SEARCH · PubMed Health

Results for “Translational repression”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 649 records · Page 36Linked to original sources

PubMed2005

A comprehensive survey of the Plasmodium life cycle by genomic, transcriptomic, and proteomic analyses.

Plasmodium berghei and Plasmodium chabaudi are widely used model malaria species. Comparison of their genomes, integrated with proteomic and microarray data, with the genomes of Plasmodium falciparum and Plasmodium yoelii revealed a conserved core of 4500 Plasmodium genes in the central regions of the 14 chromosomes and highlighted genes evolving rapidly because of stage-specific selective pressures. Four strategies for gene expression are apparent during the parasites' life cycle: (i) housekeeping; (ii) host-related; (iii) strategy-specific related to invasion, asexual replication, and sexual development; and (iv) stage-specific. We observed posttranscriptional gene silencing through translational repression of messenger RNA during sexual development, and a 47-base 3' untranslated region motif is implicated in this process.

3' Untranslated Regions↗

PubMed2006

Characterization of the piRNA complex from rat testes.

Small noncoding RNAs regulate processes essential for cell growth and development, including mRNA degradation, translational repression, and transcriptional gene silencing (TGS). During a search for candidate mammalian factors for TGS, we purified a complex that contains small RNAs and Riwi, the rat homolog to human Piwi. The RNAs, frequently 29 to 30 nucleotides in length, are called Piwi-interacting RNAs (piRNAs), 94% of which map to 100 defined (< or = 101 kb) genomic regions. Within these regions, the piRNAs generally distribute across only one genomic strand or distribute on two strands but in a divergent, nonoverlapping manner. Preparations of piRNA complex (piRC) contain rRecQ1, which is homologous to qde-3 from Neurospora, a gene implicated in silencing pathways. Piwi has been genetically linked to TGS in flies, and slicer activity cofractionates with the purified complex. These results are consistent with a gene-silencing role for piRC in mammals.

Adenosine Triphosphatases↗

PubMed2006

Structure of dual function iron regulatory protein 1 complexed with ferritin IRE-RNA.

Iron regulatory protein 1 (IRP1) binds iron-responsive elements (IREs) in messenger RNAs (mRNAs), to repress translation or degradation, or binds an iron-sulfur cluster, to become a cytosolic aconitase enzyme. The 2.8 angstrom resolution crystal structure of the IRP1:ferritin H IRE complex shows an open protein conformation compared with that of cytosolic aconitase. The extended, L-shaped IRP1 molecule embraces the IRE stem-loop through interactions at two sites separated by approximately 30 angstroms, each involving about a dozen protein:RNA bonds. Extensive conformational changes related to binding the IRE or an iron-sulfur cluster explain the alternate functions of IRP1 as an mRNA regulator or enzyme.

Apoferritins↗

PubMed1996

Amino acid substitutions in membrane-spanning domains of Hol1, a member of the major facilitator superfamily of transporters, confer nonselective cation uptake in Saccharomyces cerevisiae.

Selection for the ability of Saccharomyces cerevisiae cells to take up histidinol, the biosynthetic precursor to histidine, results in dominant mutations at HOL1. The DNA sequence of HOL1 was determined, and it predicts a 65-kDa protein related to the major facilitator family (drug resistance subfamily) of putative transport proteins. Two classes of mutations were obtained: (i) those that altered the coding region of HOL1, conferring the ability to take up histidinol; and (ii) cis-acting mutations (selected in a mutant HOL1-1 background) that increased expression of the Hol1 protein. The ability to transport histidinol and other cations was conferred by single amino acid substitutions at any of three sites located within putative membrane-spanning domains of the transporter. These mutations resulted in the conversion of a small hydrophobic amino acid codon to a phenylalanine codon. Selection for spontaneous mutations that increase histidinol uptake by such HOL1 mutants resulted in mutations that abolish the putative start codon of a six-codon open reading frame located approximately 171 nucleotides downstream of the transcription initiation site and 213 nucleotides upstream of the coding region of HOL1. This single small upstream open reading frame (uORF) confers translational repression upon HOL1; genetic disruption of the putative start codon of the uORF results in a 5- to 10-fold increase in steady-state amounts of Hol1 protein without significantly affecting the level of HOL1 mRNA expression.

Alleles↗

PubMed2002

Evolution of bacteriophage in continuous culture: a model system to test antiviral gene therapies for the emergence of phage escape mutants.

