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Results for “Translational control”

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PubMed2001

A plant viral "reinitiation" factor interacts with the host translational machinery.

The cauliflower mosaic virus transactivator, TAV, controls translation reinitiation of major open reading frames on polycistronic RNA. We show here that TAV function depends on its association with polysomes and eukaryotic initiation factor eIF3 in vitro and in vivo. TAV physically interacts with eIF3 and the 60S ribosomal subunit. Two proteins mediating these interactions were identified: eIF3g and 60S ribosomal protein L24. Transient expression of eIF3g and L24 in plant protoplasts strongly affects TAV-mediated reinitiation activity. We demonstrate that TAV/eIF3/40S and eIF3/TAV/60S ternary complexes form in vitro, and propose that TAV mediates efficient recruitment of eIF3 to polysomes, allowing translation of polycistronic mRNAs by reinitiation, overcoming the normal cell barriers to this process.

Amino Acid Sequence↗

PubMed1990

Post-transcriptional control in the polycistronic operon environment: studies of the atp operon of Escherichia coli.

Post-transcriptional control mechanisms assume special significance in polycistronic operons. Differential gene expression in the atp operon of Escherichia coli is primarily attributable to translational control and, to a lesser extent, to control of mRNA stability. At the same time, the polycistronic environment influences, to varying degrees, the relative importance of the different types of post-transcriptional control. The present article briefly reviews more recent results obtained through studies of the atp operon. Investigations of the pathway and kinetics of mRNA decay have yielded new information about the role of degradative mechanisms in the overall scheme of control. Moreover, translational coupling has been shown to feature as a major form of interaction between the atp genes. The relevance of these and other data is discussed in the wider context of the post-transcriptional control mechanisms generally available to E. coli.

Escherichia coli↗

PubMed1988

Control of replication of plasmid R1: kinetics of in vitro interaction between the antisense RNA, CopA, and its target, CopT.

The frequency of replication of IncFII plasmids is regulated by the availability of a rate-limiting protein, RepA. This protein acts to promote initiation of replication and its synthesis is negatively controlled both at the transcriptional and translational level. The translational control is exerted by the binding of a small antisense RNA, CopA RNA, to its target, CopT, which is located in the leader region of the RepA mRNA. As a consequence, formation of RepA is inhibited. Here we demonstrate the binding of CopA RNA to CopT RNA in vitro; the rate constant of binding was determined to be approximately 1 X 10(6) M-1 s-1 at 37 degrees C. We have also shown that in vitro synthesized RepA mRNA molecules differing in length, but which contain the whole CopT region, are able to bind CopA RNA with similar rates. Analysis of the binding of CopA/CopT molecules derived from a copy-number mutant plasmid showed that the effect of the mutation on the rate of in vitro binding correlates well with its phenotypic effect in vivo, i.e. the binding rate constant is lowered in proportion to the increase in copy number. Likewise, the result of an in vitro incompatibility test is in agreement with in vivo data.

DNA Replication↗

PubMed2000

Crystallization and characterization of Pumilo: a novel RNA binding protein.

Axis determination in early Drosophila embryos is controlled, in part, by regulation of translation of mRNAs transcribed in maternal cells during oogenesis. The Pumilio protein is essential in posterior determination, binding to hunchback mRNA in complex with Nanos to suppress hunchback translation. In order to understand the structural basis of RNA binding, Nanos recruitment, and translational control, we have crystallized a domain of the Drosophila Pumilio protein that binds RNA. The crystals belong to the space group P6(3) with unit cell dimensions of a = b = 94.5 A, c = 228.9 A, alpha = beta = 90 degrees, gamma = 120 degrees and diffract to 2.6 A with synchrotron radiation. We show that the purified protein actively binds RNA and is likely to have a novel RNA binding fold due to a very high content of alpha-helical secondary structure.

Animals↗

PubMed1983

Vectors for high conditional expression of cloned genes.

