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Results for “Translational control”

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PubMed2002

A common translational control mechanism functions in axial patterning and neuroendocrine signaling in Drosophila.

Translational repression of maternal nanos (nos) mRNA by a cis-acting Translational Control Element (TCE) in the nos 3'UTR is critical for anterior-posterior patterning of the Drosophila embryo. We show, through ectopic expression experiments, that the nos TCE is capable of repressing gene expression at later stages of development in neuronal cells that regulate the molting cycle. Our results predict additional targets of TCE-mediated repression within the nervous system. They also suggest that mechanisms that regulate maternal mRNAs, like TCE-mediated repression, may function more widely during development to spatially or temporally control gene expression.

Animals↗

PubMed1996

Transcriptional and post-translational control of the plant plasma membrane H(+)-ATPase by mechanical treatments.

The activity of the plant plasma membrane (PM) H(+)-ATPase was studied with fresh, cut or aged tissues of sugar beet (Beta vulgaris L.) leaves. The rate of acidification of the medium by tissue samples was strongly stimulated by ageing, but unaffected by cutting. The proton-pumping activity and the specific activity of the vanadate-sensitive ATPase of purified PM vesicles prepared from aged tissues were much higher than that of fresh tissues, whereas cutting had no effect. Yet, both ageing and cutting increased the amount of PM H(+)-ATPase detected by enzyme-linked immunosorbent assays. Likewise, both ageing and cutting increased the levels of pma4 and pma2 ATPase transcripts, as assayed with the corresponding probes from Nicotiana plumbaginifolia. Ageing increases, within a few hours, the levels of the transcripts, the translation and the activity of several PM H(+)-ATPase families. Cutting, which represents a milder mechanical stress, only increases the levels of the transcripts and their translation, without detectable effect on the activity at the biochemical or physiological level, which suggests a post-translational control of this activity. Thus, upon mechanical stress, the activity of the H(+)-ATPase, a key enzyme of the plant PM is rapidly and tightly regulated by transcriptional and post-translational controls.

Cell Membrane↗

PubMed1995

Translational control of maturation-protein synthesis in phage MS2: a role for the kinetics of RNA folding?

The gene for the maturation (A) protein of the single-stranded RNA coliphage MS2 is preceded by an untranslated leader of 130 nt. Secondary structure of the leader was deduced by phylogenetic comparison and by probing with enzymes and chemicals. The RNA folds into a cloverleaf, i.e., three stem-loop structures enclosed by a long-distance interaction (LDI). This LDI is essential for translational control. Its 3'moiety contains the Shine-Dalgarno region of the A-protein gene, whereas its complement is located 80 nt upstream, i.e., about 30 nt from the 5'-terminus of the RNA chain. Mutational analysis shows that this base pairing represses expression of the A-protein gene. We present a model in which translational starts can only take place on nonequilibrated RNA, in which base pairing between the complementary regions has not yet taken place. We suggest that this pairing is kinetically delayed by the intervening sequence, which contains the three hairpins of the cloverleaf. The model is mainly based on the observation that reducing the length of the intervening sequence reduces expression, whereas increasing the length has the opposite effect. In addition, further stabilization of the LDI by a stronger base pair does not lead to a decrease in A-protein synthesis. Such a decrease is predicted to occur if translation would be controlled by the equilibrium structure of the leader RNA. These and other observations fit a kinetic model of translational control by RNA folding.

Base Sequence↗

PubMed2002

Molecular characterization of a calcium binding translationally controlled tumor protein homologue from the filarial parasites Brugia malayi and Wuchereria bancrofti.

We have cloned homologues of the mammalian translationally controlled tumor protein (TCTP) from the human filarial parasites Wuchereria bancrofti and Brugia malayi. TCTP genes from B. malayi and W. bancrofti were expressed in a T7 promoter vector as histidine tagged fusion proteins. Both the recombinant B. malayi TCTP (rBm-TCTP) and recombinant W. bancrofti TCTP (rWb-TCTP) have a molecular mass of approximately 28 kDa with the histidine tag. Sequence analyses showed that there is a 98% similarity between the two filarial TCTPs at amino acid levels and are immunologically cross-reactive. Analysis of soluble proteins from various lifecycle stages of B. malayi suggested that the expression of Bm-TCTP might be differentially regulated and occurs in multimeric form. Recombinant TCTP were found to form multimers in solution under non-reducing conditions. The tendency for filarial TCTPs to become multimers was predicted by the presence of the Lupas coiled coil structure in their sequence. Despite the absence of a signal sequence, Bm-TCTP is present abundantly in the excretory/secretions (ES) of microfilariae. Characterization studies showed that both Bm- and Wb-TCTPs are calcium-binding proteins and have histamine-releasing function in vitro. When injected intraperitoneally both the filarial TCTPs induced inflammatory infiltration of eosinophils into the peritoneal cavity of mice suggesting that the filarial TCTPs may have a role in the allergic inflammatory responses associated with filarial infections.

