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PubMed1993

Translational control of ornithine-delta-aminotransferase (OAT) by estrogen.

Ornithine-delta-aminotransferase (OAT) catalyzes the reversible transamination of ornithine to glutamate semialdehyde. OAT is abundant in liver, kidney and retina; hereditary deficiency of the enzyme leads to chorioretinal degeneration. Studies of OAT regulation in retinoblastomas have revealed an alternatively spliced OAT mRNA, which contains an additional exon (exon 2) in the 5' untranslated region. Estrogen and thyroid hormone were previously shown to increase OAT mRNA levels approximately 3-fold and 5-fold, respectively, in these cells. To determine the mechanism of hormonal action in retinoblastomas, we performed nuclear transcription assays and analyzed the distribution of OAT mRNAs in individual fractions of a polysome gradient. Thyroid hormone increased the rate of transcription of the OAT mRNA in these cells. Estrogen did not stimulate transcription; it was associated with increased translation, since it resulted in a shift of the major (spliced) OAT mRNA species into denser fractions of the polysome gradient. Cycloheximide treatment suggested that the latter effect was due to increased initiation of translation. The unspliced OAT mRNA, which is inefficiently compared to the spliced mRNA, was insensitive to estrogen in these experiments.

Alternative Splicing↗
PubMed2003

Fibroblast growth factor 2-mediated translational control of IAPs blocks mitochondrial release of Smac/DIABLO and apoptosis in small cell lung cancer cells.

The mitochondrial release of cytochrome c and Smac/DIABLO has been implicated in the activation of apoptosis in response to cell stress. Smac promotes cytochrome c-induced activation of caspases by sequestering the inhibitor of apoptosis protein (IAP) family of potent caspase suppressors. Differential release from mitochondria of cytochrome c and Smac can occur, but the underlying mechanism and physiological significance of this are unclear. Here we show that the mechanism by which fibroblast growth factor 2 (FGF-2) protects small cell lung cancer (SCLC) cells from etoposide-induced cell death involves inhibition of Smac release but not of cytochrome c release. This process is MEK dependent and correlates with an increased expression of XIAP and cellular IAP-1, mediated principally through translational regulation. Exogenous expression of XIAP is sufficient to inhibit caspase 9 activation, Smac release, and cell death induced by etoposide. Prevention of the FGF-2-promoted increase in levels of functional IAPs by RNA interference or the cell-permeant Smac amino-terminal peptide blocked FGF-2-induced protection. FGF-2 can thus protect SCLC cells from chemotherapeutic drugs by modulating IAP levels via posttranscriptional regulation, providing a mechanism for postmitochondrial survival signaling by the MEK/mitogen-activated protein kinase pathway.

Apoptosis↗
PubMed1986

Translational control of exported proteins in Escherichia coli.

We recently described the suppression of export of a class of periplasmic proteins of Escherichia coli caused by overproduction of a C-terminal truncated periplasmic enzyme (GlpQ'). This truncated protein was not released into the periplasm but remained attached to the inner membrane and was accessible from the periplasm. The presence of GlpQ' in the membrane strongly reduced the appearance in the periplasm of some periplasmic proteins, including the maltose-binding protein (MBP), but did not affect outer membrane proteins, including the lambda receptor (LamB) (R. Hengge and W. Boos, J. Bacteriol., 162:972-978, 1985). To investigate this phenomenon further we examined the fate of MBP in comparison with the outer membrane protein LamB. We found that not only localization but also synthesis of MBP was impaired, indicating a coupling of translation and export. Synthesis and secretion of LamB were not affected. The possibility that this influence was exerted via the level of cyclic AMP could be excluded. Synthesis of MBP with altered signal sequences was also reduced, demonstrating that export-defective MBP which ultimately remains in the cytoplasm abortively enters the export pathway. When GlpQ' was expressed in a secA51(Ts) strain, the inhibition of MBP synthesis caused by GlpQ' was dominant over the precursor accumulation usually caused by secA51(Ts) at 41 degrees C. Therefore, GlpQ' acts before or at the level of recognition by SecA. For LamB the usual secA51(Ts) phenotype was observed. We propose a mechanism by which GlpQ' blocks an yet unknown membrane protein, the function of which is to couple translation and export of a subclass of periplasmic proteins.

