Chromosomal localization of tumor protein, translationally-controlled 1 (TPT1) encoding the human histamine releasing factor (HRF) to 13q12-->q14.
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Animals↗
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Results for “Translational control”
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Translational control and metastatic progression: enhanced activity of the mRNA cap-binding protein eIF-4E selectively enhances translation of metastasis-related mRNAs.
To form metastases, tumors must break from the primary tumor site, invade surrounding tissues, enter and survive within the circulation and ultimately colonize a distal tissue. Each of these steps requires the cooperative function of numerous proteins--proteins that facilitate angiogenesis (e.g., VEGF), cell survival (e.g., Bcl-2), invasion (e.g., MMPs), and autocrine growth stimulation (e.g., c-myc, cyclin D1). Although expression of these proteins is regulated at many levels by disparate stimuli, translation of these key malignancy-related proteins is regulated primarily by the activity of the mRNA cap-binding protein eIF-4E, the rate-limiting member of the eIF-4F translation initiation complex. By binding the cap structure at the 5' terminus of cellular mRNAs, eIF-4E recruits mRNAs to the eIF-4F complex, which then scans from the 5' cap through the untranslated region (5'UTR), unwinding secondary structure to reveal the translation initiation codon and to enable ribosome loading. Messenger RNAs with short unstructured 5' UTRs are more easily translated than mRNAs harboring lengthy, highly structured 5' UTRs, as these prohibit efficient scanning and start codon recognition. As such, the translation of these mRNAs, which typically encode proteins involved in angiogenesis (e.g., VEGF), tumor growth (cyclin D1) and survival (Bcl-2), is suppressed except when eIF-4E is engaged with the eIF-4F complex--a common event in many human and experimental cancers. This review focuses on the hypothesis that enhanced eIF-4E function contributes to metastatic progression by selectively upregulating the translation of key malignancy-related proteins that together conspire to drive the metastatic process.
Animals↗
Translational control of putative protooncogene Nm23-M2 by cytokines via phosphoinositide 3-kinase signaling.
The expansion and differentiation of hematopoietic progenitors is regulated by cytokine and growth factor signaling. To examine how signal transduction controls the gene expression program required for progenitor expansion, we screened ATLAS filters with polysome-associated mRNA derived from erythroid progenitors stimulated with erythropoietin and/or stem cell factor. The putative proto-oncogene nucleoside diphosphate kinase B (ndpk-B or nm23-M2) was identified as an erythropoietin and stem cell factor target gene. Factor-induced expression of nm23-M2 was regulated specifically at the level of polysome association by a phosphoinositide 3-kinase-dependent mechanism. Identification of the transcription initiation site revealed that nm23-M2 mRNA starts with a terminal oligopyrimidine sequence, which is known to render mRNA translation dependent on mitogenic factors. Recently, the nm23-M2 locus was identified as a common leukemia retrovirus integration site, suggesting that it plays a role in leukemia development. The expression of Nm23 from a retroviral vector in the absence of its 5'-untranslated region caused constitutive polysome association of nm23-M2. Polysome-association and protein expression of endogenous nm23-M2 declined during differentiation of erythroid progenitors, suggesting a role for Nm23-M2 in progenitor expansion. Taken together, nm23-m2 exemplifies that cytokine-dependent control of translation initiation is an important mechanism of gene expression regulation.
5' Untranslated Regions↗
Translational controls impinging on the 5'-untranslated region and initiation factor proteins.
Translation of eukaryotic mRNAs is generally initiated by the scanning ribosome mechanism. This can be downregulated by high affinity protein binding to cap-proximal RNA motifs. Translation can also be regulated by short open reading frames within the 5' -untranslated region. A key factor for initiation is elF4F, in which one of the polypeptide chains, elF4G, seems to have a bridging function and binds three other factors at separate sites: elF4E (the cap-binding factor), the helicase elF4A, and elF3, which also interacts with 40S ribosomal subunits. Initiation is regulated by the MAP kinase and rapamycin-sensitive signalling pathways, which control phosphorylation of elF4E and 4E-BP1, a protein which in the dephosphorylated form binds and sequesters elF4E.
