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Results for “Translational repression”

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PubMed1997

Sex lethal controls dosage compensation in Drosophila by a non-splicing mechanism.

Dosage compensation in Drosophila requires the male-specific lethal (msl) proteins (MSL) to make gene expression from the single male X chromosome equivalent to that from both female X chromosomes. Expression of ms12 is repressed post-transcriptionally by Sex lethal (SXL), a female-specific RNA-binding protein that regulates alternative splicing in the sex-determination hierarchy. Although msl2 RNA is alternatively spliced in males and females, this does not alter its coding potential and splicing is not required for male-specific expression of MSL2 protein. Instead, our results suggest that the association of SXL protein with multiple sites in the 5' and 3' untranslated regions of the mx12 transcript represses its translation in females. Thus, this well characterized alternative splicing factor regulates at least one target transcript by a distinct mechanism.

Alternative Splicing↗

PubMed2003

The genes orthodenticle and hunchback substitute for bicoid in the beetle Tribolium.

In Drosophila, the morphogen Bicoid organizes anterior patterning in a concentration-dependent manner by activating the transcription of target genes such as orthodenticle (otd) and hunchback (hb), and by repressing the translation of caudal. Homologues of the bicoid gene have not been isolated in any organism apart from the higher Dipterans. In fact, head and thorax formation in other insects is poorly understood. To elucidate this process in a short-germband insect, I analysed the function of the conserved genes orthodenticle-1 (otd-1) and hb in the flour beetle Tribolium castaneum. Here I show that, in contrast to Drosophila, Tribolium otd-1 messenger RNA is maternally inherited by the embryo. Reduction of Tribolium otd-1 levels by RNA interference (RNAi) results in headless embryos. This shows that otd-1 is required for anterior patterning in Tribolium. As in Drosophila, Tribolium hb specifies posterior gnathal and thoracic segments. The head, thorax and the anterior abdomen fail to develop in otd-1/hb double-RNAi embryos. This phenotype is similar to that of strong bicoid mutants in Drosophila. I propose that otd-1 and hb are part of an ancestral anterior patterning system.

Animals↗

PubMed2002

The 3D's of apoptosis: death, degradation and DIAPs.

Inhibitor of apoptosis proteins (IAPs) are critical regulators of apoptosis. Recent evidence suggests that in some situations, induction of apoptosis initiates general repression of translation, as well as the targeted ubiquitination and degradation of IAPs.

Animals↗

PubMed2004

MicroRNA-143 regulates adipocyte differentiation.

MicroRNAs (miRNAs) are endogenously expressed 20-24 nucleotide RNAs thought to repress protein translation through binding to a target mRNA (1-3). Only a few of the more than 250 predicted human miRNAs have been assigned any biological function. In an effort to uncover miRNAs important during adipocyte differentiation, antisense oligonucleotides (ASOs) targeting 86 human miRNAs were transfected into cultured human pre-adipocytes, and their ability to modulate adipocyte differentiation was evaluated. Expression of 254 miRNAs in differentiating adipocytes was also examined on a miRNA microarray. Here we report that the combination of expression data and functional assay results identified a role for miR-143 in adipocyte differentiation. miR-143 levels increased in differentiating adipocytes, and inhibition of miR-143 effectively inhibited adipocyte differentiation. In addition, protein levels of the proposed miR-143 target ERK5 (4) were higher in ASO-treated adipocytes. These results demonstrate that miR-143 is involved in adipocyte differentiation and may act through target gene ERK5.

Adipocytes↗

PubMed2004

BCL-2 translation is mediated via internal ribosome entry during cell stress.

