Zeitschriftenartikel: „Translational silencing“

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Sampath, Prabha, Barsanjit Mazumder, Vasudevan Seshadri und Paul L. Fox. „Transcript-Selective Translational Silencing by Gamma Interferon Is Directed by a Novel Structural Element in the Ceruloplasmin mRNA 3′ Untranslated Region“. Molecular and Cellular Biology 23, Nr. 5 (01.03.2003): 1509–19. http://dx.doi.org/10.1128/mcb.23.5.1509-1519.2003.

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ABSTRACT Transcript-selective translational control of eukaryotic gene expression is often directed by a structural element in the 3′ untranslated region (3′-UTR) of the mRNA. In the case of ceruloplasmin (Cp), induced synthesis of the protein by gamma interferon (IFN-γ) in U937 monocytic cells is halted by a delayed translational silencing mechanism requiring the binding of a cytosolic inhibitor to the Cp 3′-UTR. Silencing requires the essential elements of mRNA circularization, i.e., eukaryotic initiation factor 4G, poly(A)-binding protein, and poly(A) tail. We here determined the minimal silencing element in the Cp 3′-UTR by progressive deletions from both termini. A minimal, 29-nucleotide (nt) element was determined by gel shift assay to be sufficient for maximal binding of the IFN-γ-activated inhibitor of translation (GAIT), an as-yet-unidentified protein or complex. The interaction was shown to be functional by an in vitro translation assay in which the GAIT element was used as a decoy to overcome translational silencing. Mutation analysis showed that the GAIT element contained a 5-nt terminal loop, a weak 3-bp helix, an asymmetric internal bulge, and a proximal 6-bp helical stem. Two invariant loop residues essential for binding activity were identified. Ligation of the GAIT element immediately downstream of a luciferase reporter conferred the translational silencing response to the heterologous transcript in vitro and in vivo; a construct containing a nonbinding, mutated GAIT element was ineffective. Translational silencing of Cp, and possibly other transcripts, mediated by the GAIT element may contribute to the resolution of the local inflammatory response following cytokine activation of macrophages.

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Baez, María Verónica, Luciana Luchelli, Darío Maschi, Martín Habif, Malena Pascual, María Gabriela Thomas und Graciela Lidia Boccaccio. „Smaug1 mRNA-silencing foci respond to NMDA and modulate synapse formation“. Journal of Cell Biology 195, Nr. 7 (26.12.2011): 1141–57. http://dx.doi.org/10.1083/jcb.201108159.

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Mammalian Smaug1/Samd4A is a translational repressor. Here we show that Smaug1 forms mRNA-silencing foci located at postsynapses of hippocampal neurons. These structures, which we have named S-foci, are distinct from P-bodies, stress granules, or other neuronal RNA granules hitherto described, and are the first described mRNA-silencing foci specific to neurons. RNA binding was not required for aggregation, which indicates that S-foci formation is not a consequence of mRNA silencing. N-methyl-d-aspartic acid (NMDA) receptor stimulation provoked a rapid and reversible disassembly of S-foci, transiently releasing transcripts (the CaMKIIα mRNA among others) to allow their translation. Simultaneously, NMDA triggered global translational silencing, which suggests the specific activation of Smaug1-repressed transcripts. Smaug1 is expressed during synaptogenesis, and Smaug1 knockdown affected the number and size of synapses, and also provoked an impaired response to repetitive depolarizing stimuli, as indicated by a reduced induction of Arc/Arg3.1. Our results suggest that S-foci control local translation, specifically responding to NMDA receptor stimulation and affecting synaptic plasticity.

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Mazumder, Barsanjit, Vasudevan Seshadri, Hiroaki Imataka, Nahum Sonenberg und Paul L. Fox. „Translational Silencing of Ceruloplasmin Requires the Essential Elements of mRNA Circularization: Poly(A) Tail, Poly(A)-Binding Protein, and Eukaryotic Translation Initiation Factor 4G“. Molecular and Cellular Biology 21, Nr. 19 (01.10.2001): 6440–49. http://dx.doi.org/10.1128/mcb.21.19.6440-6449.2001.

