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PubMed2002

Beta -oxidation of free fatty acids is required to maintain translational control of protein synthesis in heart.

The study described herein investigated the role of free fatty acids (FFAs) in the maintenance of protein synthesis in vivo in rat cardiac and skeletal muscle. Suppression of FFA beta-oxidation by methyl palmoxirate caused a marked reduction in protein synthesis in the heart. The effect on protein synthesis was mediated in part by changes in the function of eukaryotic initiation factors (eIFs) involved in the initiation of mRNA translation. The guanine nucleotide exchange activity of eIF2B was repressed, phosphorylation of the alpha-subunit of eIF2 was enhanced, and phosphorylation of eIF4E-binding protein-1 and ribosomal protein S6 kinase was reduced. Similar changes in protein synthesis and translation initiation were not observed in the gastrocnemius following treatment with methyl palmoxirate. In heart, repressed beta-oxidation of FFA correlated, as demarcated by changes in the ATP/AMP ratio and phosphorylation of AMP-activated kinase, with alterations in the energy status of the tissue. Therefore, the activation state of signal transduction pathways that are responsive to cellular energy stress represents one mechanism whereby translation initiation may be regulated in cardiac muscle.

Adenosine Monophosphate↗
PubMed1982

Heat shock and recovery are mediated by different translational mechanisms.

When Drosophila cells are shifted from 25 degrees C to 37 degrees C, protein synthesis is rapidly redirected from the complex pattern characteristic of normal growth to the simple pattern of heat shock proteins (HSPs). On return to 25 degrees C, synthesis of normal proteins is gradually reactivated and that of HSPs is repressed. In quantifying many different recovery experiments, we found that preexisting mRNAs always behaved as a cohort, with messages for different proteins returning to translation at the same rate. Heat shock mRNAs (HS mRNAs), on the other hand, never behaved as a cohort. Their repression was asynchronous, with translation of hsp70 always the first and translation of hsp82 always the last to be repressed. Although recovery times varied enormously (depending on the severity of the heat treatment), repression of hsp70 was always correlated with restoration of normal synthesis, suggesting a link between the two events, hsp70 repression was not simply due to competition with reactivated 25 degrees C mRNAs. A general decline in the translation efficiency of hsp70 mRNA was not observed. Instead, an increasing number of messages were translationally inactivated, while those remaining in the translational pool retained full ribosome loading. Unlike inactive 25 degrees C mRNAs, which are stable during heat shock, inactive HSP mRNAs are degraded during recovery.

Animals↗
PubMedDate not supplied

Control of the hypoxic response through regulation of mRNA translation.

Hypoxia is a common feature of most solid tumors which negatively impacts their treatment response. This is due in part to the biological changes that result from a coordinated cellular response to hypoxia. A large part of this response is driven by a transcriptional program initiated via stabilization of HIF, promoting both angiogenesis and cell survival. However, hypoxia also results in a rapid inhibition of protein synthesis which occurs through the repression of the initiation step of mRNA translation. This inhibition is fully reversible and occurs in all cell lines tested to date. Inhibition of translation is mediated by two distinct mechanisms during hypoxia. The first is through phosphorylation and inhibition of an essential eukaryotic initiation factor, eIF2alpha. Phosphorylation of this factor occurs through activation of the PERK kinase as part of a coordinated ER stress response program known as the UPR. Activation of this program promotes cell survival during hypoxia and facilitates tumor growth. Translation during hypoxia can also be inhibited through the inactivation of a second eukaryotic initiation complex, eIF4F. At least part of this inhibition is mediated through a REDD1 and TSC1/TSC2 dependent inhibition of the mTOR kinase. Inhibition of mRNA translation is hypothesized to affect the cellular tolerance to hypoxia in part by promoting energy homeostasis. However, regulation of translation also results in a specific increase in the synthesis of a subset of hypoxia induced proteins. Consequently, both arms of translational control during hypoxia influence hypoxia induced gene expression and the hypoxic phenotype.

Animals↗
PubMed2005

Mechanisms of translational control by the 3' UTR in development and differentiation.

Translational control plays a major role in early development, differentiation and the cell cycle. In this review, we focus on the four main mechanisms of translational control by 3' untranslated regions: 1. Cytoplasmic polyadenylation and deadenylation; 2. Recruitment of 4E binding proteins; 3. Regulation of ribosomal subunit binding; 4. Post-initiation repression by microRNAs. Proteins with conserved functions in translational control during development include cytoplasmic polyadenylation element binding proteins (CPEB/Orb), Pumilio, Bruno, Fragile X mental retardation protein and RNA helicases. The translational regulation of the mRNAs encoding cyclin B1, Oskar, Nanos, Male specific lethal 2 (Msl-2), lipoxygenase and Lin-14 is discussed.