Amino Acid Sequence↗

PubMed1999

The growth-related, translationally controlled protein P23 has properties of a tubulin binding protein and associates transiently with microtubules during the cell cycle.

The translationally controlled protein P23 was discovered by the early induction of its rate of synthesis after mitogenic stimulation of mouse fibroblasts. P23 is expressed in almost all mammalian tissues and it is highly conserved between animals, plants and yeast. Based on its amino acid sequence, P23 cannot be attributed to any known protein family, and its cellular function remains to be elucidated. Here, we present evidence that P23 has properties of a tubulin binding protein that associates with microtubules in a cell cycle-dependent manner. (1) P23 is a cytoplasmic protein that occurs in complexes of 100-150 kDa, and part of P23 can be immunoprecipitated from HeLa cell extracts with anti-tubulin antibodies. (2) In immunolocalisation experiments we find P23 associated with microtubules during G1, S, G2 and early M phase of the cell cycle. At metaphase, P23 is also bound to the mitotic spindle, and it is detached from the spindle during metaphase-anaphase transition. (3) A GST-P23 fusion protein interacts with alpha- and beta-tubulin, and recombinant P23 binds to taxol-stabilised microtubules in vitro. The tubulin binding domain of P23 was identified by mutational analysis; it shows similarity to part of the tubulin binding domain of the microtubule-associated protein MAP-1B. (4) Overexpression of P23 results in cell growth retardation and in alterations of cell morphology. Moreover, elevation of P23 levels leads to microtubule rearrangements and to an increase in microtubule mass and stability.

3T3 Cells↗

PubMed2000

Translational control of cyclin B1 mRNA during meiotic maturation: coordinated repression and cytoplasmic polyadenylation.

Translational control is prominent during meiotic maturation and early development. In this report, we investigate a mode of translational repression in Xenopus laevis oocytes, focusing on the mRNA encoding cyclin B1. Translation of cyclin B1 mRNA is relatively inactive in the oocyte and increases dramatically during meiotic maturation. We show, by injection of synthetic mRNAs, that the cis-acting sequences responsible for repression of cyclin B1 mRNA reside within its 3'UTR. Repression can be saturated by increasing the concentration of reporter mRNA injected, suggesting that the cyclin B1 3'UTR sequences provide a binding site for a trans-acting repressor. The sequences that direct repression overlap and include cytoplasmic polyadenylation elements (CPEs), sequences known to promote cytoplasmic polyadenylation. However, the presence of a CPE per se appears insufficient to cause repression, as other mRNAs that contain CPEs are not translationally repressed. We demonstrate that relief of repression and cytoplasmic polyadenylation are intimately linked. Repressing elements do not override the stimulatory effect of a long poly(A) tail, and polyadenylation of cyclin B1 mRNA is required for its translational recruitment. Our results suggest that translational recruitment of endogenous cyclin B1 mRNA is a collaborative effect of derepression and poly(A) addition. We discuss several molecular mechanisms that might underlie this collaboration.

3' Untranslated Regions↗

PubMed2005

Translational control by viral proteinases.

Most RNA viruses have evolved strategies to regulate cellular translation in order to promote preferential expression of the viral genome. Positive strand RNA viruses express large portions, or all of their proteome via translation of large polyproteins that are processed by embedded viral proteinases or host proteinases. Several of these viral proteinases are known to interact with host proteins, particularly with the host translation machinery, and thus, encompass the dual functions of processing of viral polyproteins and exerting translation control. Picornaviruses are perhaps the best characterized in regards to interaction of their proteinases with the host translation machinery and will be emphasized here. However, new findings have shown that similar paradigms exist in other viral systems which will be discussed.

Animals↗

PubMed2005

The translationally controlled tumor protein is a novel calcium binding protein of the human placenta and regulates calcium handling in trophoblast cells.

