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Results for “Translational repression”

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PubMed2004

Ischaemic preconditioning in the rat brain: effect on the activity of several initiation factors, Akt and extracellular signal-regulated protein kinase phosphorylation, and GRP78 and GADD34 expression.

Translational repression induced during reperfusion of the ischaemic brain is significantly attenuated by ischaemic preconditioning. The present work was undertaken to identify the components of the translational machinery involved and to determine whether translational attenuation selectively modifies protein expression patterns during reperfusion. Wistar rats were preconditioned by 5-min sublethal ischaemia and 2 days later, 30-min lethal ischaemia was induced. Several parameters were studied after lethal ischaemia and reperfusion in rats with and without acquired ischaemic tolerance (IT). The phosphorylation pattern of the alpha subunit of eukaryotic initiation factor 2 (eIF2) in rats with IT was exactly the same as in rats without IT, reaching a peak after 30 min reperfusion and returning to control values within 4 h in both the cortex and hippocampus. The levels of phosphorylated eIF4E-binding protein after lethal ischaemia and eIF4E at 30 min reperfusion were higher in rats with IT, notably in the hippocampus. eIF4G levels diminished slightly after ischaemia and reperfusion, paralleling calpain-mediated alpha-spectrin proteolysis in rats with and without IT, but they did not show any further decrease after 30 min reperfusion in rats with IT. The phosphorylated levels of eIF4G, phosphatidylinositol 3-kinase-protein B (Akt) and extracellular signal-regulated kinases (ERKs) were very low after lethal ischaemia and increased following reperfusion. Ischaemic preconditioning did not modify the observed changes in eIF4G phosphorylation. All these results support that translation attenuation may occur through multiple targets. The levels of the glucose-regulated protein (78 kDa) remained unchanged in rats with and without IT. Conversely, our data establish a novel finding that ischaemia induces strong translation of growth arrest and DNA damage protein 34 (GADD34) after 4 h of reperfusion. GADD34 protein was slightly up-regulated after preconditioning, besides, as in rats without IT, GADD34 levels underwent a further clear-cut increase during reperfusion, this time as earlier as 30 min and coincident with translation attenuation.

Animals↗

PubMed2025

DDX3X acts as a selective dual switch regulator of mRNA translation in acute ER stress.

Regulation of eukaryotic mRNA translation initiation greatly impacts gene expression and is critical for cellular stress response. DDX3X is a ubiquitous DEAD-box RNA helicase whose precise role in scanning and translation regulation in non-stressed and stressed cells remains incompletely understood. Here, we show that DDX3X associates with thousands of mRNAs as part of the eIF4F-mediated 48S scanning complex and exerts dual regulatory effects, promoting or repressing translation of select mRNAs under basal conditions and reversing this regulation during acute endoplasmic reticulum stress. Initiation profiling reveals mechanistically distinct modes of DDX3X action linked to its binding patterns across the 5' UTR and coding sequence. We further uncover that mRNAs selectively regulated by DDX3X exhibit specific patterns of cytidine N4-acetylation near start codons, with shared de-repression observed upon NAT10 knockdown. Together, our findings reveal DDX3X as a context-sensitive regulator that has a possible functional connection with epitranscriptomic features in translation control.

DEAD-box RNA Helicases↗

PubMed2003

Involvement of Xenopus Pumilio in the translational regulation that is specific to cyclin B1 mRNA during oocyte maturation.