3' Untranslated Regions↗
PubMed2000

Two zebrafish (Danio rerio) antizymes with different expression and activities.

Cellular polyamines are regulated by a unique feedback mechanism involving ornithine decarboxylase (ODC) antizyme. The synthesis of mammalian antizyme requires a programmed translational frameshift event induced by polyamines. Antizyme represses ODC, a key enzyme for polyamine synthesis, through accelerating enzyme degradation by the 26 S proteasome. Antizyme also inhibits the cellular uptake of polyamines. In the present study we isolated two distinct zebrafish (Danio rerio) antizyme cDNA clones (AZS and AZL) from an embryonic library. Their sequences revealed that both clones required translational frameshifting for expression. Taking account of +1 frameshifting, AZS and AZL products were 214 and 218 residues long respectively and shared 51.8% amino acid identity. In rabbit reticulocyte lysates, both mRNA species were translated through spermidine-induced frameshifting. The presence of the two antizyme mRNA species in embryos, adult fish and a cultured cell line was confirmed by Northern blot analysis. The ratio of AZS mRNA to AZL mRNA in the adult fish was 1.8-fold higher than in the embryos. Whole-mount hybridization in situ demonstrated that both mRNA species are expressed in every tissue in embryo, but predominantly in the central nervous system and the eyes. Bacterial expression products of both cDNA species inhibited ODC activity, but only the AZS product accelerated ODC degradation in vitro. These results show that both zebrafish antizymes are induced by polyamines but their mRNA species are expressed differently during development. The difference in activities on ODC degradation suggests their functional divergence.

Amino Acid Sequence↗
PubMed1988

Regulation of translation and stability of an mRNA coding for a 40-kDa polypeptide in rat L6 muscle cells.

The mRNA coding for a 40-kDa polypeptide (P-40) was previously cloned and sub-cellular distribution of this mRNA was examined in rat L6 myoblast cells under different conditions [Pramanik, S. & Bag, J. (1987) Eur. J. Biochem. 170, 59-67]. The translation of this mRNA was found to be regulated during differentiation of myoblasts. This mRNA was translated in proliferating myoblasts but not in the non-dividing differentiated myotubes. We have further examined whether the mRNA present in the polysomal fraction of myoblasts and that in the free non-polysomal fraction in myotubes was identical by nuclease S1 mapping. The coding strand of the 600-base-pair PstI fragment of the recombinant clone was 3'-end-labeled with cordycepin 5'-[alpha-32P]triphosphate and hybridized with RNA from either myoblasts or myotubes. The results of these studies have shown that RNA from both preparations was fully able to hybridize with the probe DNA and, therefore, protected the 600-nucleotide-long fragment from nuclease S1 digestion, thus suggesting that the sequence of 600 nucleotides at 3' ends of both translationally active polysomal mRNA of myoblasts and repressed free mRNA of myotubes are identical. These results also confirmed the results of our earlier studies on the subcellular distribution of this mRNA by Northern blot analysis. Further studies were also performed to determine whether withdrawal of muscle cells from the cell cycle during differentiation to form myotubes alone was responsible for regulating translation of P-40 mRNA. The results of the subcellular distribution of this mRNA in proliferating myoblasts following inhibition of DNA synthesis by cytosine arabinoside have shown that translation of P-40 mRNA continued in absence of DNA synthesis. This observation suggests that an additional signal is necessary to block the translation of P-40 mRNA in myotubes. The relationship between the translation of P-40 mRNA and its stability was examined. Two different methods were used to determine the stability of mRNAs. The first approach was by determining the steady-state levels of this mRNA following inhibition of RNA synthesis by actinomycin D. In the second method, we have determined the amount of 3H-labeled P-40 mRNA during pulse and chase experiments. Both methods produced similar results. It was found that the stability of P-40 mRNA was not altered during differentiation of rat L6 cells. The results of pulse and chase studies have also shown that P-40 mRNA was synthesized in both myoblasts and myotubes.(ABSTRACT TRUNCATED AT 400 WORDS)

Amanitins↗
PubMed1995

Differential modulation of the RNA-binding proteins IRP-1 and IRP-2 in response to iron. IRP-2 inactivation requires translation of another protein.

