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Results for “Translational repression”

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PubMed2007

Repression of protein synthesis by miRNAs: how many mechanisms?

MicroRNAs are approximately 21-nucleotide-long regulators of gene expression that gain access to their target mRNAs by complementary base pairing. Recent studies have revealed that animal microRNAs might take diverse routes to repress gene expression, affecting both target mRNA levels and translation. Mechanistic details of microRNA-mediated repression are starting to emerge but a comprehensive picture of the inhibition, and particularly the effects on mRNA translation, is still lacking. Recent data support different microRNA mechanisms and a role for cytoplasmic processing bodies in the degradation and storage of mRNAs targeted by microRNA regulators.

Animals↗

PubMed2005

Posttranscriptional repression of GacS/GacA-controlled genes by the RNA-binding protein RsmE acting together with RsmA in the biocontrol strain Pseudomonas fluorescens CHA0.

In the plant-beneficial soil bacterium Pseudomonas fluorescens CHA0, the production of biocontrol factors (antifungal secondary metabolites and exoenzymes) is controlled at a posttranscriptional level by the GacS/GacA signal transduction pathway involving RNA-binding protein RsmA as a key regulatory element. This protein is assumed to bind to the ribosome-binding site of target mRNAs and to block their translation. RsmA-mediated repression is relieved at the end of exponential growth by two GacS/GacA-controlled regulatory RNAs RsmY and RsmZ, which bind and sequester the RsmA protein. A gene (rsmE) encoding a 64-amino-acid RsmA homolog was identified and characterized in strain CHA0. Overexpression of rsmE strongly reduced the expression of target genes (hcnA, for a hydrogen cyanide synthase subunit; aprA, for the main exoprotease; and phlA, for a component of 2,4-diacetylphloroglucinol biosynthesis). Single null mutations in either rsmA or rsmE resulted in a slight increase in the expression of hcnA, aprA, and phlA. By contrast, an rsmA rsmE double mutation led to strongly increased and advanced expression of these target genes and completely suppressed a gacS mutation. Both the RsmE and RsmA levels increased with increasing cell population densities in strain CHA0; however, the amount of RsmA showed less variability during growth. Expression of rsmE was controlled positively by GacA and negatively by RsmA and RsmE. Mobility shift assays demonstrated specific binding of RsmE to RsmY and RsmZ RNAs. The transcription and stability of both regulatory RNAs were strongly reduced in the rsmA rsmE double mutant. In conclusion, RsmA and RsmE together account for maximal repression in the GacS/GacA cascade of strain CHA0.

Amino Acid Sequence↗

PubMed1985

The preferential translation of Drosophila hsp70 mRNA requires sequences in the untranslated leader.

When Drosophila cells are heat shocked, the translation of normal cellular mRNAs is repressed, while mRNAs encoding the heat-shock proteins are translated at high rates. We have found that the hsp70 message is not translated at high temperatures when its leader sequence is deleted. This message is translated when the cells are allowed to recover at 25 degrees C, but the translation ceases when the cells are given a second heat shock. A message with an extra 39 bases added onto the 5' end of the leader behaves in the same way. However, if either of two conserved sequence elements in the leader is deleted, the message is still translated during heat shock. Although the specific feature responsible for the preferential translation of heat-shock messages is not yet identified, we conclude that it must reside in the 5' untranslated leader.

Amino Acid Sequence↗

PubMed2005

A minicircuitry comprised of microRNA-223 and transcription factors NFI-A and C/EBPalpha regulates human granulopoiesis.