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ABSTRACT Ceruloplasmin (Cp) is a glycoprotein secreted by the liver and monocytic cells and probably plays roles in inflammation and iron metabolism. We showed previously that gamma interferon (IFN-γ) induced Cp synthesis by human U937 monocytic cells but that the synthesis was subsequently halted by a transcript-specific translational silencing mechanism involving the binding of a cytosolic factor(s) to the Cp mRNA 3′ untranslated region (UTR). To investigate how protein interactions at the Cp 3′-UTR inhibit translation initiation at the distant 5′ end, we considered the “closed-loop” model of mRNA translation. In this model, the transcript termini are brought together by interactions of poly(A)-binding protein (PABP) with both the poly(A) tail and initiation factor eIF4G. The effect of these elements on Cp translational control was tested using chimeric reporter transcripts in rabbit reticulocyte lysates. The requirement for poly(A) was shown since the cytosolic inhibitor from IFN-γ-treated cells minimally inhibited the translation of a luciferase reporter upstream of the Cp 3′-UTR but almost completely blocked the translation of a transcript containing a poly(A) tail. Likewise, a requirement for poly(A) was shown for silencing of endogenous Cp mRNA. We considered the possibility that the cytosolic inhibitor blocked the interaction of PABP with the poly(A) tail or with eIF4G. We found that neither of these interactions were inhibited, as shown by immunoprecipitation of PABP followed by quantitation of the poly(A) tail by reverse transcription-PCR and of eIF4G by immunoblot analysis. We considered the alternate possibility that these interactions were required for translational silencing. When PABP was depleted from the reticulocyte lysate with anti-human PABP antibody, the cytosolic factor did not inhibit translation of the chimeric reporter, thus showing the requirement for PABP. Similarly, in lysates treated with anti-human eIF4G antibody, the cytosolic extract did not inhibit the translation of the chimeric reporter, thereby showing a requirement for eIF4G. These data show that translational silencing of Cp requires interactions of three essential elements of mRNA circularization, poly(A), PABP, and eIF4G. We suggest that Cp mRNA circularization brings the cytosolic Cp 3′-UTR-binding factor into the proximity of the translation initiation site, where it silences translation by an undetermined mechanism. These results suggest that in addition to its important function in increasing the efficiency of translation, transcript circularization may serve as an essential structural determinant for transcript-specific translational control.

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Nair, Asha P. K., Hans H. Hirsch, Marco Colombi und Christoph Moroni. „Cyclosporin A Promotes Translational Silencing of Autocrine Interleukin-3 via Ribosome-Associated Deadenylation“. Molecular and Cellular Biology 19, Nr. 1 (01.01.1999): 889–98. http://dx.doi.org/10.1128/mcb.19.1.889.

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ABSTRACT Translation is regulated predominantly by an interplay betweencis elements at the 3′ and 5′ ends of mRNAs andtrans-acting proteins. Cyclosporin A (CsA), a calcineurin antagonist and blocker of interleukin-2 (IL-2) transcription in T cells, was found to inhibit translation of IL-3 mRNA in autocrine mast cell tumor lines. The mechanism involved ribosome-associated poly(A) shortening and required an intact AU-rich element in the 3′ untranslated region. FK506, another calcineurin inhibitor, shared the effect. The translational inhibition by CsA was specific to oncogenically induced lymphokines IL-3 and IL-4 but not to IL-6, c-jun, and c-myc, which are expressed in the nonmalignant precursor cells. Furthermore, no translational down-regulation of the mRNA was observed in IL-3-transfected precursor cells. These data suggest that translational silencing is associated with the tumor phenotype.

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Chapat, Clément, Seyed Mehdi Jafarnejad, Edna Matta-Camacho, Geoffrey G. Hesketh, Idit A. Gelbart, Jan Attig, Christos G. Gkogkas et al. „Cap-binding protein 4EHP effects translation silencing by microRNAs“. Proceedings of the National Academy of Sciences 114, Nr. 21 (09.05.2017): 5425–30. http://dx.doi.org/10.1073/pnas.1701488114.

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MicroRNAs (miRNAs) play critical roles in a broad variety of biological processes by inhibiting translation initiation and by destabilizing target mRNAs. The CCR4–NOT complex effects miRNA-mediated silencing, at least in part through interactions with 4E-T (eIF4E transporter) protein, but the precise mechanism is unknown. Here we show that the cap-binding eIF4E-homologous protein 4EHP is an integral component of the miRNA-mediated silencing machinery. We demonstrate that the cap-binding activity of 4EHP contributes to the translational silencing by miRNAs through the CCR4–NOT complex. Our results show that 4EHP competes with eIF4E for binding to 4E-T, and this interaction increases the affinity of 4EHP for the cap. We propose a model wherein the 4E-T/4EHP interaction engenders a closed-loop mRNA conformation that blocks translational initiation of miRNA targets.