Iron regulatory proteins (IRPs)-1 and -2 bind specific mRNA hairpin structures known as iron-responsive elements and thereby post-transcriptionally regulate proteins involved in iron uptake, storage, and utilization. In this study, we compared modulation of the RNA-binding activities of IRP-1 and IRP-2. We show that in vitro RNA-binding can be inhibited for each IRP by the alkylation of free sulfhydryl groups with N-ethylmaleimide, or by oxidation with diamide. The in vivo iron regulation of IRP-1 and IRP-2 appeared to involve different pathways. Both proteins are activated in Ltk- cells following iron chelation. This induction, however, was distinguishable by the addition of translation inhibitors, which temporarily delayed activation of IRP-1 by up to 8 h, but fully blocked IRP-2 induction for up to 20 h. The activation of IRP-2 was also prevented by transcription inhibition with actinomycin D. Further analysis revealed that, while both IRPs are rapidly inactivated following iron treatment of iron-depleted cells, the repression of IRP-2 was again completely translation dependent. Immunoblot analysis suggests that iron modulation of IRP-1 activity is predominantly a posttranslational process. This contrasts with IRP-2, whose activation reflected the accumulation of stable IRP-2 protein by de novo synthesis. IRP-2 inactivation/degradation occurred upon readdition of iron, but it required translation of another protein. The existence of an independent regulator of IRP-2 may help explain the differential regulation and expression of the two IRP proteins in different tissues and cell lines.

3T3 Cells↗
PubMed1996

Translational control during recovery from heat shock in the absence of heat shock proteins.

Heat shock results in a reduction in translational efficiency and an increase in mRNA stability in plants that is proportional to the severity of the stress. To determine whether the absence of heat shock proteins may affect the observed changes during translation or mRNA turnover, the effect that inhibiting transcription during a heat shock has on the subsequent translation of a reporter mRNA was examined. The presence of actinomycin D repressed heat shock protein synthesis in response to the application of a heat shock by more than 80%. The translational efficiency of the reporter mRNA was subject to a greater degree of repression following a heat shock when transcription was inhibited than it was in heat-shocked cells in which transcription was not inhibited. In contrast, inhibiting transcription during a heat shock did not prevent the heat-mediated increase in mRNA stability. These data suggest that ongoing transcription is needed during a heat shock to support a basal level of translational activity in the subsequent recovery from the stress but does not appear to be required for the heat-mediated increase in mRNA stability.

Animals↗
PubMed2003

Principles of cell-free genetic circuit assembly.

Cell-free genetic circuit elements were constructed in a transcription-translation extract. We engineered transcriptional activation and repression cascades, in which the protein product of each stage is the input required to drive or block the following stage. Although we can find regions of linear response for single stages, cascading to subsequent stages requires working in nonlinear regimes. Substantial time delays and dramatic decreases in output production are incurred with each additional stage because of a bottleneck at the translation machinery. Faster turnover of RNA message can relieve competition between genes and stabilize output against variations in input and parameters.

Animals↗
PubMed2003

Fat facets interacts with vasa in the Drosophila pole plasm and protects it from degradation.

Anterior-posterior patterning and germ cell specification in Drosophila requires the establishment, during oogenesis, of a specialized cytoplasmic region termed the pole plasm. Numerous RNAs and proteins accumulate to the pole plasm and assemble in polar granules. Translation of some of these RNAs is generally repressed and active only in pole plasm. Vasa (VAS) protein, an RNA helicase and a component of polar granules, is essential maternally for posterior patterning and germ cell specification, and VAS is a candidate translational activator in the pole plasm. VAS is stabilized within the pole plasm in that it is initially present throughout the entire embryo but strictly limited to the pole cells by the cellular blastoderm stage. hsp83 mRNA, which accumulates in the pole plasm through a stabilization-degradation mechanism, is another example. Here, we used a biochemical approach to identify proteins that copurify with VAS in crosslinked extracts. Prominent among these proteins was the ubiquitin-specific protease Fat facets (FAF), a pole plasm component [7], but one whose roles in posterior patterning and germ line specification have remained unclear. We present evidence that FAF interacts with VAS physically and reverses VAS ubiquitination, thereby stabilizing VAS in the pole plasm.

Animals↗
PubMed1975

Parameters of gene expression in the bipolar argECBH operon of E. coli K12. The question of translational control.