Several multicopy plasmids carrying the control region of bacteriophage lambda lysogeny, including the gene of a thermosensitive repressor CI857 have been constructed. The phages allow high expression of proteins under the transcription control of lambda promoter PR and translation control of Cro. The method has been assayed by measuring expression of either intact beta-galactosidase, truncated beta-galactosidase or beta-galactosidase fused to a mitochondrial gene product. It is shown that use of a strain with low endogeneous proteolytic activities strongly improves the conditional yield of foreign proteins, so that a high overproduction can be achieved (10-20 per cent of the total protein content of the cell).

Bacteriophage lambda↗

PubMed2004

Signaling control of mRNA translation in cancer pathogenesis.

The regulation of translation and the control of ribosome biogenesis are essential cellular processes whose impact on cell growth and proliferation is manifested at a number of specific levels. Disruption in one or more of the steps that control protein biosynthesis has been associated with alterations in the regulation of cell growth and cell cycle progression. Consistent with this, tumor suppressors and proto-oncogenes have been found to act on these functions and may therefore regulate malignant progression by affecting the protein synthetic machinery. Although many studies have correlated deregulation of protein biosynthesis with cancer, it remains to be established whether this process is necessary and/or sufficient for neoplastic transformation and metastasis.

Animals↗

PubMed2004

A new yeast PUF family protein, Puf6p, represses ASH1 mRNA translation and is required for its localization.

In yeast Saccharomyces cerevisiae, Ash1p, a protein determinant for mating-type switching, is segregated within the daughter cell nucleus to establish asymmetry of HO expression. The accumulation of Ash1p results from ASH1 mRNA that is sorted as a ribonucleoprotein particle (mRNP or locasome) to the distal tip of the bud where translation occurs. To study the mechanism regulating ASH1 mRNA translation, we isolated the ASH1 locasome and characterized the associated proteins by MALDI-TOF. One of these proteins was Puf6p, a new member of the PUF family of highly conserved RNA-binding proteins such as Pumilio in Drosophila, responsible for translational repression, usually to effect asymmetric expression. Puf6p-bound PUF consensus sequences in the 3'UTR of ASH1 mRNA and repressed the translation of ASH1 mRNA both in vivo and in vitro. In the puf6 Delta strain, asymmetric localization of both Ash1p and ASH1 mRNA were significantly reduced. We propose that Puf6p is a protein that functions in the translational control of ASH1 mRNA, and this translational inhibition is necessary before localization can proceed.

3' Untranslated Regions↗

PubMed1995

The transcriptional activator GCN4 contains multiple activation domains that are critically dependent on hydrophobic amino acids.

GCN4 is a transcriptional activator in the bZIP family that regulates amino acid biosynthetic genes in the yeast Saccharomyces cerevisiae. Previous work suggested that the principal activation domain of GCN4 is a highly acidic segment of approximately 40 amino acids located in the center of the protein. We conducted a mutational analysis of GCN4 with a single-copy allele expressed under the control of the native promoter and translational control elements. Our results indicate that GCN4 contains two activation domains of similar potency that can function independently to promote high-level transcription of the target genes HIS3 and HIS4. One of these domains is coincident with the acidic activation domain defined previously; the other extends over the N-terminal one-third of the protein. Both domains are partially dependent on the coactivator protein ADA2. Each domain appears to be composed of two or more small subdomains that have additive effects on transcription and that can cooperate in different combinations to promote high-level expression of HIS3 and HIS4. At least three of these subdomains are critically dependent on bulky hydrophobic amino acids for their function. Five of the important hydrophobic residues, Phe-97, Phe-98, Met-107, Tyr-110, and Leu-113, fall within a region of proposed sequence homology between GCN4 and the herpesvirus acidic activator VP16. The remaining three residues, Trp-120, Leu-123, and Phe-124, are highly conserved between GCN4 and its Neurospora counterpart, cpc-1. Because of the functional redundancy in the activation domain, mutations at positions 97 and 98 must be combined with mutations at positions 120 to 124 to observe a substantial reduction in activation by full-length GCN4, and substitution of all eight hydrophobic residues was required to inactivate full-length GCN4. These hydrophobic residues may mediate important interactions between GCN4 and one or more of its target proteins in the transcription initiation complex.

Alcohol Oxidoreductases↗

PubMed1999

The mitogen-activated protein kinase signaling pathway stimulates mos mRNA cytoplasmic polyadenylation during Xenopus oocyte maturation.

