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Results for “Translational repression”

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PubMed2001

Global and specific translational regulation in the genomic response of Saccharomyces cerevisiae to a rapid transfer from a fermentable to a nonfermentable carbon source.

The global gene expression program that accompanies the adaptation of Saccharomyces cerevisiae to an abrupt transfer from a fermentable to a nonfermentable carbon source was characterized by using a cDNA microarray to monitor the relative abundances and polysomal distributions of mRNAs. Features of the program included a transient reduction in global translational activity and a severe decrease in polysome size of transcripts encoding ribosomal proteins. While the overall translation initiation of newly synthesized and preexisting mRNAs was generally repressed after the carbon source shift, the mRNA encoded by YPL250C was an exception in that it selectively mobilized into polysomes, although its relative abundance remained unchanged. In addition, splicing of HAC1 transcripts, which has previously been reported to occur during accumulation of unfolded proteins in the endoplasmic reticulum, was observed after the carbon shift. This finding suggests that the nonconventional splicing complex, composed of the kinase-endonuclease Ire1p and the tRNA ligase Rlg1p, was activated. While spliced HAC1 transcripts mobilized into polysomes, the vast majority of unspliced HAC1 RNA accumulated in nonpolysomal fractions before and after the carbon source shift, indicating that translation of unspliced HAC1 RNA is blocked at the translation initiation step, in addition to the previously reported elongation step. These findings reveal that S. cerevisiae reacts to the carbon source shift with a remarkable variety of responses, including translational regulation of specific mRNAs and activation of specific enzymes involved in a nonconventional splicing mechanism.

Base Sequence↗

PubMed2004

Simultaneous yet independent regulation of actin cytoskeletal organization and translation initiation by glucose in Saccharomyces cerevisiae.

Acute glucose deprivation rapidly but transiently depolarizes the actin cytoskeleton and inhibits translation initiation in Saccharomyces cerevisiae. Neither rapid actin depolarization nor translation inhibition upon glucose removal occurs in a reg1 disruptant, which is defective in glucose repression, or in the tpk1(w) mutant, which has weak cAPK activity. In the absence of additional glucose, recovery of either actin polarization or translation initiation relies upon respiration, the Snf1p protein kinase, and the transcription factors Msn2p and Msn4p. The readdition of glucose to glucose-starved cells causes a rapid recovery of actin polarization as well as translation initiation without respiration. These results indicate that the simultaneous regulation of actin polarization and translation initiation is divided into three reactions: 1) rapid shutdown depending on Reg1p and cAPK after glucose removal, 2) slow adaptation depending on Snf1p and Msn2p/4p in the absence of glucose, and 3) rapid recovery upon readdition of glucose. On glucose removal, translation initiation is rapidly inhibited in a rom2 disruptant, which is defective in rapid actin depolarization, whereas rapid actin depolarization occurs in a pop2/caf1 disruptant, which is defective in rapid inhibition of translation initiation. Thus, translation initiation and actin polarization seem to be simultaneously but independently regulated by glucose deprivation.

Actins↗

PubMed2001

Translational regulation of the mRNA encoding the eukaryotic translation initiation factor 4E in Xenopus.

We have cloned the cDNA for Xenopus eukaryotic translation initiation factor 4E (eIF4E). Here we show that translation of a luciferase mRNA that contains the 5' untranslated region derived from Xenopus eIF4E is active in fertilized eggs, but is repressed in oocytes. The results suggest that the expression of Xenopus eIF4E is regulated at the translation level.

5' Untranslated Regions↗

PubMed2026

Feeding the epigenome: EZH2 as a metabolic integrator of cell fate in development and cancer.

