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Results for “Translational control”

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PubMed2004

TSAP6 facilitates the secretion of translationally controlled tumor protein/histamine-releasing factor via a nonclassical pathway.

Translationally controlled tumor protein (TCTP) is cytoplasmic and structurally related to guanine-nucleotide free chaperones. TCTP (also called histamine-releasing factor) has been described previously as a secreted protein that participates in inflammatory responses by promoting the release of histamine. How TCTP is eventually exported out of the cell to promote such activities is unknown. Here we show that TCTP secretion was insensitive to either brefeldin A or monensin, suggesting that it proceeds via an endoplasmic reticulum/Golgi-independent or nonclassical pathway. Moreover, our analyses also suggest that secreted TCTP originates from pre-existing pools. TSAP6, a p53-inducible 5-6 transmembrane protein, was found to interact with TCTP in a yeast two-hybrid hunt. GST pull down assays confirmed their direct interaction, and immunofluorescence analysis revealed their partial co-distribution to vesicular-like structures at the plasma membrane and around the nucleus. Functionally, the overexpression of TSAP6 consistently leads to enhanced secretion of both endogenously and exogenously expressed TCTP. Finally, we found TCTP in preparations of small secreted vesicles called exosomes, which have been suggested as a possible pathway for nonclassical secretion. Overexpression of TSAP6 also increased TCTP levels in exosome preparations. Altogether, these data identify a novel role for TSAP6 in the export of TCTP and indicate that this multipass membrane protein could have a general role in the regulation of vesicular trafficking and secretion.

Biomarkers, Tumor↗

PubMed2005

To replicate or not to replicate: achieving selective oncolytic virus replication in cancer cells through translational control.

To ensure that their mRNAs are translated and that the viral proteins necessary for assembling the next generation of infectious progeny are produced, viruses must effectively seize control of the translational machinery within their host cells. In many cases, the ability to productively engage host translational components can determine if a given cell type can support viral replication, illustrating the critical importance of this task in the viral life cycle. Failure to interface properly with the host translational apparatus can compromise the productive growth cycle, resulting in an abortive infection and radically restricting viral replication. Not only have viruses become facile at commandeering this machinery, they are also particularly adept at manipulating cellular translation control pathways for their own ends. In this review, the mechanisms by which numerous viruses manipulate host translational control circuits are discussed. Furthermore, particular attention is devoted to understanding how interfering with the ability of a virus to properly regulate translation in its host can be exploited to generate oncolytic strains that selectively replicate in cancer cells.

Eukaryotic Initiation Factor-2↗

PubMed1996

Translational control of cellular and viral mRNAs.

We are becoming increasingly aware of the role that translational control plays in regulating gene expression in plants. There are now many examples in which specific mechanisms have evolved at the translational level that directly impact the amount of protein produced from an mRNA. All regions of an mRNA, i.e., the 5' leader, the coding region, and the 3'-untranslated region, have the potential to influence translation. The 5'-terminal cap structure and the poly(A) tail at the 3' terminus serve as additional elements controlling translation. Many viral mRNAs have evolved alternatives to the cap and poly(A) tail that are functionally equivalent. Nevertheless, for both cellular and viral mRNAs, a co-dependent interaction between the terminal controlling elements appears to be the universal basis for efficient translation.

Nucleic Acid Conformation↗

PubMed1997

The 5' terminal oligopyrimidine tract confers translational control on TOP mRNAs in a cell type- and sequence context-dependent manner.

TOP mRNAs are vertebrate transcripts which contain a 5'terminal oligopyrimidine tract (5'TOP), encode for ribosomal proteins and elongation factors 1alpha and 2, and are candidates for growth-dependent translational control mediated through their 5'TOP. In the present study we show that elongation factor 2 (EF2) mRNA is translationally regulated in a growth-dependent manner in cells of hematopoietic origin, but not in any of three different non-hematopoietic cell lines studied. Human beta1-tubulin mRNA is a new member of the family which contains all the hallmarks of a typical TOP mRNA, yet its translation is refractory to growth arrest of any of the examined cell lines. Transfection experiments indicate that the first 29 and 53 nucleotides of the mRNAs encoding EF2 and beta1-tubulin, respectively, contain all the translational cis-regulatory elements sufficient for ubiquitously conferring growth-dependent translational control on a reporter mRNA. These results suggest that the distinct translational regulation of TOP mRNAs reflects downstream sequences which can override the regulatory features of the 5'TOP in a cell type-specific manner. This notion is further supported by the fact that mutations within the region immediately downstream of the 5'TOP of rpS16 mRNA confer onto the resulting transcripts growth-dependent translational control with a cell type specificity similar to that displayed by EF2 mRNA.

