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Results for “Translational control”

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At least 19 recordsLinked to original sources

PubMed1989

Sequences that surround the stop codons of upstream open reading frames in GCN4 mRNA determine their distinct functions in translational control.

Translational control of the GCN4 gene of Saccharomyces cerevisiae requires at least two of the four short upstream open reading frames (URFs) in the leader of GCN4 mRNA. URF4 is a strong negative element that is sufficient for repression of GCN4 expression in normal growth conditions. URF1 is approximately 30-fold less effective as a translational barrier when it is the single URF present in the mRNA leader and is required upstream from URF4 for efficient derepression of GCN4 expression under amino acid starvation conditions. We show that the last codon plus 10 bp immediately after the stop codon of URF4 are sufficient to convert URF1 into a strong translational barrier when it is present as a solitary URF. This result suggests that the characteristics of translation termination at URF4 are responsible largely for its strong inhibitory effect on translation initiation at the GCN4 AUG codon. Introduction of the same URF4 sequences at URF1 also reduces GCN4 expression under derepressing conditions when URF1 is upstream from URF4. This fact suggests that URF1 translation normally is compatible with efficient scanning and initiation downstream and that this property is required for its ability to overcome the translational barrier at URF4. These findings are consistent with the idea that ribosomes must first translate URF1 and then resume scanning in order to traverse URF4 sequences under starvation conditions. Our results indicate that nucleotides located 3' to the stop codon can be as important as those located 5' to the start site in determining the inhibitory effect of an URF on translation initiation downstream.

Base Sequence↗

PubMed1979

Regulation of the threonine operon: tandem threonine and isoleucine codons in the control region and translational control of transcription termination.

The DNA sequence of 178 base pairs preceding the first structural gene of the threonine operon of Escherichia coli has been determined. A region of perfect 2-fold rotational symmetry, involving 28 base pairs, precedes the first structural gene. The structural similarity of this sequence to known RNA polymerase termination sites suggests that this region is the termination site of the threonine operon leader RNA. Moreover a mutation (thr 79-20), which confers a depressed, constitutive phenotype, was sequenced and found to be a G.C insertion in the putative terminator. A potential coding region for a 21-amino acid leader peptide ends approximately 18 base pairs before the terminator. This peptide contains eight threonine and four isoleucine codons. Eleven of these codons are in tandem. A model for threonine operon regulation, involving alternative secondary RNA structures and translation of leader RNA, is discussed.

Base Sequence↗

PubMed1978

Control of protein synthesis by hemin. An association between the formation of the hemin-controlled translational repressor and the phosphorylation of a 100 000 molecular weight protein.

The control of protein synthesis by hemin in rabbit reticulocytes is mediated by the formation of a high molecular weight protein inhibitor of polypeptide chain initiation, termed the hemin-controlled translational repressor, from a presynthesized prorepressor. The prorepressor, purified approx. 600-fold, was used to study the mechanism of hemin-controlled translational repressor formation. When the prorepressor is converted to the hemin-controlled translational repressor, either by prolonged warming in the absence of hemin or by incubation with N-ethylmaleimide for 5 min, and then incubated briefly with [gamma-32P]-ATP and Mg2+, a protein that migrates as a 100 000 molecular weight component on sodium dodecyl sulfate-polyacrylamide gels becomes phosphorylated. The extent of phosphorylation of this component is directly proportional to the amount of prorepressor converted to the hemin-controlled translational repressor. In addition, the 100 000 molecular weight protein is not labeled when phosphorylation is attempted with the prorepressor or prorepressor warmed in the presence of hemin, indicating that the protein kinase responsible is probably the hemin-controlled translational repressor. Since the 100 000 molecular protein copurifies with the prorepressor and since the phosphorylation reaction is very rapid (50% complete within 30 s at 34 degrees C), relatively insensitive to dilution, and behaves like an intramolecular reaction, the data suggest that the hemin-controlled translational repressor, once activated, may autophosphorylate a 100 000 molecular weight subunit of itself. Approx. 5 mol phosphate are incorporated per mol of 100 000 molecular weight protein, when the prorepressor is completely converted to the hemin-controlled translational repressor by N-ethylmaleimide. Neither the rate of conversion of prorepressor to the hemin-controlled translational repressor nor the subsequent phosphorylation of the 100 000 molecular weight protein is enhanced by cyclic AMP or reduced by incubation with 3':5'-cyclic nucleotide phosphodiesterase, indicating that cyclic AMP plays no role in hemin-controlled translational repressor formation.