MicroRNAs play important roles in cell differentiation by acting as translational inhibitors of specific target genes. Here we show that human granulocytic differentiation is controlled by a regulatory circuitry involving miR-223 and two transcriptional factors, NFI-A and C/EBPalpha. The two factors compete for binding to the miR-223 promoter: NFI-A maintains miR-223 at low levels, whereas its replacement by C/EBPalpha, following retinoic acid (RA)-induced differentiation, upregulates miR-223 expression. The competition by C/EBPalpha and the granulocytic differentiation are favored by a negative-feedback loop in which miR-223 represses NFI-A translation. In line with this, both RNAi against NFI-A and ectopic expression of miR-223 in acute promyelocytic leukemia (APL) cells enhance differentiation, whereas miR-223 knockdown inhibits the differentiation response to RA. Altogether, our data indicate that miR-223 plays a crucial role during granulopoiesis and point to the NFI-A repression as an important molecular pathway mediating gene reprogramming in this cell lineage.

Binding Sites↗

PubMed1996

Translation of a testis-specific Cu/Zn superoxide dismutase (SOD-1) mRNA is regulated by a 65-kilodalton protein which binds to its 5' untranslated region.

Mouse testes contain two distinct superoxide dismutase (SOD-1) transcripts which differ by 114 nucleotides in their 5' untranslated regions (UTRs) (W. Gu, C. Morales, and N. B. Hecht, J. Biol. Chem. 270:236-243, 1995). The shorter SOD-1 mRNA, a somatic type SOD-I mRNA (SSOD-1), is ubiquitously expressed in all somatic tissues as well as in testes. The larger SOD-1 mRNA, a testis-specific SOD-1 mRNA (TSOD-1), derived from an alternative upstream start site, is transcribed solely in postmeiotic germ cells and is translationally regulated during spermiogenesis. Since the two mRNAs have identical nucleotides except that TSOD-1 has an additional sequence at its 5' terminus, we have proposed that the extra 5' UTR sequence may be involved in the translational control of the TSOD-1 mRNA during spermiogenesis. Here we show that, when assayed in a cell-free system, TSOD-1 is translated only slightly less efficiently than SSOD-1. RNA gel retardation and UV cross-linking assays reveal that a testicular cytoplasmic protein (Cu/Zn superoxide dismutase RNA-binding protein [SOD-RBP]) of about 65 kDa specifically binds to the extended 5' UTR of TSOD-1. After purification of SOD-RBP by RNA affinity chromatography, we demonstrate that SOD-RBP can repress the in vitro translation of TSOD-1 mRNA but not SSOD-1 mRNA or cotranslated luciferase mRNA. We conclude that SOD-RBP serves as a repressor in the translation of TSOD-1 mRNA during spermiogenesis and thereby fine-tunes the level of Cu/Zn superoxide dismutase produced in maturing germ cells.

Amino Acid Sequence↗

PubMed1984

DNA sequence of the carA gene and the control region of carAB: tandem promoters, respectively controlled by arginine and the pyrimidines, regulate the synthesis of carbamoyl-phosphate synthetase in Escherichia coli K-12.

The carAB operon of Escherichia coli K-12, which encodes the two subunits of carbamoyl-phosphate synthetase (glutamine hydrolyzing) [carbon-dioxide: L-glutamine amido-ligase (ADP-forming, carbamate-phosphorylating); EC 6.3.5.5], is cumulatively repressed by arginine and the pyrimidines. We describe the structure of the control region of carAB and the sequence of the carA gene. Nuclease S1 mapping experiments show that two adjacent tandem promoters within the carAB control region serve as initiation sites. The upstream promoter P1 is controlled by pyrimidines; the downstream promoter P2 is regulated by arginine. Attenuation control does not appear to be involved in the expression of carAB. A possible mechanism by which control at these promoters concurs to produce a cumulative pattern of repression is discussed. The translational start of carA is atypical; it consists of a UUG or AUU codon.

Amino Acid Sequence↗

PubMed1997

Dual regulation of Escherichia coli secA translation by distinct upstream elements.