Animals↗
Eukaryotic translational control: adeno-associated virus protein synthesis is affected by a mutation in the adenovirus DNA-binding protein.
Growth of adeno-associated virus (AAV) requires expression of certain adenovirus (Ad) genes in the same cell. AAV particles contain three proteins, VP1 (Mr 85,700), VP2 (Mr 72,000), and VP3 (Mr 61,500). These proteins have overlapping peptide maps. We recently reported that AAV RNAs make up a 3'-coterminal family of overlapping molecules. We report here that the most abundant AAV mRNA, a 2.3-kilobase spliced RNA, codes for all three proteins--VP1, VP2, and VP3--when translated in an in vitro reticulocyte lysate. This shows that the AAV capsid proteins are coded by the genome sequence between map positions 48.0 and 96.0 (1 map unit is 1% of the genome or 47 base pairs). When AAV was grown in human KB cells with the Ad temperature-sensitive mutant Ad5ts125 at the nonpermissive temperature (40 degrees C), the accumulation in vivo of AAV capsid proteins VP1, VP2, and VP3 was decreased to less than 1/50th. However, normal amounts of the 2.3-kilobase mRNA were accumulated, and this RNA could be efficiently translated in an in vitro reticulocyte lysate system to yield VP1, VP2, and VP3. These experiments suggest that in infected cells control is exerted upon the AAV 2.3-kilobase mRNA at the translational level and that this control can be influenced by mutations in Ad. These Ad mutations map in the region 2 early gene for the Ad DNA-binding protein. The temperature-sensitive system that we have studied may be useful for analysis of translational control of a eukaryotic mRNA.
Adenoviridae↗
Post-translational control of collagen fibrillogenesis in mineralizing cultures of chick osteoblasts.
Cultured osteoblasts from chick embryo calvaria were used as a model system to investigate the post-translational extracellular mechanisms controlling the macroassembly of collagen fibrils. The results of these studies demonstrated that cultured osteoblasts secreted a collagenous extracellular matrix that assembled and mineralized in a defined temporal and spatial sequence. The assembly of collagen occurred in a polarized fashion, such that successive orthogonal arrays of fibrils formed between successive cell layers proceeding from the culture surface toward the media. Mineralization followed in the same manner, being observed first in the deepest and oldest fibril layers. Collagen fibrillogenesis, the kinetics of cross-link formation, and collagen stability in the extracellular matrix of the cultures were examined over a 30 day culture period. Between days 8 and 12 in culture, collagen fibril diameters increased from < 30 nm to an average of 30-45 nm. Thereafter, diameters ranged in size from 20 to 200 nm. Quantitation of the collagen cross-linking residues, hydroxylysyl pyridinoline (HP) and lysyl pyridinoline (LP), showed that these mature cross-links increased from undetectable levels to concentrations found in normal chick bone. Analysis of the kinetics of their formation by pulse-chase labeling the cultures with [3H]lysine showed a doubling time of approximately 5 days. The relationships between cross-link formation, fibrillogenesis, and collagen stability were examined in cultures treated with beta-aminopropionitrile (beta-APN), a potent inhibitor of lysyl oxidase and cross-link formation. In beta-APN-treated cultures, total collagen synthesis was increased twofold, with no change in mRNA levels for type I collagen, whereas the amount of collagen accumulated in the cell layer was decreased by 50% and mineral deposition was reduced. The rate of collagen retention in the matrix was assessed by pulse-chase analysis of [3H]proline over a 16 day period in control and beta-APN-treated cultures. In control cultures, about 20% of the labeled collagen was lost from the cell layers over a 16 day period compared with > 80% in the presence of beta-APN. The beta-APN-treated cultures also showed a wider diversity of fibril diameters with a median in the > 45-60 nm range. In summary, these data suggest that cross-linking and assembly of collagen fibrils secreted by osteoblasts in vitro occur in a fashion similar to that found in vivo. The rate of cross-link formation is relatively constant and may be correlated with increasing collagen mass.(ABSTRACT TRUNCATED AT 400 WORDS)
Aminopropionitrile↗
MMI1 (YKL056c, TMA19), the yeast orthologue of the translationally controlled tumor protein (TCTP) has apoptotic functions and interacts with both microtubules and mitochondria.
