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PubMed1980

Translational control of protein synthesis after infection by vesicular stomatitis virus.

Four hours after infection of BHK cells by vesicular stomatitis virus (VSV), the rate of total protein synthesis was about 65% that of uninfected cells and synthesis of the 12 to 15 predominant cellular polypeptides was reduced to a level about 25% that of control cells. As determined by in vitro translation of isolated RNA and both one- and two-dimensional gel analyses of the products, all predominant cellular mRNA's remained intact and translatable after infection. The total amount of translatable mRNA per cell increased about threefold after infection; this additional mRNA directed synthesis of the five VSV structural proteins. To determine the subcellular localization of cellular and viral mRNA before and after infection, RNA from various sizes of polysomes and nonpolysomal ribonucleoproteins (RNPs) was isolated from infected and noninfected cells and translated in vitro. Over 80% of most predominant species of cellular mRNA was bound to polysomes in control cells, and over 60% was bound in infected cells. Only 2 of the 12 predominant species of translatable cellular mRNA's were localized to the RNP fraction, both in infected and in uninfected cells. The average size of polysomes translating individual cellular mRNA's was reduced about two- to threefold after infection. For example, in uninfected cells, actin (molecular weight 42,000) mRNA was found predominantly on polysomes with 12 ribosomes; after infection it was found on polysomes with five ribosomes, the same size of polysomes that were translating VSV N (molecular weight 52,000) and M (molecular weight 35,000) mRNA. We conclude that the inhibition of cellular protein synthesis after VSV infection is due, in large measure, to competition for ribosomes by a large excess of viral mRNA. The efficiency of initiation of translation on cellular and viral mRNA's is about the same in infected cells; cellular ribosomes are simply distributed among more mRNA's than are present in growing cells. About 20 to 30% of each of the predominant cellular and viral mRNA's were present in RNP particles in infected cells and were presumably inactive in protein synthesis. There was no preferential sequestration of cellular or viral mRNA's in RNPs after infection.

Animals↗
PubMed2005

Translational control of tetracycline resistance and conjugation in the Bacteroides conjugative transposon CTnDOT.

The tetQ-rteA-rteB operon of the Bacteroides conjugative transposon CTnDOT is responsible for tetracycline control of the excision and transfer of CTnDOT. Previous studies revealed that tetracycline control of this operon occurred at the translational level and involved a hairpin structure located within the 130-base leader sequence that lies between the promoter of tetQ and the start codon of the gene. This hairpin structure is formed by two sequences, designated Hp1 and Hp8. Hp8 contains the ribosome binding site for tetQ. Examination of the leader region sequence revealed three sequences that might encode a leader peptide. One was only 3 amino acids long. The other two were 16 amino acids long. By introducing stop codons into the peptide coding regions, we have now shown that the 3-amino-acid peptide is the one that is essential for tetracycline control. Between Hp1 and Hp8 lies an 85-bp region that contains other possible RNA hairpin structures. Deletion analysis of this intervening DNA segment has now identified a sequence, designated Hp2, which is essential for tetracycline regulation. This sequence could form a short hairpin structure with Hp1. Mutations that made the Hp1-Hp2 structure more stable caused nearly constitutively high expression of the operon. Thus, stalling of ribosomes on the 3-amino-acid leader peptide could favor formation of the Hp1-Hp2 structure and thus preclude formation of the Hp1-Hp8 structure, releasing the ribosome binding site of tetQ. Finally, comparison of the CTnDOT tetQ leader regions with upstream regions of five tetQ genes found in other elements reveals that the sequences are virtually identical, suggesting that translational attenuation is responsible for control of tetracycline resistance in these other cases as well.

Bacteroides↗
PubMed1995

Translational control of mammalian serine hydroxymethyltransferase expression.

We have investigated the role of an open reading frame upstream of and overlapping that coding for rabbit cytosolic serine hydroxymethyltransferase in the post-transcriptional regulation of enzyme expression. Elimination of the AUG codon initiating translation of the upstream open reading frame by site-directed mutagenesis (to an AUC codon) was assessed by a transfection assay in COS-1 cells. The mutation relieves translational repression with a 100-fold increase in expressed serine hydroxymethyltransferase activity compared to control-transfected cells and in the absence of any increase in the level of serine hydroxymethyltransferase mRNA. The upstream open reading frame may play a regulatory role in changing levels of expression of serine hydroxymethyltransferase through a translational control mechanism.

