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Results for “Translational control”

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PubMed2005

Can stooped posture explain multidirectional postural instability in patients with Parkinson's disease?

To determine the effects of the stooped posture of patients with Parkinson's disease (PD) on postural stability, we compared the kinetic, kinematic, and electromyographic responses of seven subjects with PD and 11 control subjects to eight directions of surface translations. Control subjects were studied in an upright posture and in a stooped posture that mimicked the posture of the PD subjects. When control subjects adopted a stooped posture, peak center of pressure displacements slowed and decreased, reducing stability margins toward values observed in PD subjects. Stooped control subjects, however, responded to translations with large joint angle displacements, whereas PD subjects exhibited small joint angle displacements. Stooping in control subjects did not lead to abnormally directed horizontal forces under each foot or antagonistic muscle co-activation at the hip and trunk, as seen in PD subjects. Upright and stooped control subjects never fell during the trials, whereas PD subjects fell in 16% of the trials. We conclude that stooped posture is a destabilizing posture, but it does not account for abnormal postural responses in PD.

Aged↗

PubMed2005

IMPACT, a protein preferentially expressed in the mouse brain, binds GCN1 and inhibits GCN2 activation.

Translational control directed by the eukaryotic translation initiation factor 2 alpha-subunit (eIF2alpha) kinase GCN2 is important for coordinating gene expression programs in response to nutritional deprivation. The GCN2 stress response, conserved from yeast to mammals, is critical for resistance to nutritional deficiencies and for the control of feeding behaviors in rodents. The mouse protein IMPACT has sequence similarities to the yeast YIH1 protein, an inhibitor of GCN2. YIH1 competes with GCN2 for binding to a positive regulator, GCN1. Here, we present evidence that IMPACT is the functional counterpart of YIH1. Overexpression of IMPACT in yeast lowered both basal and amino acid starvation-induced levels of phosphorylated eIF2alpha, as described for YIH1 (31). Overexpression of IMPACT in mouse embryonic fibroblasts inhibited phosphorylation of eIF2alpha by GCN2 under leucine starvation conditions, abolishing expression of its downstream target genes, ATF4 (CREB-2) and CHOP (GADD153). IMPACT bound to the minimal yeast GCN1 segment required for interaction with yeast GCN2 and YIH1 and to native mouse GCN1. At the protein level, IMPACT was detected mainly in the brain. IMPACT was found to be abundant in the majority of hypothalamic neurons. Scattered neurons expressing this protein at higher levels were detected in other regions such as the hippocampus and piriform cortex. The abundance of IMPACT correlated inversely with phosphorylated eIF2alpha levels in different brain areas. These results suggest that IMPACT ensures constant high levels of translation and low levels of ATF4 and CHOP in specific neuronal cells under amino acid starvation conditions.

Amino Acid Sequence↗

PubMed2000

Temporal control of protein synthesis during spermatogenesis.

During oogenesis and spermatogenesis transcription ceases prior to the differentiation of the mature cells. To complete germ cell differentiation and initiate early embryogenesis, proteins are synthesized from pre-existing mRNAs that are stored for several days. It is well established that important regulatory elements functioning in spatial localization, temporal translation or messenger RNA stability are located in the 3' untranslated region (3' UTR) of mRNAs. During mammalian spermatogenesis temporal translational regulation of the protamine 1 (Prm1) mRNA is dependent on a highly conserved sequence located in the distal region of its 3' UTR. The 17-nucleotide translational control element (TCE) mediates translational repression of the Prm1 mRNA. Mutation of the TCE causes premature synthesis of protamine protein and sterility. The Prm1 mRNA is stored as a cytoplasmic ribonucleoprotein (mRNP) particle in spermatids. Contained within the particle are several members of the Y box family of nucleic acid binding proteins. In the yeast three-hybrid system the murine Y box proteins MSY1, MSY2 and MSY4 bind in a sequence-dependent manner to a conserved region in the proximal portion of the Prm1 3' UTR. Sequence-specific binding by MSY4 to the Y box recognition sequence (YRS) is dependent on the highly conserved cold shock domain, possibly through the RNP1 and RNP2 motifs present within it. The Y box proteins may function as translational repressors in vivo. Alternatively, their primary function may be to protect mRNAs from degradation during their extended period of storage. Translational activation of stored mRNAs is essential for the completion of gametogenesis. Proper translational activation of the Prm1 mRNA in elongated spermatids requires the cytoplasmic double-stranded RNA binding protein TARBP2. Tarbp2 is expressed at low levels in many cells but is expressed at robust levels in late stage meiotic cells and in postmeiotic spermatids. Mice mutant for Tarbp2 are defective in proper translational activation of the Prm1 and Prm2 mRNAs and are sterile. Current studies are designed to determine the mechanism by which proteins bound to the 3' UTR communicate with the 5' end of the message to control translational silencing and activation.

