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Results for “Translational repression”

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PubMed1984

Heat shock-induced translational control of HSP70 and globin synthesis in chicken reticulocytes.

Incubation of chicken reticulocytes at elevated temperatures (43 to 45 degrees C) resulted in a rapid change in the pattern of protein synthesis, characterized by the decreased synthesis of normal proteins, e.g., alpha and beta globin, and the preferential and increased synthesis of only one heat shock protein, HSP70. The repression of globin synthesis was not due to modifications of globin mRNA because the level of globin mRNA and its ability to be translated in vitro were unaffected. The HSP70 gene in reticulocytes was transcribed in non-heat-shocked cells, yet HSP70 was not efficiently translated until the cells had been heat shocked. In non-heat-shocked reticulocytes, HSP70 mRNA was a moderately abundant mRNA present at 1 to 2% of the level of globin mRNA. The rapid 20-fold increase in the synthesis of HSP70 after heat shock was not accompanied by a corresponding increase in the rate of transcription of the HSP70 gene or accumulation of HSP70 mRNA. These results suggest that the elevated synthesis of HSP70 is due to the preferential utilization of HSP70 mRNA in the heat-shocked reticulocyte. The heat shock-induced alterations in the reticulocyte protein-synthetic apparatus were not reversible. Upon return to control temperatures (37 degrees C), heat-shocked reticulocytes continued to synthesize HSP70 at elevated levels whereas globin synthesis continued to be repressed. Despite the presence of HSP70 mRNA in non-heat-shocked reticulocytes, we found that continued transcription was necessary for the preferential translation of HSP70 in heat-shocked cells. Preincubation of reticulocytes with the transcription inhibitor actinomycin D or 5,6-dichloro-1-beta-D-ribofuranosylbenzimidazole blocked the heat shock-induced synthesis of HSP70. Because the level of HSP70 mRNA was only slightly diminished in cells treated with actinomycin D, we suggest two possible mechanisms for the preferential translation of HSP70 mRNA: the translation of only newly transcribed HSP70 mRNA or the requirement of a newly transcribed RNA-containing factor.

Animals↗

PubMed1976

Initial trp operon sequence in Escherichia coli is transcribed without coupling to translation.

The transcription of the "leader" region (Bronson et al., 1973) of the trp operon in Escherichia coli was studied in normal mutants which delete most of the operator-distal region of the operon [a deletion strain (trp OAEG) retaining only about one third of the "leader" region and two deletion strains (trpOAE14 and trpOAE2) retaining the whole "leader" region and an initial portion of the trpE], as well as in a strain with an intact trp operon, but with a temperature-sensitive lesion in ribosomal protein factor EFTs (strain HAK88). In these deletion mutants, mRNA molecules corresponding to the "leader" region were detected as most of the trp-specific mRNA. Less inhibition of transcription, of the promoter-proximal portion of the trp "leader" region than that of more distal genes of the operon, was found in chloramphenicol-treated cells of strain trpOAE14. It was also observed that transcription of the initial one third portion of the "leader" region was not repressed by tryptophan in strains trpOAE6 and trp OAE14. A similar effect of a translation block on transcription of the distal part of the "leader" region was observed with strain HAK88 at the nonpermissive temperature. In sedimentation analysis of polyribosomes containing the trp mRNA molecules from the deletion mutants, trp mRNA from strain trpOAE14 was found in monosomes and small polyribosomes, whereas the majority of the trp mRNA from strain trpOAE6 was found joined to a single ribosome or ribosomal subunit. These results suggest that ribosomes bind in vivo to a site(s) located in the middle of the "leader" mRNA sequence, and that the initial transcription of the trp operon does not require any connection to functional translational machinery, while continuation of RNA synthesis beyond a first ribosome binding site seems indispensably coupled to ribosome function.

DNA, Bacterial↗

PubMed2001

Proteasome activity is required for T lymphocyte aggregation after mitogen activation.

