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PubMed1981

Does the capacity of ribosomes to control translation fidelity change with age?

The stress of increased magnesium concentration and of antibiotic action was used to test for changes in the capacity of ribosomes to maintain the fidelity of translation in protein synthesis during aging. Elongation fidelity of ribosomes isolated from livers of young adult (6-10 months, n=9) and old (23-24 months, n=11) rats was assessed for poly(U) message through the error co-incorporation of leucine (Leu) with phenylalanine (Phe), using controlled rate measurements. No statistically significant difference in the error response of ribosomes from young and old animals was detected on manipulating magnesium. The maximum Phe and Leu rates occurred at approximately 8 and approximately 11 mM Mg2+, respectively; the relative error frequency (Leu/Phe ratio) at the Leu maximum was approximately 2%. The aminoglycoside paromomycin (PM) elicited a considerably higher degree of error incorporation: 12-14% Leu/Phe in the range of the Leu rate maximum, 40-60 microM paromomycin, at 9 mM Mg2+. A statistically significant increase was detected in the error frequency for ribosomes from old as compared with young animals (at p less than 0.02) between 20 and 60 microM paromomycin, the largest increase (approximately 9%) occurring at the Leu rate maximum. Also, the ribosomes from the old animals, in terms of the error frequency, were found to be significantly more sensitive to paromomycin concentration (at p less than 0.02) up to the Leu maximum. These results indicate that liver ribosomes of old rats may have a slightly decreased capacity to maintain fidelity, which can be expressed under particular conditions.

Aging↗
PubMed1987

Translational control of ribosomal protein synthesis during early Dictyostelium discoideum development.

Throughout the developmental program of Dictyostelium discoideum there are substantial changes in the rates of both ribosome utilization and rRNA transcription and processing. We examined the regulation of ribosomal protein (r-protein) gene expression and found that, at the start of development, expression of these genes was drastically and specifically reduced by a block to translational initiation. An apparently separate event signals a sudden decrease in the relative amount of r-protein mRNA at about 10 h of development, a time when aggregated amoebae are forming tight cell-cell contacts. For the first 9 h of development, the relative amount of r-protein mRNA remained essentially unchanged and comparable to levels detected in growing cells. While the r-protein mRNAs were almost fully loaded on polysomes during vegetative growth, they were specifically excluded from polysomes at the start of development. The translational block was not the result of irreversible structural changes which inactivate the r-protein mRNAs since they remained translatable both in vitro, in wheat germ extracts, and in vivo, where they were recruited onto polysomes in the presence of the elongation inhibitor cycloheximide. In addition, precise measurements of poly(A) tail lengths on individual hybrid-selected mRNA species showed that there is no difference in the poly(A) tail length of r-protein mRNA isolated from growing cells and 1-h developing cells. Therefore, changes in translational efficiency cannot be attributed to cleavage of poly(A) tails.

Dictyostelium↗
PubMed1991

Translational control of transposition activity of the bacterial insertion sequence IS1.

The experiments reported here provide strong evidence indicating that the transposition frequency of the bacterial insertion sequence IS1 is determined principally by two IS1-specified proteins. The first, InsA, was previously shown to bind to the ends of the element and to act as a repressor. We present both physical and genetic evidence which reveals that the second, the InsAB' transposase, is a fusion of InsA with the product of a downstream reading frame, InsB'. Synthesis of this protein occurs by a -1 frameshift between the insA and insB' frames. It requires the presence of an intact retroviral-like frameshift signal composed of an A6C motif and a downstream region able to form several alternative secondary structures. In vivo studies show that IS1 transposition activity depends on the relative rather than on the absolute levels of InsA and InsAB'. The ratio is determined primarily at the translational level by frameshifting and appears to be relatively insensitive to large variations in levels of transcription. This novel homeostatic control could therefore protect IS1 from activation as a consequence of insertion into active transcription units.

Base Composition↗
PubMed2002

Transcriptional and translational control in the Mammalian unfolded protein response.

Cells monitor the physiological load placed on their endoplasmic reticulum (ER) and respond to perturbations in ER function by a process known as the unfolded protein response (UPR). In metazoans the UPR has a transcriptional component that up-regulates expression of genes that enhance the capacity of the organelle to deal with the load of client proteins and a translational component that insures tight coupling between protein biosynthesis on the cytoplasmic side and folding in the ER lumen. Together, these two components adapt the secretory apparatus to physiological load and protect cells from the consequences of protein malfolding.