The regulation of the Escherichia coli secA gene, whose translation is auto-repressed except when protein secretion becomes limiting, was investigated using a combination of genetic and biochemical approaches. Oligonucleotide-directed deletion and point mutagenesis was used to show that only the last quarter of the upstream gene, geneX, and the geneX-secA intergenic are essential for proper regulation. This region previously shown to contain a secretion-responsive element contains two predicted helices, helix I and II, the latter of which would occlude the secA Shine-Dalgarno sequence. Mutations that destabilized the lower portion of helix II increased secA basal expression, reduced auto-repression by SecA protein, but retained a normal pattern of derepression of secA expression during a protein export block. The introduction of compensatory mutations into helix II that were predicted to restore base-pairing restored secA regulation to wild-type levels or nearly so, suggesting that this helix does play a role in secA auto-regulation in vivo. In contrast, mutations in the lower portion of helix I decreased secA basal expression, reduced auto-repression by SecA protein, and abolished the responsiveness of secA expression to a protein export block. In this latter case introduction of compensatory mutations into helix I that were predicted to restore base-pairing did not restore proper secA regulation, indicating that specific nucleotides in this region are required for normal secA regulation. Primer-extension inhibition (toeprint) analysis with 30 S ribosoma subunits, tRNAMet, and a model segment of geneX-secA RNA carrying the relevant mutations was used to show that mutations that destabilized helix II increased ribosome binding at the secA translation initiation site, while mutations that perturbed helix I decreased ribosome binding at this site. Our results suggest strongly that there is a system of dual regulation of secA translation, whereby helix I serves as an activator element while helix II serves as a repressor element.

Adenosine Triphosphatases↗

PubMed2002

A cancer gene therapy approach through translational control of a suicide gene.

The translation initiation factor eIF4E is elevated in most solid tumors resulting in translation of mRNAs that are normally repressed by their structured 5' untranslated region. We have introduced a translational repressor element in a vector (BK-UTK) designed to express herpes thymidine kinase (HTK). This and a control vector (BK-TK) were used to treat experimental tumors of a murine breast cancer line. Both vectors were equally effective in reducing subcutaneous tumors and lung metastases following ganciclovir administration. However, the BK-TK vector was found to be highly toxic, resulting in severe weight loss, degeneration of various organs, and early death of mice following systemic vector delivery, whereas the BK-UTK increased mean survival without toxicity.

5' Untranslated Regions↗

PubMed1994

Poly(A) binds to initiation factors and increases cap-dependent translation in vitro.

Both the 5' cap (m7GpppN) and the 3' poly(A) tail of eukaryotic mRNAs are important regulators of translation efficiency in vivo. Their function, however, is markedly reduced in in vitro translation systems derived from either rabbit reticulocytes or wheat germ. The impact of exogenous poly(A) on cap-dependent translation was examined in vitro. The translation of uncapped mRNA was preferentially repressed in the presence of exogenous poly(A). As a result, translation became increasingly cap-dependent with the increase in exogenous poly(A). The translation in wheat germ lysate was stimulated by the addition of purified eukaryotic initiation factor (eIF)-4B or eIF-4F; however, addition of poly(A) prevented this eIF-4B- or eIF-4F-mediated stimulation. Addition of eIF-4F or eIF-4B, alone, was not sufficient to restore translation in lysate to which poly(A) had been added. Restoration, however, was observed when eIF-4F, eIF-4B, and eIF-4A were added in combination. These data suggest that 1) exogenous poly(A) may bind to and sequester factors required for translation and 2) that capped messages compete with poly(A) more efficiently for these factors than do uncapped mRNAs. Gel shift analysis of purified initiation factors isolated from wheat germ confirmed that eIF-4B and eIF-4F do in fact form complexes with poly(A) in vitro.

Animals↗

PubMed1979

Transcription and translation in a pleiotropic streptomycin-resistant mutant of Escherichia coli.