Animals↗

PubMed1991

Oligopyrimidine tract at the 5' end of mammalian ribosomal protein mRNAs is required for their translational control.

Mammalian ribosomal protein (rp) mRNAs are subject to translational control, as illustrated by their selective release from polyribosomes in growth-arrested cells and their underrepresentation in polysomes in normally growing cells. In the present experiments, we have examined whether the translational control of rp mRNAs is attributable to the distinctive features of their 5' untranslated region, in particular to the oligopyrimidine tract adjacent to the cap structure. Murine lymphosarcoma cells were transfected with chimeric genes consisting of selected regions of rp mRNA fused to non-rp mRNA segments, and the translational efficiency of the resulting chimeric mRNAs was assessed in cells that either were growing normally or were growth-arrested by glucocorticoid treatment. We observed that translational control of rpL32 mRNA was abolished when its 5' untranslated region was replaced by that of beta-actin. At the same time, human growth hormone (hGH) mRNA acquired the typical behavior of rp mRNAs when it was preceded by the first 61 nucleotides of rpL30 mRNA or the first 29 nucleotides of rpS16 mRNA. Moreover, the translational control of rpS16-hGH mRNA was abolished by the substitution of purines into the pyrimidine tract or by shortening it from eight to six residues with a concomitant cytidine----uridine change at the 5' terminus. These results indicate that the 5'-terminal pyrimidine tract plays a critical role in the translational control mechanism. Possible factors that might interact with this translational cis regulatory element are discussed.

Animals↗

PubMed1989

Translational control of gene expression in the human brain.

1. Translational control is the regulation of protein synthesis as an alteration in the efficiency of mRNA translation and is a common mechanism by which cells regulate gene expression. 2. Alternations of total protein synthesis are often the responses of cells to various stress stimuli including starvation, viral infection, and heat shock. 3. Numerous specific genes including ferritin heavy chain, tubulin, vimentin and the lck proto-oncogene have also been shown to be under translational control. 4. Unlike cultured cells or intact organisms, the investigation of translational control in the human brain requires the measurement of components of protein synthesis, especially polysomes. Therefore, we have purified and characterized polysomes from human postmortem brain tissues and compared them to polysomes purified from the adult rat brain. 5. The yield (as A260 units per gram brain tissue), size (as number of ribosomes per message), translational efficiency (as amount protein synthesized per A260 unit), and ability to reinitiate (as amount of protein synthesis prevented by initiation inhibitors) were all significantly lower as exhibited by the human polysomes compared with the rat polysomes. However, the human and rat polysomes synthesized similar polypeptides. 6. Thus, the human polysomes differed from the rat polysomes principally in the efficiency of mRNA translation which is likely due to the greatly reduced ability of the human polysomes to initiate protein synthesis.

Animals↗

PubMed1992

Phosphorylation of initiation factor 2 alpha by protein kinase GCN2 mediates gene-specific translational control of GCN4 in yeast.

We show that phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF-2) by the protein kinase GCN2 mediates translational control of the yeast transcriptional activator GCN4. In vitro, GCN2 specifically phosphorylates the alpha subunit of rabbit or yeast eIF-2. In vivo, phosphorylation of eIF-2 alpha increases in response to amino acid starvation, which is dependent on GCN2. Substitution of Ser-51 with alanine eliminates phosphorylation of eIF-2 alpha by GCN2 in vivo and in vitro and abolishes increased expression of GCN4 and amino acid biosynthetic genes under its control in amino acid-starved cells. The Asp-51 substitution mimics the phosphorylated state and derepresses GCN4 in the absence of GCN2. Thus, an established mechanism for regulating total protein synthesis in mammalian cells mediates gene-specific translational control in yeast.

Animals↗

PubMed1990

Regulation of transmembrane signalling elements: transcriptional, post-transcriptional and post-translational controls.