Animals↗

PubMed2004

eIF4E--from translation to transformation.

Over the years, studies have focused on the transcriptional regulation of oncogenesis. More recently, a growing emphasis has been placed on translational control. The Ras and Akt signal transduction pathways play a critical role in regulating mRNA translation and cellular transformation. The question arises: How might the Ras and Akt signaling pathways affect translation and mediate transformation? These pathways converge on a crucial effector of translation, the initiation factor eIF4E, which binds the 5'cap of mRNAs. This review focuses on the role of eIF4E in oncogenesis. eIF4E controls the translation of various malignancy-associated mRNAs which are involved in polyamine synthesis, cell cycle progression, activation of proto-oncogenes, angiogenesis, autocrine growth stimulation, cell survival, invasion and communication with the extracellular environment. eIF4E-mediated translational modulation of these mRNAs plays a pivotal role in both tumor formation and metastasis. Interestingly, eIF4E activity is implicated in mitosis, embryogenesis and in apoptosis. Finally, the finding that eIF4E is overexpressed in several human cancers makes it a prime target for anticancer therapies.

Animals↗

PubMed2001

Diversity in translational regulation.

Translational control of individual mRNAs relies on cis-regulatory elements, which are often found in the 3' untranslated region. The best characterized of these regulate cytoplasmic polyadenylation, and much of this process can now be defined in terms of molecular interactions, protein modifications and their consequences. Biochemical and genetic approaches have advanced the understanding of the many instances of translational regulation that are crucial for body patterning in Drosophila. For example, in vitro translation systems have been used to study the regulatory mechanisms, and genetic interactions have been instrumental in establishing a link between a regulatory factor and a component of the translational apparatus. Although most examples of control are thought to affect the initiation of translation, two classes of regulatory factors, one a protein and one a short non-coding RNA now appear to inhibit protein synthesis during elongation. Diversity seems to be a central feature of translational control, both in the mechanisms themselves and in the situations where this form of regulation is used.

3' Untranslated Regions↗

PubMed1988

Regulation of pyrC expression in Salmonella typhimurium: identification of a regulatory region.

Deletion analysis of a plasmid carrying the entire pyrC gene of Salmonella typhimurium served to localize the regulatory region within a 120 base pair DNA fragment comprising the promoter-leader region and the first 10 codons of pyrC. A region of dyad symmetry is present in the leader DNA and may result in the formation of a stable hairpin in the transcript with part of the Shine-Dalgarno sequence included in the stem. Four independently-isolated regulatory mutants, overexpressing pyrC, were found to have point mutations within the symmetry region and, significantly, the mutations occurred in sequences pertaining to either side of the stem of the putative hairpin of the transcript. All four mutations would decrease the stability of the hairpin, suggesting that pyrC expression is controlled at the level of translation. Additional evidence for translational control was provided by the finding that synthesis of galactokinase mediated from a pyrC-galK transcriptional fusion is not regulated by pyrimidines. The importance of the symmetry region in the leader was further emphasized by showing that pyrC expression is strongly affected when this region is deleted, inverted, or structured as a tandem duplication.

