retroregulation of the int gene of bacteriophage lambda: control of translation completion.

Bacteriophage lambda regulates the integration--excision reaction as a crucial aspect of the choice of pathway during lysogenic or lytic viral development. This control involves differential expression of the tightly linked, partially overlapping int and xis genes from two promoter sites: pI, positively regulated by cII/cIII proteins, and pL, positively regulated by N protein. After lambda infection, Int is synthesized from the pI transcript under cII regulation; however, very little Int is produced from the pL RNA because of the existence of a cis-acting regulatory element, sib, on the opposite side of the int gene from the pL promoter. Presumably sib serves to prevent unwanted synthesis of Int protein during the lytic response; the Int protein necessary for excisive recombination from a prophage can be supplied by pL transcription because sib is separated from int by prophage insertion. We have studied the effect of sib on nearby lambda genes by means of gel electrophoresis of labeled proteins from infected cells. Deletion of the sib region greatly enhances production of Int protein without substantial effect on Xis production; thus, sib regulation normally is highly specific for Int. When the sib region is moved past int and xis by deletion, regulation of the adjacent gene for the protein Ea22 occurs, suggesting that sib regulation can work on other genes. Although synthesis of wild-type Int is severely inhibited by sib, shorter Int protein fragments generated by nonsense mutations escape sib regulation, indicating that the regulation is translational and occurs near the completion stage of protein synthesis. Regulation by sib thus exhibits novel regulatory features: distal location, recombinational control, and regulation of the completion of protein synthesis. Because Int and Ea22 control is lost in a RNase III- host, we suggest that sib regulation might involve RNase III cleavage of a RNA duplex region that includes sib and the regulatory target (normally the int gene). We note such a potential site within int.

Bacteriophage lambda↗

PubMed1996

A conserved 90 nucleotide element mediates translational repression of nanos RNA.

Correct formation of the Drosophila body plan requires restriction of nanos activity to the posterior of the embryo. Spatial regulation of nanos is achieved by a combination of RNA localization and localization-dependent translation such that only posteriorly localized nanos RNA is translated. Cis-acting sequences that mediate both RNA localization and translational regulation lie within the nanos 3' untranslated region. We have identified a discrete translational control element within the nanos 3' untranslated region that acts independently of the localization signal to mediate translational repression of unlocalized nanos RNA. Both the translational regulatory function of the nanos 3'UTR and the sequence of the translational control element are conserved between D. melanogaster and D. virilis. Furthermore, we show that the RNA helicase Vasa, which is required for nanos RNA localization, also plays a critical role in promoting nanos translation. Our results specifically exclude models for translational regulation of nanos that rely on changes in polyadenylation.

Animals↗

PubMedDate not supplied

[French translation of the Chapman Social and Physical Anhedonia Questionnaire: validation of the French translation in controls and schizophrenic patients].

Whereas Chapman's social and physical scales are the most used instruments for the assessment of anhedonia in schizophrenia, no French translation has been still validated by the authors. Therefore, the aim of this study was first to translate into French the both scales, and after back translation, to obtain the agreement of the original authors. Second, the aim was to establish values and to establish the cut-off beyond of which French subjects could be considered as anhedonic. One hundred and twenty-three subjects were included: 72 control subjects without mental disorders and 51 stable schizophrenic patients defined by the DSM III-R, ICD 9, ICD 10, RDC or Feighner criteria. According to the literature, schizophrenic patients had higher scores for both scales than control subjects (p < 0.001; Student t test). The social anhedonia scores are different due to cultural variations. The distribution of physical anhedonia scores in control subjects or in schizophrenic patients differed from normal distributions (respectively, p < 0.05; p < 0.0001; Shapiro-Wilks test). The distribution of social anhedonia scores differed from normal distributions (p < 0.01) only in schizophrenic patients but not in control subjects. By maximising the Younden indice [Sensitivity + Specificity -1], the cut-off of the physical anhedonia score was 18 (Younden indice = 0.45), and the cut-off of the social anhedonia score was 12 (Younden indice = 0.24). In using this cut-off, the French physical anhedonia scale had a good positive predictive value (evaluated by logistic regression) for schizophrenia. Therefore, a patient with a physical anhedonia score beyond 18 have a probability of 64% to be schizophrenic. In contrast, the social anhedonia scale was less discriminant for schizophrenia. Indeed, patient with a social anhedonia score beyond 12 have a probability of 52% to be schizophrenic. This French version of Chapman's anhedonia scales could be considered as an useful instrument to assess anhedonia, in particular physical anhedonia, in schizophrenic patients.