ATP-Binding Cassette Transporters↗
PubMed1989

Translational control of germ cell-expressed mRNA imposed by alternative splicing: opioid peptide gene expression in rat testis.

The three genes encoding the opioid peptide precursors (prodynorphin, proenkephalin, and proopiomelanocortin) are expressed in the rat testis. The sizes of the three opioid mRNAs in the testis differ from the sizes of the corresponding mRNAs in other rat tissues in which these genes are expressed. The smaller testicular proopiomelanocortin mRNA has previously been demonstrated to arise from alternative transcriptional initiation. In the present study, we found that the smaller testicular prodynorphin mRNA, expressed in Sertoli cells, results from alternative mRNA processing. Exon 2, which makes up 5' untranslated sequence, is removed from the mature transcript. Polysome analysis of brain and testis RNA indicates that the alteration of the prodynorphin leader sequence in the testis-specific transcript does not affect the efficiency of translation of this mRNA. The larger testicular proenkephalin transcript, expressed in developing germ cells, also results from alternative mRNA processing. Alternative acceptor site usage in the splicing of intron A results in a germ cell-specific proenkephalin transcript with a 491-nucleotide 5' untranslated leader sequence preceding the preproenkephalin-coding sequence. Polysome analysis indicates that this germ cell-specific proenkephalin mRNA is not efficiently translated. Mechanisms by which alternative mRNA splicing may serve to confer translational regulation upon the testicular proenkephalin transcript are discussed.

Animals↗
PubMed1994

Down-regulation of human adenovirus E1a by E3 gene products: evidence for translational control of E1a by E3 14.5K and/or E3 10.4K products.

The mechanism for down-regulation of E1a expression by products encoded in the E3 transcription unit of human adenovirus types 2 and 5, that occurs in infected L929 cells, has been investigated further. We show that the phenomenon occurs in different mouse cells and also in some human cells suggesting that the observations have relevance to natural human infections. We also provide evidence that probably all viral proteins are down-regulated by E3 products, although to different extents, but that host proteins are unaffected. Whereas E1a protein levels and synthesis are reduced in the presence of E3 products, E1a protein half-life and polysomal E1a RNA levels and size distribution are not. These data suggest that E3 products down-regulate E1a protein levels by interfering with the translation of E1a-specific mRNA. Studies were additionally carried out with mutant adenoviruses containing different defects in the E3 transcription unit. Based on these studies it seems likely that the E3 14.5K and 10.4K proteins are crucially involved in E1a down-regulation. Our data are discussed in terms of strategies for immune evasion by group C human adenoviruses.

Adenovirus E1A Proteins↗
PubMed1987

Regulated expression of multiple chicken erythroid membrane skeletal protein 4.1 variants is governed by differential RNA processing and translational control.

Protein 4.1 is an extrinsic membrane protein that facilitates the interaction of spectrin and actin in the erythroid membrane skeleton and exists as several structurally related polypeptides in chickens. The ratio of protein 4.1 variants is developmentally regulated during terminal differentiation of chicken erythroid and lenticular cells. To examine the mechanisms by which multiple chicken protein 4.1 variants are differentially expressed, we have isolated cDNA clones specific for chicken erythroid protein 4.1. We show that a single protein 4.1 gene gives rise to multiple 6.6-kilobase mRNAs by differential RNA processing. Furthermore, the ratios of protein 4.1 mRNAs change during chicken embryonic erythropoiesis. We observe a quantitative difference in variant ratios when protein 4.1 is synthesized in vivo or in a rabbit reticulocyte lysate in vitro. Our results show that the expression of multiple protein 4.1 polypeptides is regulated at the levels of translation and RNA processing.

Amino Acid Sequence↗
PubMed2005

In vitro and in vivo effects of deoxynivalenol (DNV) on regulators of cap dependent translation control in porcine endometrium.

