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Results for “Translational control”

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PubMed1987

Three types of muscle-specific gene expression in fusion-blocked rat skeletal muscle cells: translational control in EGTA-treated cells.

When rat skeletal muscle cells were treated with EGTA, an inhibitor of cell fusion, a battery of muscle-specific mRNAs was synthesized but not translated despite the synthesis of many other proteins. Most of the muscle-specific mRNAs were associated with polysomes in fused myotubes, whereas they were found in postpolysomal fractions in EGTA-treated cells. Therefore, in addition to the well-documented transcriptional and posttranscriptional control of muscle-specific genes, translational control of this specific group of genes, presumably involving a Ca2+-dependent process, is also observed in these fusion-blocked cells. These findings and results obtained with other fusion inhibitors demonstrate that three types of muscle-specific gene expression take place in the fusion-blocked cells depending on the inhibitors used: one, neither muscle-specific mRNAs nor proteins are synthesized; two, the mRNAs are synthesized but not translated; and three, both the mRNAs and the proteins are synthesized.

Animals↗

PubMed2004

Translational control in virus-infected cells: models for cellular stress responses.

Protein synthesis is regulated at the translational level by a variety of mechanisms in virus-infected cells. Viruses often induce the shut-off of host translation in order to favour the expression of their own genetic information, but cells possess a number of strategies for counteracting such effects of infection. Important regulatory mechanisms include the phosphorylation of the alpha subunit of polypeptide chain initiation factor eIF2, RNA degradation mediated by the 2'5'-oligoadenylate/RNase L system, control of availability of the cap-binding protein eIF4E by its interaction with the 4E-binding proteins and specific proteolytic cleavage of several key initiation factors. Most of these mechanisms are also utilised in uninfected cells in response to a variety of physiological stresses and during the early stages of apoptosis. Thus, mechanisms of translational control during virus infection can provide models for the cellular stress responses observed in a wide range of other circumstances.

2',5'-Oligoadenylate Synthetase↗

PubMed2004

Translational control: a cup half full.

Repression of translation of oskar and nanos mRNAs prior to their posterior localization in the egg and embryo is essential for body patterning in Drosophila. The Cup protein is now found to have an important role in repression of both mRNAs, and apparently does so in a manner similar to the action of the Xenopus Maskin protein.

Animals↗

PubMed2002

Leaderless mRNAs in bacteria: surprises in ribosomal recruitment and translational control.

It is commonly believed that the translational efficiency of prokaryotic mRNAs is intrinsically determined by both primary and secondary structures of their translational initiation regions. However, for leaderless mRNAs starting with the AUG initiating codon occurring in bacteria, archaea and eukaryotes, there is no evidence for ribosomal recruitment signals downstream of the 5'-terminal AUG that seems to be the only necessary and constant element. Studies in Escherichia coli have brought to light that the ratio of initiation factors IF2 and IF3 plays a decisive role in translation initiation of leaderless mRNA, indicating that the translational efficiency of this mRNA class can be modulated depending on the availability of components of the translational machinery. Recent data suggested that the start codon of bacterial leaderless mRNAs is recognized by a ribosome-IF2-fMet-tRNA complex, an intermediate equivalent to that obligatorily formed during translation initiation in eukaryotes, which points to a conceptual similarity in all initiation pathways. In fact, the faithful translation of leaderless mRNAs in heterologous systems shows that the ability to translate leaderless mRNAs is an evolutionarily conserved function of the translational apparatus.

5' Untranslated Regions↗

PubMed1986

Heat-shock protein synthesis in Chlamydomonas reinhardi. Translational control at the level of initiation of a poly(A)-rich-RNA coded 22-KDa protein in a cell-free system.