Adult↗

PubMed1998

The lambda holin accumulates beyond the lethal triggering concentration under hyperexpression conditions.

Most bacteriophages terminate infection by creating lesions in the cytoplasmic membrane, which not only cause immediate cell death but also allow escape of a phage-encoded endolysin. Destruction of the peptidoglycan and cell lysis follows very rapidly, allowing efficient release of the progeny virions. These membrane lesions are formed by a small integral membrane protein called a holin. Holins have highly charged carboxyl-termini that are thought to have two transmembrane alpha-helical domains. Holins are believed to oligomerize and form large holes in the inner membrane. The prototype holin is the S protein from bacteriophage lambda. Scheduling of the lytic event is determined in part by the "structure directed initiation" or sdi translational control region. Inductions of S, cloned under a variety of native and nonnative promoters but with native translational control, resulted in cell lysis at about 1000 molecules of holin per cell, and thus do not produce biochemically useful amounts of S protein. By utilizing a plasmid-based system with the T7 RNA polymerase promoter in tandem with a consensus ribosome binding site, Coomassie blue-detectable quantities of S protein were obtained upon induction, corresponding to an approximately 100-fold increase over the normal lethal level of holin. Characterization of this expression system is presented and discussed with respect to the current model of holin function.

Amino Acid Sequence↗

PubMed2003

A potent and specific morpholino antisense inhibitor of hepatitis C translation in mice.

Hepatitis C virus (HCV) is an RNA virus infecting one in every 40 people worldwide. Current treatments are ineffective and HCV is the leading cause of liver failure leading to transplantation in the United States and Europe. Translational control of HCV is a prime therapeutic target. We assessed the inhibitory potential of morpholino phosphoramidate antisense oligonucleotides (morpholinos) on HCV translation by codelivering them with reporter plasmids expressing firefly luciferase under the translational control of the HCV internal ribosome entry site (IRES) into the livers of mice. Real-time imaging of HCV IRES luciferase reporter messenger RNA (mRNA) translation in living mice showed that a 20-mer complementary to nucleotides 345-365 of the IRES inhibited translation by greater than 95% for at least 6 days and showed mismatch specificity. No significant nonspecific inhibition of a cap-dependent luciferase or encephalomyocarditis virus (EMCV) IRES luciferase reporter translation was observed. Inhibition by the 20-mer morpholino was dose dependent, with 1 nmol/mouse giving the highest inhibition. In conclusion, morpholino antisense oligonucleotides are potent inhibitors of HCV IRES translation in a preclinical mouse model; morpholinos have potential as molecular therapeutics for treating HCV and other viral infections. The in vivo model described is a broadly applicable, straightforward, and rapid readout for inhibitor efficacy. As such, it will greatly facilitate the development of novel therapeutic strategies for viral hepatitis. Notably, the level of antisense inhibition observed in this in vivo model is similar to the maximal inhibition we have obtained previously with RNA interference in mice.

Animals↗

PubMed1995

The intracellular localization of messenger RNAs.

As I hope this review has made clear, mRNA localization plays an important role in directing specific proteins to their correct position within a cell. Although the study of this process is still in its infancy, it is already apparent that there are several ways that mRNAs can be targeted to particular subcellular sites. However, the molecular mechanisms responsible for these different localization pathways are still largely obscure, and their elucidation must await the identification of the specific factors that mediate the interactions between the localized mRNAs and more general components such as the cytoskeleton. Most examples of localized mRNAs are likely to share several common features. First, the site of localization will be determined by the preexisting polarity of the cell, and this will most often depend on the organization of the cytoskeleton, either directly, in the case of active transport, or indirectly, when localization is mediated by localized anchoring sites or stability factors. Second, mRNA localization is likely to be tightly coupled to translational control. If it is important for a cell to synthesize a protein in a particular place, then the translation of the mRNA must be repressed until it is localized. Indeed, there are already several examples where the direct linkage between translational control and localization has been demonstrated, and these are discussed in the accompanying review by Curtis et al. (1995).

Animals↗