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PubMed2004

Influence of the mycotoxins alpha- and beta-zearalenol (ZOL) on regulators of cap-dependent translation control in pig endometrial cells.

The molecular mechanisms that control the mycotoxin-mediated effects in porcine endometrial cells are far from being completely understood. Recent results show that they could inhibit cell proliferation. Therefore, the present study investigated the effects of the mycotoxins alpha-zearalenol (alpha-ZOL) and beta-zearalenol (beta-ZOL) on a cellular level. Mainly, the abundance and phosphorylation state (activity) of the cell cycle-dependent kinases MAPK and Akt (PKB) and their potential targets eIF4E (eukaryotic initiation factor 4E) and 4E-BP1 (4E binding protein, eIF4E repressor protein) were investigated. The results show that alpha-ZOL has apparently only a slight influence on the phosphorylation state of MAP kinases, Akt and on eIF4E and 4E-BP1. In contrast, their phosphorylation was strongly reduced in beta-ZOL-treated cells in a concentration-dependent manner. Therefore, our results indicate that beta-ZOL potentially not only influences transcription but also effects gene expression on translational level. The effect of alpha- and beta-ZOL on endometrial cell proliferation and their toxicology are discussed.

Animals↗
PubMed1990

A region of the 5' noncoding region of foot-and-mouth disease virus RNA directs efficient internal initiation of protein synthesis within cells: involvement with the role of L protease in translational control.

Plasmids encoding bicistronic mRNAs have been constructed and used to identify a region from the 5' noncoding region of foot-and-mouth disease virus (FMDV) which directs efficient internal initiation of protein synthesis within cells. The loss of about 30 nucleotides (nt) from the 5' terminus or about 50 nt from the 3' terminus of the 435-nt region completely abolished the activity of this region. The expression of the FMDV L protease severely inhibited the expression of other genes unless they were preceded by this element. The regulation of protein synthesis mediated by FMDV is discussed.

Animals↗
PubMed1975

Regulation of ornithine decarboxylase in 3T3 cells by putrescine and spermidine: indirect evidence for translational control.

Addition of putrescine of spermidine prevents the increase in ornithine decarboxylase activity in cultures of 3T3 cells brought about by pituitary growth factors and results in a rapid, specific, and reversible reduction of enzyme activity in cultures previously stimulated by the growth factors. These effects are not due to polyamine toxicity and do not require other organic medium components. The amines apparently share a single carrier-mediated transport system in 3T3 cells. Methylglyoxal bis(guanylhydrazone), an inhibitor of spermidine synthesis from putrescine was found to also inhibit uptake of each amine. Studies with this drug indicate that each amine is effective without further metabolism. Since ornithine decarboxylase activity decays more rapidly in the presence of each polyamine after addition of camptothecin, the major locus of amine action appears to be in the cytoplasm. However, direct inhibition of the enzyme in vivo by assimilated amines appears to account for at most a small part of the reduction in activity, a conclusion supported by the inability to recover activity in vitro. Also, neither amine seems to act by accelerating enzyme inactivation. When amines are removed from the medium, the subsequent recovery of enzyme activity is totally prevented by trichodermin, an inhibitor of protein synthesis, but is only slightly reduced by camptothecin. It is suggested that both putrescine and spermidine reduce ornithine decarboxylase activity by selectively inhibiting translation.

Camptothecin↗
PubMed1989

Neurospecific translation control and the problem of potent danger of drugs and chemicals: a caution.

