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At least 19 recordsLinked to original sources
PubMed2001

Diversity in translational regulation.

Translational control of individual mRNAs relies on cis-regulatory elements, which are often found in the 3' untranslated region. The best characterized of these regulate cytoplasmic polyadenylation, and much of this process can now be defined in terms of molecular interactions, protein modifications and their consequences. Biochemical and genetic approaches have advanced the understanding of the many instances of translational regulation that are crucial for body patterning in Drosophila. For example, in vitro translation systems have been used to study the regulatory mechanisms, and genetic interactions have been instrumental in establishing a link between a regulatory factor and a component of the translational apparatus. Although most examples of control are thought to affect the initiation of translation, two classes of regulatory factors, one a protein and one a short non-coding RNA now appear to inhibit protein synthesis during elongation. Diversity seems to be a central feature of translational control, both in the mechanisms themselves and in the situations where this form of regulation is used.

3' Untranslated Regions↗
PubMed2002

Regulated translation of heparan sulfate N-acetylglucosamine N-deacetylase/n-sulfotransferase isozymes by structured 5'-untranslated regions and internal ribosome entry sites.

We report the full-length 5'-untranslated region (5'-UTR) sequences of the four vertebrate heparan sulfate/heparin GlcNAc N-deacetylase/N-sulfotransferases (NDSTs) and their role in translational regulation in vivo and in vitro. All four NDST 5'-UTR sequences are unusually long, have a high degree of predicted secondary structure, and contain multiple upstream AUG codons, which together impose a major barrier to conventional, cap-dependent ribosomal scanning. At least two alternatively spliced forms of NDST2 differing in their 5'-UTRs exist, and two forms of NDST4 arise from alternative transcriptional start sites. The 5'-UTRs do not show any significant sequence similarity between isozymes, but possess highly conserved regions between mouse and human orthologs, pointing toward evolutionarily conserved functions. Expression of bicistronic vector constructs showed that the 5'-UTRs of NDST1-4 are capable of regulating translation differentially in vivo dependent on cell type and culture conditions. In vitro translation of a reporter gene located downstream of the UTRs demonstrated the presence of internal ribosome entry sites, providing an additional, cap-independent step in fine-tuning NDST expression. Comparative studies of NDST1-3 mRNAs and protein expression in brain and embryonic extracts revealed striking differences in translational efficiency. Other genes necessary for glycosaminoglycan synthesis in addition to the NDST isozymes have long, structured 5'-UTRs. Because several growth factors and morphogens that bind heparan sulfate also contain structured 5'-UTRs, translational regulation may coordinate the action of these factors and their heparan sulfate co-receptors.

5' Untranslated Regions↗
PubMed1987

Identification of the iron-responsive element for the translational regulation of human ferritin mRNA.

Regulated translation of messenger RNA offers an important mechanism for the control of gene expression. The biosynthesis of the intracellular iron storage protein ferritin is translationally regulated by iron. A cis-acting element that is both necessary and sufficient for this translational regulation is present within the 5' nontranslated leader region of the human ferritin H-chain messenger RNA. In this report the iron-responsive element (IRE) was identified by deletional analysis. Moreover, a synthetic oligodeoxynucleotide was shown to be able to transfer iron regulation to a construct that would otherwise not be able to respond to iron. The IRE has been highly conserved and predates the evolutionary segregation between amphibians, birds, and man. The IRE may prove to be useful for the design of translationally regulated expression systems.

Base Sequence↗
PubMed1998

Biochemical pathways by which serotonin regulates translation in the nervous system of Aplysia.