The proteasome is a multicatalytic complex of proteases involved in T lymphocyte proliferation and activation through multiple mechanisms. In this study, we investigated its role in lymphocyte aggregation. We found that blocking proteasome activity by a proteasome-specific inhibitor lactacystin (LAC) prevented clustering of T lymphocytes after stimulation with various mitogens. Expression of adhesion molecules ICAM-1 and LFA-1 at cell surfaces of activated T cells was decreased after treatment with LAC. Mechanisms by which the proteasome intervenes in the expression of these adhesion molecules were different. LAC inhibited ICAM-1 expression at the mRNA level, whereas LFA-1 inhibition was probably at a post-translational level. Downregulation of these molecules after proteasome inhibition likely contributes to the observed repression of T cell aggregation. Our results show that the proteasome plays an important role in cell-cell interaction during T cell activation.

Acetylcysteine↗

PubMed2004

The histone-like nucleoid structuring protein H-NS represses the Escherichia coli bgl operon downstream of the promoter.

Specificity of repression by the histone-like nucleoid structuring protein and pleiotropic regulator, H-NS, is exceptionally high in case of the Escherichia coli bgl (beta-glucoside) operon. Here we present evidence that H-NS represses the operon at two levels. The binding of H-NS to an upstream silencer results in an approximately threefold repression of the catabolite gene regulator protein (CRP) dependent bgl promoter. In addition, H-NS binds to a silencer region located approximately 600-700 base pairs downstream of the promoter, within the coding region of first gene, bglG, resulting in a approximately sevenfold further decrease of expression. Repression by H-NS at the downstream silencer requires termination factor Rho and is reduced by translation of the bglG mRNA, but is independent of the promoter. This suggests that H-NS induces polarity of transcription by acting as a roadblock to the elongating RNA polymerase. The control of the bgl operon by H-NS at two levels results in a highly specific repression.

Bacterial Proteins↗

PubMedDate not supplied

[The regulator effect of fructose-1,6-diphosphate and cyclic adenosine monophosphate on protein and RNA synthesis by isolated mitochondria].

Effects of fructoso-1,6-diphosphate (FDP) and cyclic 3',5'-adenosine monophosphate (cAMP) on various steps of protein biosynthesis in isolated rat liver mitochondria were investigated. It was shown that FDP repressed and cAMP depressed the incorporation of both 14C-amino acid and [3H]uridine into mitochondrial polysomes. Cyclic 2',3'-adenosine monophosphate, a physiologically inactive analog of cAMP, had no depressing effect on the polysomes formation in mitochondria. Effects of FDP and cAMP on the synthesis of mitochondrial RNA at different periods of incubation (5, 10, 30 min) were studied. It was found that FDP repressed the high molecular weight mitochondrial RNA biosynthesis and prevented the mRNA formation. cAMP derepressed the FDP effect. Rifampicin prevented the derepressing action of cAMP. The rate of protein synthesis in the translation system isolated from mitochondria was affected neither by FDP nor by cAMP. Authors concluded that in the mammalian mitochondria the repression of protein synthesis by a glycolytic metabolite (FDP) and its derepression by cAMP represented regulatory mechanism acting at the transcription level like catabolite repression-derepression in microorganisms.

Animals↗

PubMed1988

[Psychoanalysis and engagement: Otto Fenichel and the political Freudians].

This essay is a critique of Russell Jacoby's The repression of psychoanalysis: Otto Fenichel and the political Freudians (New York, Basic Books, 1983), translated into French by P.U.F. Jacoby depicts Fenichel and his circle of colleagues as political Freudians whose early years were decisively colored by radical youth movements, leftwing politics, the early inspiration of the Russian Revolution, a serious immersion in Marxist culture, a commitment to either socialist or communist parties, and a desire to integrate classical psychoanalysis into a a broader framework of Marxist social theorizing. He centers his book around the archival discovery of the Rundbriefe, 119 circular letters written during Fenichel's exile from 1934 to 1945. He discusses the impact of Wilhelm Reich's ideas and career on the Fenichel circle. Fascism and exile from Europe shattered the lives and commitments of the political Freudians. This essay focuses on Jacoby's use and abuse of the concepts of Americanization, medicalization, the competition from the neo-Freudians, and the apparent silence and "self-repression" of this group's past and leftwing identity once in America. It concludes with a critical analysis of Fenichel's psychoanalytic ethic, which, while engagé, was not Marxist. Fenichel was oriented toward contributing to both psychoanalytic practice and theory. His ethic precluded the intrusion of politics into clinical work, supervision, and teaching.