Amino Acid Sequence↗
PubMed1986

Translational control of mRNA expression during the early mitogenic response in Swiss mouse 3T3 cells: identification of specific proteins.

Addition of serum or epidermal growth factor to quiescent Swiss mouse 3T3 cells in culture leads to a number of specific changes in the pattern of protein synthesis. Earlier experiments with actinomycin D suggested that the altered expression of these proteins was controlled at either the pretranslational or translational level. Here we have identified and further characterized the regulation of mRNA expression for ten of these proteins, including protein synthesis elongation factor eEF-1 alpha, poly A binding protein, vimentin, the multiple forms of the actin protein family, and alpha- and beta-tubulin. Using an in vitro translation system, we determined the change in the level of mRNA encoding for each of these proteins after serum stimulation. The results showed that the amount of mRNA coding for eEF-1 alpha, poly A binding protein, vimentin, and alpha- and beta-tubulin remains unchanged during this time, whereas that of the actin family increases. Thus, with the exception of the actin family, the results argue that the expression of all the proteins identified is regulated at the translational level. The importance of this latter group of proteins in cell growth and the abundance of their cognate mRNAs should prove them useful tools in elucidating the mechanisms involved in the activation of translationally repressed mRNA during the mitogenic response.

Actins↗
PubMed2006

Dual regulation of translation initiation and peptide chain elongation during BDNF-induced LTP in vivo: evidence for compartment-specific translation control.

Protein synthesis underlying activity-dependent synaptic plasticity is controlled at the level of mRNA translation. We examined the dynamics and spatial regulation of two key translation factors, eukaryotic initiation factor 4E (eIF4E) and elongation factor-2 (eEF2), during long-term potentiation (LTP) induced by local infusion of brain-derived neurotrophic factor (BDNF) into the dentate gyrus of anesthetized rats. BDNF-induced LTP led to rapid, transient phosphorylation of eIF4E and eEF2, and enhanced expression of eIF4E protein in dentate gyrus homogenates. Infusion of the extracellular signal-regulated kinase (ERK) inhibitor U0126 blocked BDNF-LTP and modulation of the translation factor activity and expression. Quantitative immunohistochemical analysis revealed enhanced staining of phospho-eIF4E and total eIF4E in dentate granule cells. The in vitro synaptodendrosome preparation was used to isolate the synaptic effects of BDNF in the dentate gyrus. BDNF treatment of synaptodendrosomes elicited rapid, transient phosphorylation of eIF4E paralleled by enhanced expression of alpha-calcium/calmodulin-dependent protein kinase II. In contrast, BDNF had no effect on eEF2 phosphorylation state in synaptodendrosomes. The results demonstrate rapid ERK-dependent regulation of the initiation and elongation steps of protein synthesis during BDNF-LTP in vivo. Furthermore, the results suggest a compartment-specific regulation in which initiation is selectively enhanced by BDNF at synapses, while both initiation and elongation are modulated at non-synaptic sites.

Animals↗
PubMed1990

Overview: phosphorylation and translation control.

Protein synthesis is controlled by the phosphorylation of proteins comprising the translational apparatus. At least 12 initiation factor polypeptides, 3 elongation factors and a ribosomal protein are implicated. Stimulation of translation correlates with enhanced phosphorylation of eIF-4F, eIF-4B, eIF-2B, eIF-3 and ribosomal protein S6, whereas inhibition correlates with phosphorylation of eEF-2 and the alpha-subunit of eIF-2. Strong evidence for regulatory roles exists for eIF-2, eIF-4F and eEF-2, whereas changes in other factor activities due to phosphorylation remain to be demonstrated. Regulation of the specific activity of the translational apparatus by phosphorylation appears to be a general mechanism for the control of rates of global protein synthesis, and may also play a role in modulating the translation of specific mRNAs.

Amino Acid Sequence↗
PubMed1996

Pseudoknot and translational control in the expression of the S15 ribosomal protein.