The cellular response to stress involves a rapid inhibition of cap-dependent translation via multiple mechanisms, yet some translation persists. This residual translation may include proteins critical to the cellular stress response. BCL-2 is a key inhibitor of intrinsic apoptotic signaling. Its primary transcript contains a 1.45-kb 5'-untranslated region (UTR) including 10 upstream AUGs that may restrict translation initiation via cap-dependent ribosome scanning. Thus, we hypothesized that this 5'-UTR may contain an internal ribosome entry site (IRES) that facilitates BCL-2 translation, particularly during cell stress. Here we show that the BCL-2 5'-UTR demonstrated IRES activity both when translated in vitro and also when m(7)G-capped and polyadenylated mRNA was transiently transfected into 293T cells. The activity of this IRES in unstressed cells was approximately 6% the strength of the hepatitis C virus IRES but was induced 3-6-fold in a dose-dependent manner following short term treatment with either etoposide or sodium arsenite. Thus, the IRES-mediated translation of BCL-2 may enable the cell to replenish levels of this critical protein during cell stress, when cap-dependent translation is repressed, thereby maintaining the balance between pro- and anti-apoptotic BCL-2 family members in the cell and preventing unwarranted induction of apoptosis.

5' Untranslated Regions↗

PubMed2006

Sensory denervation modulates eIF-2 alpha kinase expression in the rabbit lacrimal gland.

PURPOSE: To investigate the hypothesis that sensory denervation of the rabbit lacrimal gland results in dysregulation of protein synthesis. We used differential display of mRNA to identify genes associated with protein synthesis and secretion that may be altered in this situation. METHODS: New Zealand white rabbits underwent unilateral sensory denervation by the ablation of the trigeminal ganglion. After 7 days, the denervated and contralateral control lacrimal glands were removed. The effects of denervation on gene expression were carried out using differential mRNA display. Northern and Western blot analyses were used to verify differential gene expression. RESULTS: Differential mRNA display identified the gene heme-regulated inhibitor eukaryotic initiation factor-2 alpha kinase (HRI eIF-2a kinase) in the lacrimal gland, the expression of which was reduced in the denervated lacrimal gland. The sequenced fragment from differential display showed 94% identity to rabbit HRI eIF-2a kinase. The decreased expression of HRI eIF-2a kinase was confirmed by Northern and Western blots, and measurement of HRI eIF-2a kinase phosphorylation activity in the lacrimal gland after ablation of sensory neurons showed that it was significantly decreased compared with that of normal and control lacrimal glands. CONCLUSIONS: The results suggest that loss of sensory innervation has a role in the lacrimal gland, contributing to the expression of HRI eIF-2a kinase, a pivotal negative regulator of protein synthesis. A reduction in control of protein synthesis may lead to the translation of repressed messages associated with cell stress responses.

Animals↗

PubMed2003

The PUF family of RNA-binding proteins: does evolutionarily conserved structure equal conserved function?

Drosophila Pumilio (Pum) protein is a founder member of a novel family of RNA-binding proteins, known as the PUF family. The PUF proteins constitute an evolutionarily highly conserved family of proteins present from yeast to humans and plants, and are characterized by a highly conserved C-terminal RNA-binding domain, composed of eight tandem repeats. The conserved biochemical features and genetic function of PUF family members have emerged from studies of model organisms. PUF proteins bind to related sequence motifs in the 3' untranslated region (3'UTR) of specific target mRNAs and repress their translation. Frequently, PUF proteins function asymmetrically to create protein gradients, thus causing asymmetric cell division and regulating cell fate specification. Thus, it was recently proposed that the primordial role of PUF proteins is to sustain mitotic proliferation of stem cells. Here we review the evolution, conserved genetic and biochemical properties of PUF family of proteins, and discuss protein interactions, upstream regulators and downstream targets of PUF proteins. We also suggest that a conserved mechanism of PUF function extends to the newly described mammalian members of the PUF family (human PUM1 and PUM2, and mouse Pum1 and Pum2), that show extensive homology to Drosophila Pum, and could have an important role in cell development, fate specification and differentiation.

3' Untranslated Regions↗

PubMed2001

Ribosomal protein S7 from Escherichia coli uses the same determinants to bind 16S ribosomal RNA and its messenger RNA.

Ribosomal protein S7 from Escherichia coli binds to the lower half of the 3' major domain of 16S rRNA and initiates its folding. It also binds to its own mRNA, the str mRNA, and represses its translation. Using filter binding assays, we show in this study that the same mutations that interfere with S7 binding to 16S rRNA also weaken its affinity for its mRNA. This suggests that the same protein regions are responsible for mRNA and rRNA binding affinities, and that S7 recognizes identical sequence elements within the two RNA targets, although they have dissimilar secondary structures. Overexpression of S7 is known to inhibit bacterial growth. This phenotypic growth defect was relieved in cells overexpressing S7 mutants that bind poorly the str mRNA, confirming that growth impairment is controlled by the binding of S7 to its mRNA. Interestingly, a mutant with a short deletion at the C-terminus of S7 was more detrimental to cell growth than wild-type S7. This suggests that the C-terminal portion of S7 plays an important role in ribosome function, which is perturbed by the deletion.