Epigenetic regulation is intimately linked to cellular metabolism, enabling environmental and nutritional cues to shape gene expression programs through dynamic modifications of chromatin structure. This metabolism-epigenetics interface is mediated, in part, by the dependence of chromatin-modifying enzymes on key metabolites, including S-adenosylmethionine (SAM), acetyl-CoA, UDP-GlcNAc, and α-ketoglutarate, which serve as substrates or cofactors for DNA and histone modifications. Among these regulators, EZH2, the catalytic subunit of Polycomb Repressive Complex 2 (PRC2), has emerged as a key mediator linking metabolic state to epigenetic regulation by translating metabolic inputs into changes in chromatin architecture and gene expression. EZH2 governs developmental cell fate through H3K27me3-mediated gene repression and is frequently dysregulated in cancer, where it promotes dedifferentiation, tumor progression, and metabolic reprogramming. Importantly, EZH2 activity is itself modulated by cellular metabolic status through posttranslational modifications, including phosphorylation, acetylation, methylation, ubiquitination, and O-GlcNAcylation, which influence its stability, catalytic activity, and chromatin-binding capacity. These modifications are responsive to nutrient availability and signaling pathways involving glucose, SAM, NAD+, and other metabolic intermediates. Consequently, disruption of this finely tuned regulatory network can contribute to developmental abnormalities, metabolic dysfunction, and oncogenesis. In this review, we examine the molecular mechanisms governing EZH2 regulation and discuss how metabolic control of EZH2 shapes chromatin dynamics, cell fate decisions, and disease pathogenesis. Elucidating how metabolic signals modulate EZH2 activity will advance our understanding of development and disease while uncovering potential therapeutic opportunities to target metabolism-driven epigenetic dysregulation.

Humans↗

PubMed1987

Factors affecting transcriptional regulation of the formate-hydrogen-lyase pathway of Escherichia coli.

The regulatory elements involved in expression of the gene (fdhF) for the selenopolypeptide of formate dehydrogenase and of a gene (or transcriptional unit) (hyd) specifically responsible for the formation of the gas-evolving hydrogenase (hydrogenase 3) in Escherichia coli were investigated. Formate (or a product of it) is required for expression of both systems since in a pyruvate-formate-lyase deficient mutant induction occurs only when formate is supplemented externally. Under this condition, formate can partially overcome repression by nitrate. The transcription of both the fdhF gene and the hydrogenase-3-encoding systems is independent of the presence of a wild-type fnr gene when formate is present, supporting the view that the Fnr effect on the formation of the formate-hydrogen-lyase pathway is indirect. Mutations blocking the synthesis of a functional molybdenum cofactor also had no major affect on fdhF and hyd expression. The nucleotide sequence of the 5' flanking region of the fdhF gene was determined and the transcription start point of the fdhF gene was localized by nuclease S1 mapping. Nuclease Bal31 generated deletion clones were constructed and the regulation of their expression was studied. Anaerobic expression and induction by formate depended on the presence of a stretch of approximately 185 nucleotides upstream of the translation start. Elements mediating formate induction and oxygen or nitrate repression could not be separated physically. The regulatory features of the fdhF upstream region bear striking resemblance to systems whose expression are dependent upon upstream activating elements.

Aldehyde Oxidoreductases↗

PubMed2004

Mitotic cyclins stimulate the activity of c-Myb-like factors for transactivation of G2/M phase-specific genes in tobacco.

Myb transcription factors, which contain three imperfect repeats in the Myb domain, are evolutionarily conserved members of the Myb superfamily. Vertebrate Myb proteins with three repeats, c-Myb, A-Myb, and BMyb, play important roles at the G(1)/S transition in the cell cycle. In plants, this type of Myb protein controls the G(2)/M phase by activating or repressing the transcription of cyclin B genes and a variety of other G(2)/M phase-specific genes. In tobacco, two genes for Myb activators, NtmybA1 and NtmybA2, are transcriptionally controlled and are expressed specifically at the G(2)/M phase. As we showed here, in addition to the control at the transcriptional level, activity of NtmybA2 is also controlled at the post-translational level. We found that the transactivation potential of NtmybA2 is repressed by a regulatory domain located at its carboxyl terminus and that specific classes of cyclins A and B enhanced NtmybA2 activity possibly by relieving this inhibitory effect. Mutations at the 20 potential sites of phosphorylation by cyclin-dependent kinase (CDK) in NtmybA2 blocked the enhancing effects of the cyclins on NtmybA2 activity. Recombinant NtmybA2 was phosphorylated in vitro by a CDK fraction prepared from tobacco BY2 cells. The kinase activity for NtmybA2 in the CDK fraction was cell cycle-regulated in BY2 cells, peaking at the G(2)/M phase when the level of transcripts of cyclin B is maximal. Taken together, our data suggest that NtmybA2 is phosphorylated by a specific cyclin/CDK complex(es) at G(2)/M and that this phosphorylation removes the inhibitory effect of its C-terminal region, thereby activating NtmybA2 specifically at G(2)/M.