In the marine mollusk Aplysia californica, serotonin initiates three phases of translational regulation: an initial decrease in translation, followed by a transient increase in protein synthesis, both of which are independent of transcription, followed by a later increase in protein synthesis that is dependent on transcription. These increases in protein synthesis may underlie translation-dependent changes in synaptic plasticity. We have characterized the second messenger pathways that underlie these changes in the pleural ganglia of Aplysia. Activation of protein kinase C was both necessary and sufficient for the initial decrease in translation. Protein kinase C, cyclic AMP-dependent protein kinase, and a tyrosine kinase were all required for the second phase, a transient increase in protein synthesis. The late increase in protein synthesis required both protein kinase A and spaced applications of serotonin. Rapamycin, a specific inhibitor of a downstream translational regulator, blocked the transient increase in protein synthesis (second phase), suggesting that this drug may be useful in determining the specific physiological consequences of this translational regulation. Indeed, we used rapamycin to demonstrate that one type of intermediate form of synaptic plasticity induced by serotonin did not require the rapamycin-sensitive increase in translation.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1991

Cytoplasmic protein binding to highly conserved sequences in the 3' untranslated region of mouse protamine 2 mRNA, a translationally regulated transcript of male germ cells.

The expression of the protamines, the predominant nuclear proteins of mammalian spermatozoa, is regulated translationally during male germ-cell development. The 3' untranslated region (UTR) of protamine 1 mRNA has been reported to control its time of translation. To understand the mechanisms controlling translation of the protamine mRNAs, we have sought to identify cis elements of the 3' UTR of protamine 2 mRNA that are recognized by cytoplasmic factors. From gel retardation assays, two sequence elements are shown to form specific RNA-protein complexes. Protein binding sites of the two complexes were determined by RNase T1 mapping, by blocking the putative binding sites with antisense oligonucleotides, and by competition assays. The sequences of these elements, located between nucleotides + 537 and + 572 in protamine 2 mRNA, are highly conserved among postmeiotic translationally regulated nuclear proteins of the mammalian testis. Two closely linked protein binding sites were detected. UV-crosslinking studies revealed that a protein of about 18 kDa binds to one of the conserved sequences. These data demonstrate specific protein binding to a highly conserved 3' UTR of translationally regulated testicular mRNA.

Animals↗
PubMed1999

Spatially regulated translation in embryos: asymmetric expression of maternal Wnt-11 along the dorsal-ventral axis in Xenopus.

Transition from symmetry to asymmetry is a central theme in cell and developmental biology. In Xenopus embryos, dorsal-ventral asymmetry is initiated by a microtubule-dependent cytoplasmic rotation during the first cell cycle after fertilization. Here we show that the cytoplasmic rotation initiates differential cytoplasmic polyadenylation of maternal Xwnt-11 RNA, encoding a member of the Wnt family of cell-cell signaling factors. Translational regulation of Xwnt-11 mRNA along the dorsal-ventral axis results in asymmetric accumulation of Xwnt-11 protein. These results demonstrate spatially regulated translation of a maternal cell-signaling factor along the vertebrate dorsal-ventral axis and represent a novel mechanism for Wnt gene regulation. Spatial regulation of maternal RNA translation, which has been established in invertebrates, appears to be an evolutionarily conserved mechanism in the generation of intracellular asymmetry and the consequential formation of the multicellular body pattern.

Animals↗
PubMedDate not supplied

Development stage-specific expression of fibroin in the silk worm Bombyx mori is regulated translationally.