Protein synthesis of cyclin B by translational activation of the dormant mRNA stored in oocytes is required for normal progression of maturation. In this study, we investigated the involvement of Xenopus Pumilio (XPum), a cyclin B1 mRNA-binding protein, in the mRNA-specific translational activation. XPum exhibits high homology to mammalian counterparts, with amino acid identity close to 90%, even if the conserved RNA-binding domain is excluded. XPum is bound to cytoplasmic polyadenylation element (CPE)-binding protein (CPEB) through the RNA-binding domain but not to its phosphorylated form in mature oocytes. In addition to the CPE, the XPum-binding sequence of cyclin B1 mRNA acts as a cis-element for translational repression. Injection of anti-XPum antibody accelerated oocyte maturation and synthesis of cyclin B1, and, conversely, over-expression of XPum retarded oocyte maturation and translation of cyclin B1 mRNA, which was accompanied by inhibition of poly(A) tail elongation. The injection of antibody and the over-expression of XPum, however, had no effect on translation of Mos mRNA, which also contains the CPE. These findings provide the first evidence that XPum is a translational repressor specific to cyclin B1 in vertebrates. We propose that in cooperation with the CPEB-maskin complex, the master regulator common to the CPE-containing mRNAs, XPum acts as a specific regulator that determines the timing of translational activation of cyclin B1 mRNA by its release from phosphorylated CPEB during oocyte maturation.

3' Untranslated Regions↗

PubMed1999

Role of two upstream open reading frames in the translational control of oncogene mdm2.

Overexpression of oncoprotein MDM2 has been found in a significant number of human soft tissue tumors. In a subset of these tumors, overexpression is a result of enhanced translation of mdm2 mRNA. There are two transcripts from the mdm2 gene that differ only in their 5' leaders: a long form (L-mdm2) and a short form (S-mdm2) that arise from the use of different promoters. L-mdm2 mRNA contains two upstream open reading frames (uORFs) and this mRNA was loaded with ribosomes inefficiently in comparison with S-mdm2. The 5' leader of L-mdm2 was sufficient to transfer translational repression to a reporter gene and the two uORFs acted synergistically to achieve full suppression. In contrast, the 5' leader of S-mdm2 allowed efficient translation of an attached reporter gene in the tumor cells. These results are consistent with a model in which overexpression of MDM2 in certain tumors results from a change in mRNA structure due to a switch in promoter usage.

5' Untranslated Regions↗

PubMed2002

Abrogation of upstream open reading frame-mediated translational control of a plant S-adenosylmethionine decarboxylase results in polyamine disruption and growth perturbations.

S-Adenosylmethionine decarboxylase (AdoMetDC) is a key enzyme in polyamine biosynthesis. We show that the plant AdoMetDC activity is subject to post-transcriptional control by polyamines. A highly conserved small upstream open reading frame (uORF) in the AdoMetDC mRNA 5' leader is responsible for translational repression of a downstream beta-glucuronidase reporter cistron in transgenic tobacco plants. Elimination of the small uORF from an AdoMetDC cDNA led to increased relative translational efficiency of the AdoMetDC proenzyme in transgenic plants. The resulting increased activity of AdoMetDC caused disruption to polyamine levels with depletion of putrescine, reduction of spermine levels, and a more than 400-fold increase in the level of decarboxylated S-adenosylmethionine. These changes were associated with severe growth and developmental defects. The high level of decarboxylated S-adenosylmethionine was not associated with any change in 5'-methylcytosine content in genomic DNA and S-adenosylmethionine levels were more or less normal, indicating a highly efficient system for maintenance of S-adenosylmethionine levels in plants. This work demonstrates that uORF-mediated translational control of AdoMetDC is essential for polyamine homeostasis and for normal growth and development.

Adenosylmethionine Decarboxylase↗

PubMed2004

Translation of the radioresistance kinase TLK1B is induced by gamma-irradiation through activation of mTOR and phosphorylation of 4E-BP1.

