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Results for “Translational control”

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PubMed1995

Translational control by influenza virus. Identification of cis-acting sequences and trans-acting factors which may regulate selective viral mRNA translation.

We have shown that sequences contained within the viral mRNA 5'-untranslated region (UTR) played a critical role in directing selective influenza viral mRNA translation. We therefore attempted to identify transacting factors that may regulate viral mRNA translation through interactions with the 5'-UTR and at the same time map the precise sequences to which these factors bind. We can now demonstrate that multiple cellular proteins interact with influenza viral but not cellular 5'-UTRs using gel mobility shift and UV cross-linking analyses. Gel supershift studies revealed that the La autoantigen was one of the cellular proteins that interacted with the viral 5'-UTR. Utilizing mutants of the viral mRNA 5' UTR, we have determined that sequences within the very 5'-conserved region and nucleotides immediately 3' are necessary but not always sufficient for binding certain cellular proteins. Northwestern analysis showed the binding of a distinct subset of cellular proteins to the viral 5'-UTR, but also demonstrated interactions of the viral nonstructural protein NS1. Gel shift analysis with purified recombinant NS1 confirmed the binding of the viral protein to a specific region of the viral 5'-UTRs. A model describing the possible role of these cellular and viral RNA-binding proteins in regulating influenza virus mRNA translation will be discussed.

Base Sequence↗

PubMed2003

A co-repressor assembly nucleated by Sex-lethal in the 3'UTR mediates translational control of Drosophila msl-2 mRNA.

Drosophila Sex-lethal (dSXL)-mediated translational repression of male-specific lethal 2 (msl-2) mRNA is essential for X-chromosome dosage compensation. Binding of dSXL to specific sites in both untranslated regions of msl-2 mRNA is necessary for inhibition of translation initiation. We describe the organization of dSXL as a translational regulator and show that the RNA binding and translational repressor functions are contained within the two RRM domains and a C-terminal heptapeptide extension. The repressor function is dormant unless dSXL binds to msl-2 mRNA with its own RRMs, because dSXL tethering via a heterologous RNA-binding peptide does not elicit translational inhibition. We reveal proteins that crosslink to the msl-2 3' untranslated region (3'UTR) and co-immunoprecipitate with dSXL in a fashion that requires its intact repressor domain and correlates with translational regulation. Translation competition and UV-crosslink experiments show that the 3'UTR msl-2 sequences adjacent to dSXL-binding sites are necessary to recruit titratable co-repressors. Our data support a model where dSXL binding to the 3'UTR of msl-2 mRNA activates the translational repressor domain, thereby enabling it to recruit co-repressors in a specific fashion.

3' Untranslated Regions↗

PubMed1998

Masking, unmasking, and regulated polyadenylation cooperate in the translational control of a dormant mRNA in mouse oocytes.

The mechanisms responsible for translational silencing of certain mRNAs in growing oocytes, and for their awakening during meiotic maturation, are not completely elucidated. We show that binding of a approximately 80-kD protein to a UA-rich element in the 3' UTR of tissue-type plasminogen activator mRNA, a mouse oocyte mRNA that is translated during meiotic maturation, silences the mRNA in primary oocytes. Translation can be triggered by injecting a competitor transcript that displaces this silencing factor, without elongation of a pre-existing short poly(A) tail, the presence of which is mandatory. During meiotic maturation, cytoplasmic polyadenylation is necessary to maintain a poly(A) tail, but the determining event for translational activation appears to be the modification or displacement of the silencing factor.

Animals↗

PubMed1990

Deadenylation of maternal mRNAs during Xenopus oocyte maturation does not require specific cis-sequences: a default mechanism for translational control.

The meiotic maturation of Xenopus oocytes initiates significant changes in the translation of a number of maternal mRNAs that coincide with alterations in their polyadenylation states. A considerable number of maternal mRNAs are deadenylated in mature oocytes, thereby reducing their translational efficiencies. In this report we demonstrate that deadenylation does not require specific cis-acting sequences. Polyadenylated RNAs derived from either ribosomal protein or beta-globin mRNAs, or that contain non-mRNA-derived sequences, are deadenylated in mature oocytes. Translation of a substrate RNA is not required for its deadenylation. G10 mRNA is representative of a class of mRNAs that is translationally activated at maturation and contains the cytoplasmic polyadenylation element (U)6AU. A deletion mutant G10 transcript that lacks the (U)6AU element is not polyadenylated in mature oocytes but is deadenylated instead. Insertion of the (U)6AU element into the 3'-untranslated region of the ribosomal protein L1 mRNA is sufficient to prevent both its deadenylation and polysomal release in mature oocytes. These results indicate that the deadenylation and translational inactivation of maternal mRNAs during Xenopus oocyte maturation occur by a default pathway in which transcripts lacking a cytoplasmic polyadenylation element undergo poly(A) removal.