3T3 Cells↗

PubMed1995

Translational control in spermatogenesis.

Translational silencing phenomena during spermatogenesis in the two model systems Drosophila and mouse are reviewed. Cis-acting sequences were identified in both species that are necessary for translational repression. While in Drosophila these elements so far have only been found in the 5' untranslated region (5' UTR), in the mammals such regions were identified both in the 5' as well as in the 3' UTR. In all cases, RNA-binding proteins interact with these regions, yet their specific role in the observed negative regulation of translation has to be established.

Animals↗

PubMed2001

Translation control: bridging the gap between genomics and proteomics?

mRNA profiling enables the expression levels of thousands of transcripts in a cell to be monitored simultaneously. Nevertheless, analyses in yeast and mammalian cells have demonstrated that mRNA levels alone are unreliable indicators of the corresponding protein abundances. This discrepancy between mRNA and protein levels argues for the relevance of additional control mechanisms besides transcription. As translational control is a major mechanism regulating gene expression, the use of translated mRNA in profiling experiments might depict the proteome more closely than does the use of total mRNA. This would combine the technical potential of genomics with the physiological relevance of proteomics.

Gene Expression Profiling↗

PubMed2004

Translationally controlled tumor protein interacts with the third cytoplasmic domain of Na,K-ATPase alpha subunit and inhibits the pump activity in HeLa cells.

Translationally controlled tumor protein (TCTP) is a growth-related protein under transcriptional as well as translational control. We screened a rat skeletal muscle cDNA library using yeast two-hybrid system and found that TCTP interacts with the third large cytoplasmic domain of alpha1 as well as alpha2 isoforms of Na,K-ATPase, believed involved in the regulation of Na,K-ATPase activity. Interaction between TCTP and Na,K-ATPase was confirmed by coimmunoprecipitation in yeast and mammalian cells. We also showed, using (86)Rb(+) uptake assay, that overexpression of TCTP inhibited Na,K-ATPase activity in HeLa cells. Northern and Western blotting studies of HeLa cells transiently transfected with GFP-tagged TCTP showed that overexpression of TCTP did not change mRNA and protein levels of Na,K-ATPase. Recombinant TCTP protein purified from an Escherichia coli expression system inhibited purified HeLa cell plasma membrane Na,K-ATPase in a dose-dependent manner. Using deletion analysis, we also found that the C-terminal 102-172-amino-acid region of rat TCTP that contains the TCTP homology region 2 is essential for its association with, and inhibition of, Na,K-ATPase.

Biomarkers, Tumor↗

PubMed2000

Expression of translationally controlled tumor protein mRNA in human colon cancer.

The translationally controlled tumor protein (TCTP) was first identified as a tumor-associated protein. Here we described the expression profile of TCTP mRNA using a panel of normal human tissues. We also investigated the cell-cycle-dependent expression of the TCTP mRNA using synchronized cultures of Saccahromyces cerevisiae. The TCTP gene was constantly expressed through the yeast cell cycle. The expression of TCTP mRNA from three human colon carcinoma cell lines and their tumors xenografted in a nude mouse was studied. Our data imply that the TCTP is a housekeeping gene and that its deregulation may be involved in the tumor development of colon carcinoma.

Adenocarcinoma↗

PubMed2001

Integrins regulate the intracellular distribution of eukaryotic initiation factor 4E in platelets. A checkpoint for translational control.