Deoxynivalenol (DNV) is the most frequently encountered trichothecene in grain-based foods, and is able to produce toxic effects resulting in various diseases in farm and laboratory animals. The molecular mechanisms that control this mycotoxin mediated effects in porcine endometrial cells are far from being completely understood. Recent results show that DNV inhibits protein synthesis in actively proliferating tissues. Therefore, the present study investigated the effects of this mycotoxin on a cellular level in an in vivo and in vitro system. The abundance and phosphorylation state (activity) of the cell cycle dependent kinases MAPk and Akt (PKB) and their potential targets eIF-4E (eukaryotic initiation factor 4E) and 4E-BP1 (4E binding protein, eIF4E repressor protein) were examined. In previous investigations it was found that these factors are involved in initiation of mRNA translation. The results show that DNV in vitro strongly reduce the abundance of p38 MAPk, protein kinase Akt and the alpha- and beta-4E-BP1 bands. The phosphorylation state of these proteins was obviously not modulated. In contrast, the eIF4E phosphorylation was strongly reduced in DNV treated cells. In summary, our in vitro results let assume that DNV potentially influences gene expression, but this work does not present a direct proof that DNV alters processes, which are involved in the initiation of mRNA translation. Surprisingly in vivo, an influence of DNV feeding on the investigated molecular events could not be demonstrated.

Animals↗
PubMed1996

Characterization of the tol-pal region of Escherichia coli K-12: translational control of tolR expression by TolQ and identification of a new open reading frame downstream of pal encoding a periplasmic protein.

The TolQ, TolR, TolA, TolB, and Pal proteins appear to function in maintaining the integrity of the outer membrane, as well as facilitating the uptake of the group A colicins and the DNA of the infecting filamentous bacteriophages. Sequence data showed that these genes are clustered in a 6-kb segment of DNA with the gene order orf1 tolQ tolR tolA tolB pal orf2 (a newly identified open reading frame encoding a 29-kD9 protein). Like those containing orf1, bacteria containing an insertion mutation in this gene showed no obvious phenotype. Analysis of beta-galactosidase activity from fusion constructs in which the lac operon was fused to various genes in the cluster showed that the genes in this region constitute two separate operons: orf1 tolQRA and tolB pal orf2. In the orf1 tolQRA operon, translation of MR was dependent on translation of the upstream tolQ region. Consistent with this result, no functional ribosome-binding site for TolR synthesis was detected.

Amino Acid Sequence↗
PubMed1998

Translational control of MHC class II I-A molecules by IFN-gamma.

MHC class II molecules are expressed in a limited number of cell types, including B lymphocytes and macrophages (M phi). IFN-gamma increases the surface expression of class II molecules in a murine B cell line without inducing detectable changes in either I-A or I-A mRNA levels. In bone marrow-derived M phi, IFN-gamma causes an increase in class II expression at both the mRNA and surface levels. In addition to the increase in transcription rates described for M phi, IFN-gamma increases the rate of synthesis of IA alpha and IA beta proteins and the ribosome loading for both mRNA molecules in both cell types. Interestingly, there is a significant peak of free I-A mRNA in noninduced cells. Therefore, IFN-gamma regulates the expression of MHC class II molecules at the translational level in both B cells and M phi and, as already reported, at the transcriptional level only in M phi. The actual mechanism of regulation causes changes in the translation initiation rates in both cell types, as demonstrated by an increase in ribosome loading in polysome gradients.

Animals↗
PubMed2004

Sequence analysis of twin ATP binding cassette proteins involved in translational control, antibiotic resistance, and ribonuclease L inhibition.

Genome sequencing has identified open reading frames which belong to the ATP binding cassette (ABC) transporter family, but which are unlikely to be involved in transport phenomena. These frequently contain a pair of nucleotide binding domains (NBD) with no associated transmembrane domains. The functions of many of these twin-NBD proteins remain unknown. In this manuscript, sequence analysis has been employed to analyse two families of twin-NBD proteins, ABCE and ABCF. The ABCE proteins, postulated to be inhibitors of RNase L, are identified by two potential Fe-S metal-binding domains in addition to two NBDs. Surprisingly, ABCE homologues are identified in numerous species which apparently lack an RNase L, questioning the proposed function of these proteins. The ABCF proteins can be sub-divided into more than a dozen sub-classes. Intriguingly, sequence similarity is shown between eukaryotic ABCF proteins, which are involved in translation initiation and elongation, and prokaryotic ABCF proteins which are implicated in resistance to macrolide inhibitors of protein synthesis.

ATP-Binding Cassette Transporters↗
PubMed1975

Parameters of gene expression in the bipolar argECBH operon of E. coli K12. The question of translational control.