The pattern of divergent transcription of the argEC BH cluster of genes previously demonstrated by the hybridization of RNA to the separated strand of a phi 80 darg transducing phage, is confirmed with the DNA of a set of different lambdadarg phages. The accurate determination of argE and argCBH m-RNA levels in different steady states of expression of the arg regulon supports the following conclusions: 1. The ratio between maximal (derepressed) and minimal (repressed) rates of expression is lower when it is expressed in terms of % hybridizable RNA than in terms of expression is lower when it is expressed in terms of % hybridizable RNA than in terms of enzyme specific activities. The discrepancy is about 3 fold. Thus in conditions of repression, the cell produces relatively more unused m-RNA than in derepression. Different interpretations of this phenomenon appear possible: a) the messenger RNA molecules synthesized in repressed cells could be degraded more rapidly or translated less efficiently than in derepressed cells. b) an untranslated segment of the RNA could account for a larger part of the RNA detected in repression than in derepression. These interpretations are not mutually exclusive. 2. The discrepancy observed between the amplitudes of variation of argE and argC BH expression, expressed in terms of enzyme specific activities, is, in fact, determined at the level of DNA transcription. This provides direct evidence for the occurrence of differential transcription effectiveness in a regulon exhibiting a correlative but not strictly coordinated pattern of enzyme synthesis. This also supports our earlier suggestion regarding the possible complexity of the internal operator region situated between argE and C.

Arginine↗
PubMed1995

Decoying the cap- mRNA degradation system by a double-stranded RNA virus and poly(A)- mRNA surveillance by a yeast antiviral system.

The major coat protein of the L-A double-stranded RNA virus of Saccharomyces cerevisiae covalently binds m7 GMP from 5' capped mRNAs in vitro. We show that this cap binding also occurs in vivo and that, while this activity is required for expression of viral information (killer toxin mRNA level and toxin production) in a wild-type strain, this requirement is suppressed by deletion of SKI1/XRN1/SEP1. We propose that the virus creates decapped cellular mRNAs to decoy the 5'-->3' exoribonuclease specific for cap- RNA encoded by XRN1. The SKI2 antiviral gene represses the copy numbers of the L-A and L-BC viruses and the 20S RNA replicon, apparently by specifically blocking translation of viral RNA. We show that SKI2, SKI3, and SKI8 inhibit translation of electroporated luciferase and beta-glucuronidase mRNAs in vivo, but only if they lack the 3' poly(A) structure. Thus, L-A decoys the SKI1/XRN1/SEP1 exonuclease directed at 5' uncapped ends, but translation of the L-A poly(A)- mRNA is repressed by Ski2,3,8p. The SKI2-SKI3-SKI8 system is more effective against cap+ poly(A)- mRNA, suggesting a (nonessential) role in blocking translation of fragmented cellular mRNAs.

Capsid↗
PubMed1988

The importance of the 3'-untranslated region in the translational control of ferritin mRNA.

Ferritin synthesis provides a dramatic example of translational control; stored ferritin mRNA is translated at relatively low rates which can increase 40-50 times when cellular iron levels increase. Although it is not known if agents other than cellular iron levels can release the repression of ferritin mRNA in vivo, the repression appears to be eliminated during the isolation of poly(A+) RNA, judged by translation in wheat germ lysates (WG). Using the bullfrog tadpole as a model, because of the abundance of ferritin-rich embryonic red cells, we now show specific repression of ferritin mRNA in the isolated poly(A+) RNA translated in rabbit reticulocyte lysates (RR) (RR/WG = 25%). Repression of ferritin mRNA was associated with the inability to form polyribosomes in analogy to iron-poor cells in vivo. The addition of various complexes of iron did not relieve the repression, suggesting that in vivo at least part of the effect of iron may be indirect and mediated by factors absent in the cell-free system; all three ferritin subunit mRNAs (H, M, and L) appeared to be regulated coordinately in vitro and in vivo as well. Comparison of transcripts of DNA encoding the M subunit of ferritin, but containing deletions in the 3'-untranslated (UT) region, showed that a region 70 nucleotides long was important for repression. Comparison of secondary structures predicted for the eight known ferritin subunit mRNAs from humans, rats, chickens, and frogs indicates that a region involved in base pairing common to all the mRNAs is eliminated when the 3'-UT region is shortened to 24 nucleotides. Although regions in the 5'-UT of mRNAs, including ferritin, have been shown to be involved in translational regulation, it is clear that complete regulation can involve both the 3'-UT and the 5'-UT regions, mediated, presumably, by secondary and tertiary interactions along the mRNA molecule.

Animals↗
PubMed1986

A study of derepression of NAD-specific glutamate dehydrogenase of Neurospora crassa.