Binding Sites↗

PubMed1999

Expression and compartmentation of the glucose repressor CRE1 from the phytopathogenic fungus Sclerotinia sclerotiorum.

The glucose repressor from the phytopathogenic fungus Sclerotinia sclerotiorum is encoded by the cre1 gene. Polyclonal antibodies were raised against a fusion protein (gluthathione S-transferase) GST-CRE1 in order to study cre1 expression. Western blot analyses revealed that CRE1 synthesis is regulated by the nature of the extracellular carbon source. High CRE1 levels are induced by glucose and remain stable after transfer into pectin medium, suggesting the existence of post-translational mechanisms which inactivate CRE1 to allow transcription of glucose-repressed genes. Subcellular fractionation demonstrated that CRE1 is localized in the nuclei of glucose grown hyphae and in the cytoplasm when glucose is removed from the culture medium. CRE1 fused to green fluorescent protein (GFP) was introduced into Aspergillus nidulans. Fluorescence microscopy showed the nuclear localization of the GFP-CRE1 fusion protein according to the presence of glucose in the culture medium, suggesting homologous post-translational regulations of glucose repressors in fungi. We propose that filamentous fungi regulate the activity of the glucose repressor by controlling its nuclear translocation.

Ascomycota↗

PubMed2004

A membrane transport defect leads to a rapid attenuation of translation initiation in Saccharomyces cerevisiae.

Transport of lipids and proteins is a highly regulated process, which is required to maintain the integrity of various intracellular organelles in eukaryotic cells. Mutations along the yeast secretory pathway repress transcription of rRNA, tRNA, and ribosomal protein genes. Here, we show that these mutations also lead to a rapid and specific attenuation of translation initiation that occurs prior to the transcriptional inhibition of ribosomal components. Using distinct vesicular transport mutants and chlorpromazine, we have identified the eIF2alpha kinase Gcn2p and the eIF4E binding protein Eap1p as major mediators of the translation attenuation response. Finally, in chlorpromazine-treated cells, this response does not require Wsc1p or the protein kinase Pkc1p, both of which are upstream of the transcriptional repression of ribosomal components. Altogether, our results suggest that yeast cells not only evolved a transcriptional but also a translational control to assure efficient attenuation of protein synthesis when membranes are stressed.

Cells, Cultured↗

PubMed1990

cDNA cloning of androgen-repressed mRNA in rat seminal vesicles: partial characterization of a cDNA clone, pSvr-1.

When the in vitro translation products of mRNAs from castrated animals (48 h) were compared with those from androgen-treated animals (48 h) to survey the molecular mechanism of androgen-responsive gene expressions in the rat seminal vesicles, some peptide bands which were repressed in response to androgen were observed. From these findings, we constructed a partial cDNA library of poly(A+)RNAs which had been isolated from the seminal vesicles of castrated rats (48 h) and modestly enriched with respect to the concentration of androgen-repressed mRNAs by sucrose density gradient centrifugation, and screened by differential colony hybridization. One cDNA clone, pSvr-1, whose mRNA is markedly induced within 24 h after castration of the animal in the seminal vesicles as well as in the ventral prostate, was isolated. pSvr-1 hybridized to a mRNA of 1,700 nucleotides in length. Partial sequence analysis showed that this clone had highly homologous but not identical sequences to those reported for rat sulfated glycoprotein-2. This cDNA clone may provide a useful probe for the study of the negative regulation mechanism of gene expression by androgens.