Base Sequence↗

PubMed2004

Mouse microRNA-23b regulates expression of Hes1 gene in P19 cells.

MicroRNAs (miRNAs) are abundant class of approximately 21-25 nts small endogenous RNAs. Recently several hundred miRNAs have been identified from diverse species; nematodes, insects, plants, and animals. These small RNAs can regulate gene expression at a post-transcriptional level by interacting with their target mRNAs. Interaction of these RNAs causes either repression of translation or RNAi-dependent cleavage of target RNAs. It has been recently found that they have critical regulatory roles in embryogenesis, development, differentiation, cellular proliferation, apoptosis, and so on. However, identifications of the target of the target of miRNAs have been almost unknown, especially in vertebrates. Here we show that Hairy/enhancer of split protein (Hes1), a bHLH transcriptional repressor functioning in neuronal differentiation, is a target of mouse miRNA-23b (miR-23b).

Animals↗

PubMed2005

Double molecular mimicry in Escherichia coli: binding of ribosomal protein L20 to its two sites in mRNA is similar to its binding to 23S rRNA.

Escherichia coli ribosomal L20 is one of five proteins essential for the first reconstitution step of the 50S ribosomal subunit in vitro. It is purely an assembly protein, because it can be withdrawn from the mature subunit without effect on ribosome activity. In addition, L20 represses the translation of its own gene by binding to two sites in its mRNA. The first site is a pseudoknot formed by a base-pairing interaction between nucleotide sequences separated by more than 280 nucleotides, whereas the second site is an irregular helix formed by base-pairing between neighbouring nucleotide sequences. Despite these differences, the mRNA folds in such a way that both L20 binding sites share secondary structure similarity with the L20 binding site located at the junction between helices H40 and H41 in 23S rRNA. Using a set of genetic, biochemical, biophysical, and structural experiments, we show here that all three sites are recognized similarly by L20.

Base Sequence↗

PubMed2006

Induction of expression of hfq by DksA is essential for Shigella flexneri virulence.

Hfq plays an important role in cellular physiology by regulating the expression of several genes. Hfq synthesis in Escherichia coli is subject to auto-repression at translational level. Studies with Shigella flexneri show that hfq transcription is regulated by a pleiotropic regulator, DksA. Comparison of gene expression profiles of wild type and dksA mutant S. flexneri determined that hfq expression was reduced in the dksA mutant. As DksA is required for stress resistance and plaque formation in cultured cell monolayers, a measure of virulence, we assessed the role of Hfq in the dksA virulence phenotype. Expression of hfq in the dksA mutant restored plaque formation, and an hfq mutant failed to form plaques. Thus, DksA plays a role in regulating hfq gene expression and this regulation is important for S. flexneri virulence. In an in vitro transcription assay, addition of DksA increased transcription of hfq and this effect was greatest with one of the known hfq promoters. Addition of ppGpp, a stringent response molecule, along with DksA in the in vitro transcription assay resulted in a further increase in transcription of hfq, indicating that DksA is required for maximal transcription of hfq during both exponential and stringent response growth conditions.

Bacterial Proteins↗

PubMed2002

The immunosuppressant rapamycin represses human immunodeficiency virus type 1 replication.