Recent evidence from our laboratory demonstrates that platelets synthesize numerous proteins in a signal-dependent fashion (Pabla, R., Weyrich, A. S., Dixon, D. A., Bray, P. F., McIntyre, T. M., Prescott, S. M., and Zimmerman, G. A. (1999) J. Cell Biol. 144, 175-184; Weyrich, A. S., Dixon, D. A., Pabla, R., Elstad, M. R., McIntyre, T. M., Prescott, S. M., and Zimmerman, G. A. (1998) Proc. Natl. Acad. Sci. U. S. A. 95, 5556-5561). Protein synthesis in platelets is controlled at the translational level; however, the mechanisms of regulation are not known. Here we demonstrate that translation initiation factors are redistributed to mRNA-rich areas in aggregated platelets, an event that induces protein synthesis. Interrogation of cDNA arrays revealed that platelet-derived mRNAs are primarily associated with the cytoskeletal core. In contrast, eukaryotic initiation factor 4E (eIF4E), the essential mRNA cap-binding protein that controls global translation rates, is localized in the membrane skeleton and soluble fraction of platelets, physically separated from most mRNAs. Platelet activation redistributes eIF4E to the cytoskeleton and increases interactions of eIF4E with mRNA cap structures. Redistribution of eIF4E to the mRNA-rich cytoskeleton coincides with a marked increase in protein synthesis, a process that is blocked when intracellular actin is disrupted. Additional studies demonstrated that beta(3) integrins are the primary membrane receptor that distributes eIF4E within the cell. These results imply that integrins link receptor-mediated pathways with mRNA-rich cytoskeletal domains and thereby modulate the organization of intracellular translational complexes. They also indicate that the functional status of eIF4E is regulated by its intracellular distribution.

Arachidonic Acid↗

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↗

PubMed2000

A mammalian homologue of GCN2 protein kinase important for translational control by phosphorylation of eukaryotic initiation factor-2alpha.

A family of protein kinases regulates translation in response to different cellular stresses by phosphorylation of the alpha subunit of eukaryotic initiation factor-2 (eIF-2alpha). In yeast, an eIF-2alpha kinase, GCN2, functions in translational control in response to amino acid starvation. It is thought that uncharged tRNA that accumulates during amino acid limitation binds to sequences in GCN2 homologous to histidyl-tRNA synthetase (HisRS) enzymes, leading to enhanced kinase catalytic activity. Given that starvation for amino acids also stimulates phosphorylation of eIF-2alpha in mammalian cells, we searched for and identified a GCN2 homologue in mice. We cloned three different cDNAs encoding mouse GCN2 isoforms, derived from a single gene, that vary in their amino-terminal sequences. Like their yeast counterpart, the mouse GCN2 isoforms contain HisRS-related sequences juxtaposed to the kinase catalytic domain. While GCN2 mRNA was found in all mouse tissues examined, the isoforms appear to be differentially expressed. Mouse GCN2 expressed in yeast was found to inhibit growth by hyperphosphorylation of eIF-2alpha, requiring both the kinase catalytic domain and the HisRS-related sequences. Additionally, lysates prepared from yeast expressing mGCN2 were found to phosphorylate recombinant eIF-2alpha substrate. Mouse GCN2 activity in both the in vivo and in vitro assays required the presence of serine-51, the known regulatory phosphorylation site in eIF-2alpha. Together, our studies identify a new mammalian eIF-2alpha kinase, GCN2, that can mediate translational control.

Amino Acid Sequence↗

PubMed1974

Translational control induced by bacteriophage T7.

Phage T7 discontinues host gene expression by translational and transcriptional control mechanisms. Translational control is exerted by the T7 translational-repressor. This protein inhibits the synthesis of beta-galactosidase (EC 3.2.1.23) in vivo and in vitro and the synthesis of the T3 enzyme S-adenosylmethioninehydrolase (EC 3.3.1.-). The translational-repressor does not interfere with T7-specific enzyme synthesis. The T7 translational-repressor purifies with the initiation factors. The repressor interacts with the initiation of translation of host enzymes. The translational-repressor gene is close to the promotor for RNA polymerase of Escherichia coli.

Chromosome Mapping↗

PubMed1987

Translational control and the cytoskeleton in Physarum polycephalum.