Translational autocontrol of the expression of the ribosomal protein S15 proceeds through the transitory formation of a pseudoknot. A synopsis of the known data is used to propose a molecular model of the mechanism involved and for the role of the pseudoknot. This latter structure is able to recruit 30S ribosomal subunits to initiate translation, but also to bind S15 and to stop translation by trapping the ribosome on its loading site. Information on the S15 protein recognition of the messenger RNA site was deduced from mutational analyses and chemical probing. A comparison of this messenger site with the S15 ribosomal binding site was conducted by analysing hydroxyl radical footprintings of these two sites. The existence of two subsites in 16S RNA suggests that the ribosomal protein S15 might present either two different binding sites or at least one common subsite. Clues for the presence of a common site between the messenger and 16S RNA are given which cannot rule out that recognition specificity is linked to a few other determinants. Whether these determinants are different or not remains an open question.

Base Sequence↗
PubMed1991

Translational control of globin chain ontogeny in hamster yolk sac erythroid cells.

Prior research has demonstrated that globin ontogeny of hamster proceeds nearly to completion during the several days that yolk sac erythroid cells (YSEC) circulate in the embryo; synthesis of embryonic globin chains gives way to synthesis of adult globin chains in these primitive cells. In the present study, we translated total cell RNA extracted from YSEC on days 9-13 of gestation in wheat germ cell-free extract, expecting to observe the same progressive rise that occurs in vivo in rates of translation of alpha- and beta-globin mRNA during ontogeny. The opposite occurred; translation rates of both globins decreased sharply. This disparity between synthesis of alpha- and beta-globins in vivo and in vitro suggested an element of control of translation attributable to the YSEC cytoplasm. We therefore assayed the effect of RNA-free clarified YSEC cytoplasm on cell-free translation of YSEC RNA. A repression of translation was detected of alpha- and beta-globin mRNA (not of embryonic globin mRNA), exercised strongly by cytoplasm from YSEC early in ontogeny (gestational day 9), and weakening as ontogeny progressed. The same effect was noted on alpha- and beta-globin mRNA of adult hamster and of rabbit. Heat treatment of cytoplasm abolished the greater part of the translation regulation, suggesting that the active agent is protein. Further characterization of this translational regulator included: (a) it binds to globin poly(A) mRNA but not to poly(A), (b) it was not detected in cell lysate of adult hamster brain, lung, or erythrocytes, and (c) it did not inhibit translation of adult hamster brain and liver RNA. We conclude that hamster globin ontogeny is substantially modulated by this translational regulation of alpha- and beta-globin expression.

Animals↗
PubMed2003

A key role for the mRNA leader structure in translational control of ribosomal protein S1 synthesis in gamma-proteobacteria.

The translation initiation region (TIR) of the Escherichia coli rpsA mRNA coding for ribosomal protein S1 is characterized by a remarkable efficiency in driving protein synthesis despite the absence of the canonical Shine-Dalgarno element, and by a strong and specific autogenous repression in the presence of free S1 in trans. The efficient and autoregulated E.coli rpsA TIR comprises not less than 90 nt upstream of the translation start and can be unambiguously folded into three irregular hairpins (HI, HII and HIII) separated by A/U-rich single-stranded regions (ss1 and ss2). Phylogenetic comparison revealed that this specific fold is highly conserved in the gamma-subdivision of proteobacteria (but not in other subdivisions), except for the Pseudomonas group. To test phylogenetic predictions experimentally, we have generated rpsA'-'lacZ translational fusions by inserting the rpsA TIRs from various gamma-proteobacteria in-frame with the E.coli chromosomal lacZ gene. Measurements of their translation efficiency and negative regulation by excess protein S1 in trans have shown that only those rpsA TIRs which share the structural features with that of E.coli can govern efficient and regulated translation. We conclude that the E.coli-like mechanism for controlling the efficiency of protein S1 synthesis evolved after divergence of Pseudomona.

5' Untranslated Regions↗
PubMed1987

Translational control of photo-induced expression of the Cat2 catalase gene during leaf development in maize.

In dark-grown leaves of Zea mays, the catalase (H2O2:H2O2 oxidoreductase; EC 1.11.1.6; CAT) isozyme CAT-2 is absent. With continuous white light, CAT-2 protein levels increase (due to de novo synthesis) and plateau after 24 hr. When total poly(A)+ RNA (mRNA), polysomes, or isolated polysomal mRNA from light- and dark-treated leaves was translated in vitro, CAT-2 was detected only among the light-treated leaf products. A Cat2 clone was used to probe blots of total mRNA and polysomal mRNA from light- and dark-treated leaves. Cat2 mRNA was found in approximately equal quantities in both. Cat2 mRNA was equally distributed in identical high molecular weight fractions in polysomes from light- and dark-treated leaves and, therefore, was probably not sequestered in ribonucleoprotein particles in dark-grown leaves. The control of Cat2 expression appears to involve a unique form of translational inhibition in dark-grown leaves, preventing translation of the isolated mRNA and preventing polypeptide elongation. These results may have important implication in studies of translational control in other systems.