Animals↗
PubMedDate not supplied

Translation control of gene expression.

The bacteriophage lambda cIII gene product is an early regulator of the lysogenic pathway. The availability of a set of cIII expression mutants allowed us to establish the structure-function relationship of the cIII mRNA. We demonstrated, using defined in vitro systems, that the cIII mRNA is present in two conformations at equilibrium. Mutations that have been shown to lead to cIII overexpression were found to freeze the RNA in one conformation (structure B), and permit efficient binding to the 30S ribosomal subunit. Mutations that have been shown to prevent cIII translation cause the mRNA to assume the alternative conformation (structure A). In this structure, the translation initiation region is occluded, thereby preventing 30S ribosomal subunit binding. Translation of the cIII gene is regulated by RNaseIII. We have localized the RNaseIII responsive element (RRE) to the cIII coding region. We suggest that the regulation of the equilibrium between the two mRNA conformations provides a mechanism for the control of cIII gene expression. The way in which RNaseIII participates in this regulation is as yet unknown.

Base Sequence↗
PubMed1990

Translational control by cytoplasmic polyadenylation during Xenopus oocyte maturation: characterization of cis and trans elements and regulation by cyclin/MPF.

The expression of certain maternal mRNAs during oocyte maturation is regulated by cytoplasmic polyadenylation. To understand this process, we have focused on a maternal mRNA from Xenopus termed G10. This mRNA is stored in the cytoplasm of stage 6 oocytes until maturation when the process of poly(A) elongation stimulates its translation. Deletion analysis of the 3' untranslated region of G10 RNA has revealed that two sequence elements, UUUUUUAU and AAUAAA were both necessary and sufficient for polyadenylation and polysomal recruitment. In this communication, we have defined the U-rich region that is optimal for polyadenylation as UUUUUUAUAAAG, henceforth referred to as the cytoplasmic polyadenylation element (CPE). We have also identified unique sequence requirements in the 3' terminus of the RNA that can modulate polyadenylation even in the presence of wild-type cis elements. A time course of cytoplasmic polyadenylation in vivo shows that it is an early event of maturation and that it requires protein synthesis within the first 15 min of exposure to progesterone. MPF and cyclin can both induce polyadenylation but, at least with respect to MPF, cannot obviate the requirement for protein synthesis. To identify factors that may be responsible for maturation-specific polyadenylation, we employed extracts from oocytes and unfertilized eggs, the latter of which correctly polyadenylates exogenously added RNA. UV crosslinking demonstrated that an 82 kd protein binds to the U-rich CPE in egg, but not oocyte, extracts. The data suggest that progesterone, either in addition to or through MPF/cyclin, induces the synthesis of a factor during very early maturation that stimulates polyadenylation.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1999

Post-translation control of Nramp metal transport in yeast. Role of metal ions and the BSD2 gene.

The Saccharomyces cerevisiae SMF1 gene encodes a member of the well conserved family of Nramp metal transport proteins. Previously, we determined that heavy metal uptake by Smf1p was down-regulated by the product of the S. cerevisiae BSD2 gene. We now demonstrate that this regulation occurs at the level of protein stability. In wild type strains, the bulk of Smf1p is normally directed to the vacuole and is rapidly degraded by vacuolar proteases in a PEP4-dependent manner. In bsd2Delta mutants, Smf1p fails to enter the vacuole, and the Nramp protein is stabilized. Metal ions themselves play an important role in the post-translational regulation of Smf1p. The depletion of heavy metals from the growth medium effects stabilization of Smf1p and additionally results in accumulation of this transporter at the cell surface. Supplementation of manganese alone is sufficient to trigger rapid degradation of Smf1p in a Bsd2p-dependent manner. Together the action of Bsd2p and metal ions provide a rapid and effective means for controlling Nramp metal transport in response to environmental changes.

Carrier Proteins↗
PubMed1989

Activation of double-stranded RNA-dependent kinase (dsl) by the TAR region of HIV-1 mRNA: a novel translational control mechanism.