The contents of fibroin H RNA as a function of development have been quantitated in the posterior silk glands of Bombyx mori larvae on different days of 4th and 5th instars. The fibroin RNA levels increased during the feeding stages of larvae and the RNA got completely degraded during the interim moult. The patterns of accumulation of fibroin RNA were similar in both the instars. Although there was considerable increase in the fibroin RNA content during the 5th larval instar, the relative abundance of fibroin RNA in the total RNA was fairly constant during the 4th and 5th instars. The increased content of fibroin RNA in 5th instar was the consequence of an overall increase in transcription accompanying the development progress, rather than specific increase only in fibroin transcription. The contents of fibroin protein in the 4th and 5th instars of development have also been quantitated making use of a sensitive radioimmune assay with a purified, antifibroin antibody. There were substantial differences between 4th and 5th instars in the absolute fibroin contents as well as the relative proportion of fibroin in the total proteins. These results implied that although the fibroin gene was transcribed at the same efficiency during the 4th and 5th instars, the translational efficiency was much lower during the 4th instar. The extent of polyadenylation of fibroin RNA was similar in both instars. However, there was a two-fold increase in the polysome association of fibroin RNA in the 5th instar. Over and above this, there was substantial increase during the 5th instar in the contents of those tRNAs. (e.g. Gly, Ala and Ser) which are abundantly represented in fibroin and therefore directly related to the expression of fibroin. The increased polysome association of fibroin mRNA and the adequate supply of cognate tRNAs in the 5th instar, together contributes to the translational regulation of fibroin in a developmental stage-specific manner. Based on these observations, we propose that translational regulation plays a major role in the development stage-specific synthesis of fibroin in Bombyx mori.

Animals↗
PubMed2004

Regulating a translational regulator: mechanisms cells use to control the activity of the fragile X mental retardation protein.

Fragile X syndrome results from the loss of a normal cellular protein, FMRP. FMRP is an RNA binding protein, and it is likely that altering the way FMRP's messenger RNA (mRNA) targets are processed results in the clinical features associated with the disease. Using complementary DNA microarray screening, a number of brain-derived mRNAs that interact directly with FMRP in vitro and associate with FMRP-containing mRNPs in vivo have been identified. These target messages encode RNA-binding proteins, transcription factors, neuronal receptors, cytoskeletal proteins, a few enzymes as well as several unknown proteins. For a subset of these mRNAs it has been shown that modulating FMRP levels in cultured cells correspondingly affects their expression. In addition, several modes by which cells modulate FMRP activity have been described; these include posttranscriptional processing and posttranslational modification. Here, the most recent results concerning the biochemical activities of FMRP and how they are affected by various modifications are reviewed. The data lead to a model signaling mechanism by which FMRP normally regulates the expression of its target mRNAs.

Amino Acid Sequence↗
PubMed2002

Structures of the pleiotropic translational regulator Hfq and an Hfq-RNA complex: a bacterial Sm-like protein.

In prokaryotes, Hfq regulates translation by modulating the structure of numerous RNA molecules by binding preferentially to A/U-rich sequences. To elucidate the mechanisms of target recognition and translation regulation by Hfq, we determined the crystal structures of the Staphylococcus aureus Hfq and an Hfq-RNA complex to 1.55 and 2.71 A resolution, respectively. The structures reveal that Hfq possesses the Sm-fold previously observed only in eukaryotes and archaea. However, unlike these heptameric Sm proteins, Hfq forms a homo-hexameric ring. The Hfq-RNA structure reveals that the single-stranded hepta-oligoribonucleotide binds in a circular conformation around a central basic cleft, whereby Tyr42 residues from adjacent subunits stack with six of the bases, and Gln8, outside the Sm motif, provides key protein-base contacts. Such binding suggests a mechanism for Hfq function.

Amino Acid Motifs↗
PubMed2026

Involvement of tRNA thiolation in uORF-mediated translational regulation during Xylogenesis in Arabidopsis thaliana.