At present, chemicals are an integral part of the surrounding biosphere. A great number of new xenobiotics for industrial, pharmaceutical, agricultural, or mode-of-life daily use (perfumes, cosmetics, food additives, etc.) may play a role of a danger health hazards. These chemicals may be environmental pollutants and due to this circumstance they promote different ecological disorders including the several epidemic-like processes such as, for instance, Minamata disease (chronic alimentary poisoning with methyl mercury), etc. Also, these chemicals may be industrial hazards promoting the origin and development of various occupational diseases. Finally, the numerous side effects of multiple new drugs may serve as causes of a number of different health disorders. Briefly, we must agree that modern man exists in the world with such inalienable elements as the steadfast increase of chemical soiling of Earths biosphere. Naturally, human health protection in our "chemically soiled" world is very difficult by urgent task. As for the solving of this task, it may be reached only in the case of successful fundamental studies of mechanisms of toxic action of different classes of chemicals performed at different biological levels (systemic, organ/tissue, cellular and molecular levels of research). A separate and special population of modern health-hazardous chemicals is a group of agents which selectively suppress protein synthesis in mammalian cells and tissues due to the direct effect on the translation machinery elements or on the messenger RNA processing steps. The agents of this group ("translation blockers" or, the same but more broadly, "protein synthesis inhibitors" (PSI) usually are quite dangerous for human health since these substances inhibit the central molecular process of life, i.e., the synthesis of protein molecules. The small but important subclass of the PSI is represented by the agents with marked neurotropic properties, i.e., by the agents which are able to promote the effective inhibition of protein synthesis in the brain, while the same agents do not essentially influence the translation processes in the liver and all other organs of the animal (human) organism. The main aim of the present monograph is to review and analyze the data obtained recently in the course of biochemical research of several neurotropic PSI (methyl mercury, lithium salts). However, this is not the single aim of the book. Thus, besides this the present monograph deals with analysis of the general peculiarities of action of some non-neurotrophic inhibitors which are able, nevertheless, to direct a number of specific neurotrophic effects (Cordycepin, tRNA).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1989

Regulation of the biosynthesis of insulin-secretory-granule proteins. Co-ordinate translational control is exerted on some, but not all, granule matrix constituents.

The regulation of the biosynthesis of the insulin-secretory-granule matrix proteins insulin II, chromogranin A and carboxypeptidase H was studied in isolated rat islets of Langerhans. Islets were labelled with [35S]-methionine, and incorporation into total protein was determined by trichloroacetic acid precipitation and that into specific proteins by immunoprecipitation followed by polyacrylamide-gel electrophoresis and fluorography. Islets incubated in the presence of 16.7 mM-glucose incorporated 3 times as much [35S]-methionine into total protein as did islets incubated with 2.8 mM-glucose. The same conditions produced more than a 20-fold increase in incorporation into both proinsulin and chromogranin A, with no observable effect on carboxypeptidase H. The concentration-dependencies of the glucose-stimulated synthesis of chromogranin A and proinsulin were parallel, and in both cases the response to 16.7 mM-glucose was typified by an initial lag of 20 min, followed by a rapid activation to a new steady state over the ensuing 40 min. Synthesis of total protein, although activated to a lesser extent, responded with similar kinetics. Extracellular Ca2+ depletion did not affect the basal or glucose-stimulated biosynthesis of any of the proteins under investigation. Mannoheptulose (20 mM) abolished glucose-stimulated synthesis of insulin, chromogranin A and total protein, but had no effect on the synthesis of carboxypeptidase H. It is concluded that the biosynthesis of insulin and chromogranin A is regulated principally at the translational level by the same intracellular signal generated from the metabolism of glucose. Such regulation is not common to all insulin-secretory-granule proteins, since the synthesis of carboxypeptidase H was unaffected by the same stimulus.

Animals↗
PubMed1993

Relationship between defective mouse mammary tumor virus envelope glycoprotein synthesis and GRP78 synthesis in glucocorticoid-treated mouse lymphoma cells. Evidence for translational control of GRP78 synthesis.