Austria↗

PubMed2005

Rgt1, a glucose sensing transcription factor, is required for transcriptional repression of the HXK2 gene in Saccharomyces cerevisiae.

Expression of HXK2, a gene encoding a Saccharomyces cerevisiae bifunctional protein with catalytic and regulatory functions, is controlled by glucose availability, being activated in the presence of glucose and inhibited when the levels of the sugar are low. In the present study, we identified Rgt1 as a transcription factor that, together with the Med8 protein, is essential for repression of the HXK2 gene in the absence of glucose. Rgt1 represses HXK2 expression by binding specifically to the motif (CGGAAAA) located at -395 bp relative to the ATG translation start codon in the HXK2 promoter. Disruption of the RGT1 gene causes an 18-fold increase in the level of HXK2 transcript in the absence of glucose. Rgt1 binds to the RGT1 element of HXK2 promoter in a glucose-dependent manner, and the repression of target gene depends on binding of Rgt1 to DNA. The physiological significance of the connection between two glucose-signalling pathways, the Snf3/Rgt2 that causes glucose induction and the Mig1/Hxk2 that causes glucose repression, was also analysed.

DNA-Binding Proteins↗

PubMed2002

Leukemia proto-oncoprotein MLL is proteolytically processed into 2 fragments with opposite transcriptional properties.

MLL (mixed lineage leukemia; also ALL-1 or HRX) is a proto-oncogene that is mutated in a variety of acute leukemias. Its product is normally required for the maintenance of Hox gene expression during embryogenesis and hematopoiesis through molecular mechanisms that remain poorly defined. Here we demonstrate that MLL (mixed lineage leukemia) is proteolytically processed into 2 fragments (MLL(N) and MLL(C)) that display opposite transcriptional properties and form an intramolecular MLL complex in vivo. Proteolytic cleavage occurs at 2 amino acids (D2666 and D2718) within a consensus processing sequence (QXD/GZDD, where X is a hydrophobic amino acid and Z is an alanine or a valine) that is conserved in TRX, the Drosophila homolog of MLL, and in the MLL-related protein MLL2, suggesting that processing is important for MLL function. Processed MLL(N) and MLL(C) associate with each other via N-terminal (1253-2254 amino acids) and C-terminal (3602-3742 amino acids) intramolecular interaction domains. MLL processing occurs rapidly within a few hours after translation and is followed by the phosphorylation of MLL(C). MLL(N) displays transcriptional repression activity, whereas MLL(C) has strong transcriptional activation properties. Leukemia-associated MLL fusion proteins lack the MLL processing sites, do not undergo cleavage, and are unable to interact with MLL(C). These observations suggest that posttranslational modifications of MLL may participate in regulating its activity as a transcription factor and that this aspect of its function is perturbed by leukemogenic fusions.

Cloning, Molecular↗

PubMed1997

Mediation of NGF signaling by post-translational inhibition of HES-1, a basic helix-loop-helix repressor of neuronal differentiation.

The induction of neurite outgrowth by NGF is a transcription-dependent process in PC12 cells, but the transcription factors that mediate this process are not known. Here we show that the bHLH transcriptional repressor HES-1 is a mediator of this process. Inactivation of endogenous HES-1 by forced expression of a dominant-negative protein induces neurite outgrowth in the absence of NGF and increases response to NGF. In contrast, expression of additional wild-type HES-1 protein represses and delays response to NGF. Endogenous HES-1 DNA-binding activity is post-translationally inhibited during NGF signaling in vivo, and phosphorylation of PKC consensus sites in the HES-1 DNA-binding domain inhibits DNA binding by purified HES-1 in vitro. Mutation of these sites generates a constitutively active protein that strongly and persistently blocks response to NGF. These results suggest that post-translational inhibition of HES-1 is both essential for and partially mediates the induction of neurite outgrowth by NGF signaling.