The role of the ribosomal protein S12 (streptomycin protein) in ribosome function and in other metabolic processes in the cell has been investigated. A spontaneous streptomycin-resistant strain of Escherichia coli (SM3) carrying a mutation in the rpsL gene is deficient in its ability to induce the synthesis of the enzyme bets-galactosidase. It was demonstrated that the reduced rate of enzyme synthesis results from deficiencies in both the transcription of the lactose operon and translation of the lactose operon mRNA. The transcription deficiency was in part due to increased catabolite repression and could therefore be partially suppressed by the addition of cyclic AMP. Streptomycin also appeared to partially suppress catabolite repression. In the SM3 mutant strain, the translation of the lactose operon mRNA was only about 60% as efficient as in the parental control, and addition of streptomycin did not alter the translation efficiency. In contrast, both transcription and translation of ribosomal protein mRNA were equally efficient in the two strains. These observations imply that mutational alterations in the ribosomal protein S12 either directly or indirectly alter (i) the extent of catabolite repression, (ii) the efficiency of transcription of the lactose operon even in the absence of catabolite repression, and (iii) the efficiency of translation of some but not all mRNA species in the cell.

Bacterial Proteins↗

PubMed1998

Regulation of gene expression at the beginning of mammalian development and the TEAD family of transcription factors.

In mouse development, transcription is first detected in late 1-cell embryos, but translation of newly synthesized transcripts does not begin until the 2-cell stage. Thus, the onset of zygotic gene expression (ZGE) is regulated at the level of both transcription and translation. Chromatin-mediated repression is established after formation of a 2-cell embryo, concurrent with the developmental acquisition of enhancer function. The most effective enhancer in cleavage stage mouse embryos depends on DNA binding sites for TEF-1, the prototype for a family of transcription factors that share the same TEA DNA binding domain. Mice contain at least four, and perhaps five, genes with the same TEA DNA binding domain (mTEAD genes). Since mTEAD-2 is the only one expressed during the first 7 days of mouse development, it is most likely responsible for the TEAD transcription factor activity that first appears at the beginning of ZGE. All four mTEAD genes are expressed at later embryonic stages and in adult tissues; virtually every tissue expresses at least one family member, consistent with a critical role for TEAD proteins in either cell proliferation or differentiation. The 72-amino acid TEA DNA binding domains in mTEAD-2, 3, and 4 are approximately 99% homologous to the same domain in mTEAD-1, and all four proteins bind specifically to the same DNA sequences in vitro with a Kd value of 16-38 nM DNA. Since TEAD proteins appear to be involved in both activation and repression of different genes and do not appear to be functionally redundant, differential activity of TEAD proteins must result either from association with other proteins or from differential sensitivity to chromatin-packaged DNA binding sites.

Amino Acid Sequence↗

PubMed1991

Identification of a novel iron-responsive element in murine and human erythroid delta-aminolevulinic acid synthase mRNA.

Iron-responsive elements (IREs) are regulatory RNA elements which are characterized by a phylogenetically defined sequence-structure motif. Their biological function is to provide a specific binding site for the IRE-binding protein (IRE-BP). Iron starvation of cells induces high affinity binding of the cytoplasmic IRE-BP to an IRE which has at least two different known biological consequences, repression of ferritin mRNA translation and stabilization of the transferrin receptor transcript. We report the identification of a novel, evolutionarily conserved IRE motif in the 5' UTR of murine and human erythroid-specific delta-aminolevulinic acid synthase (eALAS) mRNA which encodes the first, and possibly rate limiting, enzyme of the heme biosynthetic pathway. We demonstrate the function of the eALAS IRE as a specific binding site for the IRE-BP by gel retardation analyses and by in vitro translation experiments. In addition, we show that the 5' UTR of eALAS mRNA is sufficient to mediate iron-dependent translational regulation in vivo. These findings strongly suggest involvement of the IRE-IRE-BP system in the control of heme biosynthesis during erythroid differentiation.

5-Aminolevulinate Synthetase↗

PubMed2000

A non-transmembrane form of Jagged-1 regulates the formation of matrix-dependent chord-like structures.