The pattern of divergent transcription of the argEC BH cluster of genes previously demonstrated by the hybridization of RNA to the separated strand of a phi 80 darg transducing phage, is confirmed with the DNA of a set of different lambdadarg phages. The accurate determination of argE and argCBH m-RNA levels in different steady states of expression of the arg regulon supports the following conclusions: 1. The ratio between maximal (derepressed) and minimal (repressed) rates of expression is lower when it is expressed in terms of % hybridizable RNA than in terms of expression is lower when it is expressed in terms of % hybridizable RNA than in terms of enzyme specific activities. The discrepancy is about 3 fold. Thus in conditions of repression, the cell produces relatively more unused m-RNA than in derepression. Different interpretations of this phenomenon appear possible: a) the messenger RNA molecules synthesized in repressed cells could be degraded more rapidly or translated less efficiently than in derepressed cells. b) an untranslated segment of the RNA could account for a larger part of the RNA detected in repression than in derepression. These interpretations are not mutually exclusive. 2. The discrepancy observed between the amplitudes of variation of argE and argC BH expression, expressed in terms of enzyme specific activities, is, in fact, determined at the level of DNA transcription. This provides direct evidence for the occurrence of differential transcription effectiveness in a regulon exhibiting a correlative but not strictly coordinated pattern of enzyme synthesis. This also supports our earlier suggestion regarding the possible complexity of the internal operator region situated between argE and C.

Arginine↗
PubMed2003

Translational control of inducible nitric oxide synthase expression by arginine can explain the arginine paradox.

L-Arginine is the only endogenous nitrogen-containing substrate of NO synthase (NOS), and it thus governs the production of NO during nervous system development as well as in disease states such as stroke, multiple sclerosis, Parkinson's disease, and HIV dementia. The "arginine paradox" refers to the dependence of cellular NO production on exogenous L-arginine concentration despite the theoretical saturation of NOS enzymes with intracellular L-arginine. Herein, we report that decreased availability of L-arginine blocked induction of NO production in cytokine-stimulated astrocytes, owing to inhibition of inducible NOS (iNOS) protein expression. However, activity of the promoter of the iNOS gene, induction of iNOS mRNA, and stability of iNOS protein were not inhibited under these conditions. Our results indicate that inhibition of iNOS activity by arginine depletion in stimulated astrocyte cultures occurs via inhibition of translation of iNOS mRNA. After stimulation by cytokines, uptake of L-arginine negatively regulates the phosphorylation status of the eukaryotic initiation factor (eIF2 alpha), which, in turn, regulates translation of iNOS mRNA. eIF2 alpha phosphorylation correlates with phosphorylation of the mammalian homolog of yeast GCN2 eIF2 alpha kinase. As the kinase activity of GCN2 is activated by phosphorylation, these findings suggest that GCN2 activity represents a proximal step in the iNOS translational regulation by availability of l-arginine. These results provide an explanation for the arginine paradox for iNOS and define a distinct mechanism by which a substrate can regulate the activity of its associated enzyme.

Animals↗
PubMed1996

Final checkpoint in the drug-promoted and poliovirus-promoted apoptosis is under post-translational control by growth factors.

The treatment of HeLa subline (HeLa-B) cells with cycloheximide or Actinomycin D resulted in a rapid (approximately 1.5 h and approximately 2.5 h, respectively) development of morphological and biochemical signs of apoptosis. The addition of fetal bovine serum to the cycloheximide-treated or Actinomycin D-treated cells suppressed the apoptotic reaction, as evidenced by the postponement of the DNA fragmentation for at least 9 and 5 h, respectively. A similar suppressive effect was observed upon the serum addition to cells undergoing abortive infection with poliovirus, which died of apoptosis in the absence of the serum. The serum appeared to exert its anti-apoptotic effect without any appreciable lag and even immediately blocked further progress of ongoing DNA fragmentation. The epidermal growth factor also suppressed, although less efficiently and more transiently, the apoptotic reaction promoted by the metabolic inhibitors. It is concluded that growth factors may affect, without modulating either transcription or translation, the balance of pro-apoptotic and anti-apoptotic activities at a final checkpoint, just preceding the irreversible effector step of apoptosis.