BACKGROUND: The mammalian protein kinase TLK1 is a homologue of Tousled, a gene involved in flower development in Arabidopsis thaliana. The function of TLK1 is not well known, although knockout of the gene in Drosophila, or expression of a dominant negative mutant in mouse cells causes loss of nuclear divisions and chromosome missegregation probably due to alterations in chromatin remodeling capacity. Overexpression of TLK1B, a spliced variant of the TLK1 mRNA, in a model mouse cell line increases their resistance to ionizing radiation, also likely through changes in chromatin remodeling. The TLK1B mRNA is translationally repressed by its 5'UTR and is regulated by the availability of eIF4E. We now report that radiation or doxorubicin result in an increase in the translation of TLK1B, and we have uncovered the likely mechanism for this effect. RESULTS: Radiation causes a shift in the polysomal distribution of TLK1B mRNA, from the untranslated region and small polysomes to the large polysomes, concomitant with an increase in the expression of TLK1B protein. This change is preceded by an increase in phosphorylation of the eIF4E inhibitory protein 4E-BP1, which releases eIF4E when it is phosphorylated. The phosphorylation of 4E-BP1 depends on mTOR, since rapamycin blocked the increase in phosphorylation induced by radiation, and prevented the increase in TLK1B protein expression. The activation of mTOR was likely due to the rapid activation of Akt following radiation. The activation of Akt could be inhibited with wortmannin, an inhibitor of PI3 kinase, hence placing PI3 kinase upstream of Akt as a very early event following radiation. Wortmannin also inhibited translation of TLK1B mRNA following activation by IR. This was shown both by western blot and by measuring the initiation capacity of the mRNA, as indicated by its distribution on polysomes. CONCLUSIONS: The translational upregulation of TLK1B elicited by DNA double strand breaks represents an interesting mechanism of translational regulation of a protein involved in radioprotection and highlights a novel mechanism of the stress response following radiation.

Adaptor Proteins, Signal Transducing↗

PubMed2007

The Drosophila PNG kinase complex regulates the translation of cyclin B.

The Drosophila PAN GU (PNG) kinase complex regulates the developmental translation of cyclin B. cyclin B mRNA becomes unmasked during oogenesis independent of PNG activity, but PNG is required for translation from egg activation. We find that although polyadenylation of cyclin B augments translation, it is not essential, and a fully elongated poly(A) is not required for translation to proceed. In fact, changes in poly(A) tail length are not sufficient to account for PNG-mediated control of cyclin B translation and of the early embryonic cell cycles. We present evidence that PNG functions instead as an antagonist of PUMILIO-dependent translational repression. Our data argue that changes in poly(A) tail length are not a universal mechanism governing embryonic cell cycles, and that PNG-mediated derepression of translation is an important alternative mechanism in Drosophila.

Animals↗

PubMed1996

Masking of mRNA by Y-box proteins.

The Y-box proteins are defined by their ability to bind to Y-box promoter elements and to help regulate transcription of a wide variety of genes. However, Y-box proteins are also identified as abundant proteins in the cytoplasm of germ cells, where they are found bound to stored mRNA molecules. Binding of Y-box proteins to mRNA sequences, both in vitro and in vivo, has been shown to effect their translational repression ("masking"). Here we discuss the ability of Y box proteins to recognize different nucleic acid structures and to become involved in regulation of both transcription and translation.

Amino Acid Sequence↗

PubMed1996

Translational regulation of human p53 gene expression.

In blast cells obtained from patients with acute myelogenous leukemia, p53 mRNA was present in all the samples examined while the expression of p53 protein was variable from patient to patient. Mutations in the p53 gene are infrequent in this disease and, hence, variable protein expression in the majority of the samples cannot be accounted for by mutation. In this study, we examined the regulation of p53 gene expression in human leukemic blasts and characterized the p53 transcripts in these cells. We found control both at the level of RNA abundance and at the level of translation. Four experiments point towards translational control of human p53 gene expression. First, there is no correlation between the level of p53 mRNA and the level of p53 protein expression in blast cells. Second, in two cell lines with similar levels of p53 protein expression but with different levels of p53 mRNA, we find that there is preferential association of p53 mRNA with large polysomes in the cells with less p53 RNA. Third, translation of synthetic human p53 transcripts in cell-free extracts is inhibited by the p53 3'UTR. Fourth, the p53 3'UTR, when present in cis, can repress translation of a heterologous transcript. These observations raise the possibility that human p53 mRNA translation may be regulated in vivo by RNA binding factors acting on the p53 3'UTR.