We have found that synthesis of the 78-kDa glucose-regulated protein, GRP78, was increased following glucocorticoid treatment of S49 and W7MG1 mouse lymphoma cell lines. These lines synthesized a 74-kDa mouse mammary tumor virus envelope glycoprotein precursor, Pr74, both constitutively and in response to glucocorticoid treatment. In these cell lines, nascent Pr74 was not processed normally but was retained within the endoplasmic reticulum where it was bound stably by GRP78. GRP78 synthesis was not increased following glucocorticoid treatment of the W7.2 mouse lymphoma cell line, which does not synthesize Pr74, suggesting that the increase in GRP78 synthesis following glucocorticoid treatment of S49 and W7MG1 cells was secondary to the glucocorticoid-induced increase in Pr74 synthesis. Consistent with this hypothesis, the glucocorticoid-induced increase in Pr74 synthesis preceded the increase in GRP78 synthesis. Also, there was a direct correlation between the level of GRP78 synthesis and the level of Pr74 synthesis among multiple subclones of the W7-ENV/N line. This line was derived from the W7.2 line by retroviral mediated transfer of a constitutively expressed sequence encoding a defective form of Pr74 that was bound stably by GRP78 within the endoplasmic reticulum. An elevation in the steady state level of GRP78 mRNA was not detected either in glucocorticoid-treated S49 cells and W7MG1 cells or in subclones of the W7-ENV/N line that have an increased level of GRP78 synthesis. Therefore, it appears that the binding of Pr74 to GRP78 induces an increase in GRP78 synthesis that is regulated at a translational level, rather than at a transcriptional level.

Animals↗
PubMed2000

Cyclic AMP-mediated regulation of GABA(A) receptor subunit expression in mature rat cerebellar granule cells: evidence for transcriptional and translational control.

Exposure of rat cerebellar granule cells cultured to maturity in vitro to forskolin, N6,2'-O-dibutyryladenosine 3',5'-cyclic monophosphate (Bt2cAMP), and 3-isobutyl-1-methylxanthine (IBMX) down-regulated GABA(A) receptor alpha6 and beta3 subunits but up-regulated alpha1 and beta2 subunits with respect to vehicle-treated controls. Dideoxyforskolin had no effect on subunit expression. Protein kinase A inhibitors, H-89 and Rp-adenosine 3',5'cyclic monophosphothioate, prevented these effects on alpha1 but not alpha6 subunit expression. Flunitrazepam-sensitive [3H]Ro 15-4513 binding sites were increased by 144 +/- 20% following forskolin treatment. [3H]Ro 15-4513 photoaffinity labelling showed that the GABA(A) receptor alpha1 subunit was the principal locus of the increased flunitrazepam-sensitive [3H]Ro 15-4513 binding. Forskolin decreased flunitrazepam-insensitive [3H]Ro 15-4513 binding sites by 25 +/- 8% and resulted in a 20% decrease in the irreversible incorporation of radioactivity in the alpha6 subunit. Steady-state levels of GABA(A) receptor subunit mRNAs were determined by semiquantitative RT-PCR in forskolin-treated cultures. Forskolin, Bt2cAMP, and IBMX down-regulated GABA(A) receptor alpha6 subunit mRNA expression; alpha1 and beta3 mRNA levels were unaffected, whereas beta2 subunit mRNA was up-regulated. Dideoxyforskolin had no significant effect on alpha1, alpha6, beta2, and beta3 mRNA levels. Thus, in mature cerebellar granule cells, GABA(A) receptor expression can be regulated by intracellular cyclic AMP levels. This occurs at the level of gene transcription and/or translation by mechanisms that are only partially governed by protein kinase A.

Affinity Labels↗
PubMed1976

Translational control of protein synthesis in stimulated WI-38 fibroblasts.

A cell-free protein synthesis system employing ribosomes from WI-38 human diploid fibroblasts was developed and its optimum MgC12 and KC1 levels and pH value found. The rate at which ribosomes are able to incorporate radioactive leucine into proteins ([14C]leucine incorporation/10 min/100 mug rRNA) and the number of growing peptide chains [3H]puromycinpeptides formed/100 mug rRNA) was determined. When confluent monolayers of WI-38 cells were stimulated to proliferate by serum, a transient increase in the rate of peptide elongation by ribosomes was observed at 60 min after stimulation. This increase was not affected by the presence of actinomycin D (10 mug/ml) in the stimulating medium. A change in the relative amount of certain ribosome-associated proteins accompanied the increased elongation rate of peptide growth. The alteration in associated proteins could not be accounted for by an increased synthesis of protein. Finally, the early activation of ribosomes in stimulated WI-38 cells appears to result from the removal of an inhibitor(s) of ribosome function.