All mRNAs of human immunodeficiency virus 1 (HIV-1) contain in their 5' untranslated region a sequence termed TAR that responds to trans-activation by the tat (trans-activating) protein. This RNA sequence assumes a stable secondary structure, and its cap structure is relatively inaccessible. Here we report that these structural properties of the TAR sequence underlie the ability of TAR to inhibit in trans the translation of other mRNAs. This mechanism of translation inhibition involves the activation of the double-stranded RNA-dependent kinase (dsl), which in turn phosphorylates the protein synthesis initiation factor 2 (eIF-2). Mutations in the TAR region that diminish the stability of the secondary structure cause a significant reduction in the trans-inhibition. A similar reduction in the dsl activation occurs when TAR is placed further downstream of the cap structure. This is a clear demonstration of a specific naturally occurring mRNA sequence that can activate dsl. We suggest a novel translational regulatory mechanism that interdigitates the activities of eIF-2 and eIF-4F.

Animals↗
PubMed1991

Regulation of the heat shock response in E coli: involvement of positive and negative cis-acting elements in translation control of sigma 32 synthesis.

When cells of E coli are transferred from 30 to 42 degrees C, the cellular level of sigma 32 (rpoH gene product) increases transiently, resulting in increased transcription of a set of heat shock genes. Both increased synthesis and increased stability of sigma 32 contribute to transient accumulation of sigma 32. Evidence suggests that synthesis of sigma 32 is enhanced primarily at the level of rpoH translation. We have constructed and examined the expression of deletion derivatives of rpoH-lacZ gene fusion at 30 degrees C and after shift to 42 degrees C. It was revealed that two cis-acting sequences within the rpoH coding region are involved in thermal regulation of fusion protein synthesis. One region immediately downstream of the initiation codon is required for high level expression, whereas the other internal region is involved in repression at low temperature. Thus, these regions act as positive and negative cis-elements in thermal regulation of rpoH translation. The rpoH mRNA secondary structure model suggesting an interplay between the two regions has been proposed to account for the temperature-induced sigma 32 synthesis as a primary cellular response to the heat shock stress.

Base Sequence↗
PubMed1990

Translational control mediated by UA-rich sequences.

Several messenger RNAs coding for cytokines, growth factors or oncoproteins contain a conserved UA-rich sequence in their 3' untranslated regions. This sequence, which is composed of several interspersed repeats of the octanucleotide UUAUUUAU, is a key element in the posttranscriptional regulation of these mRNAs. Previously shown to be involved in mRNA destabilization, these UA-rich elements can also strongly influence mRNA translation. A translation inhibition mediated by these sequences has indeed been observed in vitro as well as in frog oocyte or in somatic cells.

Animals↗
PubMed2005

Unshackling the links between reovirus oncolysis, Ras signaling, translational control and cancer.

Reovirus has an inherent preference for replicating in cells with dysregulated growth factor signaling cascades that comprise Ras activation. Precisely how reovirus exploits the host cell Ras pathway is unclear, but there is evidence suggesting that activated Ras signaling is important for efficient viral protein synthesis. Defining the molecular mechanism of reovirus oncolysis will shed light on reovirus replication and important aspects of cellular transformation, Ras signaling cascades and regulation of protein translation.

Cell Transformation, Neoplastic↗
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↗
PubMed1981

The effects of haem on translational control of protein synthesis in cell-free extracts from fed and lysine-derived Ehrlich ascites tumour cells.

1. Addition of haem to cell-free extracts from Ehrlich ascites tumour cells stimulates protein synthesis only in extracts from cells previously incubated in nutritionally complete conditions. Extracts from amino-acid-deprived cells do not respond to haem. The stimulation of protein synthesis in fed cell extracts is due to increased initiation on endogenous mRNA mediated by an increase in the levels of 40-S-subunit X Met-tRNA initiation complexes. Extracts from starved cells exhibit a defect in 40-S initiation complex formation which cannot be overcome by haem. 2. Experiments to test for the presence of an inhibitor of initiation in Ehrlich cell extracts by monitoring effects on translation in haem-supplemented reticulocyte lysates have revealed that extracts from both fed and starved cells contain one or more inhibitory activities which shut off protein synthesis, dissagregate polysomes and reduce the level of 40-S initiation complexes in the lysate. Extracts from starved cells are more inhibitory for protein synthesis than those from fed cells. 3. Initiation factor eIF-2 is phosphorylated by an endogenous Ehrlich cell protein kinase in vitro, but this occurs to the same extent in extracts from fed and starved cells. 4. We propose a possible model for the role of eIF-2 in the control of protein synthesis by amino acid supply in Ehrlich cells.