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Huarte, Joaquin, André Stutz, Marcia L. O'Connell, Pascale Gubler, Dominique Belin, Andrew L. Darrow, Sidney Strickland und Jean-Dominique Vassalli. „Transient translational silencing by reversible mRNA deadenylation“. Cell 69, Nr. 6 (Juni 1992): 1021–30. http://dx.doi.org/10.1016/0092-8674(92)90620-r.

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Vyas, Keyur, Sujan Chaudhuri, Douglas W. Leaman, Anton A. Komar, Alla Musiyenko, Sailen Barik und Barsanjit Mazumder. „Genome-Wide Polysome Profiling Reveals an Inflammation-Responsive Posttranscriptional Operon in Gamma Interferon-Activated Monocytes“. Molecular and Cellular Biology 29, Nr. 2 (10.11.2008): 458–70. http://dx.doi.org/10.1128/mcb.00824-08.

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ABSTRACT We previously showed that ribosomal protein L13a is required for translational silencing of gamma interferon (IFN-γ)-induced ceruloplasmin (Cp) synthesis in monocytes. This silencing also requires the presence of the GAIT (IFN-gamma activated inhibitor of translation) element in the 3′ untranslated region (UTR) of Cp mRNA. Considering that Cp is an inflammatory protein, we hypothesized that this mechanism may have evolved to silence a family of proinflammatory proteins, of which Cp is just one member. To identify the other mRNAs that are targets for this silencing, we performed a genome-wide analysis of the polysome-profiled mRNAs by using an Affymetrix GeneChip and an inflammation-responsive gene array. A cluster of mRNAs encoding different chemokines and their receptors was identified as common hits in the two approaches and validated by real-time PCR. In silico predicted GAIT hairpins in the 3′ UTRs of the target mRNAs were confirmed as functional cis-acting elements for translational silencing by luciferase reporter assays. Consistent with Cp, the newly identified target mRNAs also required L13a for silencing. Our studies have identified a new inflammation-responsive posttranscriptional operon that can be regulated directly at the level of translation in IFN-γ-activated monocytes. This regulation of a cohort of mRNAs encoding inflammatory proteins may be important to resolve inflammation.

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Stutz, A., J. Huarte, P. Gubler, B. Conne, D. Belin und J. D. Vassalli. „In vivo antisense oligodeoxynucleotide mapping reveals masked regulatory elements in an mRNA dormant in mouse oocytes.“ Molecular and Cellular Biology 17, Nr. 4 (April 1997): 1759–67. http://dx.doi.org/10.1128/mcb.17.4.1759.

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In mouse oocytes, tissue-type plasminogen activator (tPA) mRNA is under translational control. The newly transcribed mRNA undergoes deadenylation and translational silencing in growing oocytes, while readenylation and translation occur during meiotic maturation. To localize regulatory elements controlling tPA mRNA expression, we identified regions of the endogenous transcript protected from hybridization with injected antisense oligodeoxynucleotides. Most of the targeted sequences in either the 5' untranslated region (5'UTR), coding region, or 3'UTR were accessible to hybridization, as revealed by inhibition of tPA synthesis and by RNase protection. Two protected regions were identified in the 3'UTR of tPA mRNA in primary oocytes: the adenylation control element (ACE) and the AAUAAA polyadenylation signal. These sequences were previously shown to be involved in the translational control of injected reporter transcripts. During the first hour of meiotic maturation, part of the ACE and the AAUAAA hexanucleotide became accessible to hybridization, suggesting a partial unmasking of the 3'UTR of this mRNA before it becomes translationally competent. Our results demonstrate that in vivo antisense oligodeoxynucleotide mapping can reveal the dynamics of regulatory features of a native mRNA in the context of the intact cell. They suggest that specific regions in the 3'UTR of tPA mRNA function as cis-acting masking determinants involved in the silencing of tPA mRNA in primary oocytes.