Jagged-Notch interactions regulate a transmembrane ligand-receptor signaling pathway involved in the regulation of cell fate determination as well as myoblast and endothelial cell differentiation. To further examine the role of the transmembrane ligand, Jagged-1, in the regulation of cell differentiation, we stably transfected NIH 3T3 cells with a truncated form of Jagged(J)-1, which results in the secretion of a soluble(s) form of the protein. Comparison of gene expression by serial analysis demonstrated that among the 227 transcripts differentially regulated in the sJ-1 transfectants, the expression of the pro-alpha-2(I) collagen transcript and pro-alpha-1(I) collagen translation product was predominantly repressed in sJ-1 transfectants. When plated on extracellular matrices, sJ-1 transfectants formed prominent chord-like structures on type I collagen but not on fibrin, fibronectin, or vitronectin. While the sJ-1 transfectants exhibited growth kinetics similar to control cells and were unable to grow in soft agar, the cells were less sensitive to contact inhibition of growth in vitro and sJ-1 allografts formed tissue masses in nude mice after a prolonged latency period and exhibited an abundance of host-derived microvascular endothelial cells. These data suggest that J-1 may be able to modulate, in a matrix-dependent manner, the organization of cell to cell interactions including its ability to promote the development of chord-like structures.

3T3 Cells↗

PubMed2005

Transcriptional regulation of chondrocyte maturation: potential involvement of transcription factors in OA pathogenesis.

The principle function of articular cartilage is to provide a low friction load-bearing surface that facilitates free movement of joints. Maintenance of this surface depends on the maturational arrest of chondrocytes before terminal hypertrophic differentiation occurs [Exp. Cell Res. 216 (1995) 191; Osteoarthritis Cartilage 7 (1999) 389; J. Cell Biol. 139 (1997) 541; J. Cell Biol. 145 (1999) 783]. In contrast to endochondral ossification which involves a programmed process of chondrocyte maturation culminating in terminal hypertrophy and mineralization [Nat. Genet. 9 (1995) 15], articular chondrocytes (ACs) are constrained from completing the maturational program as evidenced by a lack of type X collagen (colX) and alkaline phosphatase expression [Arthritis Res. 3 (2001) 107; Biochem. J. 362 (2002) 473]. Also, ACs are not responsive to factors that impact the maturational process, including bone morphogenetic protein-2 (BMP-2), a potent stimulator of chondrocyte maturation [J. Orthop. Res. 14 (1996) 937]. Factors that constrain AC maturation are only relieved under unique circumstances such as in osteoarthritis (OA), where proliferation and an increase in the expression of hypertrophic hallmarks indicates that the cells have differentiated into a mature phenotype [Calcif. Tissue Int. 63 (2000) 230]. OA may thus involve the functional loss of mechanisms that arrest articular cartilage differentiation. Responsiveness to various growth or systemic factors translates into activation or repression of specific genes through transcriptional mediators. Understanding the downstream mechanisms involved in this process is of paramount importance. Thus, unraveling the molecular interplay between various factors that regulate chondrocyte maturation during OA occurrence and progression is the main focus of ongoing efforts.

Animals↗

PubMed2003

Light-regulated translation mediates gated induction of the Arabidopsis clock protein LHY.

The transcription factor LHY and the related protein CCA1 perform overlapping functions in a regulatory feedback loop that is closely associated with the circadian oscillator of Arabidopsis: Overexpression of LHY abolished function of the circadian clock in constant light, but rhythmic expression of several circadian clock-regulated transcripts was observed under light- dark cycles. These oscillations correlated with high amplitude changes in LHY protein levels, caused by light-induced translation of the LHY transcript. Increases in LHY protein levels were also observed in light-grown wild-type plants, when light signals coincided with the circadian-regulated peak of LHY transcription at dawn. Unexpectedly, translational induction coincided with acute downregulation of LHY transcript levels. We suggest that the simultaneous translational induction and transcriptional repression of LHY expression play a role to narrow the peak of LHY protein synthesis at dawn and increase the robustness and accuracy of circadian oscillations. Strong phase shifting responses to light signals were observed in plants lacking function of LHY, CCA1 or both, suggesting that light-regulated expression of these proteins does not mediate entrainment of the clock to light-dark cycles.