Post-transcriptional modification of tRNAs is an important mechanism for regulating translation efficiency and cellular homeostasis, yet its contribution to upstream open reading frame (uORF)-mediated translational control remains largely unexplored. In this study, we investigated the role of tRNA thiolation in thermospermine-dependent regulation of xylem development in Arabidopsis thaliana. Using a suppressor screen of the thermospermine-deficient mutant acaulis5 (acl5), which exhibits dwarfism and excessive xylem differentiation, we identified suppressor-of-acl502 (sac502) as a recessive loss-of-function allele of CTU2, a gene encoding a key enzyme in the biosynthesis of the wobble uridine modification 5-methoxycarbonylmethyl-2-thiouridine. Mutations in other components of the same modification pathway, including ROL5 and TRM9, similarly suppressed the acl5 phenotype. Translational analyses using 5' leader-GUS reporter constructs revealed that the ctu2 mutation did not enhance translation of the mRNA containing a thermospermine-responsive uORF of SAC51, but instead significantly reduced translation of that of SACL3, a member of the SAC51 family, and that of LONESOME HIGHWAY (LHW), which contains another conserved uORF in the 5' leader region. Polysome profiling further demonstrated decreased association of SACL3 and LHW mRNAs with actively translating ribosomes in ctu2. Genetic interaction analyses supported the conclusion that the suppression of excessive xylem formation in acl5 by ctu2 is attributable to reduced LHW activity. In addition, ctu2 mutants displayed increased sensitivity to exogenous thermospermine, resembling the response of lhw mutants. Together, our results reveal that tRNA thiolation contributes to uORF-mediated translational regulation of key developmental regulators and identify tRNA modification as an important regulatory layer controlling vascular development.

Arabidopsis↗
PubMed2005

Translational regulation during oogenesis and early development: the cap-poly(A) tail relationship.

Metazoans rely on the regulated translation of select maternal mRNAs to control oocyte maturation and the initial stages of embryogenesis. These transcripts usually remain silent until their translation is temporally and spatially required during early development. Different translational regulatory mechanisms, varying from cytoplasmic polyadenylation to localization of maternal mRNAs, have evolved to assure coordinated initiation of development. A common feature of these mechanisms is that they share a few key trans-acting factors. Increasing evidence suggest that ubiquitous conserved mRNA-binding factors, including the eukaryotic translation initiation factor 4E (eIF4E) and the cytoplasmic polyadenylation element binding protein (CPEB), interact with cell-specific molecules to accomplish the correct level of translational activity necessary for normal development. Here we review how capping and polyadenylation of mRNAs modulate interaction with multiple regulatory factors, thus controlling translation during oogenesis and early development.

Adenosine↗
PubMed2004

Features of a leader peptide coding region that regulate translation initiation for the anti-TRAP protein of B. subtilis.

The rtpA gene of Bacillus subtilis encodes the Anti-TRAP protein, AT. AT can bind and inhibit the TRAP regulatory protein, preventing TRAP from promoting transcription termination in the trpEDCFBA operon leader region. AT synthesis is upregulated transcriptionally and translationally in response to the accumulation of uncharged tRNA(Trp). Here we analyze AT's translational regulation by rtpLP, a 10 residue leader peptide coding region located immediately preceding the rtpA Shine-Dalgarno sequence. Our findings suggest that, whenever the charged tRNA(Trp) level is sufficient to allow the ribosome translating rtpLP to reach its stop codon, it blocks the adjacent rtpA Shine-Dalgarno sequence, inhibiting AT synthesis. However, when there is a charged tRNA(Trp) deficiency, the translating ribosome presumably stalls at one of three adjacent rtpLP Trp codons. This stalling exposes the rtpA Shine-Dalgarno sequence, permitting AT synthesis. RNA-RNA pairing may also influence AT synthesis. Production of AT would inactivate TRAP, thereby increasing trp operon expression.

Bacillus subtilis↗
PubMed1995

Translational regulation: versatile mechanisms for metabolic and developmental control.

It has become clear that many vital metabolic circuits and early developmental programs are regulated translationally. Until recently, the mechanisms underlying most of these observations were poorly understood. The past year has witnessed several important advances in the understanding of how the translational apparatus is controlled by different regulatory mechanisms.

Animals↗
PubMed1999

Activation of a meiotic checkpoint regulates translation of Gurken during Drosophila oogenesis.