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Ostareck-Lederer, Antje, Dirk H. Ostareck, Christophe Cans, Gitte Neubauer, Karol Bomsztyk, Giulio Superti-Furga und Matthias W. Hentze. „c-Src-Mediated Phosphorylation of hnRNP K Drives Translational Activation of Specifically Silenced mRNAs“. Molecular and Cellular Biology 22, Nr. 13 (01.07.2002): 4535–43. http://dx.doi.org/10.1128/mcb.22.13.4535-4543.2002.

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ABSTRACT hnRNPK and hnRNP E1/E2 mediate translational silencing of cellular and viral mRNAs in a differentiation-dependent way by binding to specific regulatory sequences. The translation of 15-lipoxygenase (LOX) mRNA in erythroid precursor cells and of the L2 mRNA of human papilloma virus type 16 (HPV-16) in squamous epithelial cells is silenced when either of these cells is immature and is activated in maturing cells by unknown mechanisms. Here we address the question of how the silenced mRNA can be translationally activated. We show that hnRNP K and the c-Src kinase specifically interact with each other, leading to c-Src activation and tyrosine phosphorylation of hnRNP K in vivo and in vitro. c-Src-mediated phosphorylation reversibly inhibits the binding of hnRNP K to the differentiation control element (DICE) of the LOX mRNA 3′ untranslated region in vitro and specifically derepresses the translation of DICE-bearing mRNAs in vivo. Our results establish a novel role of c-Src kinase in translational gene regulation and reveal a mechanism by which silenced mRNAs can be translationally activated.

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Zekri, Latifa, Eric Huntzinger, Susanne Heimstädt und Elisa Izaurralde. „The Silencing Domain of GW182 Interacts with PABPC1 To Promote Translational Repression and Degradation of MicroRNA Targets and Is Required for Target Release“. Molecular and Cellular Biology 29, Nr. 23 (21.09.2009): 6220–31. http://dx.doi.org/10.1128/mcb.01081-09.

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ABSTRACT GW182 family proteins are essential in animal cells for microRNA (miRNA)-mediated gene silencing, yet the molecular mechanism that allows GW182 to promote translational repression and mRNA decay remains largely unknown. Previous studies showed that while the GW182 N-terminal domain interacts with Argonaute proteins, translational repression and degradation of miRNA targets are promoted by a bipartite silencing domain comprising the GW182 middle and C-terminal regions. Here we show that the GW182 C-terminal region is required for GW182 to release silenced mRNPs; moreover, GW182 dissociates from miRNA targets at a step of silencing downstream of deadenylation, indicating that GW182 is required to initiate but not to maintain silencing. In addition, we show that the GW182 bipartite silencing domain competes with eukaryotic initiation factor 4G for binding to PABPC1. The GW182-PABPC1 interaction is also required for miRNA target degradation; accordingly, we observed that PABPC1 associates with components of the CCR4-NOT deadenylase complex. Finally, we show that PABPC1 overexpression suppresses the silencing of miRNA targets. We propose a model in which the GW182 silencing domain promotes translational repression, at least in part, by interfering with mRNA circularization and also recruits the deadenylase complex through the interaction with PABPC1.

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Meister, Gunter. „miRNAs Get an Early Start on Translational Silencing“. Cell 131, Nr. 1 (Oktober 2007): 25–28. http://dx.doi.org/10.1016/j.cell.2007.09.021.

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Geck, P., V. Denes, M. Pilichowska, A. Makarovskiy und G. A. Carpinito. „Translational disequilibrium as an interference marker to study miRNA and methylation silencing of APRIN, a stem cell regulator in breast cancer microchimerism“. Journal of Clinical Oncology 27, Nr. 15_suppl (20.05.2009): 11109. http://dx.doi.org/10.1200/jco.2009.27.15_suppl.11109.