Animals↗

PubMed1991

Translational control during early development.

Early development in many animals is programmed by maternally inherited messenger RNAs. Many of these mRNAs are translationally dormant in immature oocytes, but are recruited onto polysomes during meiotic maturation, fertilization, or early embryogenesis. In contrast, other mRNAs that are translated in oocytes are released from polysomes during these later stages of development. Recent studies have begun to define the cis and trans elements that regulate both translational repression and translational induction of maternal mRNA. The inhibition of translation of some mRNAs during early development is controlled by discrete sequences residing in the 3' and 5' untranslated regions, respectively. The translation of other RNAs is due to polyadenylation which, at least in oocytes of the frog Xenopus laevis, is regulated by a U-rich cytoplasmic polyadenylation element (CPE). Although similar, the CPE sequences of various mRNAs are sufficiently different to be bound by different proteins. Two of these proteins and their interactions are described here.

Animals↗

PubMed1993

Sequence analysis of translationally controlled maternal mRNAs from Urechis caupo.

Fertilization of Urechis caupo oocytes stimulates dramatic changes in the pattern of protein synthesis. This shift is brought about entirely through selective translation of the large pool of maternal mRNAs synthesized and stored during oogenesis. My laboratory has identified cDNA clones to more than 20 different Urechis maternal mRNAs. These have been used to determine whether the complementary mRNAs are translated in oocytes or embryos, and to analyze the polyadenylation status of the mRNAs at different stages. For 14 of the mRNAs, multiple, overlapping cDNA clones were isolated, and the complete sequence of the mRNA molecule was determined. Of these 14 mRNAs, half are from the subset that is translated in growing and full-grown oocytes, but not in embryos. These 7 mRNAs have poly(A) tails before fertilization. The other 7 are from the subset that is not translated at any time before fertilization, and has very short poly(A) tails in oocytes. After fertilization these mRNAs are recruited onto polysomes and extensively polyadenylated. The sequence data from the two classes of maternal mRNAs was compared in an attempt to identify consensus sequences that could regulate translation directly, or indirectly, by controlling polyadenylation or secondary structure formation. Two features of the sequences correlate very well with the translation and polyadenylation of the different mRNAs--the identity of the base immediately preceding the AUG start codon, and the presence of the sequences UUUUA and UUUUUA in the 3' untranslated region.

Animals↗

PubMed1986

Translational control of an intestinal microvillar enzyme.

The rates of biosynthesis of adult and foetal pig small-intestinal aminopeptidase N (EC 3.4.11.2) were compared to determine at which level the expression of the microvillar enzyme is developmentally controlled. In organ-cultured explants, the rate of biosynthesis of foetal aminopeptidase N is only about 3% of the adult rate. The small amount synthesized occurs in a high-mannose-glycosylated, membrane-bound, form that is processed to the mature, complex-glycosylated, form at a markedly slower rate than that of the adult enzyme. Extracts of total RNA from adult and foetal intestine contained comparable amounts of aminopeptidase N mRNA, encoding gel-electrophoretically identical primary translation products. Together, these data indicate that the expression of aminopeptidase N is controlled at a translational level.

Aminopeptidases↗

PubMed1996

A long-range RNA-RNA interaction forms a pseudoknot required for translational control of the IF3-L35-L20 ribosomal protein operon in Escherichia coli.