G-protein-mediated transmembrane signalling is a common motif in biology. The actions of a populous group of G-protein-linked receptors in hormone action, olfaction and vision in vertebrates are examples in which input signals are transferred from a receptor molecule (or photopigment) to an effector unit(s) via G-proteins. The expression and functional status of the receptors, G-proteins, and effectors that constitute these transmembrane signalling systems are regulated physiologically. Altering the abundance, function, or both of these elements provides the means for modulating transmembrane signalling and integration of information among separate pathways. Recent advances in the cell and molecular biology of transmembrane signalling elements provide insight as to the mechanisms by which regulation occurs. Transcriptional control is exemplified by glucocorticoid induction of beta-adrenergic receptor expression. Agonist-induced down-regulation of beta-adrenergic receptor mRNA via message destabilization best highlights post-transcriptional control. Examples of post-translational control of transmembrane signalling elements include protein phosphorylation, thioldisulphide exchange, and altered rates of protein degradation. Simultaneous analysis of physiological regulation at the levels of the gene, mRNA, and protein provide new opportunities for understanding how information processing extends from the plasma membrane to the genome.

Cell Membrane↗

PubMed1989

Mutations in the structural genes for eukaryotic initiation factors 2 alpha and 2 beta of Saccharomyces cerevisiae disrupt translational control of GCN4 mRNA.

The SUI2 and SUI3 genes of Saccharomyces cerevisiae encode the alpha and beta subunits, respectively, of translation initiation factor eIF-2 (eukaryotic initiation factor 2). Previously isolated mutations in these genes restore expression from his4 mutant alleles lacking an ATG initiation codon. The SUI mutations also lead to increased levels of HIS4 mRNA. We show that the latter phenotype exists because the SUI mutations elevate expression of GCN4, an activator of HIS4 transcription. Increased GCN4 expression in the SUI mutants occurs independently of the GCN2 and GCN3 gene products that are normally required to stimulate translation of GCN4 mRNA under conditions of amino acid starvation. Derepression of GCN4 expression in the SUI mutants requires the multiple AUG codons in the leader of the GCN4 transcript that normally mediate its translational control by amino acid availability. In these respects, the SUI mutations resemble mutations in GCD genes whose products function as translational repressors of GCN4. Thus, in addition to its general role in AUG start codon selection, eIF-2 appears to be an important factor in GCN4 translational control. We also show that deletion of GCN3 in sui2-1 strains is lethal, suggesting that GCN3 contributes to eIF-2 alpha function in addition to its role as a translational activator of GCN4.

Chromosome Deletion↗

PubMed1988

The importance of the 3'-untranslated region in the translational control of ferritin mRNA.

Ferritin synthesis provides a dramatic example of translational control; stored ferritin mRNA is translated at relatively low rates which can increase 40-50 times when cellular iron levels increase. Although it is not known if agents other than cellular iron levels can release the repression of ferritin mRNA in vivo, the repression appears to be eliminated during the isolation of poly(A+) RNA, judged by translation in wheat germ lysates (WG). Using the bullfrog tadpole as a model, because of the abundance of ferritin-rich embryonic red cells, we now show specific repression of ferritin mRNA in the isolated poly(A+) RNA translated in rabbit reticulocyte lysates (RR) (RR/WG = 25%). Repression of ferritin mRNA was associated with the inability to form polyribosomes in analogy to iron-poor cells in vivo. The addition of various complexes of iron did not relieve the repression, suggesting that in vivo at least part of the effect of iron may be indirect and mediated by factors absent in the cell-free system; all three ferritin subunit mRNAs (H, M, and L) appeared to be regulated coordinately in vitro and in vivo as well. Comparison of transcripts of DNA encoding the M subunit of ferritin, but containing deletions in the 3'-untranslated (UT) region, showed that a region 70 nucleotides long was important for repression. Comparison of secondary structures predicted for the eight known ferritin subunit mRNAs from humans, rats, chickens, and frogs indicates that a region involved in base pairing common to all the mRNAs is eliminated when the 3'-UT region is shortened to 24 nucleotides. Although regions in the 5'-UT of mRNAs, including ferritin, have been shown to be involved in translational regulation, it is clear that complete regulation can involve both the 3'-UT and the 5'-UT regions, mediated, presumably, by secondary and tertiary interactions along the mRNA molecule.

Animals↗

PubMed1991

Translational control of equine herpesvirus type 1 gene expression.