The immunosuppressive macrolide rapamycin is used in humans to prevent graft rejection. This drug acts by selectively repressing the translation of proteins that are encoded by an mRNA bearing a 5'-polypyrimidine tract (e.g., ribosomal proteins, elongation factors). The human immunodeficiency virus type 1 (HIV-1) carries a polypyrimidine motif that is located within the tat exon 2. Treatment of human T lymphoid cells with rapamycin resulted in a marked diminution of HIV-1 transcription when infection was performed with luciferase reporter T-tropic and macrophage-tropic viruses. Replication of fully infectious HIV-1 particles was abolished by rapamycin treatment. The rapamycin-mediated inhibitory effect on HIV-1 production was reversed by FK506. The anti-HIV-1 effect of rapamycin was also seen in primary human cells (i.e., peripheral blood lymphocytes) from different healthy donors. Rapamycin was shown to diminish basal HIV-1 long terminal repeat gene expression, and the observed effect of rapamycin on HIV-1 replication seems to be independent of the virus-specific transactivating Tat protein. A constitutive beta-actin promoter-based reporter gene vector was unaffected by rapamycin treatment. Kinetic virus infection studies and exposure to reporter viruses pseudotyped with heterologous envelope proteins (i.e., amphotropic murine leukemia virus and vesicular stomatitis virus G) suggested that rapamycin is primarily affecting the life cycle of HIV-1 at a transcriptional level. Northern blot analysis confirmed that this compound is selectively targeting HIV-1 mRNA synthesis.

Actins↗

PubMed1978

Mechanism of poliovirus inactivation by ammonia.

Poliovirus inactivation by ammonia causes a slight reduction in the sedimentation coefficients of viral particles, but has no detectable effect on either the electrophoretic pattern of viral capsid proteins or the isoelectric points of inactivated particles. These virions still attach to cells, but are unable to repress host translation or stimulate the synthesis of detectable amounts of viral RNA. Although ammonia has no detectable effect on naked poliovirus RNA, it causes cleavage of this RNA when still within viral particles. Therefore, the RNA genome appears to be the only component of poliovirus significantly affected by ammonia.

Ammonia↗

PubMed1989

Regulation of c-myc mRNA stability in vitro by a labile destabilizer with an essential nucleic acid component.

The turnover rates of some mRNAs vary by an order of magnitude or more when cells change their growth pattern or differentiate. To identify regulatory factors that might be responsible for this variability, we investigated how cytosolic fractions affect mRNA decay in an in vitro system. A 130,000 X g supernatant (S130) from the cytosol of exponentially growing erythroleukemia cells contains a destabilizer that accelerates the decay of polysome-bound c-myc mRNA by eightfold or more compared with reactions lacking S130. The destabilizer is deficient in or absent from the S130 of cycloheximide-treated cells, indicating that it is labile or is repressed when translation is blocked. It is not a generic RNase, because it does not affect the turnover of delta-globin, gamma-globin, or histone mRNA and does not destabilize a major portion of polysomal polyadenylated mRNA. The destabilizer accelerates the turnover of the c-myc mRNA 3' region, as well as subsequent 3'-to-5' degradation of the mRNA body. It is inactivated in vitro by mild heating and by micrococcal nuclease, suggesting that it contains a nucleic acid component. c-myb mRNA is also destabilized in S130-supplemented in vitro reactions. These results imply that the stability of some mRNAs is regulated by cytosolic factors that are not associated with polysomes.

Cytosol↗

PubMed2005

MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells.

MicroRNAs (miRNAs) are small noncoding RNA molecules that regulate protein expression by targeting the mRNA of protein-coding genes for either cleavage or repression of translation. The roles of miRNAs in lineage determination and proliferation as well as the location of several miRNA genes at sites of translocation breakpoints or deletions has led to the speculation that miRNAs could be important factors in the development or maintenance of the neoplastic state. Here we show that the highly malignant human brain tumor, glioblastoma, strongly over-expresses a specific miRNA, miR-21. Our studies show markedly elevated miR-21 levels in human glioblastoma tumor tissues, early-passage glioblastoma cultures, and in six established glioblastoma cell lines (A172, U87, U373, LN229, LN428, and LN308) compared with nonneoplastic fetal and adult brain tissues and compared with cultured nonneoplastic glial cells. Knockdown of miR-21 in cultured glioblastoma cells triggers activation of caspases and leads to increased apoptotic cell death. Our data suggest that aberrantly expressed miR-21 may contribute to the malignant phenotype by blocking expression of critical apoptosis-related genes.

Apoptosis↗

PubMed2004

Homologous up-regulation of androgen receptor expression by androgen in vascular smooth muscle cells.