The translationally controlled tumor protein (TPT1, also known as TCTP) is a highly conserved, abundantly expressed protein found in mammals as well as in a wide range of other organisms of both the animal and plant kingdom. Initially considered as a growth-related protein, later studies showed TPT1 is endowed with multiple biological activities, including calcium binding. The present study aimed to evaluate the expression of TPT1 in the human placenta and to examine the functional role of the protein in the calcium binding and homeostasis of trophoblast cells. Samples were analyzed by Western blot, reverse transcription-polymerase chain reaction and immunohistochemistry. The effect of TPT1 knockdown by small interfering RNA (siRNA) on calcium uptake and buffering was assessed in the HTR-8/SVneo cell line. TPT1 protein and mRNA were detected in first-trimester and term placenta. In the tissue, TPT1 was localized in the villous trophoblast. TPT1 expression significantly increased during gestation, with the higher protein and mRNA levels reached at term. Recombinant placental TPT1 bound calcium in vitro, while downregulation of the protein levels by siRNA in HTR-8/SVneo cells was associated with a reduced cellular calcium-uptake activity and buffering capacity. These data demonstrate, for the first time, the expression of TPT1 in the human placenta and support a direct role of the protein in placental calcium transport.

Biological Transport↗

PubMed2001

Cellular distribution of translationally controlled tumor protein in rat and human testes.

In a recent proteomic study we identified 53 spermatogonial proteins among which was the translationally controlled tumor protein (TCTP). This is a protein previously reported as being implicated in proliferation events in normal and tumoral tissues that had never previously been seen in the testis. The present study was aimed at establishing the complete cellular distribution of TCTP and its transcript and the ontogenetic expression of this gene within the testis. Using an immunohistochemistry technique, an intense TCTP signal was detected in gonocytes (the prespermatogonia) in the fetal rat testis and in spermatogonia within adult human and neonatal and adult rat testes. Meiotic spermatocytes and postmeiotic haploid spermatids were also strongly immunostained in a stage-dependent manner in human and rat testes. In addition, different levels of TCTP expression were also observed in the testicular somatic cells, with strong expression in Leydig cells and peritubular cells, and weak expression in Sertoli cells. Western and Northern blot analyses confirmed the presence of TCTP at all ages studied, with higher levels of RNA expression at 9 and 20 d postpartum, when spermatogonia and primary spermatocytes represent the highest proportion of germ cells: it was also confirmed that TCTP is present in all populations of isolated testicular cells. A transcript of 0.85 kb corresponding to TCTP, was expressed at all ages studied. This transcript was found to be expressed strongly in spermatogonia, somewhat less in isolated Leydig, resident macrophage, peritubular and Sertoli cells, weakly in the primary spermatocytes but not at all in spermatids. Interestingly, in the latter, a different transcript of 1.1 kb was present. The same 1.1 kb transcript appeared in testis extracts from 35 days postpartum onwards, corresponding to an age when spermatids accumulate within the tubules. Of note is that resident macrophages were found to express both the 0.85 and the 1.1 kb transcripts. We conclude that the strong expression of TCTP in spermatogonia makes it highly likely that the protein plays a significant role in spermatogenesis.

Adult↗

PubMed1998

Translational control of viral and host protein synthesis during the course of herpes simplex virus type 1 infection: evidence that initiation of translation is the limiting step.

Herpes simplex virus type 1 (HSV-1) infection induces the selective shut-off of host protein synthesis, other than ribosomal proteins, and the successive synthesis of viral proteins. Because viral mRNAs persist in the cytoplasm after viral protein synthesis has been inhibited, we hypothesized that viral gene expression may be under translational control. Expression of genes encoding immediate early ICP27, early DBP and late US11 proteins, together with glyceraldehyde-3-phosphate dehydrogenase (GAPDH), was monitored over the course of infection at the level of mRNA and protein synthesis. After an efficient synthesis beginning with the appearance of successive viral mRNAs in the cytoplasm, synthesis of viral proteins was shut off similarly to the synthesis of GAPDH. This shut-off was not achieved by mRNA degradation but by progressive shifts of viral mRNAs from large polyribosomes to smaller ones, then to 40S ribosomal subunits. Transient expression of the UL41 gene alone, directing synthesis of virion-associated host shut-off (VHS) protein, induced efficient mRNA degradation, but did not impair recruitment of the remaining GAPDH and beta-actin mRNAs into polyribosomes. These results indicate that HSV-1 induces a selective repression of initiation of mRNA translation which is probably the main cause of the shut-off of viral protein synthesis, and which contributes to the repression of host protein synthesis. VHS protein is not directly involved in this repression, at least in the absence of other viral proteins.