Androgens↗

PubMed2005

Global gene repression in hepatocellular carcinoma and fetal liver, and suppression of dudulin-2 mRNA as a possible marker for the cirrhosis-to-tumor transition.

BACKGROUND/AIMS: Whether the transcriptional reprogramming process induced by hepatocellular carcinoma recapitulates that of the developing liver is at present unclear. METHODS: With a complete coverage of the liver transcriptome by microarray using adult livers as controls, we searched for similarities and differences in mRNA abundances between hepatocellular carcinoma nodules and fetal livers taken before (early) or after (late) the 22-24th week of gestation. Changes in some mRNA levels were studied in further liver samples by quantitative RT-PCR. RESULTS: Altered gene expression in hepatocellular carcinoma mostly results in down-regulated mRNAs which largely overlap with those repressed in the late fetal liver. Different frequencies of transcription factor binding sites in the down-regulated genes vs control genes as well as changes in abundance of mRNAs for relevant transcription factors point to a transcriptional repression. The down-regulated mRNAs code for proteins involved in (i) transcription and translation, (ii) specific functions of the differentiated hepatocyte or (iii) activation of proliferation and apoptosis. CONCLUSIONS: Apoptosis limitation is likely to predominate over active proliferation during liver development and hepatocellular carcinoma. Repression of the apoptosis-associated dudulin-2 mRNA points to a potential marker for the transition from a carcinoma-free to carcinoma-associated cirrhosis.

Aged↗

PubMed1990

cis-acting sequences involved in the translational control of GCN4 expression.

Four short upstream open reading frames (uORFs) in the mRNA leader are required for the translational control of GCN4 expression in response to amino acid availability. Data are reviewed demonstrating that the fourth (3' proximal) uORF is sufficient to establish the repressed levels of GCN4 expression, while the first uORF functions as a positive regulatory element under starvation conditions to stimulate GCN4 translation. Furthermore, positive and negative trans-acting regulatory factors, the activities of which appear to be modulated according to amino acid availability, exert their effects on GCN4 expression through the uORFs. Direct comparison of the uORFs indicates that there are important nucleotide sequence differences between uORF1 and 4, and that these are located primarily around the termination codons of these elements. Recent findings suggest that the sequences that mediate repression of GCN4 expression are complex, but can be overcome under starvation conditions by ribosomes that have previously translated uORF1.

Alleles↗

PubMed1990

Molecular genetics of a three-gene cluster in the Amy region of Drosophila.

Analysis of amylase RNA levels in the anterior and posterior midgut regions of flies from the Amy1,6 mapA and c Amy2,3 mapC strains of D. melanogaster, reared on yeast and on yeast supplemented with glucose, indicates that the trans-acting map gene controls the abundance of amylase RNA tissue-specifically, i.e., in the adult posterior midgut. This is consistent with the view that its role in controlling Amy expression is that of a transcription factor. Dietary glucose represses Amy expression in the anterior and posterior midgut regions of adults, reducing the abundance of amylase RNA, which suggests that it also controls Amy transcriptional activity. However, the mechanism for glucose repression appears to act systemically in the midgut, in a manner that is independent of the effects of map on Amy expression. A new glucose repressible TU was identified that is located just proximal to the Amy locus in region 54A of polytene chromosome 2R. It is transcribed in the direction opposite to that of the proximal Amy gene and encodes an RNA about 1500 bases long. Its RNA is expressed in both larvae and adults of the above strains of D. melanogaster, but the nature of the product it encodes is unknown. We speculate that all three genes in the cluster at 54A, namely the two Amy gene copies and the new glucose repressible TU, are coordinately controlled by the same mechanism that regulates Amy gene expression in response to dietary glucose. Somatic transformation experiments suggest that 5' cis-regulatory mechanisms required for the correct spatial expression of the proximal and distal Amylase genes from a Canton-S strain of D. melanogaster, Amy-p1 and Amy-d3, are located within 450 bp and 463 bp of their respective translation start sites. These regions also contain sequences responsive to dietary glucose repression, which is mediated at the DNA level of exogenous Amy genes in somatically transformed larvae reared on a yeast + glucose diet. A positive activator is located in the upstream region of Amy-d3 between the nucleotide pairs at -365 and -252 from the translation start site, but a comparable activator does not appear to exist in the upstream region of Amy-p1. Deletion analysis of the 5' sequence flanking the coding region of Amy-d3 indicates 125 nucleotide pairs of flanking DNA is sufficient for its functional activity. A model is proposed for coordinate control, in part, of the duplicated Amy genes.