Acute Disease↗

PubMed2002

The identification of thymidylate synthase peptide domains located in the interface region that bind thymidylate synthase mRNA.

Thymidylate synthase (TS) is a critical chemotherapeutic target and intracellular levels of TS are an important determinant of sensitivity to TS inhibitors. Translational autoregulation represents one cellular mechanism for controlling the level of expression of TS. This mechanism involves the binding of TS protein to its own messenger RNA (mRNA), thus, repressing translational efficiency. The presence of excess substrate or inhibitors of TS leads to derepression of protein binding to mRNA, resulting in increased translational efficiency and ultimately increased levels of TS protein. TS protein has been shown to bind to two distinct areas on its mRNA. The goal of the present work is to define the TS domains responsible for this interaction. Using a separate series of overlapping 17-mer peptides spanning the length of both the human and Escherichia coli TS sequences, we have identified six potential domains located in the interface region of the TS protein that bind TS mRNA. The identified domains that bind TS mRNA include three concordant regions in both the human and E. coli peptide series. Five of the six binding peptides contain at least one invariant arginine residue, which has been shown to be critical in other well-defined protein-RNA interactions. These data suggest that the identified highly conserved protein domains, which occur at the homodimeric interface of TS, represent potential participating sites for binding of TS protein to its mRNA.

Amino Acid Sequence↗

PubMed1992

Molecular mimicry in translational control of E. coli threonyl-tRNA synthetase gene. Competitive inhibition in tRNA aminoacylation and operator-repressor recognition switch using tRNA identity rules.

We previously showed that: (i) E.coli threonyl-tRNA synthetase (ThrRS) binds to the leader of its mRNA and represses translation by preventing ribosome binding to its loading site; (ii) the translational operator shares sequence and structure similarities with tRNA(Thr); (iii) it is possible to switch the specificity of the translational control from ThrRS to methionyl-tRNA synthetase (MetRS) by changing the CGU anticodon-like sequence to CAU, the tRNA(Met) anticodon. Here, we show that the wild type (CGU) and the mutated (CAU) operators act as competitive inhibitors of tRNA(Thr) and tRNA(fMet) for aminoacylation catalyzed by E.coli ThrRS and MetRS, respectively. The apparent Kd of the MetRS/CAU operator complex is one order magnitude higher than that of the ThrRS/CGU operator complex. Although ThrRS and MetRS shield the anticodon- and acceptor-like domains of their respective operators, the relative contribution of these two domains differs significantly. As in the threonine system, the interaction of MetRS with the CAU operator occludes ribosome binding to its loading site. The present data demonstrate that the anticodon-like sequence is one major determinant for the identity of the operator and the regulation specificity. It further shows that the tRNA-like operator obeys to tRNA identity rules.

Acylation↗

PubMed2005

siRNA and miRNA: an insight into RISCs.

Two classes of short RNA molecule, small interfering RNA (siRNA) and microRNA (miRNA), have been identified as sequence-specific posttranscriptional regulators of gene expression. siRNA and miRNA are incorporated into related RNA-induced silencing complexes (RISCs), termed siRISC and miRISC, respectively. The current model argues that siRISC and miRISC are functionally interchangeable and target specific mRNAs for cleavage or translational repression, depending on the extent of sequence complementarity between the small RNA and its target. Emerging evidence indicates, however, that siRISC and miRISC are distinct complexes that regulate mRNA stability and translation. The assembly of RISCs can be traced from the biogenesis of the small RNA molecules and the recruitment of these RNAs by the RISC loading complex (RLC) to the transition of the RLC into the active RISC. Target recognition by the RISC can then take place through different interacting modes.