The genes okra and spindle-B act during meiosis in Drosophila to repair double-stranded DNA breaks (DSBs) associated with meiotic recombination. Unexpectedly, mutations in these genes cause dorsoventral patterning defects during oogenesis. These defects result from a failure to accumulate Gurken protein, which is required to initiate dorsoventral patterning during oogenesis. Here we find that the block in Gurken accumulation in the oocyte cytoplasm reflects activation of a meiotic checkpoint in response to the persistence of DSBs in the nucleus. We also show that Vasa is a target of this meiotic checkpoint, and so may mediate the checkpoint-dependent translational regulation of Gurken.

Animals↗
PubMed1986

Sequence and expression of the Cc gene, a member of the dopa decarboxylase gene cluster of Drosophila: possible translational regulation.

A transcript has been localized proximal to the dopa decarboxylase (Ddc) gene within a cluster of genes involved in cuticle formation and catecholamine metabolism in Drosophila. This gene, which has been identified as I(2)37Cc, maps 2.0kb from the 5' end of the Ddc gene and is transcribed in the same direction as Ddc. We describe a new deficiency which in conjunction with previous deficiencies localizes the I(2)37Cb and I(2)37Cc loci to the cytogenetic interval 5' to Ddc. We present the sequence of the Cc gene and corresponding cDNA. The Cc message contains several open reading frames 5' to the large open reading frame responsible for the lethal complementation group, suggesting that expression of Cc function may be regulated translationally. The Cc transcript is expressed in early embryos, late embryos, late third instar larvae and adults. We discuss the implications of these findings with respect to the gene organization in the region.

Animals↗
PubMedDate not supplied

Translational regulation of the N-methyl-D-aspartate receptor subunit NR1.

Formation of functional N-methyl-D-aspartate (NMDA) receptor channels requires the essential NMDA receptor subunit NR1 and one or more of the modulatory subunits NR2A-D and in some cases an additional subunit NR3A or NR3B. Recent studies indicate that NR1 expression is regulated at translation under both physiological and pathological conditions. The rat pheochromocytoma cell line (PC12) has been used as a model system for NR1 gene expression studies. Characterization of the posttranscriptional regulatory mechanisms suggested the posttranslational degradation and translational regulation of NR1 protein in PC12 cells. In addition a recent study on the translational regulation of NR1 mRNA in intact brain identified two translationally distinct pools of NR1 mRNA. In this review we summarize the evidence for translational regulation of NR1 expression in PC12 cells and the brain.

Animals↗
PubMed1996

Expression of a translationally regulated, dominant-negative CCAAT/enhancer-binding protein beta isoform and up-regulation of the eukaryotic translation initiation factor 2alpha are correlated with neoplastic transformation of mammary epithelial cells.

A translationally regulated, dominant-negative isoform of CCAAT/enhancer-binding protein beta is expressed in transplantable and primary mouse mammary tumors of different etiologies but is not expressed in preneoplastic mammary hyperplasias or in primary prostate, lung, lens, ovary or lymphoid tumors. The eukaryotic initiation factor 2alpha protein is also expressed at significantly higher levels (69.8 +/- 7.2%) in these mammary tumors compared with normal and hyperplastic tissues. Thus, misregulation of eukaryotic initiation factor 2alpha may promote the expression of a dominant-negative CCAAT/enhancer-binding protein beta isoform, which may inhibit terminal differentiation and facilitate uncontrolled proliferation of mammary epithelial cells.

Animals↗
PubMed2005

Mechanisms of translational regulation in Drosophila.

Translational regulation plays an essential role in many phases of the Drosophila life cycle. During embryogenesis, specification of the developing body pattern requires co-ordination of the translation of oskar, gurken and nanos mRNAs with their subcellular localization. In addition, dosage compensation is controlled by Sex-lethal-mediated translational regulation while dFMR1 (the Drosophila homologue of the fragile X mental retardation protein) controls translation of various mRNAs which function in the nervous system. Here we describe some of the mechanisms that are utilized to regulate these various processes. Our review highlights the complexity that can be involved with multiple factors employing different mechanisms to control the translation of a single mRNA.

Animals↗