The emergence of viral escape mutants is usually a highly undesirable phenomenon. This phenomenon is frequently observed in antiviral drug applications for the treatment of viral infections and can undermine long-term therapeutic success. Here, we propose a strategy for evaluating a given antiviral approach in terms of its potential to provoke the appearance of resistant virus mutants. By use of Q beta RNA phage as a model system, the effect of an antiviral gene therapy, i.e., a virus-specific repressor protein expressed by a recombinant Escherichia coli host, was studied over the course of more than 100 generations. In 13 experiments carried out in parallel, 12 phage populations became resistant and 1 became extinct. Sequence analysis revealed that only two distinct phage mutants emerged in the 12 surviving phage populations. For both escape mutants, sequence variations located in the repressor binding site of the viral genomic RNA, which decrease affinity for the repressor protein, conferred resistance to translational repression. The results clearly suggest the feasibility of the proposed strategy for the evaluation of antiviral approaches in terms of their potential to allow resistant mutants to appear. In addition, the strategy proved to be a valuable tool for observing virus-specific molecular targets under the impact of antiviral drugs.

Allolevivirus↗

PubMed1996

Two distinct regions in the 3' untranslated region of tumor necrosis factor alpha mRNA form complexes with macrophage proteins.

The production of tumor necrosis factor alpha (TNF-alpha), a key proinflammatory cytokine essential for the function of the immune system, is regulated at both the transcriptional and posttranscriptional levels. In this report, we focus on the interaction of TNF-alpha mRNA with macrophage proteins, likely mediators of its post-transcriptional control. Mapping of murine TNF-alpha mRNA by using a combination of RNase protection and RNA gel shift assays revealed that two distinct sites within the 3' untranslated region (3'-UTR) engage in the formation of four major RNA-protein complexes, while no protein binding to the 5'-UTR or coding sequences was detected. The protein-binding site of three RNA-protein complexes, A, B, and C, is positioned between bases 1291 and 1320 inside the AU-rich sequence, a region previously shown to be crucial for both translational repression and lipopolysaccharide inducibility of TNF-alpha. An additional protein complex (complex D) whose binding to the TNF-alpha 3'-UTR was independent of the presence of AU-rich sequences was identified. At least six protein species with apparent molecular masses of 48, 52, 54, 81, 101, and 150 kDa are in direct contact with TNF-alpha mRNA. The RNA-binding proteins are differentially distributed in the cell: complexes A and D are present predominantly in the cytosol, while complexes B and C are found in the nucleus and associated with particulate cytoplasmic fractions. Cytosolic complex A displays comparatively high specificity for TNF-alpha mRNA, while the binding of complexes B and C to TNF-alpha mRNA is readily competed for by other AU-rich sequence-containing RNAs. In summary, these findings demonstrate that two regions of the TNF-alpha mRNA molecule interact with macrophage RNA-binding protein complexes that differ in their core protein composition, cellular distribution, and affinity to TNF-alpha mRNA.

Animals↗

PubMed2001

MSY2 and MSY4 bind a conserved sequence in the 3' untranslated region of protamine 1 mRNA in vitro and in vivo.

Y-box proteins are major constituents of ribonucleoprotein particles (RNPs) which contain translationally silent mRNAs in gametic cells. We have recently shown that a sequence-specific RNA binding activity present in spermatogenic cells contains the two Y-box proteins MSY2 and MSY4. We show here that MSY2 and MSY4 bind a sequence, 5'-UCCAUCA-3', present in the 3' untranslated region of the translationally repressed protamine 1 (Prm1) mRNA. Using pre- and post-RNase T1-digested substrate RNAs, it was determined that MSY2 and MSY4 can bind an RNA of eight nucleotides containing the MSY2 and MSY4 binding site. Single nucleotide mutations in the sequence eliminated the binding of MSY2 and MSY4 in an electrophoretic mobility shift assay, and the resulting mutants failed to compete for binding in a competition assay. A consensus site of U(AC)C(A)CAU(C)CA(CU) (subscripts indicate nucleotides which do not disrupt YRS binding by MSY2 and MSY4), denoted the Y-box recognition site (YRS), was defined from this mutational analysis. These mutations in the YRS were further characterized in vivo using a novel application of the yeast three-hybrid system. Experiments with transgenic mice show that disruption of the YRS in vivo relieves Prm1-like repression of a reporter gene. The conservation of the RNA binding motifs among Y-box protein family members raises the possibility that other Y-box proteins may have previously unrecognized sequence-specific RNA binding activities.