Catalase↗
PubMed1993

Immunological evidences for post-translational control of the parathyroid function by ionized calcium in dogs.

To outline the role of post-translational events in the control of the parathyroid function in vivo, we have studied the parathyroid function of normal dogs receiving i.v. infusions of CaCl2 and Na2EDTA with intact (I), carboxylterminal (C) and midcarboxylterminal (M) iPTH assays and evaluated the influence of ionized calcium on circulating molecular forms of iPTH via alterations in C/I, M/I and M/C iPTH ratios. Furthermore, the use of the mathematical model fitting the sigmoidal relationship between ionized calcium and iPTH ratios was improved through the generation of more iPTH ratio points in the ascending part of the sigmoid function. Quantitatively, the response to hypocalcemia was highest with M (98.7 +/- 36.8 pmol/l; P < 0.0167 vs. L and P < 0.0001 vs. I) and higher with L (83.1 +/- 26.1 pmol/l; P < 0.0001 vs. I) than with I (12.1 +/- 3.2 pmol/l). Similar results were observed for the non-suppressible fraction of iPTH measured by the three iPTH assays in hypercalcemia. The slope of the sigmoid function was more acute for I than for C or M, while all three secretion set-points were similar at 1.30 mmol/l. Qualitatively, all iPTH ratios increased from hypo- to hypercalcemia, results being more pronounced for the M/I and C/I iPTH ratios (7.66 +/- 2.57 to 73.9 +/- 41.4 and 6.76 +/- 1.93 to 49.8 +/- 27.5) than for the M/C iPTH ratio (1.24 +/- 0.48 to 1.82 +/- 1.16). The slopes of the three ratios were similar as were the set-points, but in this last case, values were higher (1.40 mmol/l) than for secretion set-points. These results indicate that dog parathyroid function is similar to that of man. The lower set-points for secretion and higher ones for regulating M/I and C/I iPTH ratios favor an optimal amount of I in face of decreasing ionized calcium and permit to control the non-suppressible fraction of iPTH secretion via M and C fragments production in face of increasing ionized calcium. These events are important to understand the implication and signification of post-translational events in the parathyroid glands and in peripheral blood in the phenomenon of PTH immunoheterogeneity. They further outline that the tools used here will be useful to study similar phenomenons in individuals in face of diseased parathyroid glands.

Animals↗
PubMedDate not supplied

Circadian synthesis of light-harvesting-chlorophyll-proteins in Euglena gracilis is under translational control.

Two proteins with apparent molecular masses of 17 and 24 kD that are synthesized in a circadian manner in the phytoflagellate Euglena gracilis, were recognized as proteins belonging to the family of light-harvesting-chlorophyll-proteins (LHCPs) of class I (17 kD) and of class II (24 kD). Identification was achieved by N-terminal sequencing of the proteins isolated from two-dimensional polyacrylamide gels and by detection with an anti-LHCP II serum. While it was found that the total amount of LHCPs remains almost constant, when Euglena is grown under diurnal conditions (12 h light and 12 h dark), we could show that the amount of newly synthesized 17 and 24 kD proteins varies about 20-fold with a maximum of synthesis in the light phase. In contrast, the analysis of the mRNA levels at different times revealed only minor differences in the stationary concentration of the LHCP specific mRNA, indicating that the control of LHCP synthesis is at the translational level. Principally, the same finding was obtained using inhibitors of transcription. Thus, it is concluded that the expression of LHCPs in Euglena gracilis in contrast to that of higher plants is primarily regulated at the translational level.

Amino Acid Sequence↗
PubMed1982

Translational control by messenger RNA competition for eukaryotic initiation factor 2.