In the IF3-L35-L20 operon encoding translation initiation factor 3 (IF3) and the two ribosomal proteins L35 and L20, the expression of the genes that code for the two ribosomal proteins is negatively regulated at the translational level by the cellular concentration of L20. This translational repressor directly regulates the expression of the gene encoding L35 and, via translational coupling, that of its own gene. Mutations that affect the control of the L35 gene were found exclusively at two sites: the first is located approximately 300 nucleotides upstream, and the second immediately 5' of the translation initiation site of the L35 gene. Mutations that fall between these two sites have little or no effect on the control, and the lack of effect of a deletion in the intervening region confirms this finding. RNA structure mapping in vitro suggests that the first site pairs with the second. We show that this pairing is also likely to occur in vivo because single mutations in either of these sites affect control, but base pair compensatory mutations re-establish control. We propose that these two distant sites can base-pair to form a long-range pseudoknot which is required for the control of the expression of the L35 gene.

Bacterial Proteins↗

PubMed2000

Glucocorticoids oppose translational control by leucine in skeletal muscle.

Glucocorticoids comprise an important class of hormonal mediators of fuel and protein homeostasis in normal and pathological scenarios. In skeletal muscle, exposure to glucocorticoids is characterized by a reduction in protein synthetic rate coincident with hampered translation initiation. However, it is unclear whether this involves attenuation of anabolic stimuli or is simply due to inhibition of the basally activated translational apparatus. Therefore, this inquiry was designed to determine whether leucine, administered orally, could rescue the translational inhibition induced by glucocorticoids. Dexamethasone, injected intraperitoneally, acutely diminished protein synthetic rates to 80% of control values in skeletal muscle from rat hindlimb. The eukaryotic initiation factor (eIF)4 regulatory element was simultaneously and negatively impacted via sequestration of eIF4E by the hypophosphorylated form of the translational suppressor, eIF4E binding protein 1 (4E-BP1). The 70-kDa ribosomal protein S6 kinase (S6K1) was also dephosphorylated, notably at T389, in response to glucocorticoids. Leucine, administered orally, effectively restored each aforementioned translational parameter to control levels. Inasmuch as leucine's potency in modulation of the translational machinery, and indeed of protein turnover in general, is widely appreciated, this amino acid may prove useful in normalizing the impairment of mRNA translation associated with various muscle-wasting pathologies, such as glucocorticoid excess.

Animals↗

PubMed1994

Translational control of GCN4: an in vivo barometer of initiation-factor activity.

Phosphorylation of translation initiation factor-2 (eIF-2) is an adaptive mechanism for downregulating protein synthesis under conditions of starvation and stress. The yeast Saccharomyces has evolved a sophisticated means of increasing translation of GCN4 mRNA when eIF-2 is phosphorylated, allowing the induction of an important stress-response protein when expression of most other genes is decreasing. Because translation of GCN4 mRNA is so tightly coupled to eIF-2 activity, genetic analysis of this system has provided unexpected insights into the regulation of eIF-2 and its guanine nucleotide exchange factor, eIF-2B.

Amino Acids↗

PubMed1987

Influence of altered transcription on the translational control of human ferritin expression.

In this paper, we examine the response of a translational regulatory mechanism when changes in mRNA levels are induced. The gene that encodes the human ferritin heavy chain has been transfected into mouse fibroblasts. Stable transformants that express the human ferritin heavy chain have been isolated. This protein assembles into ferritin polymers and can co-assemble with host mouse ferritin. Biosynthetic rates of the expressed human ferritin varied over a wide range in response to perturbations in iron supply, but total and cytoplasmic messenger RNA levels remained unchanged. When changes in ferritin mRNA levels were induced by treatment with sodium butyrate, proportional changes in the biosynthetic rates of ferritin were observed, but the capacity for modulating biosynthesis in response to alterations in iron availability was preserved. These findings suggest that the final protein biosynthetic rate of a translationally regulated gene depends on both translational regulatory signals and underlying transcription rates.

Butyrates↗

PubMed2006

mTOR-independent translational control of the extrinsic cell death pathway by RalA.

Oncogenic potential is associated with translational regulation, and the prevailing view is that oncogenes use mTOR-dependent pathways to up-regulate the synthesis of proteins critical for transformation. In this study, we show that RalA, a key mediator of Ras transformation, is also linked to the translational machinery. At least part of this linkage, however, is independent of mTOR and acts through RalBP1 to suppress cdc42-mediated activation of S6 kinase and the translation of the antiapoptotic protein FLIP(S). This action, rather than contributing to transformation, opens a latent tumor-suppressive mechanism that can be activated by tumor necrosis factor-related apoptosis-inducing ligand. These results show that the translational machinery is linked to tumor suppression as well as cell-proliferative pathways and that the reestablishment of cell death pathways by activation of the Ral oncogenic program provides a means for selective therapeutic targeting of Ral-driven malignancies.