The yeast orthologue of mammalian TCTP is here proposed to be named Mmi1p (microtubule and mitochondria interacting protein). This protein displays about 50% amino acid sequence identity with its most distantly related orthologs in higher organisms and therefore probably belongs to a small class of yeast proteins which have housekeeping but so far incompletely known functions needed for every eukaryotic cell. Previous investigations of the protein in both higher cells and yeast revealed that it is highly expressed during active growth, but transcriptionally down-regulated in several kinds of stress situations including starvation stress. In human cells, TCTP presumably has anti-apoptotic functions as it binds to Bcl-XL in vivo. TCTP of higher cells was also shown to interact with the translational machinery. It has acquired an additional function in the mammalian immune system, as it is identical with the histamine releasing factor. Here, we show that in S. cerevisiae induction of apoptosis by mild oxidative stress, replicative ageing or mutation of cdc48 leads to translocation of Mmi1p from the cytoplasm to the mitochondria. Mmi1p is stably but reversibly attached to the outer surface of the mitochondria and can be removed by digestion with proteinase K. Glutathionylation of Mmi1p, which is also induced by oxidants, is not a prerequisite or signal for translocation as shown by replacing the only cysteine of Mmi1p by serine. Mmi1p probably interacts with yeast microtubules as deletion of the gene confers sensitivity to benomyl. Conversely, the deletion mutant displays resistance to hydrogen peroxide stress and shows a small but significant elongation of the mother cell-specific lifespan. Our results so far indicate that Mmi1p is one of the few proteins establishing a functional link between microtubules and mitochondria which may be needed for correct localization of mitochondria during cell division.
Adenosine Triphosphatases↗
Evidence for prokaryotic transcription and translation control regions in the human factor IX gene.
A human factor IX cDNA clone isolated from a liver cDNA library constructed in phage lambda gt11 vector was shown to express factor IX protein in Escherichia coli. A factor IX immunospecific protein of 46.8 kDa was expressed, but was not a beta-galactosidase-factor IX fusion protein. Expression was seen when the factor IX cDNA was cloned into two different vector systems, lambda gt11 and pUC9, in both orientations with respect to the vector lacZ promoter. The expression of factor IX was not under control of the lacZ promoter of either vector system. In addition, when the factor IX cDNA fragment was subcloned in both orientations into a promoterless cloning vector (p CPP3), the factor IX cDNA fragment demonstrated promoter activity when inserted in only one orientation resulting in expression of chloramphenicol acetyl transferase in E. coli and Bacillus subtilis. A DNA computer search of the N-terminal sequences of the factor IX gene revealed prokaryotic-like promoter and ribosome-binding site (RBS) sequences with strong homology to the E. coli consensus sequences. The predicted sites homologous with prokaryotic promoter and RBS consensus sequences are followed by an in-frame methionine which could correspond to the translation start codon of the expressed factor IX. This report provides the first evidence that a eukaryotic gene encodes the information necessary for both transcription and translation to control gene expression in a prokaryotic host.
Bacteriophage lambda↗
Copper ion-sensing transcription factor Mac1p post-translationally controls the degradation of its target gene product Ctr1p.
Copper ion uptake must be regulated to avoid both deficiency and excess because its essential yet toxic biological nature depends on the concentration. Yeast copper uptake is controlled at both the transcriptional and post-translational levels. The transcription of CTR1 and CTR3, encoding high affinity copper ion transporters, is regulated by the copper ion-sensing transcription factor Mac1p through the cis-acting copper ion-responsive elements in CTR1 and CTR3 promoters. Ctr1p is known to undergo degradation in cells exposed to high copper levels. We report that Mac1p is also required for copper-dependent Ctr1p degradation. Both mutations within a conserved copper ion binding motif, the "Cu-fist" in the Mac1p DNA-binding domain, and within a metal ion binding motif, REP-III located in the cytosolic domain of Ctr1p, cause defects in Ctr1p turnover. Furthermore, we show that the Mac1p limits intracellular copper accumulation likely by controlling Ctr1p degradation. The findings have uncovered an unprecedented mechanism by which a transcription factor not only regulates its target gene transcription but also controls the degradation of its target gene product.