Animals↗

PubMed2003

Expression and characterization of the celcflB gene from Cellulomonas flavigena encoding an endo-beta-1,4-glucanase.

An endoglucanase gene called celcflB was isolated from a genomic library of C. flavigena. Its nucleotide sequence showed an ORF of 1725 bp with a GTG start codon. A promoter sequence was found inside the adjacent gene upstream from the start point of translation of celcflB gene. The gene celcflB was induced by sugarcane bagasse and repressed by glucose when C. flavigena was grown on these carbon sources, suggesting that celcflB gene is regulated at transcriptional level. The predicted amino acid sequence of the CelcflB protein presented a catalytic domain with a high homology to family 5 of glycosil hydrolases, and a cellulose binding domain identical to cellulose binding domains type II. The coding region of the celcflB gene was cloned into the expression vector pQE30 and the recombinant protein of 58 kDa presented endoglucanase activity towards carboxymethyl cellulose (CMC).

Carboxymethylcellulose Sodium↗

PubMed2000

Germ plasm and molecular determinants of germ cell fate.

One mechanism for the specification of cell types during embryonic development is the cytoplasmic localization of determinants in the egg into certain blastomeres. Primordial germ cell (PGC) development in many organisms is characterized by the inheritance of germ plasm, a cytologically distinct assembly of mitochondria and electron-dense germinal granules. This chapter reviews the structure of germ plasm and the experimental evidence for its importance in PGC specification in Caenorhabditis elegans, Drosophila, and Xenopus. It then compares and contrasts recent data on the identification of germ plasm components in these organisms. Many components are potentially RNA-binding proteins, implicating the regulation of RNA metabolism, transport, and translation as critical processes in PGC development. Germ plasm components also mediate transcriptional repression, regulate migration, and control mitotic divisions in PGCs. The chapter concludes with a discussion on the general roles of germ plasm components and how they might act to specify PGC fate.

Animals↗

PubMed2006

The cytohesin Steppke is essential for insulin signalling in Drosophila.

In metazoans, the insulin signalling pathway has a key function in regulating energy metabolism and organismal growth. Its activation stimulates a highly conserved downstream kinase cascade that includes phosphatidylinositol-3-OH kinase (PI(3)K) and the serine-threonine protein kinase Akt. This study identifies a new component of insulin signalling in Drosophila, the steppke gene (step). step encodes a member of the cytohesin family of guanine nucleotide exchange factors (GEFs), which have been characterized as activators for ADP-ribosylation factor (ARF) GTPases. In step mutant animals both cell size and cell number are reduced, resulting in decreased body size and body weight in larvae, pupae and adults. step acts upstream of PI(3)K and is required for the proper regulation of Akt and the transcription factor FOXO. Temporally controlled interference with the GEF activity of the Step protein by feeding the chemical inhibitor SecinH3 causes a block of insulin signalling and a phenocopy of the step mutant growth defect. Step represses its own expression and the synthesis of growth inhibitors such as the translational repressor 4E-BP. Our findings indicate a crucial role of an ARF-GEF in insulin signalling that has implications for understanding insulin-related disorders, such as diabetes and obesity.

Animals↗

PubMed2003

Importance of nuclear localization of apoptin for tumor-specific induction of apoptosis.