Translation of globin mRNA in a micrococcal nuclease-treated reticulocyte lysate was studied in the presence of increasing amounts of Mengovirus RNA, under conditions in which the number of translation initiation events remains constant as judged by the transfer of label from N-formyl[35S]methionyl-tRNAf into protein. The translation of globin mRNA is progressively inhibited by low concentrations of Mengovirus RNA, free of detectable traces of double-stranded RNA, concomitant with the increasing synthesis of Mengovirus RNA-directed products. On a molar basis, Mengovirus RNA apparently competes about 35 times more effectively than globin mRNA for a critical component in translation. The competition is relieved by the addition of highly purified eukaryotic initiation factor 2 (eIF-2). Addition of eIF-2 does not stimulate overall protein synthesis, but shifts it in favor of globin synthesis. No stimulation of globin mRNA translation by eIF-2 is seen when Mengovirus RNA is absent. These experiments show that Mengovirus RNA competes, directly or indirectly, with globin mRNA for eIF-2. In direct binding experiments using isolated mRNA and eIF-2, Mengovirus RNA is shown to compete with globin mRNA for eIF-2 and to exhibit a 30-fold higher affinity for this factor. The binding of Mengovirus RNA to eIF-2 is much more resistant to increasing salt concentrations than is the binding of globin mRNA, again reflecting its high affinity. These results reveal a direct correlation between the ability of these mRNA species to compete in translation and their ability to bind to initiation factor eIF-2. They suggest that the affinity of a given mRNA species for eIF-2 is essential in determining its translation, relative to that of other mRNA species. Messenger RNA competition for eIF-2 may contribute significantly to the selective translation of viral RNA in infected cells.

Animals↗
PubMed1991

Interplay of two cis-acting mRNA regions in translational control of sigma 32 synthesis during the heat shock response of Escherichia coli.

When Escherichia coli cells are transferred from 30 degrees C to 42 degrees C, transcription from specific promoters recognized by RNA polymerase containing sigma 32 (the rpoH gene product) is transiently activated, resulting in induction of heat shock proteins. Transcription from heat shock promoters is activated by an increased cellular concentration of sigma 32 due to enhanced synthesis and stabilization. We have constructed and examined the expression of mutant derivatives (deletions and base substitutions) of rpoH-lacZ gene fusion. Synthesis of a sigma 32-beta-galactosidase fusion protein was found to be regulated at the translational level involving two distinct 5'-proximal rpoH coding regions. A small region immediately downstream of the initiation codon is required for potentially high-level expression, whereas a much larger internal region is required for thermal regulation--namely, repression at low temperature or nonstress conditions. The two mRNA regions act as positive and negative cis elements, respectively, in controlling rpoH translation. We propose that an interplay between these RNA regions involving secondary structure formation is important in regulating translation initiation and that transient disruption of secondary structure represents a primary step of the heat shock response.

Base Sequence↗
PubMed1998

The increased level of beta1,4-galactosyltransferase required for lactose biosynthesis is achieved in part by translational control.

beta1,4-Galactosyltransferase (beta4GalT-I) participates in both glycoconjugate biosynthesis (ubiquitous activity) and lactose biosynthesis (mammary gland-specific activity). In somatic tissues, transcription of the mammalian beta4GalT-I gene results in a 4.1-kb mRNA and a 3.9-kb mRNA as a consequence of initiation at two start sites separated by approximately 200 bp. In the mammary gland, coincident with the increased beta4GalT-I enzyme level ( approximately 50-fold) required for lactose biosynthesis, there is a switch from the 4.1-kb start site to the preferential use of the 3.9-kb start site, which is governed by a stronger tissue-restricted promoter. The use of the 3.9-kb start site results in a beta4GalT-I transcript in which the 5'- untranslated region (UTR) has been truncated from approximately 175 nt to approximately 28 nt. The 5'-UTR of the 4.1-kb transcript [UTR(4.1)] is predicted to contain extensive secondary structure, a feature previously shown to reduce translational efficiency of an mRNA. In contrast, the 5'-UTR of the 3.9-kb mRNA [UTR(3.9)] lacks extensive secondary structure; thus, this transcript is predicted to be more efficiently translated relative to the 4.1-kb mRNA. To test this prediction, constructs were assembled in which the respective 5'-UTRs were fused to the luciferase-coding sequence and enzyme levels were determined after translation in vitro and in vivo. The luciferase mRNA containing the truncated UTR(3.9) was translated more efficiently both in vitro (approximately 14-fold) and in vivo (3- to 5-fold) relative to the luciferase mRNA containing the UTR(4.1). Consequently, in addition to control at the transcriptional level, beta4GalT-I enzyme levels are further augmented in the lactating mammary gland as a result of translational control.

Animals↗