Amidohydrolases↗

PubMed1990

A difference in the regulation of mRNA expression between the phenotypic and the embryonic alkaline phosphatase genes in human cancer cells.

The steady-state levels of mRNAs encoding alkaline phosphatase isoenzymes were examined in two human breast carcinoma cell lines. MDA-MB-157 cells expressed the phenotypic breast alkaline phosphatase and BT20 cells expressed the nonphenotypic placental alkaline phosphatase isoenzyme, frequently reexpressed in neoplasms. Dexamethasone (DEX), which elicits a general effect on phosphatase expression, and 1,25-dihydroxy vitamin D3 (1,25(OH)2D3), a promoter of cell differentiation that correspondingly effects embryonic phosphatase expression, were chosen as perturbing agents for these experiments. RNA blot analysis showed a single RNA species of approximately 2.6 kb under all treatment conditions in BT20 cells and a single RNA species of 2.6 kb under each condition in MDA-MB-157 cells. The results showed that the expression of both the AP isoenzyme mRNA phenotypic of breast produced by MDA-MB-157 cells and the embryonic alkaline phosphatase isoenzyme (PLAP) mRNA produced by BT20 cells was increased by treatment with DEX. By comparison 1,25(OH)2D3 caused an increase in the tissue-unspecific AP mRNA in the MDA-MB-157 cells, but caused a decrease in PLAP mRNA levels in BT20 cells. The level of each isoenzyme mRNA species is altered by either hormone in a dose- and time-dependent manner in both cell lines. In BT20 cells, treatment with cycloheximide showed that ongoing protein synthesis is not required to potentiate the PLAP mRNA response to DEX, but is required for the action of 1,25(OH)2D3. However, protein synthesis is required for the action of both hormones in the MDA-MB-157 cells which make the breast phenotypic AP. These data demonstrate that the DEX- and 1,25(OH)2D3-regulated expression of both of these alkaline phosphatase isoenzymes occurs via a complex mechanism involving control of mRNA abundance, not translational control of constant message levels.

Alkaline Phosphatase↗

PubMed1995

The mode of actions of glyceraldehyde-3-phosphate dehydrogenase identified as an immunoglobulin production stimulating factor.

Immunoglobulin production stimulating factor-II alpha, which enhances immunoglobulin production of human and mouse hybridomas was purified from cell lysate of human Burkitt's lymphoma, Namalwa cells, and identified as glyceraldehyde-3-phosphate dehydrogenase. The enhancement of immunoglobulin production with this enzyme was not linked with its enzymatic activity. The enzyme enhanced immunoglobulin productivity of transcription-suppressed hybridomas, but did not enhance that of translation-suppressed hybridomas. From these results, it is suggested that this enzyme takes part in the post-translational control or the enhancement of translation activity to stimulate immunoglobulin production of hybridomas.

Glyceraldehyde-3-Phosphate Dehydrogenases↗

PubMed1991

The cell-cycle-regulated budding yeast gene DBF2, encoding a putative protein kinase, has a homologue that is not under cell-cycle control.

The budding yeast cell-cycle gene, DBF2, encoding a putative protein kinase, was shown to have a homologue, designated DBF20. This gene was cloned, sequenced, and confirmed to be highly homologous to DBF2, with over 80% identity in the 490 most C-terminal amino acid residues. Either gene could be deleted by itself, but deletion of both genes simultaneously was lethal, indicating that they are redundant for at least one vital function in yeast. In contrast to the DBF2 mRNA, which is expressed under cell-cycle control at or near START [Johnston et al., Mol. Cell. Biol. 10 (1990) 1358-1366], the DBF20 mRNA is expressed at a low level and not under cell-cycle control. Assuming there is no translational control, the differential expression of the mRNAs would result in a cell-cycle fluctuation of the relative levels of the gene products, which may constitute a novel form of regulation.