Animals↗

PubMed1986

Stable repression of ribosomal protein L1 synthesis in Xenopus oocytes by microinjection of antisense RNA.

The synthesis of an endogenous ribosomal protein, L1, is selectively and efficiently inhibited by microinjection of antisense L1 RNAs into Xenopus oocytes. Repression of L1 synthesis is achieved within 12 hr and is maintained for 48 hr. RNase-protection assays reveal the formation of RNA X RNA duplexes in vivo between the endogenous L1 mRNA and injected antisense transcripts. Partial-length antisense RNAs, complementary to only the 3'-terminal region of L1 mRNA, repress translation as effectively as a full-length antisense RNA, indicating that complementarity to the 5' region of L1 mRNA is not required for efficient inhibition. The use of antisense RNA to repress synthesis of an endogenous ribosomal protein provides a functional basis for determining mechanisms that integrate ribosomal protein synthesis with ribosome assembly during oogenesis.

Animals↗

PubMed2000

The temporal control of Wee1 mRNA translation during Xenopus oocyte maturation is regulated by cytoplasmic polyadenylation elements within the 3'-untranslated region.

The Wee1 protein tyrosine kinase is a key regulator of cell cycle progression. Wee1 activity is necessary for the control of the first embryonic cell cycle following the fertilization of meiotically mature Xenopus oocytes. Wee1 mRNA is present in immature oocytes, but Wee1 protein does not accumulate in immature oocytes or during the early stages of progesterone-stimulated maturation. This delay in Wee1 translation is critical since premature Wee1 protein accumulation has been shown to inhibit oocyte maturation. In this study we provide evidence that Wee1 protein accumulation is regulated at the level of mRNA translation. This translational control is directed by sequences within the Wee1 mRNA 3'-untranslated region (3' UTR). Specifically, cytoplasmic polyadenylation element (CPE) sequences within the Wee1 3' UTR are necessary for full translational repression in immature oocytes. Our data further indicate that while CPE-independent mechanisms may regulate the levels of Wee1 protein accumulation during progesterone-stimulated oocyte maturation, the timing of Wee1 mRNA translational induction is directed through a CPE-dependent mechanism.

3' Untranslated Regions↗

PubMed1992

Role of the RNA-dependent protein kinase in the regulated expression of genes in transfected cells.

The RNA-dependent P1/eIF-2 alpha protein kinase is a highly specific protein-serine/threonine kinase that catalyzes the phosphorylation of the alpha subunit of protein synthesis initiation factor eIF-2. The kinase plays a central role in translational control. The activity of the kinase is regulated by a variety of naturally occurring effector RNAs which bind to the regulatory domain of the enzyme. Certain RNAs are able to activate the eIF-2 alpha kinase activity inherent within protein P1, a process which involves an autophosphorylation of protein P1, whereas other RNAs are able to antagonize the activation process. Translational repression mediated by the kinase may also be disrupted by RNA binding proteins that sequester activator double-stranded RNAs and by site-directed mutants and homologs of the eIF-2 alpha translation factor substrate. The P1/eIF-2 alpha protein kinase is an important regulator of the translation of plasmid-derived mRNAs in transfected eukaryotic cells.

Enzyme Activation↗

PubMed1985

A hierarchy of trans-acting factors modulates translation of an activator of amino acid biosynthetic genes in Saccharomyces cerevisiae.