The Mos protein kinase is a key regulator of vertebrate oocyte maturation. Oocyte-specific Mos protein expression is subject to translational control. In the frog Xenopus, the translation of Mos protein requires the progesterone-induced polyadenylation of the maternal Mos mRNA, which is present in the oocyte cytoplasm. Both the Xenopus p42 mitogen-activated protein kinase (MAPK) and maturation-promoting factor (MPF) signaling pathways have been proposed to mediate progesterone-stimulated oocyte maturation. In this study, we have determined the relative contributions of the MAPK and MPF signaling pathways to Mos mRNA polyadenylation. We report that progesterone-induced Mos mRNA polyadenylation was attenuated in oocytes expressing the MAPK phosphatase rVH6. Moreover, inhibition of MAPK signaling blocked progesterone-induced Mos protein accumulation. Activation of the MAPK pathway by injection of RNA encoding Mos was sufficient to induce both the polyadenylation of synthetic Mos mRNA substrates and the accumulation of endogenous Mos protein in the absence of MPF signaling. Activation of MPF, by injection of cyclin B1 RNA or purified cyclin B1 protein, also induced both Mos protein accumulation and Mos mRNA polyadenylation. However, this action of MPF required MAPK activity. By contrast, the cytoplasmic polyadenylation of maternal cyclin B1 mRNA was stimulated by MPF in a MAPK-independent manner, thus revealing a differential regulation of maternal mRNA polyadenylation by the MAPK and MPF signaling pathways. We propose that MAPK-stimulated Mos mRNA cytoplasmic polyadenylation is a key component of the positive-feedback loop, which contributes to the all-or-none process of oocyte maturation.

Animals↗

PubMed1992

Changes in skeletal muscle gene expression consequent to altered weight bearing.

Skeletal muscle is a dynamic organ that adapts to alterations in weight bearing. This brief review examines changes in muscle gene expression resulting from the removal of weight bearing by hindlimb suspension and from increased weight bearing due to eccentric exercise. Acute (less than or equal to 2 days) non-weight bearing of adult rat soleus muscle alters only the translational control of muscle gene expression, while chronic (greater than or equal to 7 days) removal of weight bearing appears to influence pretranslational, translational, and posttranslational mechanisms of control. Acute and chronic eccentric exercise are associated with alterations of translational and posttranslational control, while chronic eccentric training also alters the pretranslational control of muscle gene expression. Thus alterations in weight bearing influence multiple sites of gene regulation.

Animals↗

PubMed1994

Regulation of translation by specific protein/mRNA interactions.

This review will focus on cases of specific translational control by protein/RNA interactions in the 5'- or 3'-UTR of eukaryote mRNA where either the cis-acting RNA determinant or the trans-acting protein (or preferably both) have been identified with fair certainty. Examples of messages that are regulated by 5' motifs, which are proposed to occlude ribosome binding when bound by their specific factors, include ferritin and ribosomal protein mRNAs and the autoregulated thymidylate synthase and poly(A)-binding mRNAs. However, it has become increasingly evident recently that 3' UTR determinants and their specific binding proteins also regulate translation efficiency either directly, or indirectly via an influence on the polyadenylation status of the mRNA. It is still unclear how events at the 3' end of mRNA influence ribosome binding. Most, if not all, of the mRNAs known to be regulated by 3' UTR motifs are subject to regulation during early development or during differentiation such as several spermatocyte and oocyte mRNAs and erythroid lipoxygenase mRNA. To date, in all cases where translation is controlled directly by specific protein/mRNA interactions, the protein seems to act as a negative regulator, a translational repressor, whose binding to the specific site on the mRNA results in inhibition of initiation. The only cases of translational activation known so far concern internal initiation of translation of picornaviral RNAs, but this topic is beyond the scope of this review.

Animals↗

PubMed2007

Proteomic profiling of murine oocyte maturation.