Animals↗
PubMed1998

The RAF family: an expanding network of post-translational controls and protein-protein interactions.

Protein kinase RAF is strategically located in the "Ras-MAP-kinase signal transduction pathway", a principle system which transmits signals from growth factor receptors to the nucleus, resulting in cell proliferation. Growth factor responses are mediated in part by activation of Ras, which in turn activates RAF to phosphorylate MEK, its downstream substrate. MEK activates MAP-kinase to influence nuclear events. It is clear, however, that a network of signals other than those carried by Ras plays a role in RAF regulation. These orthogonal influences are mediated by: serine/threonine kinases, tyrosine kinases, and protein-protein interactions. As a further complication to the RAF network, three isoforms of RAF have been established which have divergent N-terminal regulatory domains. Whereas these divergent regulatory domains implicate isoform-specific functions, no clear evidence or hypothesis for distinct functions for individual isoforms has been presented. Recently, "isoform-specific protein interactions" have been identified among numerous proteins interacting with RAF. These studies may serve to delineate independent functions for RAF isoforms.

14-3-3 Proteins↗
PubMedDate not supplied

Translational control of eukaryotic gene expression. Role of the guanine nucleotide exchange factor and chain initiation factor-2.

In mammalian cells, the guanine nucleotide exchange factor (GEF or eIF-2B) is a key regulator of polypeptide chain initiation. The exchange of GDP bound to chain initiation factor 2 (eIF-2) for GTP by GEF is a rate limiting step in protein synthesis. The multisubunit characteristics of GEF suggest that this protein is composed of several distinct structural and functional domains, and is regulated by allosteric means and by phosphorylation. The activity of GEF may be regulated indirectly by the phosphorylation state of the smallest subunit of eIF-2 (alpha-subunit). On the other hand, phosphorylation of the largest subunit of GEF (82-kD subunit) by casein kinase (CK) I or II stimulates GDP/GTP exchange. GEF contains NADPH which is required for structural integrity of the protein. Upon stimulation of cells by insulin and growth factors, allosteric activation of GEF by sugar phosphates and other effector molecules may also play an important role in the regulation of polypeptide chain initiation. In this article, recent information about structure-function relationship of eIF-2 and GEF in nucleotide exchange and the regulatory mechanisms that influence the rate of polypeptide chain initiation under various physiological and pathological conditions are presented.

Animals↗
PubMed1999

Post-translational control of the MEF2A transcriptional regulatory protein.

Myocyte enhancer factor 2 (MEF2) transcriptional regulatory proteins are key regulators of muscle-specific gene expression and also play a general role in the cellular response to growth factors, cytokines and environmental stressors. To identify signaling pathway components that might mediate these events, the potential role of MAP kinase and PKC signaling in the modulation of MEF2A phosphorylation and transcriptional activity were therefore studied. In transient transfection reporter assays, activated p38 MAP kinase potently increased MEF2A trans -activating potential, PKC[delta] and [epsiv] isotypes enhanced MEF2A transactivation to a lesser extent, while the ERK1/2 and JNK/SAPK pathways were without effect. A GAL4-based assay system showed that p38 MAP kinase and PKC[delta] target the MEF2A transactivation domain. We also observed an increase in p38 MAP kinase activity in congruence with the increase in MEF2A expression in differentiating primary muscle cells. COS cells overexpressing MEF2A alone or with one of the kinases were metabolically labeled with [32P]orthophosphate and MEF2A was immunoprecipitated using specific anti-MEF2A antibodies. MEF2A from cells co-transfected with activated p38 MAP kinase showed a decreased electrophoretic mobility due to phosphorylation. Subsequent phosphopeptide mapping and phosphoamino acid analysis indicated the appearance of several phoshopeptides due to p38 MAP kinase activation of MEF2A which were due to phosphorylation on serine and threonine residues. These studies position MEF2A as a nuclear target for the p38 MAP kinase signaling pathway.