Amylases↗

PubMed1991

Suppression of ribosomal reinitiation at upstream open reading frames in amino acid-starved cells forms the basis for GCN4 translational control.

GCN4 encodes a transcriptional activator of amino acid-biosynthetic genes in Saccharomyces cerevisiae that is regulated at the translational level by upstream open reading frames (uORFs) in its mRNA leader. uORF4 (counting from the 5' end) is sufficient to repress GCN4 under nonstarvation conditions; uORF1 is required to overcome the inhibitory effect of uORF4 and stimulate GCN4 translation in amino acid-starved cells. Insertions of sequences with the potential to form secondary structure around uORF4 abolish derepression, indicating that ribosomes reach GCN4 by traversing uORF4 sequences rather than by binding internally to the GCN4 start site. By showing that wild-type regulation occurred even when uORF4 was elongated to overlap GCN4 by 130 nucleotides, we provide strong evidence that those ribosomes which translate GCN4 do so by ignoring the uORF4 AUG start codon. This conclusion is in accord with the fact that translation of a uORF4-lacZ fusion was lower in a derepressed gcd1 mutant than in a nonderepressible gcn2 strain. We also show that increasing the distance between uORF1 and uORF4 to the wild-type spacing that separates uORF1 from GCN4 specifically impaired the ability of uORF1 to derepress GCN4 translation. As expected, this alteration led to increased uORF4-lacZ translation in gcd1 cells. Our results suggest that under starvation conditions, a substantial fraction of ribosomes that translate uORF1 fail to reassemble the factors needed for reinitiation by the time they scan to uORF4, but become competent to reinitiate after scanning the additional sequences to GCN4. Under nonstarvation conditions, ribosomes would recover more rapidly from uORF1 translation, causing them all to reinitiate at uORF4 rather than at GCN4.

Amino Acids↗

PubMed1982

Overlapping genes at the DNA primase locus of the large plasmid ColI.

The sog gene of the large plasmid ColIdrd-1 has previously been shown to encode a DNA primase and a smaller antigenically related polypeptide. Genesis of these two products has been examined using Sog+ recombinant plasmids. Effects of amber mutations, isolated after in vitro mutagenesis, and deletions into or within sog suggest that the smaller polypeptide is a separate translation product which is encoded by DNA specifying the C-terminal region of the larger protein. Under control of the lac promotor, synthesis of both polypeptides is reduced when transcription is repressed. These findings imply that transcription of sog yields a single transcript which is translated from two initiation sites.

Acetyltransferases↗

PubMed1986

Genetic definition of the translational operator of the threonine-tRNA ligase gene in Escherichia coli.

The Escherichia coli gene thrS that codes for threonine-tRNA ligase (tRNAThr ligase, formerly threonine-tRNA synthetase, EC 6.1.1.3) has previously been shown to be negatively autoregulated at the level of translation. Here we describe the use of several thrS-lac gene fusions to isolate cis-acting regulatory mutations that increase the translation but not the transcription of the thrS gene. These mutations lead to a total loss of control of repression and derepression of thrS. DNA sequence analysis locates the mutations between 10 and 40 base pairs upstream of the translation initiation codon of thrS and more than 100 base pairs downstream of the transcription initiation site. The mRNA region where these mutations are located shares primary and secondary structure homologies with specific parts of several isoacceptor tRNAThr species. These findings suggest that the ligase regulates its translation by binding to its mRNA at a place that shares some homology with its natural substrate.