OBJECTIVE: Androgens play an important role in the arterial vascular system, and androgen receptors (AR) have been identified in vascular smooth muscle cells (VSMCs). This study examined the effects of testosterone exposure on AR gene expression in cultured rat aortic smooth muscle cells. METHODS: Changes in AR protein and messenger RNA (mRNA) levels after androgen exposure were determined using immunoblotting and Northern blotting analysis respectively. RESULTS: Treatment of synchronized VSMCs with testosterone increased both cytoplasmic and nuclear AR protein expression in a dose- and time-dependent fashion, whereas exposure of VSMCs to androgen for 10 min induced a transient down-regulation of AR protein. Meanwhile, AR mRNA level was also up-regulated, but to a much smaller extent. Pretreatment with transcription inhibitor and translation inhibitor repressed cytoplasmic AR protein levels to 46 and 12% (means) of the androgen treatment control level respectively. Furthermore, androgen up-regulation of intracellular AR protein was partially inhibited by androgen antagonist. CONCLUSIONS: Androgen increases AR expression in VSMCs at the level of both transcription and non-transcription.

Animals↗

PubMed2003

Regulation of muscle protein synthesis in neonatal pigs during prolonged endotoxemia.

In adults, protein synthesis in skeletal muscle is reduced by as much as 50% after a septic challenge, and is associated with repression of translation initiation. Neonates are highly anabolic and their muscle protein synthesis rates are elevated and uniquely sensitive to amino acid and insulin stimulation. In the present study, neonatal piglets were infused with Endotoxin (lipopolysaccharide, LPS) for 20 h at 0 (n = 6) and 13 microg/kg*h (n = 8). During the last 2 h, dextrose and an amino acid mixture were infused to attain fed plasma concentrations of amino acids, glucose, and insulin. Fractional protein synthesis rates and translational control mechanisms were examined. LPS reduced protein synthesis in glycolytic muscles by only 13% and had no significant effect in oxidative muscles. This depression was associated with reductions in the phosphorylation of 4E-BP1 (-31%) and S6 K1 (-78%), and a decrease in eIF4G binding to eIF4E (-62%), an event required for formation of the active mRNA binding complex. By comparison, LPS increased protein synthesis in the liver (+29%), spleen (+32%), and kidney (+27%), and in the liver, this increase was associated with augmented eIF4G to eIF4E binding (+88%). In muscle and liver, LPS did not alter eIF2B activity, an event that regulates initiator met-tRNA(i) binding to the 40S ribosomal complex. These findings suggest that during sustained endotoxemia, the high rate of neonatal muscle protein synthesis is largely maintained in the presence of substrate supply, despite profound changes in translation initiation factors that modulate the mRNA binding step in translation initiation.

Animals↗

PubMed1998

Nanos and Pumilio have critical roles in the development and function of Drosophila germline stem cells.

The zinc-finger protein Nanos and the RNA-binding protein Pumilio act together to repress the translation of maternal hunchback RNA in the posterior of the Drosophila embryo, thereby allowing abdomen formation. nanos RNA is localized to the posterior pole during oogenesis and the posteriorly synthesized Nanos protein is sequestered into the germ cells as they form in the embryo. This maternally provided Nanos protein is present in germ cells throughout embryogenesis. Here we show that maternally deposited Nanos protein is essential for germ cell migration. Lack of zygotic activity of nanos and pumilio has a dramatic effect on germline development of homozygous females. Given the coordinate function of nanos and pumilio in embryonic patterning, we analyzed the role of these genes in oogenesis. We find that both genes act in the germline. Although the nanos and pumilio ovarian phenotypes have similarities and both genes ultimately affect germline stem cell development, the focus of these phenotypes appears to be different. While pumilio mutant ovaries fail to maintain stem cells and all germline cells differentiate into egg chambers, the focus of nanos function seems to lie in the differentiation of the stem cell progeny, the cystoblast. Consistent with the model that nanos and pumilio have different phenotypic foci during oogenesis, we detect high levels of Pumilio protein in the germline stem cells and high levels of Nanos in the dividing cystoblasts. We therefore suggest that, in contrast to embryonic patterning, Nanos and Pumilio may interact with different partners in the germline.

Animals↗