Translational control mechanisms modulate gene expression in a variety of cellular and viral systems. Using hypertonic conditions to block protein synthesis in vivo, we observed that the synthesis of several major equine herpesvirus type 1 proteins was selectively inhibited. Although sensitivity to hypertonic conditions was graded across a continuum, messages coding for proteins of 203, 130.5, and 31.5 kDa were significantly more resistant to higher salt concentrations in vivo than those coding for polypeptides of 148, 116, and 74 kDa. Similar results were observed in vitro when potassium acetate was used to block initiation. In addition, Northern blot analyses demonstrated that steady-state levels of cellular mRNAs declined beginning at about 6 hr after infection. Taken together, these results indicate that the expression of several major equine herpesvirus type 1 genes was controlled in part at the post-transcriptional level.

Acetates↗

PubMed1990

Involvement of an initiation factor and protein phosphorylation in translational control of GCN4 mRNA.

Regulation of the GCN4 gene of Saccharomyces cerevisiae is one of the best-documented instances of gene-specific translational control in an eukaryote. Upstream open reading frames (uORFs) in GCN4 mRNA modulate the flow of scanning ribosomes to the GCN4 start codon according to the availability of amino acids. Recent results suggest that sequences at the termination codons of the uORFs, a general initiation factor, and a protein kinase all make important contributions to the proper functioning of this interesting translational-control element.

Base Sequence↗

PubMed1989

The growth-related protein P23 of the Ehrlich ascites tumor: translational control, cloning and primary structure.

p23 is a protein of Ehrlich ascites tumor cells, preferentially synthesized in the exponentially growing tumor. In vitro, serum and actinomycin D rapidly induce p23 synthesis. Using transcription inhibitors and a wheat germ cell-free translation system, evidence is provided that the synthesis of p23 is under translational control. Actinomycin D even results in superinduction of p23. Polymerase chain reaction, cloning and sequencing of p23 cDNA suggest p23 to be identical with a 21 kDa protein of mouse erythroleukemia cells, the synthesis of which was shown to be controlled also at the translational level (Chitpatima, S. T., Makrides, S., Bandyopadhyay, R., and Brawerman, G. (1988) Nucleic Acids Res. 16, 2350).

Amino Acid Sequence↗

PubMed1992

5' end-dependent translation initiation of hepatitis C viral RNA and the presence of putative positive and negative translational control elements within the 5' untranslated region.

Hepatitis C virus (HCV) is a distant relative of pestiviruses and flaviviruses, but it has a 5' untranslated region (UTR) with some features structurally similar to that of picornaviruses. In order to test the role of the 5' UTR in controlling the expression of the HCV polyprotein, we fused full-length or deleted versions of the 5' UTR of HCV-1 RNA to chloramphenicol acetyl transferase (CAT) mRNA to monitor CAT activity in vivo. We found: (1) the full-length 5' UTR of HCV-1 RNA is translationally inactive while 5' deletions which mimic a 5' subgenomic RNA detected in vivo are active, (2) an efficient cis-acting element which represses translation is found at the 5' terminus, (3) a putative element which enhances translation is found near the 3' terminus of the 5' UTR, (4) additional cis-acting elements including small open reading frames (ORFs) upstream from the putative enhancer element downregulate translation. We did not find evidence supporting the existence of an internal ribosome entry site in the 5' UTR of HCV-1 RNA. These data suggest that HCV may employ a distinctive translation control strategy such as the generation of subgenomic viral mRNA in infected cells. Translational control of HCV might be responsible for some of the characteristic pathobiology seen in viral infection.

Base Sequence↗

PubMed1975

Studies concerning the mechanism by which translational-control RNA regulates protein synthesis in embryonic muscle.

Muscle translational-control RNA (tcRNA) has been separated into two classes, polysomal and messenger ribonuclear protein (mRNA - protein), which have different sizes as determined by acrylamide gel electrophoresis. While normally translation of mRNA - protein mRNA is inhibited by tcRNA derived from the same mRNA - proteins, this inhibition does not occur if the messenger is previously de-adenylated. This suggests that the poly(A) segment of mRNA is required for the tcRNA activity. Utilizing different mRNA - protein fractions from muscle, myosin mRNA - protein and small mRNA - proteins ( less than 30 S), we have been able to demonstrate that a degree of specificity exists in the interaction of tcRNA and mRNA derived from the same mRNA - proteins. This is illustrated by the facts that (a) each tcRNA only inhibits the translation of its respective mRNA and (b) the highest percentage of structural change occurs when each tcRNA is hybridized to its respective mRNA as measured by its resistance to T1 and T2 RNase.