Animals↗
PubMed1994

Translational control of maternal glp-1 mRNA establishes an asymmetry in the C. elegans embryo.

In C. elegans, the glp-1 gene encodes a membrane receptor that is required for anterior cell fates in the early embryo. We report that GLP-1 protein is localized to anterior blastomeres in 2- to 28-cell embryos. By contrast, glp-1 mRNA is present in all blastomeres until the 8-cell stage. Furthermore, the glp-1 3' untranslated region can restrict translation of a reporter mRNA to anterior blastomeres. Therefore, the translation of maternal glp-1 mRNA is temporally and spatially regulated in the C. elegans embryo. The regulation of maternal glp-1 mRNA has striking parallels to the regulation of maternal hunchback mRNA in the Drosophila embryo. Thus, the establishment of embryonic asymmetry in diverse organisms may involve conserved mechanisms of maternal mRNA regulation.

Animals↗
PubMed1994

Cloning and analysis of translational control for genes encoding the Cfr9I restriction-modification system.

The complete type-II Cfr9I restriction-modification (R-M) system of Citrobacter freundii strain RFL9, recognizing the DNA sequence CCCGGG, has been cloned and expressed, and functionally active enzymes have been produced in Escherichia coli. Both the methyltransferase (MTase; M.Cfr9I) and restriction endonuclease (ENase; R.Cfr9I) were found to be encoded on a 2.3-kb cloned fragment in the same transcriptional orientation, but differing in translational phases. The last codon (underlined) (ATGA) of the MTase-encoding gene (Cfr9IM) overlaps with the start codon for the ENase-encoding gene (overlined) (cfr9IR). A nucleotide sequence complementary to a predicted Shine-Dalgarno sequence preceding cfr9IR is within this gene. Predicted free energy (delta G) for formation of the mRNA secondary structure involving these complementary sequences was found to be -16.1 kcal/mol. Amino-acid sequence homology of 80% was found between R.Cfr9I and R.XcyI.

Amino Acid Sequence↗
PubMed2026

Translational control by RPL22L1-specific ribosomes enhances DNA repair and chemoresistance.

Ribosome heterogeneity has emerged as a regulatory layer in gene expression, yet its biological roles in cancers remain poorly characterized. Here, we identify RPL22L1, a paralog of the ribosomal protein RPL22, as a key modulator of DNA damage response (DDR) in colorectal cancer cells. DNA damage induces RPL22L1 upregulation and ribosomal incorporation, forming RPL22L1-specific ribosomes. Ribosome profiling reveals that RPL22L1-containing ribosomes preferentially translate mRNAs with highly structured 5' untranslated region (5'UTR). In particular, RPL22L1 enhances the translation of ATRX through a cap-independent mechanism. ATRX subsequently recruits DNA-PKcs to DNA damage sites, thereby enhancing the DNA repair capacity. RPL22L1 loss creates exploitable DDR vulnerabilities, sensitizing cancer cells to cisplatin and PARP inhibitors in vitro and in vivo. Collectively, these findings uncover a specialized ribosome-mediated translational program in DDR and highlight RPL22L1 as a potential therapeutic target in DDR-based cancer therapy.

DNA Repair↗
PubMed1996

Translational control of puf operon expression in Rhodobacter sphaeroides 2.4.1.

The puf operon of Rhodobacter sphaeroides 2.4.1 encode the beta- and alpha-polypeptides of the B875 complex, the L and M polypeptides of the reaction centre and the pufX gene product. A previous report from the authors' laboratory indicated the potential existence of a 20-codon open reading frame (orfK, now designated pufK) located immediately upstream of the pufB structural gene. It is now demonstrated that pufK is translated in vivo and that the specific levels or nature of the rare codons within pufK affect the expression of pufK. Using a series of pufK-specific mutations, both in trans as lacZ translational fusions and incorporated into the genome in single copy, evidence has been obtained that translation initiation through pufK may be essential to translation of pufB. Further, the abundance, quality and distribution of rare codons within pufK may serve to 'gate' the entry of ribosomes at pufB. The data also suggest that translation of pufB is uncoupled from that of pufA, with the latter capable of being produced in excess of the former. It is also revealed that the secondary structure at the 5' end of the large and small puf transcripts may play a role in mRNA stability and that stability of the small puf transcript is independent of translation.

Amino Acid Sequence↗