Amino Acyl-tRNA Synthetases↗

PubMed1996

Translational coupling in the Escherichia coli operon encoding translation initiation factor IF3 and ribosomal proteins L20 and L35.

The Escherichia coli IF3-L35-L20 operon encodes translation initiation factor IF3 and the ribosomal proteins L35 and L20, respectively. The expression of the genes encoding the two ribosomal proteins is negatively regulated at the translational level by L20, which acts at an operator located within the IF3 gene and just upstream of the L35 gene. We have previously shown that L20 directly represses the expression of the L35 gene, and indirectly that of the L20 gene, via translational coupling. On the basis of mutational analysis and in vitro RNA structure probing experiments, we proposed that a large secondary structure in which the translation initiation site of the L20 gene is sequestered by base-pairing, is responsible for coupling. The ribosome binding site of the L20 gene becomes available when the secondary structure is melted by ribosomes translating the L35 mRNA. Here we describe that this secondary structure forms in vivo by showing that single mutations in either strand reduce coupling and that compensatory mutations that re-establish pairing also re-establish coupling. In vitro 'toeprinting' analysis enabled us to show that the wild-type inhibitory secondary structure directly blocks ribosome binding to the ribosome binding site of rpIT.

Bacterial Proteins↗

PubMed2000

Groucho/TLE family proteins and transcriptional repression.

The Drosophila Groucho (Gro) protein is the prototype for a large family of corepressors, examples of which are found in most metazoans. This family includes the human transducin-like Enhancer of split (TLE) proteins. As corepressors, Gro/TLE family proteins do not bind to DNA directly, but rather are recruited to the template by DNA-bound repressor proteins. Gro/TLE family proteins are required for many developmental processes, including lateral inhibition, segmentation, sex determination, dorsal/ventral pattern formation, terminal pattern formation, and eye development. These proteins are characterized by a conserved N-terminal glutamine-rich domain and a conserved C-terminal WD-repeat domain. The primary role of the glutamine-rich domain is apparently to mediate tetramerization, while the WD-repeat domain may mediate interactions with DNA-bound repressors. The glutamine rich and WD-repeat domains are separated by a less conserved region containing domains that have been implicated in transcriptional repression and nuclear localization. In addition to encoding full-length Gro/TLE family proteins, most metazoan genomes encode truncated family members that contain the N-terminal oligomerization domain, but lack the C-terminal WD-repeat domain. These truncated proteins may negatively regulate full-length Gro/TLE proteins, perhaps by sequestering them in non-productive complexes. Gro/TLE family proteins probably repress transcription by multiple mechanisms. For example, a glycine/proline-rich domain in the central variable region functions to recruit the histone deacetylase Rpd3 to the template. This histone deacetylase then presumably silences transcription by altering local chromatin structure. Other repression domains in Gro may function in a histone deacetylase-independent manner. Many aspects of Gro/TLE protein function remain to be explored, including the possible post-translational regulation of Gro/TLE activity as well as the mechanisms by which Gro/TLE proteins direct repression at a distance.

Animals↗

PubMed1999

Transcriptional regulation of the Bacillus ohbensis cyclodextrin glucanotransferase gene in B. subtilis.

The expression of the cyclodextrin glucanotransferase (CGTase) gene (cgt) of Bacillus ohbensis, when introduced into an alpha-amylase-defective strain of B. subtilis on a multicopy plasmid, pHY300PLK, was induced in the presence of starch and was subject to catabolite repression by glucose as well as in the original strain, B. ohbensis. We constructed a cgt'::'lacZ translational fusion to study the expression in B. subtilis, and this construct was confirmed to be subject to both starch induction and catabolite repression. In order to define the region involved in the regulation of the cgt gene, a series of cgt'::'lacZ gene with various lengths of deletion in the promoter region was constructed on pHY300PLK. DNA regions responsible for starch induction and catabolite repression by glucose could be separated in the deletion experiment. Primer extension analysis showed that the catabolite repression was controlled at the initiation of transcription, while the starch induction is likely to be controlled by a transcriptional termination-antitermination mechanism.

5' Untranslated Regions↗