The effect of temperature on the in vitro translation of control and heat-shock poly(A)-rich RNA, obtained from Chlamydomonas reinhardi cells, incubated for 2 h at 25 degrees C respectively, was studied using the wheat-germ translation system. Incubation of the cells at 42 degrees C induces the synthesis of RNAs coding for several heat-shock proteins, including a 22-kDa major polypeptide as well as several proteins of 45-94 kDa, as demonstrated by run-off translation of polyribosomes isolated from intact cells. However, the high-molecular-mass heat-shock proteins are poorly translated in the wheat-germ system. The poly(A)-rich RNA coding for the 22-kDa heat-induced polypeptide has an apparent sedimentation coefficient higher than that expected from the molecular mass of its translation product, and was preferentially translated in vitro at temperatures above 31 degrees C as compared with pre-existing RNAs. Raising the temperature of translation, slightly inhibited (10%) the runoff translation of polyribosomes isolated from intact cells. However, when initiation was carried out in vitro for a short time at increasing temperatures and translation continued at 25 degrees C in the presence of aurintricarboxylic acid, the 22-kDa heat-shock polypeptides was preferentially translated. Aurintricarboxylic acid did not significantly inhibit incorporation of [35S]methionine when added to polyribosomes isolated from control or heat-shocked cells. From the above data we conclude that the translation of the 22-kDa heat-shock protein is controlled in vitro at the initiation level.

Cell-Free System↗

PubMed2001

A progress report on translational control in eukaryotes.

An extraordinary amount of regulation goes into making sure that protein expression is controlled correctly. Several layers of regulation function to achieve the proper levels and proper timing of protein expression. Much is known about the protein machinery involved in translation, but we are lagging behind in understanding the mechanisms of control in eukaryotes. Kozak reviews the new second edition of Translational Control of Gene Expression, which attempts to catalog the mechanisms used by prokaryotes and eukaryotes, and the viruses that infect them and subvert their translational machinery.

Animals↗

PubMed1983

Translational control of IS10 transposition.

We present genetic evidence that insertion sequence IS10, the active element in transposon Tn10, can negatively control expression of its own transposase protein at the translational level. This control process is manifested in trans in a phenomenon called "multicopy inhibition": the presence of a multicopy plasmid containing IS10 inhibits transposition of a single copy chromosomal Tn10 element by reducing its ability to express transposition functions. Fusion analysis suggests that expression is reduced at the translational and not the transcriptional level. Only the outer 180 bp of IS10-Right are required on the plasmid for full inhibition. Plasmid-encoded transposase protein is not involved. The genetic structure of the essential plasmid region and the effects of point and deletion mutations on multicopy inhibition lead us to propose that inhibition of transposase translation occurs by direct pairing between the transposase messenger RNA and a small, complementary, regulatory RNA specified by the IS10-encoded pOUT promoter.

DNA Transposable Elements↗

PubMed2001

Non-canonical mechanism for translational control in bacteria: synthesis of ribosomal protein S1.

Translation initiation region (TIR) of the rpsA mRNA encoding ribosomal protein S1 is one of the most efficient in Escherichia coli despite the absence of a canonical Shine-Dalgarno-element. Its high efficiency is under strong negative autogenous control, a puzzling phenomenon as S1 has no strict sequence specificity. To define sequence and structural elements responsible for translational efficiency and autoregulation of the rpsA mRNA, a series of rpsA'-'lacZ chromosomal fusions bearing various mutations in the rpsA TIR was created and tested for beta-galactosidase activity in the absence and presence of excess S1. These in vivo results, as well as data obtained by in vitro techniques and phylogenetic comparison, allow us to propose a model for the structural and functional organization of the rpsA TIR specific for proteobacteria related to E.coli. According to the model, the high efficiency of translation initiation is provided by a specific fold of the rpsA leader forming a non-contiguous ribosome entry site, which is destroyed upon binding of free S1 when it acts as an autogenous repressor.

5' Untranslated Regions↗

PubMed2005

Local translational control in dendrites and its role in long-term synaptic plasticity.

Local protein synthesis in dendrites has emerged as a key mechanism contributing to enduring forms of synaptic plasticity. Although the translational capability of dendrites has been appreciated for over 20 years, it is only recently that significant progress has been made in elucidating mechanisms that contribute to its regulation. It is clear from work over the last few years that the control of translation in dendrites is complex, involving a host of unique (and often surprising) mechanisms that can operate together or in parallel to tightly control gene expression in time and space. Here, we discuss the strategies used by neurons to regulate translation in dendrites and how these are implemented in the service of long-term information storage.