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11109 Background: Gene silencing is universally observed in cancer and involves promoter DNA methylation. We found that a cohesin-related stem cell regulator, APRIN (Pds5B) was silenced in breast cancer clinical samples. Surprisingly, in 40% of these samples DNA methylation was not involved. Furthermore, in some breast cancer cell lines the APRIN protein was silenced without transcript downregulation or promoter methylation. This “translational disequilibrium” has been frequently reported with other proteins, but without mechanistic explanations. Recent results with RNA interference indicate that gene repression through microRNAs (typically mismatched) is mostly translational without transcript degradation. We propose, therefore, that the puzzling translational disequilibrium phenomenon is a new form of epigenetic silencing by miRNA mechanisms. We aim (i) to verify miRNA epigenetics of APRIN silencing in breast cancer cell lines; (ii) to study clinical breast cancer samples for methylation vs. miRNAs mechanisms in APRIN translational disequilibrium; and (iii) to investigate if miRNA silencing of APRIN affects a fetal embryonic stem cell pool in breast cancer (microchimerism). Methods: (i) We used miRNA mimics and miRNA inhibitors in breast cancer cell lines to verify specific miRNA involvement in APRIN silencing. (ii) We used immunohistochemistry with bisulfite converted DNA for methylation and microdissected RNA for microRNA interference studies from 56 clinical breast cancer samples. (iii) We used Y-chromosome markers on microdissected DNA for fetal microchimerism studies. Results: (i) We found that in breast cancer cell lines with APRIN translational disequilibrium a set of microRNAs correlate with APRIN silencing. (ii) We found miRNA related mechanisms in about 35 percent of breast cancer samples where APRIN was silenced and (iii) APRIN may specifically affect stem cells of fetal origin in the mother's mammary gland and contribute to cancer. Conclusions: The novel miRNA-based mechanism maybe a new epigenetic factor of gene silencing in cancer. We experimentally confirmed a set of APRIN specific miRNAs and established preliminary correlations with fetal microchimerism in breast cancer. No significant financial relationships to disclose.

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Tehfe, Ali, Talia Roseshter, Yulong Wei und Xuhua Xia. „Does Saccharomyces cerevisiae Require Specific Post-Translational Silencing against Leaky Translation of Hac1up?“ Microorganisms 9, Nr. 3 (17.03.2021): 620. http://dx.doi.org/10.3390/microorganisms9030620.

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HAC1 encodes a key transcription factor that transmits the unfolded protein response (UPR) from the endoplasmic reticulum (ER) to the nucleus and regulates downstream UPR genes in Saccharomyces cerevisiae. In response to the accumulation of unfolded proteins in the ER, Ire1p oligomers splice HAC1 pre-mRNA (HAC1u) via a non-conventional process and allow the spliced HAC1 (HAC1i) to be translated efficiently. However, leaky splicing and translation of HAC1u may occur in non-UPR cells to induce undesirable UPR. To control accidental UPR activation, multiple fail-safe mechanisms have been proposed to prevent leaky HAC1 splicing and translation and to facilitate rapid degradation of translated Hac1up and Hac1ip. Among proposed regulatory mechanisms is a degron sequence encoded at the 5′ end of the HAC1 intron that silences Hac1up expression. To investigate the necessity of an intron-encoded degron sequence that specifically targets Hac1up for degradation, we employed publicly available transcriptomic data to quantify leaky HAC1 splicing and translation in UPR-induced and non-UPR cells. As expected, we found that HAC1u is only efficiently spliced into HAC1i and efficiently translated into Hac1ip in UPR-induced cells. However, our analysis of ribosome profiling data confirmed frequent occurrence of leaky translation of HAC1u regardless of UPR induction, demonstrating the inability of translation fail-safe to completely inhibit Hac1up production. Additionally, among 32 yeast HAC1 surveyed, the degron sequence is highly conserved by Saccharomyces yeast but is poorly conserved by all other yeast species. Nevertheless, the degron sequence is the most conserved HAC1 intron segment in yeasts. These results suggest that the degron sequence may indeed play an important role in mitigating the accumulation of Hac1up to prevent accidental UPR activation in the Saccharomyces yeast.

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Rüdel, Sabine, und Gunter Meister. „Phosphorylation of Argonaute proteins: regulating gene regulators“. Biochemical Journal 413, Nr. 3 (15.07.2008): e7-e9. http://dx.doi.org/10.1042/bj20081244.

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Members of the Ago (Argonaute) protein family are the mediators of small RNA-guided gene-silencing pathways including RNAi (RNA interference), translational regulation by miRNAs (microRNAs) and transcriptional silencing. Recent findings by Zeng et al. in this issue of the Biochemical Journal demonstrate that Ago proteins are post-translationally modified by phosphorylation of Ser387. Mutating Ser387 to alanine leads to reduced localization of human Ago2 to cytoplasmic P-bodies (processing bodies), cellular sites where RNA turnover and, at least in part, miRNA-guided gene regulation occurs. Zeng et al. further show that a member of the MAPK (mitogen-activated protein kinase) signalling pathway phosphorylates Ago2 at Ser387, suggesting that Ago2-mediated gene silencing might be linked to distinct signalling pathways.