Amino Acid Sequence↗

PubMed2006

Expression of vitellogenin and cortical rod proteins during induced ovarian development by eyestalk ablation in the kuruma prawn, Marsupenaeus japonicus.

In penaeid shrimp species, ovarian development is characterized by the accumulation of a major yolk protein (vitellin) and the formation of cortical rods in the oocytes. The process is considered to be under the control of a neuroendocrine organ in the eyestalk (the X-organ sinus gland complex). In the present study, the synthesis of vitellogenin (VTG, precursor of vitellin) and two kinds of cortical rod proteins (cortical rod protein, CRP; thrombospondin, MjTSP) was induced by bilateral eyestalk ablation (removal of the X-organ sinus gland complex) in immature female kuruma prawn, Marsupenaeus japonicus, and the synthesis process was monitored over a 7-day period after the ablation. The ovarian weight and hemolymph VTG levels increased in the ablated females. The VTG mRNA levels in the ovary increased concomitantly with vitellin accumulation in the ovary after eyestalk ablation. On the other hand, the CRP and MjTSP protein levels in the ovary increased after eyestalk ablation, whereas the CRP and MjTSP mRNA levels in the ovary did not change concomitantly. The results suggest that the regulatory mechanism of gene expression by eyestalk hormones is different between VTG (transcriptional control) and CRP-MjTSP (translational control).

Animals↗

PubMed2005

Overproduction of Pichia pastoris or Plasmodium falciparum protein disulfide isomerase affects expression, folding and O-linked glycosylation of a malaria vaccine candidate expressed in P. pastoris.

Production of recombinant malaria proteins in the methylotrophic yeast Pichia pastoris has been difficult due to constraints in transcription, translation and/or post-translation controls. Use of codon-optimized genes has resolved many of the transcriptional controls; however, efforts to overcome translational and post-translational modifications involving disulfide bond formation and glycosylation have been mostly restricted to knocking-out putative N-linked glycosylation sites. We report now on the effect of overproduction of P. pastoris protein disulfide isomerase (PpPDI) and Plasmodium falciparum (PfPDI) on production of a disulfide-rich P. falciparum transmission-blocking vaccine candidate, Pfs25. Pfs25 is expressed in P. pastoris as two isoforms (A and B); the A form has been selected for Phase I human studies. Overproduction of PpPDI in the P. pastoris Pfs25 production clone markedly enhanced the expression level of Pfs25(A) and (B) by 3-fold, while overproduction of PfPDI increased the proportion of Pfs25(A) compared to (B). The resultant Pfs25 products were purified and fully characterized biochemically. In addition to differences in production levels, the mass spectra of PpPDI-Pfs25(A) compared to Pfs25(A) and PfPDI-Pfs25(A) were different due to the pattern and level of O-linked glycosylation. The overproduction of PpPDI or PfPDI provides new platforms for expression of disulfide-rich malaria proteins.

Animals↗

PubMed2004

Translation modulation of acid beta-glucosidase in HepG2 cells: participation of the PKC pathway.

Acid beta-glucosidase (GCase) is the enzyme deficient in Gaucher disease, a prototypical inherited metabolic error for enzyme and gene therapy. An 80 kDa mammalian cytoplasmic translational control protein (TCP80) modulates GCase translation in vitro and ex vivo by interacting with the 5' coding region of GCase RNA. Ten predicted PKC phosphorylation sites (Ser- or Thr-) are in the TCP80 protein. Phosphorylation of TCP80 in vitro by PKC greatly enhanced its translational inhibitory function using in vitro translation assays; binding of GCase mRNA to TCP80 was unaltered. Conversely, de-phosphorylation of TCP80 reduced its translational inhibitory function. Phosphorylation-related modulation of GCase mRNA translation also was studied in HepG2 cells. GCase expression (protein and activity levels) in HepG2 cells increased (>2-fold) in cells treated with bisindolylmaleimide (BIM), a highly selective PKC specific inhibitor. This correlated with a 90% reduction in TCP80 phosphorylation in the presence of BIM. The amount of TCP80 protein in cytoplasm and its RNA-binding activity were unchanged. These experiments indicate that GCase mRNA translation is modulated by PKC signaling pathways that are mediated through TCP80. These findings indicate potential broader impacts of the TCP/PKC system on expression of this and other genes of therapeutic interest.