Animals↗

PubMed2003

Translational control of maternal glp-1 mRNA by POS-1 and its interacting protein SPN-4 in Caenorhabditis elegans.

The translation of maternal glp-1 mRNAs is regulated temporally and spatially in C. elegans embryos. The 3' UTR (untranslated region) of the maternal glp-1 mRNA is important for both kinds of regulation. The spatial control region is required to suppress translation in the posterior blastomeres. The temporal one is required to suppress translation in oocytes and one-cell stage embryos. We show that a CCCH zinc-finger protein, POS-1, represses glp-1 mRNA translation by binding to the spatial control region. We identified an RNP-type RNA-binding protein, SPN-4, as a POS-1-interacting protein. SPN-4 is present developmentally from the oocyte to the early embryo and its distribution overlaps with that of POS-1 in the cytoplasm and P granules of the posterior blastomeres. SPN-4 binds to a subregion of the temporal control region in the 3' UTR and is required for the translation of glp-1 mRNA in the anterior blastomeres. We propose that the balance between POS-1 and SPN-4 controls the translation of maternal glp-1 mRNA.

3' Untranslated Regions↗

PubMed1963

TRANSLATIONAL CONTROL OF PROTEIN SYNTHESIS IN A CELL-FREE SYSTEM DIRECTED BY A POLYCISTRONIC VIRAL RNA.

Observations with RNA isolated from the RNA virus indicate that regulation of protein synthesis occurs during translation. At least three electrophoretically separable proteins, one of which lacks histidine, appear as a result of adding purified viral RNA to a cell-free extract of Escherichia coli. This establishes that the RNA contains at least three cistrons. Comparison of the kinetics of appearance of the proteins that do and do not contain histidine reveals a control mechanism which determines the temporal order and the frequency of translation of each cistron. Such translational controls at the stage of message use provide additional devices for regulating protein synthesis which can supplement those functioning at the transcription step where genetic messages are produced.

Carbon Isotopes↗

PubMed2004

Postgenomic global analysis of translational control induced by oncogenic signaling.

It is commonly assumed that developmental and oncogenic signaling achieve their phenotypic effects primarily by directly regulating the transcriptional profile of cells. However, there is growing evidence that the direct effect on transcription may be overshadowed by differential effects on the translational efficiency of specific existing mRNA species. Global analysis of this effect using microarrays indicates that this mechanism of controlling protein production provides a highly specific, robust, and rapid response to oncogenic and developmental stimuli. The mRNAs so affected encode proteins involved in cell-cell interaction, signal transduction, and growth control. Furthermore, a large number of transcription factors capable of secondarily rearranging the transcriptional profile of the cell are controlled at this level as well. To what degree this translational control is either necessary or sufficient for tumor formation or maintenance remains to be determined.

3' Untranslated Regions↗

PubMedDate not supplied

Mechanism of interferon action. Translational control and the RNA-dependent protein kinase (PKR): antagonists of PKR enhance the translational activity of mRNAs that include a 161 nucleotide region from reovirus S1 mRNA.

The interferon-inducible, RNA-dependent protein kinase (PKR) is an important regulator of viral protein synthesis. Activated PKR inhibits protein synthesis by phosphorylating initiation factor eIF-2 alpha. The reovirus S4 gene, whose 1196 nucleotide mRNA transcript does not activate the PKR kinase, is efficiently expressed in vector-transfected monkey COS cells. By contrast, the 1463 nucleotide S1 gene of reovirus, which is a potent activator of PKR, is poorly expressed in COS cells. Virus genetic engineering was therefore used to examine the effect of the PKR activator sequence from the reovirus S1 gene on the expression of chimeric genes of reovirus in transfected COS cells. Chimeric S1/S4 and S4/S1/S4 reovirus constructions that included the PKR activator sequence from S1 in the sigma 3 ORF of S4 were expressed much less efficiently than wild-type S4. However, expression of sigma 3 from S4 (3'UTR/S1), which included the PKR activator sequence from S1 within the 3'-UTR of S4, was comparable to that from wild-type S4. Treatment of COS cells with 2-aminopurine, an inhibitor of PKR, increased the expression of the reovirus S1, S1/S4, and S4/S1/S4 chimeric genes but not the S4 gene or S4 (3'UTR/S1) chimera in transfected COS cells. Likewise, coexpression of the phosphotransfer-negative mutant PKR (K296R) increased the expression of reovirus S1, S1/S4 and S4/S1/S4 chimeric genes but not the S4 gene or S4 (3'UTR/S1) chimera in cotransfected COS cells. Truncated PKR(1-243) which includes the dsRNA binding domain but not the kinase catalytic subdomains was able to enhance the expression of reovirus S1, but did not affect S4 expression. The dsRNA binding protein E3L encoded by vaccinia virus also increased S1 expression similar to PKR (1-243) and PKR(K296R). These results suggest that the translational repression in vivo mediated by PKR is selective for mRNAs that possess the kinase activator region, and that the dominant negative effect of PKR on gene expression is likely mediated by the RNA binding activity of the PKR protein.