Cell Line↗

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↗

PubMed2006

Large-scale analysis of mRNA translation states during sucrose starvation in arabidopsis cells identifies cell proliferation and chromatin structure as targets of translational control.

Sucrose starvation of Arabidopsis (Arabidopsis thaliana) cell culture was used to identify translationally regulated genes by DNA microarray analysis. Cells were starved by subculture without sucrose, and total and polysomal RNA was extracted between 6 and 48 h. Probes were derived from both RNA populations and used to screen oligonucleotide microarrays. Out of 25,607 screened genes, 224 were found to be differentially accumulated in polysomal RNA following starvation and 21 were found to be invariant in polysomal RNA while their total RNA abundance was modified. Most of the mRNA appears to be translationally repressed (183/245 genes), which is consistent with a general decrease in metabolic activities during starvation. The parallel transcriptional analysis identifies 268 regulated genes. Comparison of transcriptional and translational gene lists highlights the importance of translational regulation (mostly repression) affecting genes involved in cell cycle and cell growth, these being overrepresented in translationally regulated genes, providing a molecular framework for the arrest of cell proliferation following starvation. Starvation-induced translational control also affects chromatin regulation genes, such as the HD1 histone deacetylase, and the level of histone H4 acetylation was found to increase during starvation. This suggests that regulation of the global nuclear transcriptional activity might be linked to cytoplasmic translational regulations.

Arabidopsis↗

PubMed2004

Translational control of apolipoprotein B mRNA: regulation via cis elements in the 5' and 3' untranslated regions.

Translational control of apolipoprotein B (apoB) mRNA has been previously documented; however, the molecular mechanisms that govern translation of apoB mRNA are unknown. We investigated the role of the untranslated regions (UTR) in the regulation of apoB mRNA translation first by analyzing apoB UTR sequences using M-fold, a program used to predict RNA secondary structure. M-fold analysis revealed hairpin-like elements within the 5'UTR and 3'UTR of apoB mRNA with potential to form stable secondary structure. Luciferase (LUC) reporter assays were conducted to assess the biological activity of the putative RNA motifs within the UTR sequences by transiently transfecting HepG2 cells with chimeric mRNAs containing the 5' and/or 3' apoB UTRs linked to a LUC reporter gene. We observed statistically significant increases in LUC activity for the 5'UTRpGL3 and 5'/3'UTRpGL3 constructs. LUC mRNA levels remained constant for all constructs, suggesting that increased LUC activity was likely posttranscriptional in nature. When RNA isolated from transfected cells was translated in vitro, parallel increases in translatable LUC activity were observed. We also examined the role of UTR sequences within the context of the apoB coding sequence, using constructs containing the N-terminal 15% of apoB (apoB15). We observed a 40% and 25% increase in total protein mass with the 5'UTR-apoB15 construct and the 5'UTR-apoB15-3'UTR, respectively, over the control construct with no apoB UTR, with only a slight stimulation observed for apoB15 3'UTR. Radiolabeling analysis of apoB15 synthetic rate showed a more striking 4.5-fold stimulation of protein synthesis by 5'UTR while addition of both UTRs caused a 3.1-fold stimulation over the control construct. Deletion mutant analysis revealed that the stimulatory effect of the 5'UTR on apoB mRNA translation may be dependent on specific hairpin elements formed within the 5'UTR secondary structure. Overall, our data suggest that putative 5'UTR motifs are important for optimal translation of the apoB message whereas the presence of the 3'UTR appears to attenuate wild-type expression. Potential cis-trans interactions of these motifs with putative RNA binding proteins/translational factors are likely to govern apoB mRNA translation and protein synthesis and may play an important role in dysregulation of atherogenic lipoprotein production in dyslipidemic states.

3' Untranslated Regions↗

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↗

PubMed1998

Identification of heavy metal induced changes in the expression patterns of the translationally controlled tumour protein (TCTP) in the earthworm Lumbricus rubellus1.