Animals↗
PubMed1984

Mechanism of translational control by partial phosphorylation of the alpha subunit of eukaryotic initiation factor 2.

Catalysis of ternary complex formation by the GDP exchange factor (GEF), in the presence of Mg2+, is blocked by phosphorylation of the alpha subunit of the eukaryotic initiation factor 2 (eIF-2). We proposed earlier that this phosphorylation interferes with the interaction between eIF-2 and GEF (then termed ESP). If so, inhibition should be related to the extent of phosphorylation. However, work in other laboratories indicated that in fully inhibited, heme-deficient lysates only 20-40% of the eIF-2 is phosphorylated. To understand the nature of the molecular lesion in eIF-2-alpha phosphorylation we used a system of pure components in which the rate of exchange of eIF-2-bound [3H]GDP with unlabeled GDP (via the reaction eIF-2-GDP + GEF in equilibrium eIF-2-GEF + GDP) was measured by using mixtures of eIF-2(alpha P) X [eH]GDP and eIF-2 X [3H]GDP in different proportions at constant concentration of eIF-2 X GEF. If, for example, the ratio of eIF-2 X GEF to total (phosphorylated and unphosphorylated) eIF-2 X [3H]GDP was 0.25, the exchange was found to be maximally inhibited when the proportion of eIF-2(alpha P) X [3H]GDP in hte mixture reached 25%. This suggests that the reaction stops because the available GEF is trapped in an inactive complex with eIF-2(alpha P). In the absence of free GEF, eIF-2 would not be able to recycle and initiation would come to a standstill when the available eIF-2 is tied up as eIF-2 X GDP. The trapping of GEF by eIF-s(alpha P) is strongly supported by the following observation. Incubation of eIF-2 X GEF with excess [3H]GDP leads to the formation of eIF-2 X [3H] GDP and free GEF and, if eIF-2(alpha 32P) X GDP is also present, all of the GEF is converted to eIF-2(alpha 32P) X GEF. This suggests that, whereas the equilibrium of the reaction eIF-2 X GEF + GDP in equilibrium eIF-2 X GDP + GEF favors the formation of free GEF, the equilibrium of the reaction eIF-2(alpha P) X GDP + GEF in equilibrium eIF-2(alpha P) X GEF + GDP is in favor of the association of GEF to eIF-2(alpha P).

Animals↗
PubMed2005

Engineered Streptomyces quorum-sensing components enable inducible siRNA-mediated translation control in mammalian cells and adjustable transcription control in mice.

BACKGROUND: Recent advances in functional genomics, gene therapy, tissue engineering, drug discovery and biopharmaceuticals production have been fostered by precise small-molecule-mediated fine-tuning of desired transgenes. METHODS: Capitalizing on well-evolved quorum-sensing regulatory networks in Streptomyces coelicolor we have designed a mammalian regulation system inducible by the non-toxic butyrolactone SCB1. Fusion of the S. coelicolor SCB1 quorum-sensing receptor ScbR to the human Kox-1-derived transsilencing domain reconstituted a mammalian transsilencer (SCS) able to repress transcription from SCS-specific operator-containing promoters in a reverse SCB1-adjustable manner. RESULTS: This quorum-sensing-derived mammalian transgene control system (Q-ON) enabled precise SCB1-specific fine-tuning of (i) desired transgene transcription in a variety of mammalian/human cell lines and human primary cells, (ii) small interfering RNA-mediated posttranscriptional knockdown (siRNA) in mammalian cells, and (iii) dosing of a human glycoprotein in mice. CONCLUSIONS: As exemplified by Q-ON technology, bacterial quorum-sensing regulons may represent a near-infinite source for the design of mammalian gene control systems compatible with molecular interventions relevant to future gene therapy and tissue engineering scenarios.

4-Butyrolactone↗