2-Aminopurine↗

PubMed1994

Casein kinase II is implicated in the regulation of heme-controlled translational inhibitor of reticulocyte lysates.

The hemin-controlled inhibitor, or HCI, is a cyclic nucleotide-independent protein kinase which specifically phosphorylates the alpha subunit of eukaryotic initiation factor 2 (eIF-2) leading to potential limitations in functional eIF-2 and decreases in protein synthesis initiation. We have recently demonstrated that hemin regulates eIF-2 alpha kinase activity by promoting formation of the inactive heterodimer between HCI and the 90-kDa heat shock protein (hsp90). The formation of the inactive form of HCI by hemin is prevented by treatment with sulfhydryl reagents such as N-ethylmaleimide or when hsp90 is previously phosphorylated (Méndez, R., Moreno, A., and de Haro, C. (1992) J. Biol. Chem. 267, 11500-11507). In this report, using isoelectric focusing and Western blot analyses with antibodies against a synthetic HCI peptide, we have demonstrated that HCI was also phosphorylated when a heme-reversible HCI preparation was preincubated with ATP. Furthermore, our results indicate that casein kinase II (CK II) is the enzyme involved in the regulation of HCI. Thus, the synthetic peptide RRREEETEEE, which is a specific substrate for CK II, acts as a competitive inhibitor of HCI and hsp90 phosphorylation and, at the same time, inhibits the activation of HCI, whereas a synthetic peptide which corresponds to residues 45-59 of the alpha subunit of eIF-2, including the Ser51 phosphorylated by HCI, only inhibits competitively the phosphorylation of eIF-2 alpha. In addition, treatments which modify hsp90 disabling the formation of the inactive dimer with HCI make unnecessary the presence of CK II for activation of HCI. The data strongly suggest that hemin promotes formation of an inactive HCI.hsp90 dimer preventing phosphorylation by CK II. Interestingly, the addition of the CK II peptide substrate also prevents the activation of HCI in a heme-deficient reticulocyte lysate. We hypothesize, therefore, that under physiological conditions, CK II activity appears to be necessary for activation of HCI.

Amino Acid Sequence↗

PubMed1993

The putative iron-responsive element in the human erythroid 5-aminolevulinate synthase mRNA mediates translational control.

The 52-nucleotide 5'-untranslated region of the human erythroid 5-aminolevulinate synthase mRNA contains a 28-nucleotide iron-responsive element-like stem-loop motif. We fused the 5'-untranslated region upstream to the coding sequence of the human growth hormone cDNA. A chimeric construct containing a mutated variant of the presumptive iron-responsive element was similarly synthesized. Translation of the wild type chimeric transcript was markedly repressed (approximately 95%) in rabbit reticulocyte lysates as opposed to the mutant. Both transcripts translated with comparable efficiency in wheat germ extracts. Purified placental iron regulatory factor selectively and markedly inhibited translation of the wild type chimeric transcript (> 90%) when tested in wheat germ extracts. By contrast, translations of either the mutant chimeric transcript or other control mRNA species were unaffected. The proximal position of the iron-responsive element relative to the cap site was shown to be important for translational control, in vitro. Our studies suggest that interaction of the iron regulatory factor with the iron-responsive element sterically hinders formation of the preinitiation complex, resulting in translational repression. Thus inactivation of the repressor protein by critical levels of iron or heme would trigger translation of this mRNA in erythroid cells. Consequently, protoporphyrin and heme synthesis would be subtly coordinated with iron supply.