3' Untranslated Regions↗

PubMed2006

Akt-mediated YB-1 phosphorylation activates translation of silent mRNA species.

YB-1 is a broad-specificity RNA-binding protein that is involved in regulation of mRNA transcription, splicing, translation, and stability. In both germinal and somatic cells, YB-1 and related proteins are major components of translationally inactive messenger ribonucleoprotein particles (mRNPs) and are mainly responsible for storage of mRNAs in a silent state. However, mechanisms regulating the repressor activity of YB-1 are not well understood. Here we demonstrate that association of YB-1 with the capped 5' terminus of the mRNA is regulated via phosphorylation by the serine/threonine protein kinase Akt. In contrast to its nonphosphorylated form, phosphorylated YB-1 fails to inhibit cap-dependent but not internal ribosome entry site-dependent translation of a reporter mRNA in vitro. We also show that similar to YB-1, Akt is associated with inactive mRNPs and that activated Akt may relieve translational repression of the YB-1-bound mRNAs. Using Affymetrix microarrays, we found that many of the YB-1-associated messages encode stress- and growth-related proteins, raising the intriguing possibility that Akt-mediated YB-1 phosphorylation could, in part, increase production of proteins regulating cell proliferation, oncogenic transformation, and stress response.

Animals↗

PubMed2006

Genome-wide analysis of mRNAs regulated by Drosha and Argonaute proteins in Drosophila melanogaster.

RNA silencing pathways are conserved gene regulation mechanisms that elicit decay and/or translational repression of mRNAs complementary to short interfering RNAs and microRNAs (miRNAs). The fraction of the transcriptome regulated by these pathways is not known, but it is thought that each miRNA may have hundreds of targets. To identify transcripts regulated by silencing pathways at the genomic level, we examined mRNA expression profiles in Drosophila melanogaster cells depleted of four Argonaute paralogs (i.e., AGO1, AGO2, PIWI, or Aubergine) that play essential roles in RNA silencing. We also profiled cells depleted of the miRNA-processing enzyme Drosha. The results reveal that transcripts differentially expressed in Drosha-depleted cells have highly correlated expression in the AGO1 knockdown and are significantly enriched in predicted and validated miRNA targets. The levels of a subset of miRNA targets are also regulated by AGO2. Moreover, AGO1 and AGO2 silence the expression of a common set of mobile genetic elements. Together, these results indicate that the functional overlap between AGO1 and AGO2 in Drosophila is more important than previously thought.

Animals↗

PubMed1983

Regulation of mRNA utilization in mouse erythroleukemia cells induced to differentiate by exposure to dimethyl sulfoxide.

Mouse erythroleukemia cells contain several abundant mRNA species that occur to a considerable extent as untranslated molecules. For two of these species, which code for polypeptides P40 and P21, the proportion of molecules engaged in translation decreases rapidly after exposure of the cells to dimethyl sulfoxide. The extent of utilization of a third species, the P36 mRNA, is not altered. The rate of production of the P40 mRNA does not appear to be affected in the dimethyl sulfoxide-treated cells. The P21 mRNA appears to be produced in increasing amounts, leading to a large accumulation of untranslated molecules in the cytoplasm. The mRNA for actin remains nearly fully utilized during this process, but its intracellular concentration decreases, thus resulting in a reduction in the amounts present in polysomes. The results indicate that some mRNA species in mouse tumor cells are subject to a translational repression process that can serve to regulate selectively the extent of expression of the corresponding genes.

Animals↗

PubMed2003

RNA binding protein sex-lethal (Sxl) and control of Drosophila sex determination and dosage compensation.

In the past two decades, scientists have elucidated the molecular mechanisms behind Drosophila sex determination and dosage compensation. These two processes are controlled essentially by two different sets of genes, which have in common a master regulatory gene, Sex-lethal (Sxl). Sxl encodes one of the best-characterized members of the family of RNA binding proteins. The analysis of different mechanisms involved in the regulation of the three identified Sxl target genes (Sex-lethal itself, transformer, and male specific lethal-2) has contributed to a better understanding of translation repression, as well as constitutive and alternative splicing. Studies using the Drosophila system have identified the features of the protein that contribute to its target specificity and regulatory functions. In this article, we review the existing data concerning Sxl protein, its biological functions, and the regulation of its target genes.

Amino Acid Sequence↗

PubMed1990

The effect of inhibitors of DNA synthesis on 40-kilodalton polypeptide translation in rat L6 myoblasts.