ATP-Binding Cassette Transporters↗

PubMed1995

Cytoplasmic 3' poly(A) addition induces 5' cap ribose methylation: implications for translational control of maternal mRNA.

During the early development of many animal species, the expression of new genetic information is governed by selective translation of stored maternal mRNAs. In many cases, this translational activation requires cytoplasmic poly(A) elongation. However, how this modification at the 3' end of an mRNA stimulates translation from the 5' end is unknown. Here we show that cytoplasmic polyadenylation stimulates cap ribose methylation during progesterone-induced oocyte maturation in Xenopus laevis. Translational recruitment of a chimeric reporter mRNA that is controlled by cytoplasmic polyadenylation coincides temporally with cap ribose methylation during this period. In addition, the inhibition of cap ribose methylation by S-isobutyladenosine significantly reduces translational activation of a reporter mRNA without affecting the increase of general protein synthesis or polyadenylation during maturation. These results provide evidence for a functional interaction between the termini of an mRNA molecule and suggest that 2'-O-ribose cap methylation mediates the translational recruitment of maternal mRNA.

Animals↗

PubMed2006

A conserved mechanism controls translation of Rubisco large subunit in different photosynthetic organisms.

We previously proposed a mechanism for control of Rubisco expression and assembly during oxidative stress in Chlamydomonas reinhardtii. The N terminus of the large subunit (LSU) comprises an RNA recognition motif (RRM) that is normally buried in the protein, but becomes exposed under oxidizing conditions when the glutathione pool shifts toward its oxidized form. Thus, de novo translation and assembly of Rubisco LSU stop with similar kinetics and the unpaired small subunit (SSU) is rapidly degraded. Here we show that the structure of the N-terminal domain is highly conserved throughout evolution, despite its relatively low sequence similarity. Furthermore, Rubisco from a broad evolutionary range of photosynthetic organisms binds RNA under oxidizing conditions, with dissociation constant values in the nanomolar range. In line with these observations, oxidative stress indeed causes a translational arrest in land plants as well as in Rhodospirillum rubrum, a purple bacterium that lacks the SSU. We highlight an evolutionary conserved element located within alpha-helix B, which is located in the center of the RRM and is also involved in the intramolecular interactions between two LSU chains. Thus, assembly masks the N terminus of the LSU hiding the RRM. When assembly is interrupted due to structural changes that occur under oxidizing conditions or in the absence of a dedicated chaperone, the N-terminal domain can become exposed, leading to the translational arrest of Rubisco LSU. Taken together, these results support a model by which LSU translation is governed by its dimerization. In the case that regulation of type I and type II Rubisco is conserved, the SSU does not appear to be directly involved in LSU translation.

Air↗

PubMed2003

Post-transcriptional regulation of the Streptomyces coelicolor stress responsive sigma factor, SigH, involves translational control, proteolytic processing, and an anti-sigma factor homolog.

The sigH gene encodes a sigma factor whose transcription is controlled by stress regulatory systems and the developmental program in Streptomyces coelicolor. Here, we describe developmentally regulated post-transcriptional control systems for SigH. sigH is expressed as three primary translation products, SigH-sigma(37), SigH-sigma(51), and SigH-sigma(52). In vitro, SigH-sigma(52) was comparable to SigH-sigma(37) in its ability to associate with RNA polymerase core enzyme and specifically initiate transcription in vitro. While SigH-sigma(51/52) were the primary gene products observed throughout early phases of growth, their abundance decreased during later stages in liquid or solid phase cultures while levels of shorter, C-terminally encoded products increased. These included SigH-sigma(37), a product of the downstream translational initiation site, as well as two proteolytic derivatives of SigH-sigma(51/52) (34kDa and 38kDa). Accumulation of SigH-sigma(37) and processing of SigH-sigma(51/52) into these stable 34kDa and 38kDa derivatives correlated with morphological changes on solid medium and physiological maturation in liquid medium. SigH-sigma(51/52) processing did not occur on medium non-permissive for aerial mycelium formation or in one particular developmental mutant (brgA). The proteolytic activity could be detected in vitro using crude extracts of stationary phase cultures, but was absent from exponential phase cultures. prsH, the gene upstream of sigH having sequence similarity to known anti-sigma factors, was able to bind to, and thus presumably inactivate SigH-sigma(52), SigH-sigma(51), and SigH-sigma(37). We have shown elsewhere that prsH was conditionally required for colonial development. Thus, while at least one transcriptional regulator is known to bring about the accumulation of sigH mRNA at different times and different locations in colonies, the post-transcriptional processes described here regulate the activity of different SigH isoforms and program their temporal accumulation pattern, i.e. the elimination of SigH-sigma(51/52) and accumulation of SigH-sigma(37)-like proteins, as a function of development.