Base Sequence↗

PubMed2004

Hrp48, a Drosophila hnRNPA/B homolog, binds and regulates translation of oskar mRNA.

Establishment of the Drosophila embryonic axes provides a striking example of RNA localization as an efficient mechanism for protein targeting within a cell. oskar mRNA encodes the posterior determinant and is essential for germline and abdominal development in the embryo. Tight restriction of Oskar activity to the posterior is achieved by mRNA localization-dependent translational control, whereby unlocalized mRNA is translationally repressed and repression is overcome upon mRNA localization. Here we identify the previously reported oskar RNA binding protein p50 as Hrp48, an abundant Drosophila hnRNP. Analysis of three hrp48 mutant alleles reveals that Hrp48 levels are crucial for polarization of the oocyte during mid-oogenesis. Our data also show that Hrp48, which binds to the 5' and 3' regions of oskar mRNA, plays an important role in restricting Oskar activity to the posterior of the oocyte, by repressing oskar mRNA translation during transport.

Amino Acid Sequence↗

PubMed2003

Regulation of translation initiation by insulin and amino acids in skeletal muscle of neonatal pigs.

Previous studies have shown that intravenous infusion of insulin and/or amino acids reproduces the feeding-induced stimulation of muscle protein synthesis in neonates and that insulin and amino acids act independently to produce this effect. The goal of the present study was to delineate the regulatory roles of insulin and amino acids on muscle protein synthesis in neonates by examining translational control mechanisms, specifically the eukaryotic translation initiation factors (eIFs), which enable coupling of initiator methionyl-tRNAi and mRNA to the 40S ribosomal subunit. Insulin secretion was blocked by somatostatin in fasted 7-day-old pigs (n = 8-12/group), insulin was infused to achieve plasma levels of approximately 0, 2, 6, and 30 microU/ml, and amino acids were clamped at fasting or fed levels or, at the high insulin dose, below fasting. Both insulin and amino acids increased the phosphorylation of ribosomal protein S6 kinase (S6K1) and the eIF4E-binding protein (4E-BP1), decreased the binding of 4E-BP1 to eIF4E, increased eIF4E binding to eIF4G, and increased fractional protein synthesis rates but did not affect eIF2B activity. In the absence of insulin, amino acids had no effect on these translation initiation factors but increased the protein synthesis rates. Raising insulin from below fasting to fasting levels generally did not alter translation initiation factor activity but raised protein synthesis rates. The phosphorylation of S6K1 and 4E-BP1 and the amount of 4E-BP1 bound to eIF4E and eIF4E bound to eIF4G were correlated with insulin level, amino acid level, and protein synthesis rate. Thus insulin and amino acids regulate muscle protein synthesis in skeletal muscle of neonates by modulating the availability of eIF4E for 48S ribosomal complex assembly, although other processes also must be involved.

Algorithms↗

PubMed1999

Apontic binds the translational repressor Bruno and is implicated in regulation of oskar mRNA translation.

The product of the oskar gene directs posterior patterning in the Drosophila oocyte, where it must be deployed specifically at the posterior pole. Proper expression relies on the coordinated localization and translational control of the oskar mRNA. Translational repression prior to localization of the transcript is mediated, in part, by the Bruno protein, which binds to discrete sites in the 3' untranslated region of the oskar mRNA. To begin to understand how Bruno acts in translational repression, we performed a yeast two-hybrid screen to identify Bruno-interacting proteins. One interactor, described here, is the product of the apontic gene. Coimmunoprecipitation experiments lend biochemical support to the idea that Bruno and Apontic proteins physically interact in Drosophila. Genetic experiments using mutants defective in apontic and bruno reveal a functional interaction between these genes. Given this interaction, Apontic is likely to act together with Bruno in translational repression of oskar mRNA. Interestingly, Apontic, like Bruno, is an RNA-binding protein and specifically binds certain regions of the oskar mRNA 3' untranslated region.