In an effort to better understand oocyte function, we utilized two-dimensional (2D) electrophoresis and mass spectrometry to identify proteins that are differentially expressed during murine oocyte maturation. Proteins from 500 germinal vesicle (GV) and metaphase II-(MII) arrested oocytes were extracted, resolved on 2D electrophoretic gels, and stained with silver. Analysis of the gels indicated that 12 proteins appeared to be differentially expressed between the GV and MII stage. These proteins were then cored from the 2D gels and identified by mass spectrometry as: transforming acidic coiled-coil protein 3 (TACC3), heat shock protein 105 (HSP105), programmed cell death six-interacting protein (PDCD6IP), stress-inducible phosphoprotein (STI1), importin alpha2, adenylsuccinate synthase (ADDS), nudix, spindlin, lipocalin, lysozyme, translationally controlled tumor protein (TCTP), and nucleoplasmin 2 (NPM2). Interestingly, PDCD6IP, importin alpha2, spindlin, and NPM2 appear slightly larger in mass and more acidic on the MII oocyte gel compared to the GV oocyte gel, suggesting that they may be post-translationally modified during oocyte maturation. Given NPM2 is an oocyte-restricted protein, we chose to further investigate its properties during oocyte maturation and preimplantation development. Real-Time RT-PCR showed that NPM2 mRNA levels rapidly decline at fertilization. Indirect immunofluorescence analysis showed that, with the exception of cortical localization in MII-arrested oocytes, NPM2 is localized to the nucleus of both GV stage oocytes and all stages of preimplantation embryos. We then performed one-dimensional (1D) western blot analysis of mouse oocytes and preimplantation embryos and found that, as implicated by the 2D gel comparison, NPM2 undergoes a phosphatase-sensitive electrophoretic mobility shift during the GV to MII transition. The slower migrating NPM2 form is also present in pronuclear embryos but by the two-cell stage, the majority of NPM2 exists as the faster migrating form, which persists to the blastocyst stage.

Amino Acid Sequence↗

PubMed1988

Expression of ribosomal protein genes during Xenopus development.

The Xenopus ribosomal protein genes provide an excellent system to elucidate the complex regulation encompassing 60 functionally related proteins present in equimolar amounts in ribosomal subunits. Oogenesis and embryogenesis provide unique opportunities to investigate ribosome biosynthesis in situations wherein gene activation of individual components is uncoupled from assembly of the ribosomal subunits. This chapter has focused on the basic parameters that control ribosomal protein gene expression during development. Translational control is clearly a major level for coordinating the regulation of these genes during development, as is posttranslational stability of the ribosomal proteins and RNA splicing of the L1 gene. In addition to these levels of control under active investigation, a number of intriguing problems remain to be addressed in any detail. For example, the mechanisms that balance ribosomal protein production with subunit assembly in oocytes remain to be determined. Resolution of these events must also define the processes by which ribosomal proteins, upon synthesis in the cytoplasm, are first translocated to the nucleus and subsequently to the nucleolus for subunit assembly. Functional approaches in which these genes are assayed for accurate developmental control in microinjected oocytes and fertilized eggs will undoubtedly provide information on the synthesis of this eukaryotic organelle and the signals responsible for altering these processes at different developmental stages.

Animals↗

PubMed1985

Multiple mechanisms of iron-induced ferritin synthesis in HeLa cells.

Iron administration to HeLa cells stimulates the accumulation of H-subunit and L-subunit rich isoferritins at similar extent. The increase in both types of isoferritins is accompanied by an increase in the amount of messenger RNAs specific for H and L subunits. The increase in the amount of these messenger RNAs, which occurs in the nucleus as well as in the cytoplasm, is proportionately lower than the increase in the protein. These results, together with analysis of transcription in isolated nuclei indicate the existence of a mechanism of transcriptional control of ferritin synthesis, associated to the translational control described so far.

Cell Nucleus↗

PubMed2006

A novel mammalian bubblegum-related acyl-CoA synthetase restricted to testes and possibly involved in spermatogenesis.

We have characterized a new, membrane-associated acyl-CoA synthetase (ACS), termed bubblegum-related protein (BGR), which upon functional analysis demonstrated ACS activity capable of activating long- and very long-chain fatty acids. By multiple tissue RNA array and Northern blot analyses, human BGR mRNA was exclusively detected in testes. Murine Bgr mRNA was specifically expressed in pubertal and adult testes and was further demonstrated to be enriched in germ cells and Sertoli cells while present at a lower level in Leydig cells both by in situ hybridization and cell type fractionation. The complex 5'-end of the BGR mRNA appears to underlie translational control leading to differential utilization of alternative translation start sites. Thus, the BGR gene expands the bubblegum ACS family with a testes-specific, developmentally regulated member that may play a role in spermatogenesis.