Transfer of Neurospora crassa mycelium from a 1% (w/v) sucrose medium to carbon-free or 1% (w/v) glutamate medium results in the onset of derepression of the catabolic NAD-specific glutamate dehydrogenase (NAD-GDH), within 30 min of the shift. Immunoprecipitation of in vivo pulse-labelled NAD-GDH demonstrated that this enzyme was synthesized de novo, correlating with increasing enzyme activity in shifted cells. Derepression was shown to be under transcriptional control by using the RNA synthesis inhibitor, picolinic acid, and by immunoprecipitation of the in vitro translation products of poly(A)-containing mRNA from repressed and derepressed cells. A brief (5 min) shift to derepression medium followed by a return to 1% (w/v) sucrose medium was sufficient to trigger synthesis of abundant NAD-GDH transcripts and low levels of the active enzyme. A secondary level of translational control is proposed to account for the discrepancy between the detectable levels of NAD-GDH transcripts and protein, following transient derepression.

Autoradiography↗
PubMed1993

An upstream open reading frame represses expression of Lc, a member of the R/B family of maize transcriptional activators.

The R/B genes of maize encode a family of basic helix-loop-helix proteins that determine where and when the anthocyanin-pigment pathway will be expressed in the plant. Previous studies showed that allelic diversity among family members reflects differences in gene expression, specifically in transcription initiation. We present evidence that the R gene Lc is under translational control. We demonstrate that the 235-nt transcript leader of Lc represses expression 25- to 30-fold in an in vivo assay. Repression is mediated by the presence in cis of a 38-codon upstream open reading frame. Furthermore, the coding capacity of the upstream open reading frame influences the magnitude of repression. It is proposed that translational control does not contribute to tissue specificity but prevents overexpression of the Lc protein. The diversity of promoter and 5' untranslated leader sequences among the R/B genes provides an opportunity to study the coevolution of transcriptional and translational mechanisms of gene regulation.

Amino Acid Sequence↗
PubMed1985

Initiation factor eIF2 associated with non-polysomal poly(A)-containing messenger ribonucleoproteins of cryptobiotic gastrulae of Artemia salina.

Non-polysomal poly(A)-containing mRNP of A. salina cryptobiotic embryos is separated in mRNP active in protein synthesis and in repressed mRNP by sucrose gradient centrifugation. In the translationally active fraction the presence of eukaryotic initiation factor 2 (eIF2) is demonstrated by electroblotting of sodium dodecylsulphate/polyacrylamide gels on nitrocellulose and anti-eIF2 antibody detection. mRNP proteins with Mr of 40 000 and 42 000 are identified as the alpha and beta subunits of eIF2. The repressed mRNP is devoid of eIF2 and is associated with an inhibitor ribonucleoprotein composed of a small 85 +/- 2-nucleotide-long RNA and a protein with Mr of 64 000. The latter ribonucleoprotein is a potent inhibitor of the translationally active mRNP.

Animals↗
PubMed1992

Function of a relaxed-like state following temperature downshifts in Escherichia coli.

Temperature downshifts of Escherichia coli throughout its growth range resulted in transient growth inhibition and a cold shock response consisting of transient induction of several proteins, repression of heat shock proteins, and, despite the growth lag, continued synthesis of proteins involved in transcription and translation. The paradoxical synthesis of the latter proteins, which are normally repressed when growth is arrested, was explored further. First, by means of a nutritional downshift, a natural stringent response was induced in wild-type cells immediately prior to a shift from 37 to 10 degrees C. These cells displayed decreased synthesis of transcriptional and translational proteins and decreased induction of cold shock proteins; also, adaptation for growth at 10 degrees C was delayed, even after restoration of the nutrient supplementation. Next, the contribution of guanosine 5'-triphosphate-3'-diphosphate and guanosine 5'-diphosphate-3'-diphosphate, collectively abbreviated (p)ppGpp, to the alteration in cold shock response was studied with the aid of a mutant strain in which overproduction of these nucleotides can be artificially induced. Induction of (p)ppGpp synthesis immediately prior to shifting this strain from 37 to 10 degrees C produced results differing only in a few details from those described above for nutritional downshift of the wild-type strain. Finally, shifting a relA spoT mutant, which cannot synthesize (p)ppGpp, from 24 to 10 degrees C resulted in a greater induction of the cold shock proteins, increased synthesis of transcriptional and translational proteins, decreased synthesis of a major heat shock protein, and faster adaptation to growth than for the wild-type strain. Our results indicate that the previously reported decrease in the (p)ppGpp level following temperature downshift plays a physiological role in the regulation of gene expression and adaptation for growth at low temperature.

Adaptation, Physiological↗