Messenger RNA coding for a polypeptide of 40 kilodaltons (P40) was translated in proliferating rat L6 myoblasts but not in the terminally differentiated myotubes. The relationship between DNA synthesis, differentiation, and P40 mRNA translation was studied. Aphidicolin, a reversible inhibitor of DNA synthesis, was shown to block DNA synthesis in proliferating myoblasts without allowing these cells to differentiate. A second inhibitor, cytosine arabinoside, when added to dividing myoblasts also prevented differentiation. In the absence of biochemical differentiation P40 mRNA remained in the translated state. Translational repression of this mRNA was, therefore, linked to the biochemical differentiation of rat L6 myoblasts.

Animals↗

PubMed1996

Rat intestinal and hepatic ferritin subunit expression during development and after dietary iron feeding.

Ferritin consists of 24 heavy (H) and light (L) subunits in varying proportions in different tissues and plays a significant role in iron metabolism. We studied rat ferritin subunit expression in the duodenum and liver during early life, when a cycle of iron depletion and repletion occurs. In both tissues, ferritin contents decreased to low levels from day 3 to day 12. The ferritin on day 3 had an H/L mRNA ration of 0.9 and an H/L subunit ratio of 0.6. The decrease of tissue ferritin levels, but not mRNA, on day 12 suggests translational repression consistent with iron depletion. In the duodenum, a twofold increase in both H and mRNA and subunit protein occurred on day 18. The subsequent increase of H mRNA was accompanied by a 50% decrease in L mRNA, resulting in the increase of H/L mRNA and subunit ratios to 7.9 and 9, respectively, by day 32. In contrast, liver H/L mRNA and subunit ratios were similar throughout development. The possibility that dietary iron regulates duodenal ferritin subunit expression was investigated. When day 12 rats were fed 6 ml of a milk formula containing 56 microgram/ml iron for 18 h, dietary iron increased the duodenal levels of L mRNA but not H mRNA. In contrast, hepatic H and L mRNA levels did not change. Dietary iron promoted greater increases in ferritin protein than mRNA in both tissues. Thus a shift from L-rich to H-rich ferritin isoforms occurs in the duodenum but not in the liver during neonatal development. This change is regulated at the pretranslational level and is independent of dietary iron.

Aging↗

PubMed2005

MicroRNA gene expression deregulation in human breast cancer.

MicroRNAs (miRNAs) are a class of small noncoding RNAs that control gene expression by targeting mRNAs and triggering either translation repression or RNA degradation. Their aberrant expression may be involved in human diseases, including cancer. Indeed, miRNA aberrant expression has been previously found in human chronic lymphocytic leukemias, where miRNA signatures were associated with specific clinicobiological features. Here, we show that, compared with normal breast tissue, miRNAs are also aberrantly expressed in human breast cancer. The overall miRNA expression could clearly separate normal versus cancer tissues, with the most significantly deregulated miRNAs being mir-125b, mir-145, mir-21, and mir-155. Results were confirmed by microarray and Northern blot analyses. We could identify miRNAs whose expression was correlated with specific breast cancer biopathologic features, such as estrogen and progesterone receptor expression, tumor stage, vascular invasion, or proliferation index.

Blotting, Northern↗

PubMed2006

MicroRNA regulates the expression of human cytochrome P450 1B1.

MicroRNAs (miRNA) are small noncoding RNAs that regulate gene expression through translational repression or mRNA cleavage. Here, we found that cytochrome P450 (CYP), a superfamily of drug-metabolizing enzymes, is a target of miRNA. Human CYP1B1, which is highly expressed in estrogen target tissues, catalyzes the metabolic activation of various procarcinogens and the 4-hydroxylation of 17beta-estradiol. CYP1B1 protein is abundant in cancerous tissues. We identified a near-perfect matching sequence with miR-27b in the 3'-untranslated region of human CYP1B1. Luciferase assays revealed that the reporter activity of the plasmid containing the miR-27b recognition element was decreased in MCF-7 cells (miR-27 positive) but not in Jurkat cells (miR-27b negative). Exogenously expressed miR-27b could decrease the luciferase activity in Jurkat cells. In MCF-7 cells, the antisense oligoribonucleotide for miR-27b restored the luciferase activity and increased the protein level and enzymatic activity of endogenous CYP1B1. These results suggested that human CYP1B1 is post-transcriptionally regulated by miR-27b. The expression levels of miR-27b and CYP1B1 protein in breast cancerous and adjacent noncancerous tissues from 24 patients were evaluated. In most patients, the expression level of miR-27b was decreased in cancerous tissues, accompanied by a high level of CYP1B1 protein. A significant inverse association was observed between the expression levels of miR-27b and CYP1B1 protein. Thus, the decreased expression of miR-27b would be one of causes of the high expression of CYP1B1 protein in cancerous tissues. This is the first study to show that miRNAs regulate not only essential genes for physiologic events but also drug-metabolizing enzymes.