Translationally active plasmodia of the syncytial slime mold Physarum polycephalum develop into translationally dormant sclerotia during starvation. Although functional mRNA and ribosomes exist in sclerotia, protein synthesis is suppressed at the level of initiation. To test the possibility that alterations in the cytoskeleton may limit protein synthesis, we have examined the distribution of polysomes and actin mRNA in the cytoskeletal (CSK) and soluble (SOL) fractions of Triton X-100-extracted plasmodia and sclerotia. Most of the polysomes and actin mRNA were located in the CSK of plasmodia, while most of the ribosomes and actin mRNA were located in the SOL of sclerotia. The results suggest that ribosomes and mRNA shift from the CSK to the SOL as protein synthesis is suppressed during starvation. Plasmodia and sclerotia can be induced to accumulate excess polysomes by treatment with low levels of the elongation inhibitor cycloheximide. Treatment of plasmodia with cycloheximide caused excess polysomes to accumulate in the SOL, suggesting that the CSK contains a limited capacity for binding translational components and that the association of polysomes with the cytoskeleton is not required for protein synthesis. Treatment of sclerotia with cycloheximide, however, caused polysomes and actin mRNA to accumulate in the CSK, suggesting that the sclerotial cytoskeleton, although depleted in ribosomes and mRNA, is capable of binding translational components. It is concluded that alterations in the sclerotial cytoskeleton are not involved in translational control.

Cytoskeletal Proteins↗

PubMed1981

Role of elongation factor 1 in the translational control of rodent brain protein synthesis.

The translational control of protein synthesis during early postnatal neural development and aging was examined in the mouse and the rat. The activity of brain elongation factor 1 (bEF-1) was found to decrease exponentially with age and to decline parallel to the age-dependent decrease in total protein synthesis in both rodents. This decrement in bEF-1 activity fell within the range of reported age-related decreases in protein synthesis in in vitro systems. The factor was present in multiple forms; the lighter species predominated in older animals, whereas the young light form apparently disappeared with increasing age, and was replaced by other arising from the heavy form. Elongation factor 1 derived from young brains functioned as a rate-limiting component in polypeptide synthesis in previously saturated adult systems. The data suggest that bEF-1 has an important modulatory effect on total brain protein synthesis.

Aging↗

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↗

PubMed2000

A cnidarian homologue of translationally controlled tumor protein (P23/TCTP).

A protein homologous to P23, or translationally controlled tumor protein (TCTP), was cloned in Hydra vulgaris, the most ancient type of metazoan from which P23/TCTP has been characterized to date. Hydra P23/TCTP is composed of 184 amino acids and is encoded by a single mRNA of 700 bp. This invertebrate P23/TCTP is well conserved compared to those of other invertebrate and vertebrate species. Expression of Hydra P23/TCTP was confirmed by western blot of Hydra cell lysates using a polyclonal antibody against murine recombinant P23/TCTP. Spatial distribution of P23/TCTP mRNA and protein in Hydra was studied using in situ hybridization and immunostaining, respectively. Hydra P23/TCTP expression along the longitudinal body axis is regulated at both the transcriptional and the translational level. High levels of P23/TCTP mRNA were detected in a subpopulation of cells in the body column. In contrast, no mRNA was evident in the differentiated cells of the head and the foot regions. Coincidentally, P23/TCTP protein also concentrates to the body column, with no detectable protein in the head and foot region. However, despite the existence of P23/TCTP mRNA in both the ectoderm and endoderm in the body column, its protein is localized to the endodermal cells, suggesting a regulatory mechanism at the translational level. Taken together, the expression pattern of P23/TCTP in Hydra correlates with regions in which cell proliferation is actively occurring and its expression is excluded from regions where terminal differentiation has occurred.

Amino Acid Sequence↗

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↗

PubMed2005

Translational control in stress and apoptosis.

Cells respond to stress stimuli through coordinated changes in gene expression. The regulation of translation is often used under these circumstances because it allows immediate and selective changes in protein levels. There are many examples of translational control in response to stress. Here we examine two representative models, the regulation of eukaryotic initiation factor-2alpha by phosphorylation and internal ribosome initiation through the internal ribosome-entry site, which illustrate the importance of translational control in the cellular stress response and apoptosis.

Animals↗