Adult↗

PubMed2005

Cap-independent translation of plant viral RNAs.

The RNAs of many plant viruses lack a 5' cap and must be translated by a cap-independent mechanism. Here, we discuss the remarkably diverse cap-independent translation elements that have been identified in members of the Potyviridae, Luteoviridae, and Tombusviridae families, and genus Tobamovirus. Many other plant viruses have uncapped RNAs but their translation control elements are uncharacterized. Cap-independent translation elements of plant viruses differ strikingly from those of animal viruses: they are smaller (<200 nt), some are located in the 3' untranslated region, some require ribosome scanning from the 5' end of the mRNA, and the 5' UTR elements are much less structured than those of animal viruses. We discuss how these elements may interact with host translation factors, and speculate on their mechanism of action and their roles in the virus replication cycle. Much remains to be learned about how these elements enable plant viruses to usurp the host translational machinery.

Base Sequence↗

PubMed2002

Phosphorylation of initiation factor-2 alpha is required for activation of internal translation initiation during cell differentiation.

The long uORF-burdened 5'UTRs of many genes encoding regulatory proteins involved in cell growth and differentiation contain internal ribosomal entry site (IRES) elements. In a previous study we showed that utilization of the weak IRES of platelet-derived growth factor (PDGF2) is activated during megakaryocytic differentiation. The establishment of permissive conditions for IRES-mediated translation during differentiation has been confirmed by our demonstration of the enhanced activity of vascular endothelial growth factor, c-Myc and encephalomyocarditis virus IRES elements under these conditions, although their mRNAs are not naturally expressed in differentiated K562 cells. In contrast with the enhancement of IRES-mediated protein synthesis during differentiation, global protein synthesis is reduced, as judged by polysomal profiles and radiolabelled amino acid incorporation rate. The reduction in protein synthesis rate correlates with increased phosphorylation of the translation initiation factor eIF2 alpha. Furthermore, IRES use is decreased by over-expression of the dominant-negative form of the eIF2 alpha kinase, PKR, the vaccinia virus K3L gene, or the eIF2 alpha-S51A variant which result in decreased eIF2 alpha phosphorylation. These data demonstrate a connection between eIF2 alpha phosphorylation and activation of cellular IRES elements. It suggests that phosphorylation of eIF2 alpha, known to be important for cap-dependent translational control, serves to fine-tune the translation efficiency of different mRNA subsets during the course of differentiation and has the potential to regulate expression of IRES-containing mRNAs under a range of physiological circumstances.

Cell Differentiation↗

PubMed1982

Regulation of synthesis of catalases and iso-1-cytochrome c in Saccharomyces cerevisiae by glucose, oxygen and heme.

The regulation of the hemoproteins catalase T, catalase A and iso-1-cytochrome c was studied in the yeast Saccharomyces cerevisiae. Levels of catalase T and catalase A mRNAs are low or undetectable in anaerobic and heme-deficient cells, and in wild type strains grown on high glucose concentrations. Regulatory mutants (cgr4 and cas1), which have previously been shown to have high catalase T activity when grown in the absence of oxygen or on high glucose concentrations, have high levels of catalase T mRNA when grown under glucose repression conditions. Whereas no catalase T mRNA could be detected in a heme-deficient (ole3) single mutant, double mutants (ole3 cgr4) and (ole3 cas1) contain mature catalase T mRNA. Catalase T and A mRNAs are accumulated rapidly during adaptation of anaerobic cells to oxygen. Anaerobic and heme-deficient cells lack or have extremely low levels of iso-1-cytochrome c mRNA, which, like catalase mRNAs, is accumulated rapidly during oxygen adaptation. The results obtained demonstrate that glucose, oxygen and heme regulate the synthesis of the hemoproteins studied by controlling mRNA levels. In addition, posttranscriptional, probably translational control has to be postulated at least in the case of catalases, to explain the results obtained.

Catalase↗