Base Sequence↗
Mechanisms of translational control in liver and skeletal muscle.
The initiation of peptide chains on ribosomes represents the first step in translation and is a dominant control point for regulation of protein synthesis in mammalian cells. An inhibition of peptide-chain initiation occurs in both rat liver treated with calcium-mobilizing hormones and in rat skeletal muscle in response to the insulin deprivation associated with diabetes mellitus or fasting. The inhibition of peptide-chain initiation in both tissues is accompanied by a shift in polysomal aggregation toward an accumulation of free ribosomal particles and a reduction in formation of 43S preinitiation complexes. Furthermore, in both tissues, the inhibition involves a reduction in the activity of a protein termed eukaryotic initiation factor (eIF)-2B. However, the mechanisms involved in the reduction in eIF-2B activity, and thus protein synthesis, in the two tissues under these conditions appear to be distinct. In liver treated with calcium-mobilizing hormones, the reduction in eIF-2B activity is the result of an increase in the phosphorylation state of the alpha-subunit of a second initiation factor, eIF-2. In contrast, the inhibition of initiation that occurs in skeletal muscle deprived of insulin is not due to a change in the phosphorylation state of eIF-2 alpha. Instead, the activity of eIF-2B may be directly modulated in response to insulin. Studies by others have shown that the epsilon-subunit of eIF-2B is a substrate for at least three different protein kinases and that phosphorylation by at least one of these kinases stimulates the activity of the factor in in vitro assays.(ABSTRACT TRUNCATED AT 250 WORDS)
Angiotensin II↗
Translation controls the expression level of a chimaeric reporter gene.
Transcriptional and translational fusions between the reading frame of the beta-D-glucuronidase gene (gusA) and the 2' as well as the 1' promoter of mannopine synthase (mas), a TR locus of Agrobacterium tumefaciens, were made. The expression of these constructs was studied in the transgenic F1 offspring of independent tobacco transformants at the protein level by assaying for GUS activity and western blot analysis of the GUS protein and at the steady-state mRNA level. In leaves, stems and roots no correlation was found between steady-state levels of GUS mRNA and enzyme activity. In older tissues significantly higher GUS activities were found. This is explained by the stable character of the GUS protein together with an accumulation of protein upon ageing. Three to ten times higher GUS activities were found for in vitro grown plants than for greenhouse-grown plants of the same offspring, despite similar levels of GUS mRNA. Roots from in vitro grown plants display three to ten times higher GUS activities than stems and leaves. In transgenic plants grown in vitro, containing a translational fusion with two AUGs in phase, the initiation of translation in leaf material occurred at both AUGs. Initiation of translation at the first AUG, however, was ten times more frequent. In contrast, initiation in roots from in vitro grown plants occurred exclusively at the second AUG.
Agrobacterium tumefaciens↗
Homeodomain position 54 specifies transcriptional versus translational control by Bicoid.
Bicoid (BCD), the anterior determinant of Drosophila, controls embryonic gene expression by transcriptional activation and translational repression. Both functions require the homeodomain (HD), which recognizes DNA motifs at target gene enhancers and a specific sequence interval in the 3' untranslated region of caudal (cad) mRNA. Here we show that the BCD HD is a nucleic acid-binding unit. Its helix III contains an arginine-rich motif (ARM), similar to the RNA-binding domain of the HIV-1 protein REV, needed for both RNA and DNA recognition. Replacement of arginine 54, within this motif, alters the RNA but not the DNA binding properties of the HD. Corresponding BCD mutants fail to repress cad mRNA translation, whereas the transcriptional target genes are still activated.
Amino Acid Motifs↗
Translational control by influenza virus: suppression of the kinase that phosphorylates the alpha subunit of initiation factor eIF-2 and selective translation of influenza viral mRNAs.