Amino Acid Sequence↗

PubMed2003

Translational control of inducible nitric oxide synthase by IL-13 and arginine availability in inflammatory macrophages.

Inducible NO synthase (iNOS) and its generation of NO from L-arginine are subject to transcriptional as well as posttranscriptional control by cytokines. In this study, we describe a novel, translational mechanism of iNOS regulation by arginine availability. Using mouse inflammatory peritoneal macrophages stimulated with IFN-gamma plus LPS, we demonstrate that the suppression of iNOS protein, which is observed after a 16-h (but not after a 6-h) pretreatment with IL-13, despite an unaltered iNOS mRNA level, results from arginine depletion by arginase. The addition of arginase inhibitors (in the pretreatment phase) or of arginine (in the stimulation phase) completely blocked the down-regulation of iNOS protein by IL-13. The rescuing effect of arginine supplementation was not due to a positive feedback regulation of iNOS expression via enhanced production of NO. A striking suppression of iNOS protein (but not of iNOS mRNA) was also seen, when IL-13 was replaced by purified arginase or when macrophages were stimulated with IFN-gamma/LPS in arginine-free medium. Arginine deficiency specifically impaired the de novo synthesis and the stability of iNOS protein, but did not affect the production of TNF and the overall protein synthesis of the macrophages. From these results, we conclude that arginine not only functions as a substrate for iNOS, but is also critical for maintaining normal levels of iNOS protein in cytokine-stimulated macrophages.

Animals↗

PubMed1982

Translational control of catalase synthesis by hemin in the yeast Saccharomyces cerevisiae.

mRNA-dependent cell-free protein synthesis systems were prepared from a heme-deficient ole3 mutant of the yeast Saccharomyces cerevisiae grown either in the absence or in the presence of the heme precursor delta-aminolevulinate. When supplemented with total yeast mRNA, the two systems-from heme-deficient and from heme-containing cells-translate most mRNAs with comparable efficiencies. mRNAs coding for the hemoproteins catalase T and catalase A, however, are translated at a low rate by the system from heme-deficient cells whereas their translation in the system from heme-containing cells is comparable to that observed in a heterologous in vitro system from wheat germ. Addition of 10 muM hemin to the system from heme-deficient cells stimulates translation of catalase mRNAs significantly. Control experiments showed that the results obtained cannot be explained by specific proteinase or nuclease action. Together with previous findings indicating lack of translation of catalase T mRNA in heme-deficient cells in vivo, the results demonstrate that specific control of yeast catalase formation occurs at the level of translation.

Catalase↗

PubMed1997

Vitamin B12 repression of the btuB gene in Salmonella typhimurium is mediated via a translational control which requires leader and coding sequences.

Expression of the Salmonella typhimurium btuB gene, which encodes an outer membrane protein required for vitamin B12 uptake, is repressed by the presence of external vitamin B12. We have, by means of a mutational analysis, investigated which btuB sequences are required for repression. Analysis of btuB::lacZ transcriptional and translational fusions of various lengths showed that the control was exerted mainly at the translational level and required both coding and leader sequences in the btuB transcript. Regulatory mutants with a B12 non-repressible phenotype were isolated and the mutations were shown to be located at several sites within the btuB leader. Analysis of constructs carrying site-directed point mutations, which either destabilized or restabilized a putative RNA hairpin that sequesters the btuB ribosomal binding site, demonstrated that this hairpin was essential for normal repression. Comparison of the S. typhimurium btuB gene with the previously characterized S. typhimurium cbiA and Escherichia coli btuB genes reveals significant similarities as well as differences in the cis-acting sequences required for repression.

Bacterial Outer Membrane Proteins↗