Animals↗

PubMed1992

Comparison of messenger RNA pools in active and dormant Artemia franciscana embryos: evidence for translational control.

In response to environmental anoxia, embryos of the brine shrimp Artemia franciscana enter a dormant state during which energy metabolism and development are arrested. The intracellular acidification that correlates with this transition into anaerobic dormancy has been linked to the inhibition of protein synthesis in quiescent embryos. In this study, we have addressed the level of control at which a mechanism mediated by intracellular pH might operate to arrest protein synthesis. Two independent lines of evidence suggest that there is an element of translational control when protein synthesis is arrested in dormant embryos. First, as determined by in vitro translation techniques, there were no significant quantitative differences in mRNA pools in dormant as compared to actively developing embryos. In addition, fluorography of the translation products showed that there are no large qualitative changes in mRNA species when embryos become dormant. These data suggest that there was no net degradation of mRNA pools in dormant embryos and that protein synthesis may therefore be controlled more strongly at translation than at transcription. Second, polysome profile studies showed that dormant embryos possess reduced levels of polysomes relative to those found in cells or active embryos. The disaggregation of polysomes is an indication that the initiation step in protein synthesis is disrupted and is further evidence that the mechanism involved in protein synthesis arrest in dormant Artemia involves translational control.

Animals↗

PubMed1978

Regulation of protein synthesis by hemin: effect of dithiothreitol on the formation and activity of the hemin-controlled translational repressor.

Previous studies have demonstrated that the hemin-controlled translational repressor (HCR), a high molecular weight protein inhibitor of polypeptide chain initiation in rabbit reticulocyte lysate, is formed from a presynthesized prorepressor over a period of 12--18 h in three stages denoted reversible, intermediate, and irreversible. The prorepressor can, however, be completely converted to irreversible HCR within 2 min by incubation with such sulfhydryl reagents as N-ethylmaleimide. The results in this report demonstrate that dithiothreitol, which stabilizes thiol groups, will, like hemin, prevent the conversion of the prorepressor to HCR and will inactivate reversible HCR. Unlike hemin, dithiothreitol also inactives the intermediate form of HCR. Neither dithiothreitol nor hemin has any effect on the activity of irreversible HCR. Since the prorepressor used in these experiments had been separated from the supernatant factor (a soluble protein that reverses the inhibition of protein synthesis due to HCR), the effect of dithiothreitol and of hemin is independent of this factor and may be mediated by direct interaction with the prorepressor and HCR. Dithioerythritol, the erythro isomer of dithiothreitol, is as effective as dithiothreitol in preventing the formation of HCR, whereas glutathione and beta-mercaptoethanol have little or no effect.

Animals↗

PubMed1975

Two classes of translational control RNA: their role in the regulation of protein synthesis.

Two classes of translation control RNA (tcRNA) have been isolated from embryonic chick muscle. One of these classes, the tcRNA isolated from messenger ribonucleoprotein particles (mRNP-tcRNA), is effective in inhibiting the translation of mRNP-mRNA while having little if any effect on polysomal mRNA. The other class, polysome-tcRNA, has no effect on mRNP-mRNA while it stimulates the translation of polysomal mRNA. The mRNP tcRNA contains approximately 50 percent uridylate residues and forms small but stable hybrids with poly (A), while polysome-tcRNA contains fewer uridylate residues and is much less effective in forming a hybrid with poly (A). A proposed model concerning the role of these two classes of tcRNA in the regulation of protein synthesis is presented.

Animals↗

PubMed1976

Purification of myosin translational control RNA and its interaction with myosin messenger RNA.

Myosin messenger ribonucleoprotein-translational control ribonucleic acid (mRNP-tcNA) from myosin mRNPs found in embryonic chick muscle has been further purified by Dowex chromatography and, from a number of controls, it is suggested that this small RNA is not an artifact produced through the degradation of RNA during its isolation. This highly purified myosin mRNP-tcRNA is shown to have a molecular weight of 10 000 on formamide-acrylamide gels, and reacts stoichometrically (on a 1:1 mole ratio) with myosin mRNA. The stoichiometric interaction between myosin mRNA and myosin mRNP-tcRNP is demonstrated by ists ability to increase the nuclease resistance of the messenger, as well as inhibit its translation in a cell-free amino acid incorporating system.

Animals↗