Selective translation of influenza viral mRNAs occurs after influenza virus superinfection of cells infected with the VAI RNA-negative adenovirus mutant dl331 (M. G. Katze, Y.-T. Chen, and R. M. Krug, Cell 37:483-490, 1984). Cell extracts from these doubly infected cells catalyze the initiation of essentially only influenza viral protein synthesis, reproducing the in vivo situation. This selective translation is correlated with a 5- to 10-fold suppression of the dl331-induced kinase that phosphorylates the alpha subunit of eucaryotic initiation factor eIF-2. This strongly suggests that influenza virus encodes a gene product that, analogous to the adenoviral VAI RNA, prevents the shutdown of overall protein synthesis caused by an eIF-2 alpha kinase turned on by viral infection. Adenoviral mRNA translation was restored to the extract from the doubly infected cells by the addition of the guanine nucleotide exchange factor eIF-2B, which is responsible for the normal recycling of eIF-2 during protein synthesis. This indicates that the residual kinase in the doubly infected cells leads to a limitation in functional (nonsequestered) eIF-2B and hence functional (GTP-containing) eIF-2 and that under these conditions influenza viral mRNAs are selectively translated over adenoviral mRNAs. Addition of double-stranded RNA to the extracts from these cells restored the eIF-2 alpha kinase to a level approaching that seen in extracts from cells infected with dl331 alone and caused the inhibition of influenza viral mRNA translation. This suggests that the putative influenza viral gene product acts against the double-stranded RNA activation of the kinase and indicates that influenza viral mRNA translation is also linked to the level of functional eIF-2. Our results thus indicate that a limitation in functional eIF-2 which causes a nonspecific reduction in the rate of initiation of protein synthesis results in the preferential translation of the better mRNAs (influenza viral mRNAs) at the expense of the poorer mRNAs (adenoviral mRNAs).
Adenoviruses, Human↗
Translational control of ferritin synthesis by iron in embryonic reticulocytes of the bullfrog.
The regulation of ferritin synthesis by iron was examined in the reticulocytes of bullfrog tadpoles where the induction was 40- to 50-fold, increasing from 0.17 +/- 0.05% of total protein synthesis ([3H]leucine incorporation in cell suspension) to 7.4 +/- 1.6% following intraperitoneal injection of ferric ammonium citrate. No significant difference was observed between the levels of ferritin mRNA in control or iron-induced cells, determined by translation of isolated mRNA in a wheat germ system, demonstrating that ferritin induction by iron occurs by a post-transcriptional mechanism. Total protein synthesis in the wheat germ system was half-saturating at 10 micrograms of mRNA/ml whereas ferritin synthesis increased linearly up to 40 micrograms of mRNA/ml, demonstrating that the ferritin mRNA is translated with high efficiency relative to the total proteins synthesized. Studies with the cap analogue 7-methylguanosine-5'-monophosphate, suggest that cap binding is not directly involved in the high translational efficiency of the ferritin mRNA in the wheat germ system. The results indicate that iron-modulated changes in the availability of ferritin mRNA for translation, coupled with the high translational efficiency of the ferritin message, can account for the induction of ferritin synthesis by iron in embryonic erythroid cells.
Animals↗
Modification of translational control elements as a new approach to design of attenuated picornavirus strains.
The translation machineries of different host cells may exhibit varying requirements for a specific structure of cis-acting control elements in the viral RNA templates. Thus, the appropriately spaced oligopyrimidine/AUG tandem (OAT), a conserved control element in the 5' noncoding region of the picornavirus genomes, is dispensable for the growth of Theiler's murine encephalomyelitis virus (TMEV) in BHK-21 cells, but is essential for the neurovirulence of this virus. Also, the replacement of the cryptic (non-initiator) AUG moiety of the wild-type poliovirus OAT by the initiator AUG affects the viral reproduction in cultured cells only slightly, whereas neurovirulence of the relevant mutants is dramatically suppressed. These observations allow us to propose a rational way to construct novel attenuated viral strains by elimination or severe modification of host-specific regulatory regions in their genomes. The relevant genetic rearrangements may be so extensive that the probability of reversion to the virulent phenotype should be negligible. The feasibility of engineering of highly attenuated and genetically stable TMEV and poliovirus variants is illustrated.
Animals↗
Role of an internal ribosome entry site in the translational control of the human transcription factor Sp3.