The chicken anemia virus-derived protein Apoptin induces apoptosis specifically in human tumor and transformed cells and not in normal, untransformed cells. The cell killing activity correlates with a predominantly nuclear localization of Apoptin in tumor cells, whereas in normal cells, it is detected mainly in cytoplasmic structures. To explore the role of nuclear localization for Apoptin-induced cell death in tumor cells, we employed a mutagenesis strategy. First, we demonstrated that the C terminus of Apoptin contains a bipartite-type nuclear localization signal. Strikingly, further investigation showed that Apoptin contains two different domains that induce apoptosis independently, and for both domains, we found a strong correlation between localization and killing activity. Using inhibitors, we ruled out the involvement of de novo gene transcription and translation and further showed that Apoptin itself does not have any significant transcriptional repression activity, suggesting that Apoptin exerts its effects in the nucleus by some other method. To determine whether nuclear localization is sufficient to enable Apoptin to kill normal, untransformed cells, we expressed full-length Apoptin fused to a heterologous nuclear localization signal in these cells. However, despite its nuclear localization, no apoptosis was induced, which suggests that nuclear localization per se is not sufficient for Apoptin to become active. These studies increase our understanding of the molecular pathway of Apoptin and may also shed light on the mechanism of cellular transformation.

Active Transport, Cell Nucleus↗

PubMed2025

RNA-RNA interactions coordinate GABA metabolism and signaling.

Production, signaling, and degradation of the inhibitory neurotransmitter GABA requires tight regulation for proper nervous system function, yet the gene regulatory mechanisms underlying this control remain poorly understood. Here, we identify a post-transcriptional mechanism that coordinates expression of the GABA synthetase Gad1 with its vesicular transporter VGAT in Drosophila. While Gad1 is transcribed specifically in GABAergic neurons, VGAT mRNA is transcribed broadly across the nervous system, but is selectively translated in GABAergic neurons. We show that this specificity depends on CG14989, a putative long non-coding RNA located adjacent to the Gad1 gene locus that shares its GABAergic expression pattern. CG14989 RNA contains sequences complementary to three predicted miR-7 sites in the VGAT 3'UTR, and ectopic expression experiments revealed that it is sufficient for VGAT translation in non-GABAergic neurons, consistent with antagonism of miR-7-mediated repression. Furthermore, complementary regions to CG14989 are present in multiple other genes related to metabolism and signaling of GABA, suggesting a broader role for this mechanism. Together, our findings suggest that CG14989 functions as a regulatory hub that coordinates the molecular identity of GABAergic neurons.

Journal Article↗

PubMed1990

Cloning, nucleotide sequence and regulation of the Salmonella typhimurium pyrD gene encoding dihydroorotate dehydrogenase.

The Salmonella typhimurium pyrD gene encoding dihydroorotate dehydrogenase was cloned and sequenced. In total, a sequence of 1286 nucleotide pairs was determined wherein a single open-reading-frame of 1011 bp, encoding a polypeptide of 336 amino acids having 95% similarity with the Escherichia coli pyrD gene product, was identified. A region of hyphenated-dyad symmetry exists within the leader region affording the potential for the formation of a stable secondary structure in the 5' end of the transcript. Mutations from several regulatory mutants were located within the region of dyad symmetry which would impart changes in the transcript within the putative secondary structure, implicating the secondary structure in regulation. Primer extension analysis revealed multiple transcriptional start sites located six to nine nucleotides downstream from the Pribnow box, with the primary initiation site differing in repressing and derepressing growth conditions. The results are discussed in terms of a translational attenuation model for regulation of pyrD expression.

Amino Acid Sequence↗

PubMed1994

In vitro studies of glucocorticoid effects on neurons and astrocytes.