Apoptosis↗
PubMed1979

Evidence for translational control of the binding of 7, 12-dimethylbenz[a]anthracene to DNA of murine epidermal cell in culture.

The effects of various inhibitors of aryl hydrocarbon hydroxylase (AHH), antioxidants, inhibitors of DNA, RNA, and protein synthesis, and protease inhibitors on the binding of [7,12-3H]dimethylbenz[a]anthracene ([3H] DMBA) to DNA of murine epidermal cells in culture have been investigated. 7,8-Benzoflavone, 5,6-benzoflavone and methyrapone (inhibitors of AAH) and antioxidants, butylated hydroxyanisole (BHA) and butylated hydroxytoluene (BHT), efficiently reduced the binding of [3H] DMBA to cellular DNA. Inhibitors of DNA and RNA synthesis did not affect this process whereas inhibitors of protein synthesis suppressed the binding of [3H] DMBA to cellular DNA. Protease inhibitors p-tosylamide-2-phenylchloromethyl ketone (TPCK) and p-tosyl-L-lysine chloromethyl ketone (TLCK) also reduced the interaction between DMBA and DNA. Thus, it appears that binding of DMBA to cellular DNA is regulated at the level of translation or/and post translation.

9,10-Dimethyl-1,2-benzanthracene↗
PubMed1985

Expression of the Drosophila 70,000 Dalton heat shock protein is translationally controlled in yeast.

Plasmid pPW229, containing the 2.25 kilobase transcribed sequence for the 70,000 Dalton heat shock protein of Drosophila, was integrated into plasmid CV13 and used to transform Saccharomyces cerevisiae. Upon a heat shock, at 41 degrees C for 20 min, a new 70,000 Dalton protein appeared in the transformants. This protein was not detected in transformants grown at 23 degrees C, nor in transformants carrying the hybrid plasmid from which the structural gene for the 70,000 Dalton protein had been deleted. RNA was isolated from transformants grown at 23 degrees C and from transformants heat shocked at 41 degrees C. RNA complementary to the Drosophila heat shock gene was present in the transformants, grown either at 23 degrees C or heat shocked. No complementary RNA was detected in yeast cells transformed with the hybrid plasmid from which the structural gene had been deleted. The Drosophila heat shock gene in yeast appears to be transcribed constitutively but translated only under heat shock conditions.

Animals↗
PubMed1982

Translational control of bacteriophage f1 gene II and gene X proteins by gene V protein.

The gene II region of bacteriophage f1 DNA codes for two proteins, the 46 kd gene II protein and the 13 kd gene X protein, which results from an in-phase start at codon 300 of gene II. Using antigene II protein IgG, we show that the intracellular concentration of both proteins is controlled by the phage gene V protein. In wild-type f1-infected cells, the amount of gene II protein reaches a plateau of about 1500 molecules per cell at 20 min after infection, as measured by blot immunoassay. Similarly, the amount of gene X protein reaches a peak of about 500 molecules per cell around 10 min after infection. In contrast, when the gene V protein is inactive, both gene II and gene X proteins continue to accumulate at a high rate for at least 40 min after infection. This difference is caused by decreased synthesis of gene II and gene X proteins in the presence of gene V protein, which represses the translation of these two proteins.

Antibodies, Viral↗
PubMed2006

TNF receptor deficiency reveals a translational control mechanism for adriamycin-induced Fas expression in cardiac tissues.

Adriamycin, ADR, a potent chemotherapeutic agent, has been demonstrated to cause cardiomyocyte apoptosis, in part, via the Fas/Fas ligand-mediated cell death pathway. Our previous studies suggested that TNF-alpha receptors may mediate cardioprotection against ADR toxicity by the suppression of the Fas-mediated pathway. However, the role of TNF-alpha receptors in this process is unclear. In the present study, we extended our initial observation to determine the molecular mechanisms by which ADR induced Fas expression in the presence and absence of TNF receptors. Our results demonstrated that ADR-mediated p53 and AP-1 interaction and increased Fas mRNA levels independent of TNF receptors. However, the levels of Fas proteins only increased in the cardiac tissues of TNF receptor-deficient mice. These results demonstrated that the suppression of ADR-induced Fas expression by TNF receptors was not regulated at transcriptional levels, but may be regulated at a translational level.

Animals↗