3' Untranslated Regions↗

PubMed1984

Evidence for transcriptional regulation of the myosin heavy chain gene during myogenesis.

One of the changes accompanying skeletal muscle cell (myoblast) fusion is a dramatic increase in synthesis of muscle specific proteins, one of which is myosin. The underlying mechanism for this burst in synthesis is not yet understood but may occur by two mechanisms: (a) gradual storage of mRNA and translational control as found by others or (b) gene activation and rapid synthesis of mRNA for immediate translation. In this paper we show that the myosin gene changes its organization such that postfusion skeletal muscle cells show an increased susceptibility to DNase I, a recognized probe for gene activation. We also show that this change accompanies an increase in rate of transcription and an increased cell content of myosin heavy chain mRNA. This work shows that transcriptional control is an important mechanism during muscle cell development in addition to the translational control shown by other workers.

Animals↗

PubMed2006

Shared stabilization functions of pyrimidine-rich determinants in the erythroid 15-lipoxygenase and alpha-globin mRNAs.

The poly(C)-binding proteins, alphaCPs, comprise a set of highly conserved KH-domain factors that participate in mRNA stabilization and translational controls in developmental and viral systems. Two prominent models of alphaCP function link these controls to late stages of erythroid differentiation: translational silencing of 15-lipoxygenase (Lox) mRNA and stabilization of alpha-globin mRNA. These two controls are mediated via association of alphaCPs with structurally related C-rich 3'-untranslated region elements: the differentiation control elements (DICE) in Lox mRNA and the pyrimidine-rich motifs in alpha-globin mRNA. In the present report a set of mRNA translation and stability assays are used to determine how these two alphaCP-containing complexes, related in structure and position, mediate distinct posttranscriptional controls. While the previously reported translational silencing by the DICE is not evident in our studies, we find that the two determinants mediate similar levels of mRNA stabilization in erythroid cells. In both cases this stabilization is sensitive to interference by a nuclear-restricted alphaCP decoy but not by the same decoy restricted to the cytoplasm. These data support a general role for alphaCPs in stabilizing a subset of erythroid mRNAs. The findings also suggest that initial binding of alphaCP to target mRNAs occurs in the nucleus. Assembly of stabilizing mRNP complexes in the nucleus prior to export may maximize their impact on cytoplasmic events.

3' Untranslated Regions↗

PubMed2004

Identification of the interaction between the human recombinant histamine releasing factor/translationally controlled tumor protein and elongation factor-1 delta (also known as eElongation factor-1B beta).

The human recombinant histamine releasing factor (HrHRF), also known as translationally controlled tumor protein (TCTP), p23 and fortilin, has been described to have both extra- and intracellular functions. To elucidate an extra- or intracellular role for HrHRF, we used the yeast two-hybrid system with HrHRF as the bait and a Jurkat T cell library. We isolated a partial cDNA clone of the human elongation factor-1 delta (EF-1delta) encoding for amino acids 12 to 281. This interaction was confirmed by co-immunoprecipitation experiments. Previously, both HrHRF and EF-1delta have been isolated and identified in association with malignancy in numerous studies. EF-1delta is part of the EF-1 complex responsible for kinetic proofreading in protein synthesis. Additionally, DNA microarray data classifies TCTP (HrHRF) as co-regulated with ribosomal proteins and recent structural analysis of TCTP (HrHRF) relates it to a guanine nucleotide-free chaperone. Our findings of an interaction between HrHRF and EF-1delta taken with some of the recently published information concerning the TCTP (HrHRF) mentioned above suggest a possible intracellular role for TCTP/HrHRF.

Biomarkers, Tumor↗