Studies using immunocytochemistry and RNase protection assay demonstrate that glucocorticoid and mineralocorticoid receptors (GR, MR) and their corresponding mRNAs are co-expressed in hippocampal neurons cultured in serum-free, defined medium and at lower levels in cultured astrocytes. Addition of serum or medium conditioned by astrocytes increases the levels of MR mRNA, but has little effect on the levels of GR mRNA. Cellular levels of both GR mRNA and MR mRNA are upregulated by growth of embryonic hippocampal neurons in corticosterone. This is in distinct contrast to regulation of receptor expression in vivo where mRNAs for these receptors are downregulated in the rat hippocampus by corticosterone treatment of the adult adrenalectomized rat. However, in cultured astrocytes, GR and MR mRNAs are also downregulated by corticosterone. To begin to define the role of glucocorticoids in gene expression in astrocytes, we have used giant two-dimensional (2D) gel electrophoresis to separate astrocyte cellular proteins and translation products synthesized in vitro from astrocyte poly A+ RNA. Analysis of approximately 1,500 in vitro translation products by giant 2D gel electrophoresis reveals 11 protein inductions and 1 repression that occur at the level of mRNA in the absence of protein synthesis following treatment of astrocytes with corticosterone. Interestingly, these changes appear to be mediated by GR, but not by MR. The in vitro studies described here are relevant to identifying the role of GR and MR in gene expression in specific cell types in the hippocampus.

Animals↗

PubMed2007

How do microRNAs regulate gene expression?

Several thousand human genes, amounting to about one-third of the whole genome, are potential targets for regulation by the several hundred microRNAs (miRNAs) encoded in the genome. The regulation occurs posttranscriptionally and involves the approximately 21-nucleotide miRNA interacting with a target site in the mRNA that generally has imperfect complementarity to the miRNA. The target sites are almost invariably in the 3'-untranslated region of the messenger RNA (mRNA), often in multiple copies. Metazoan miRNAs were previously thought to down-regulate protein expression by inhibiting target mRNA translation at some stage after the translation initiation step, without much effect on mRNA abundance. However, recent studies have questioned these suppositions. With some targets, an increase in the rate of mRNA degradation by the normal decay pathway contributes to the decrease in protein expression. miRNAs can also inhibit translation initiation, specifically the function of the cap-binding initiation factor, eIF4E. Repressed target mRNAs as well as miRNAs themselves accumulate in cytoplasmic foci known as P-bodies, where many enzymes involved in mRNA degradation are concentrated. However, P-bodies may also serve as repositories for the temporary and reversible storage of untranslated mRNA, and reducing the expression (knockdown) of several distinct P-body protein components can alleviate miRNA-mediated repression of gene expression.

Animals↗

PubMed1991

Characterization of a defective diphtheria toxin repressor (dtxR) allele and analysis of dtxR transcription in wild-type and mutant strains of Corynebacterium diphtheriae.

The production of diphtheria toxin and siderophore by the Corynebacterium diphtheriae regulatory mutant C7(beta)hm723 is resistant to the inhibitory effects of iron, and the mutant strain is defective for function of the regulatory gene dtxR. A 2.8-kb HindIII fragment carrying the C7(beta)hm723 dtxR allele was cloned and characterized in Escherichia coli. The restriction endonuclease maps of the 2.8-kb HindIII fragment from C7(beta)hm723 and the corresponding fragment from wild-type C. diphtheriae C7 were identical. RNA dot blot analysis with total RNA isolated from wild-type C. diphtheriae C7 and C7(beta)hm723 indicated that the dtxR gene was transcribed at very low but equivalent levels in both strains and was not regulated by iron. beta-Galactosidase synthesis from a tox-lacZ translational fusion construct in E. coli in high-iron medium was not repressed by the C7(beta)hm723dtxR allele, but was strongly repressed by the wild-type dtxR gene. The 28- to 29-kDa polypeptide expressed from the mutant dtxR allele in E. coli had the same electrophoretic mobility as the wild-type dtxR gene product in sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The nucleotide sequence of the coding region and the 5' upstream region of the C7(beta)hm723 dtxR allele was determined and compared with the wild-type nucleotide sequence. The dtxR allele from C7(beta)hm723 contained a single-base change located 140 nucleotides from the 5' start of the gene, which resulted in replacement of arginine in the wild-type sequence by histidine in the mutant protein. These data demonstrate that C7(beta)hm723 expresses a mutant DtxR repressor protein that is severely defective in repressor activity.

Amino Acid Sequence↗