Arabidopsis↗

PubMed1998

Regulation of yeast glycogen metabolism and sporulation by Glc7p protein phosphatase.

Glc7p is an essential serine/threonine type 1 protein phosphatase (PP1) from the yeast Saccharomyces cerevisiae, which has a role in many processes including cell cycle progression, sporulation, glycogen accumulation, translation initiation, and glucose repression. Two hallmarks of PP1 enzymes are very high amino acid sequence conservation and association of the catalytic subunit with a variety of noncatalytic, regulatory subunits. We tested the hypothesis that PP1 sequence conservation was the result of each PP1 residue playing a role in multiple intermolecular interactions. Analysis of 24 glc7 mutants, isolated primarily by their glycogen accumulation traits, revealed that every mutated Glc7p residue altered many noncatalytic subunit affinities and conferred unselected sporulation traits to various degrees. Furthermore, quantitative analysis showed that Glc7p affinity for the glycogen-binding noncatalytic subunit Gac1p was not the only parameter that determines the glycogen accumulation by a glc7 mutant. Sds22p is one Glc7p noncatalytic subunit that is essential for mitotic growth. Surprisingly, several mutant Glc7p proteins had undetectable affinity for Sds22p, yet grew apparently normally. The characterization of glc7 diploid sporulation revealed that Glc7p has at least two meiotic roles. Premeiotic DNA synthesis was undetectable in glc7 mutants with the poorest sporulation. In the glc7 diploids examined, expression of the meiotic inducer IME1 was proportional to the glc7 diploid sporulation frequency. Moreover, IME1 hyperexpression could not suppress glc7 sporulation traits. The Glc7p/Gip1p holoenzyme may participate in completion of meiotic divisions or spore packaging because meiotic dyads predominate when some glc7 diploids sporulate.

Alleles↗

PubMed1998

DAZ (Deleted in AZoospermia) genes encode proteins located in human late spermatids and in sperm tails.

We analysed the location of proteins encoded by the DAZ (Deleted in AZoospermia) genes in human testis tissue and in mature spermatozoa. The DAZ genes are known to be expressed exclusively in the human male germ line, and are candidate genes for the expression of the azoospermia factor AZFc mapped recently to distal Yq11. They encode testis-specific RNA binding proteins, the function of which is not yet known. Immunostaining experiments with antibodies prepared for the specific peptide domain encoded by the DAZ2 transcript (formerly SPGY1) revealed the presence of DAZ proteins in the innermost layer of the male germ cell epithelium and in the tails of spermatozoa. This suggests a function for DAZ proteins in the RNA metabolism of late spermatids, presumably in the storage or transport of testis-specific mRNA, the translation of which is repressed until the formation of mature spermatozoa. Deletion of DAZ genes is supposed not to interfere with human sperm maturation but to result in a gradual reduction of mature spermatozoa.

Amino Acid Sequence↗

PubMed1991

Homology between IRE-BP, a regulatory RNA-binding protein, aconitase, and isopropylmalate isomerase.

Iron-responsive elements (IREs) are regulatory RNA elements which serve as specific binding sites for the IRE-binding protein (IRE-BP). Interaction between IREs and IRE-BP induces repression of ferritin mRNA translation and transferrin receptor mRNA stabilization. We describe the identification of extensive amino acid sequence homology between IRE-BP and two known isomerases, aconitase and isopropylmalate (IPM) isomerase. We discuss the implications of this observation with regard to structure/function relationships of IRE-BP. The structural conservation between a regulatory RNA-binding protein and two enzymes involved in intermediary metabolism provides a surprising example of the functional flexibility in biological structures.

Aconitate Hydratase↗