Heavy metal contaminated soils are assessed for specific human health and ecological risk by governmental regulatory agencies utilizing the abundant soil invertebrate, the earthworm, in a biomonitoring process. Fingerprinting the molecular genetic responses resulting from heavy metal exposure facilitates the identification of biomarkers for assessing the impact of such pollution on individual organisms. This paper reports the identification of a novel translationally controlled tumour protein (TCTP) in the earthworm Lumbricus rubellus. In addition to the standard molecular biological technique of differential Southern blotting, a fully quantitative approach (fluorescent microvolume PCR) was performed to assess the specific expression profiles of TCTP in earthworms exposed to different heavy metal regimes. After normalizing with actin as an invariant control, the results showed that TCTP was upregulated by at least a factor of 4 in the population originating from a Pb/Zn/Cd polluted mine, compared to an unpolluted control population. An even more pronounced increase was identified in earthworms native to a Cu polluted mine, where TCTP increased 335-fold. TCTP copies in earthworms exposed to artificial soil with a single stressor (Cd) were 14 times higher than in the appropriate control earthworms (maintained on artificial soil without Cd). The data presented are novel in two ways: first, they provide evidence for an upregulation that is induced by heavy metals (especially copper); second, they show that TCTP can also be under transcriptional control, therefore upregulation is not limited to translational modifications as TCTP's nomenclature suggests.

Amino Acid Sequence↗

PubMed2003

Translational control of SCL-isoform expression in hematopoietic lineage choice.

We investigated the translational regulation of SCL protein expression and its role in hematopoietic lineage choice. We show that the expression of different SCL protein isoforms is regulated by signal transduction pathways that modulate translation initiation factor (eIF) function. A conserved small upstream open reading frame (uORF) in SCL transcripts acts as a cis-regulatory element for isoform expression. At the onset of erythroid differentiation, truncated SCL protein isoforms arise by alternative translation initiation and favor the erythroid lineage. In comparison, full-length SCL proteins are more efficient at enhancing the megakaryocyte lineage. Together, our studies unravel translational control as a novel mechanism regulating hematopoietic outcome.

Animals↗

PubMed2006

Expression of the human TPT1 gene coding for translationally controlled tumor protein (TCTP) is regulated by CREB transcription factors.

Re-evaluation of genomic and cDNA data revealed that the human TPT1 gene coding for the translationally controlled tumor protein (TCTP) consists of at least 4211 base pairs. It is transcribed into two transcripts of about 0.8 and 1.2 kb, which contain the same coding region and 5'-UTR, but differ in the length of 3'-UTRs by the use of alternative polyadenylation signals. 459 bp promoter sequences were analyzed by theoretical evaluation, reporter-gene assays, gelshift and footprinting experiments to search for transcription factor binding sites. The promoter contains two highly conserved CRE sites between -50 and -89 in close vicinity to a TATA-box at -30. Supershift assays identified CREB I and Fra II of the CREB/ATF1/AP1 family as factors interacting with the CRE/AP1 site. A 3-5-fold stimulation of TCTP synthesis by forskolin and phorbolester in T24 cells and promoter-reporter experiments using CRE-deletion constructs suggested a transcriptional control by cAMP signaling via phosphorylation dependent activation of CRE/CREB interaction.

5' Flanking Region↗

PubMed1988

A highly conserved, 5' untranslated, inverted repeat sequence is ineffective in translational control of the alpha 1(I) collagen gene.

An inverted repeat sequence, extending from the 5' untranslated region of the first exon through the translation initiation codon, is highly conserved in the alpha 1(I), alpha 2(I) and alpha 1(III) collagen genes of mammals and birds. It has been suggested that this sequence functions in translational control of collagen gene expression. When the upstream axis of the dyad of symmetry was deleted, the efficiency of translation of transcripts from a human alpha 1(I) collagen-bovine growth hormone fusion gene was unchanged in either transiently or stably transfected cells. Furthermore, mRNA levels were not affected when the same deletion was transferred to a collagen-human growth hormone fusion gene in which the collagen sequence retained the first intron. Examination of human alpha 1(I) DNA, extending from the start of transcription to the start of translation, by the DNAse I protection procedure revealed evidence for protein binding to a sequence just upstream of the inverted repeat sequence but not to the inverted repeat itself. Our studies therefore indicate that this highly conserved DNA sequence does not function generally in translational or transcriptional control of type I procollagen synthesis.

Animals↗