3' Untranslated Regions↗

PubMed2005

Microcytic anemia, erythropoietic protoporphyria, and neurodegeneration in mice with targeted deletion of iron-regulatory protein 2.

Iron-regulatory proteins (IRPs) 1 and 2 posttranscriptionally regulate expression of transferrin receptor (TfR), ferritin, and other iron metabolism proteins. Mice with targeted deletion of IRP2 overexpress ferritin and express abnormally low TfR levels in multiple tissues. Despite this misregulation, there are no apparent pathologic consequences in tissues such as the liver and kidney. However, in the central nervous system, evidence of abnormal iron metabolism in IRP2-/- mice precedes the development of adult-onset progressive neurodegeneration, characterized by widespread axonal degeneration and neuronal loss. Here, we report that ablation of IRP2 results in iron-limited erythropoiesis. TfR expression in erythroid precursors of IRP2-/- mice is reduced, and bone marrow iron stores are absent, even though transferrin saturation levels are normal. Marked overexpression of 5-aminolevulinic acid synthase 2 (Alas2) results from loss of IRP-dependent translational repression, and markedly increased levels of free protoporphyrin IX and zinc protoporphyrin are generated in IRP2-/- erythroid cells. IRP2-/- mice represent a new paradigm of genetic microcytic anemia. We postulate that IRP2 mutations or deletions may be a cause of refractory microcytic anemia and bone marrow iron depletion in patients with normal transferrin saturations, elevated serum ferritins, elevated red cell protoporphyrin IX levels, and adult-onset neurodegeneration.

Anemia↗

PubMed2006

Identification by Real-time PCR of 13 mature microRNAs differentially expressed in colorectal cancer and non-tumoral tissues.

MicroRNAs (miRNAs) are short non-coding RNA molecules playing regulatory roles by repressing translation or cleaving RNA transcripts. Although the number of verified human miRNA is still expanding, only few have been functionally described. However, emerging evidences suggest the potential involvement of altered regulation of miRNA in pathogenesis of cancers and these genes are thought to function as both tumours suppressor and oncogenes. In our study, we examined by Real-Time PCR the expression of 156 mature miRNA in colorectal cancer. The analysis by several bioinformatics algorithms of colorectal tumours and adjacent non-neoplastic tissues from patients and colorectal cancer cell lines allowed identifying a group of 13 miRNA whose expression is significantly altered in this tumor. The most significantly deregulated miRNA being miR-31, miR-96, miR-133b, miR-135b, miR-145, and miR-183. In addition, the expression level of miR-31 was correlated with the stage of CRC tumor. Our results suggest that miRNA expression profile could have relevance to the biological and clinical behavior of colorectal neoplasia.

Cluster Analysis↗

PubMed2004

HIV-1 nef suppression by virally encoded microRNA.

BACKGROUND: MicroRNAs (miRNAs) are 21 to approximately 25-nucleotides (nt) long and interact with mRNAs to trigger either translational repression or RNA cleavage through RNA interference (RNAi), depending on the degree of complementarity with the target mRNAs. Our recent study has shown that HIV-1 nef dsRNA from AIDS patients who are long-term non-progressors (LTNPs) inhibited the transcription of HIV-1. RESULTS: Here, we show the possibility that nef-derived miRNAs are produced in HIV-1 persistently infected cells. Furthermore, nef short hairpin RNA (shRNA) that corresponded to a predicted nef miRNA (approximately 25 nt, miR-N367) can block HIV-1 Nef expression in vitro and the suppression by shRNA/miR-N367 would be related with low viremia in an LTNP (15-2-2). In the 15-2-2 model mice, the weight loss, which may be rendered by nef was also inhibited by shRNA/miR-N367 corresponding to suppression of nef expression in vivo. CONCLUSIONS: These data suggest that nef/U3 miRNAs produced in HIV-1-infected cells may suppress both Nef function and HIV-1 virulence through the RNAi pathway.

Acquired Immunodeficiency Syndrome↗