5-Aminolevulinate Synthetase↗

PubMed2004

Translational control by MAPK signaling in long-term synaptic plasticity and memory.

Enduring forms of synaptic plasticity and memory require new protein synthesis, but little is known about the underlying regulatory mechanisms. Here, we investigate the role of MAPK signaling in these processes. Conditional expression of a dominant-negative form of MEK1 in the postnatal murine forebrain inhibited ERK activation and caused selective deficits in hippocampal memory retention and the translation-dependent, transcription-independent phase of hippocampal L-LTP. In hippocampal neurons, ERK inhibition blocked neuronal activity-induced translation as well as phosphorylation of the translation factors eIF4E, 4EBP1, and ribosomal protein S6. Correspondingly, protein synthesis and translation factor phosphorylation induced in control hippocampal slices by L-LTP-generating tetanization were significantly reduced in mutant slices. Translation factor phosphorylation induced in the control hippocampus by memory formation was similarly diminished in the mutant hippocampus. These results suggest a crucial role for translational control by MAPK signaling in long-lasting forms of synaptic plasticity and memory.

Adaptor Proteins, Signal Transducing↗

PubMed1998

Yellow fever 5' noncoding region as a potential element to improve hepatitis C virus production through modification of translational control.

The lengthy 5' noncoding region (5' NCR) of hepatitis C virus (HCV) RNA forms a highly ordered secondary structure, very conserved among different strains. It includes an internal ribosome entry site (IRES) element, responsible for the cap-independent translation initiation of HCV RNA. Similarly to the IRES of hepatitis A virus (HAV), another human hepatitis virus, HCV IRES, activity in internal initiation of translation is weak. Furthermore, both viruses exhibit a poor growth phenotype that may result at least partially from an inhibitory control of translation. To enhance HCV translation, as a preliminary step in designing constructs for improvement in viral production, we sought to evaluate a chimeric construct containing the yellow fever virus (YFV) 5' NCR fused to the initiation codon of the HCV coding sequence. YF viral RNA, as the majority of eukaryotic messenger RNAs, is translated by a ribosome scanning mechanism in a cap-dependent manner. The efficiency of translation initiation of the parental HCV construct was compared in vitro in rabbit reticulocyte lysates with that of the chimeric construct containing YFV 5' NCR. Surprisingly, the related distanced YFV 5' NCR was fivefold more active than was the wild-type HCV IRES in directing that function. Furthermore, chimeric transcripts were shown to be effective in vivo after transfection of eukaryotic cells. Taken together, these results raise the following question: why has the HCV genus evolved to the acquisition of an IRES element within its 5' NCR among the Flaviviridae family?

5' Untranslated Regions↗

PubMed1977

Mechanism of translational control by hemin in reticulocyte lysates.

The formation of translational inhibitor (active eIF-2 kinase) from proinhibitor (inactive eIF-2 kinase) in reticulocyte lysates, known to be controlled by hemin, can, as we recently reported, be induced by 3':5'-cyclic AMP(cAMP)-dependent protein kinase (ATP:protein phosphotransferase, EC 2.7.1.37) or its catalytic subunit. We find that in crude preparations from rabbit reticulocyte lysates, hemin inhibits the conversion of proinhibitor to inhibitor catalyzed by endogenous cAMP-dependent protein kinase upon addition of cAMP, but not that caused by the addition of free protein kinase catalytic subunit. Hemin prevents the binding of cAMP to the regulatory subunit of cAMP-dependent protein kinase and blocks the cAMP-induced dissociation of regulatory and catalytic subunits of the enzyme whereby the enzyme is inactivated. The mechanism by which hemin prevents the formation of the inhibitor and maintains protein synthesis in reticulocyte lysates is thus explained.

Animals↗