Sp1 and Sp3 are transcription factors involved in the regulation of numerous genes involved in oncogenesis. Sp3 is a bi-functional transcription factor with three different isoforms. Its bi-functional activity may in part be regulated by the relative expression of these isoforms. Northern blot analysis of Sp3 detects only a single transcript. Analysis of the known Sp3 cDNA sequence shows a high GC content and seven out-of-frame AUG codons located between the 5'-end of the mRNA and the two internal AUG initiation sites. This makes it highly unlikely that cap-recruited, translation initiation competent ribosomes could reach the internal start sites. A full human Sp3 expression construct was cloned. A bicistronic vector using Renilla and firefly luciferase showed internal ribosome entry site (IRES) activity in Sp3 RNA immediately 5' to the internal AUG sites. Also, the two smaller isoforms were translated more efficiently when full-length, uncapped transcripts were used, while the larger isoform was not translated. Mutants of Sp3 with AUG codons introduced 5' of the two internal start sites were generated. Results showed that they were unable to suppress the smaller isoforms in vitro. Furthermore, dual non-AUG to AUG mutations showed occlusion of the second introduced isoform (i.e., the isoform situated more 3') but not of the internally initiated isoforms. These experiments are consistent with IRES-mediated translation of the two smaller isoforms of Sp3. The presence of an IRES allows the possibility that Sp3 isoform ratios and activity are controlled at the translational level. This mechanism may allow cells to control the expression of numerous genes during mitosis and, thus, have profound effects on cell cycle regulation and tumorigenesis.
Animals↗
Coping with stress: eIF2 kinases and translational control.
In response to environmental stresses, a family of protein kinases phosphorylate eIF2 (eukaryotic initiation factor 2) to alleviate cellular injury or alternatively induce apoptosis. Phosphorylation of eIF2 reduces global translation, allowing cells to conserve resources and to initiate a reconfiguration of gene expression to effectively manage stress conditions. Accompanying this general protein synthesis control, eIF2 phosphorylation induces translation of specific mRNAs, such as that encoding the bZIP (basic leucine zipper) transcriptional regulator ATF4 (activating transcription factor 4). ATF4 also enhances the expression of additional transcription factors, ATF3 and CHOP (CCAAT/enhancer-binding protein homologous protein)/GADD153 (growth arrest and DNA-damage-inducible protein), that assist in the regulation of genes involved in metabolism, the redox status of the cells and apoptosis. Reduced translation by eIF2 phosphorylation can also lead to activation of stress-related transcription factors, such as NF-kappaB (nuclear factor kappaB), by lowering the steady-state levels of short-lived regulatory proteins such as IkappaB (inhibitor of NF-kappaB). While many of the genes induced by eIF2 phosphorylation are shared between different environmental stresses, eIF2 kinases function in conjunction with other stress-response pathways, such as those regulated by mitogen-activated protein kinases, to elicit gene expression programmes that are tailored for the specific stress condition. Loss of eIF2 kinase pathways can have important health consequences. Mice devoid of the eIF2 kinase GCN2 [general control non-derepressible-2 or EIF2AK4 (eIF2alpha kinase 4)] show sensitivity to nutritional deficiencies and aberrant eating behaviours, and deletion of PEK [pancreatic eIF2alpha kinase or PERK (RNA-dependent protein kinase-like endoplasmic reticulum kinase) or EIF2AK3] leads to neonatal insulin-dependent diabetes, epiphyseal dysplasia and hepatic and renal complications.
Activating Transcription Factor 4↗
Further evidence of transcriptional and translational control of histone messenger RNA during the HeLa S3 cycle.
Using a translational assay and new analytical procedures we have found that: -Histone mRNA can be detected both associated with polyribosomes and in the postribosomal supernatant of S phase HeLa S3 cells.-Inhibition of DNA replication by cytosine arabinoside treatment causes histone mRNA to completely disappear from polyribosomes, and little histone mRNA can be detected in the postribosomal supernatant of inhibited cells. These data indicate that histone mRNA does not accumulate in the cytoplasm after the inhibition of DNA replication. -Histone mRNA species cannot be detected in the postribosomal supernatant of G1 cells synchronized by selective detachment. This observation, together with the previous finding that histone mRNA is not present on G1 polyribosomes, is consistent with the idea of a transcriptional block in histone mRNA production and transport to the cytoplasm during G1.
Carbon Radioisotopes↗