The GCN4 gene encodes a positive effector of amino acid biosynthetic genes in Saccharomyces cerevisiae. Genetic analysis has suggested that GCN4 is regulated by a hierarchy of interacting positive and negative effectors in response to amino acid starvation. Results presented here for a GCN4-lacZ gene fusion support this regulatory model and suggest that the regulators of GCN4 exert their effects primarily at the level of translation of GCN4 mRNA. Both the GCN2 and GCN3 products appear to stimulate translation of GCN4 mRNA in response to amino acid starvation, because a recessive mutation in either gene blocked derepression of GCN4-lacZ fusion enzyme levels but did not reduce the fusion transcript level relative to that in wild-type cells grown in the same conditions. The GCD1 product appears to inhibit translation of GCN4 mRNA because under certain growth conditions, the gcd1-101 mutation led to derepression of the GCN4-lacZ fusion enzyme level in the absence of any increase in the fusion transcript level. In addition, the gcd1-101 mutation suppressed the low translational efficiency of GCN4-lacZ mRNA observed in gcn2- and gcn3- cells. A deletion of four small open reading frames in the 5' leader of GCN4-lacZ mRNA mimicked the effect of a gcd1 mutation and derepressed translation of the fusion transcript in the absence of either starvation conditions or the GCN2 and GCN3 products. By contrast, in a gcd1- strain, the deletion resulted in little additional increase in the translational efficiency of the fusion transcript. These results suggest that GCD1 mediates the translational repression normally exerted by the GCN4 leader sequences and that GCN2 and GCN3 antagonize these negative elements in response to amino acid starvation. The effects of the trans-acting mutations on the translation of GCN4-lacZ mRNA remained intact even when transcription of the fusion gene was placed under the control of the S. cerevisiae GAL1 transcriptional control element.

Amino Acids↗

PubMed1993

Selective recruitment of masked maternal mRNA from messenger ribonucleoprotein particles containing FRGY2 (mRNP4).

In Xenopus, the germ cell-specific Y-box (CTGATTGGCCAA) factor, FRGY2, facilitates in vitro transcription in egg extracts from oocyte-selective promoters containing a Y-box. This same factor is a major component of the messenger ribonucleoprotein (mRNP) storage particles of the oocyte. These particles store maternal mRNAs and inhibit their translation. FRGY2 is identical to mRNP4 and homologous to mRNP3, two previously described oocyte-specific mRNP proteins. We demonstrate that FRGY2 associates with a broad spectrum of mRNAs exhibiting no apparent sequence specificity. These interactions suggest that FRGY2 has a general role in packaging mRNA analogous to that of histone with DNA. All mRNAs examined that accumulate in oocytes appear within these mRNP storage particles, including messages coding for proteins such as FRGY2 and TFIIIA, which are translated in the oocyte. Moreover, we show that mRNAs that are translationally repressed in oocytes, such as messages coding for the proteins histone H1 and FRGY1, accumulate only within the particles. These mRNAs are subsequently recruited from the particles to the ribosomes and utilized for translation during embryogenesis prior to transcriptional activation of the zygotic genome. We propose that the assembly of mRNP storage particles represents a default state and that translational regulation is achieved via specific recruitment of the messages from the mRNP fraction to the ribosomes.

Animals↗

PubMed2006

GLP-1 receptor activation improves beta cell function and survival following induction of endoplasmic reticulum stress.

Perturbation of endoplasmic reticulum (ER) homeostasis impairs insulin biosynthesis, beta cell survival, and glucose homeostasis. We show that a murine model of diabetes is associated with the development of ER stress in beta cells and that treatment with the GLP-1R agonist exendin-4 significantly reduced biochemical markers of islet ER stress in vivo. Exendin-4 attenuated translational downregulation of insulin and improved cell survival in purified rat beta cells and in INS-1 cells following induction of ER stress in vitro. GLP-1R agonists significantly potentiated the induction of ATF-4 by ER stress and accelerated recovery from ER stress-mediated translational repression in INS-1 beta cells in a PKA-dependent manner. The effects of exendin-4 on the induction of ATF-4 were mediated via enhancement of ER stress-stimulated ATF-4 translation. Moreover, exendin-4 reduced ER stress-associated beta cell death in a PKA-dependent manner. These findings demonstrate that GLP-1R signaling directly modulates the ER stress response leading to promotion of beta cell adaptation and survival.

Activating Transcription Factor 4↗