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El Gazzar, Mohamed, und Charles E. McCall. „MicroRNAs Distinguish Translational from Transcriptional Silencing during Endotoxin Tolerance“. Journal of Biological Chemistry 285, Nr. 27 (30.04.2010): 20940–51. http://dx.doi.org/10.1074/jbc.m110.115063.

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Cannell, Ian G., Yi Wen Kong und Martin Bushell. „How do microRNAs regulate gene expression?“ Biochemical Society Transactions 36, Nr. 6 (19.11.2008): 1224–31. http://dx.doi.org/10.1042/bst0361224.

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miRNAs (microRNAs) are short non-coding RNAs that regulate gene expression post-transcriptionally. They generally bind to the 3′-UTR (untranslated region) of their target mRNAs and repress protein production by destabilizing the mRNA and translational silencing. The exact mechanism of miRNA-mediated translational repression is yet to be fully determined, but recent data from our laboratory have shown that the stage of translation which is inhibited by miRNAs is dependent upon the promoter used for transcribing the target mRNA. This review focuses on understanding how miRNA repression is operating in light of these findings and the questions that still remain.

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Mazan-Mamczarz, Krystyna, Ashish Lal, Jennifer L. Martindale, Tomoko Kawai und Myriam Gorospe. „Translational Repression by RNA-Binding Protein TIAR“. Molecular and Cellular Biology 26, Nr. 7 (01.04.2006): 2716–27. http://dx.doi.org/10.1128/mcb.26.7.2716-2727.2006.

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ABSTRACT The RNA-binding protein TIAR has been proposed to inhibit protein synthesis transiently by promoting the formation of translationally silent stress granules. Here, we report the selective binding of TIAR to several mRNAs encoding translation factors such as eukaryotic initiation factor 4A (eIF4A) and eIF4E (translation initiation factors), eEF1B (a translation elongation factor), and c-Myc (which transcriptionally controls the expression of numerous translation regulatory proteins). TIAR bound the 3′-untranslated regions of these mRNAs and potently suppressed their translation, particularly in response to low levels of short-wavelength UV (UVC) irradiation. The UVC-imposed global inhibition of the cellular translation machinery was significantly relieved after silencing of TIAR expression. We propose that the TIAR-mediated inhibition of translation factor expression elicits a sustained repression of protein biosynthesis in cells responding to stress.

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Mazumder, Barsanjit, und Paul L. Fox. „Delayed Translational Silencing of Ceruloplasmin Transcript in Gamma Interferon-Activated U937 Monocytic Cells: Role of the 3′ Untranslated Region“. Molecular and Cellular Biology 19, Nr. 10 (01.10.1999): 6898–905. http://dx.doi.org/10.1128/mcb.19.10.6898.

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ABSTRACT Ceruloplasmin (Cp) is an acute-phase protein with ferroxidase, amine oxidase, and pro- and antioxidant activities. The primary site of Cp synthesis in human adults is the liver, but it is also synthesized by cells of monocytic origin. We have shown that gamma interferon (IFN-γ) induces the synthesis of Cp mRNA and protein in monocytic cells. We now report that the induced synthesis of Cp is terminated by a mechanism involving transcript-specific translational repression. Cp protein synthesis in U937 cells ceased after 16 h even in the presence of abundant Cp mRNA. RNA isolated from cells treated with IFN-γ for 24 h exhibited a high in vitro translation rate, suggesting that the transcript was not defective. Ribosomal association of Cp mRNA was examined by sucrose centrifugation. When Cp synthesis was high, i.e., after 8 h of IFN-γ treatment, Cp mRNA was primarily associated with polyribosomes. However, after 24 h, when Cp synthesis was low, Cp mRNA was primarily in the nonpolyribosomal fraction. Cytosolic extracts from cells treated with IFN-γ for 24 h, but not for 8 h, contained a factor which blocked in vitro Cp translation. Inhibitor expression was cell type specific and present in extracts of human cells of myeloid origin, but not in several nonmyeloid cells. The inhibitory factor bound to the 3′ untranslated region (3′-UTR) of Cp mRNA, as shown by restoration of in vitro translation by synthetic 3′-UTR added as a “decoy” and detection of a binding complex by RNA gel shift analysis. Deletion mapping of the Cp 3′-UTR indicated an internal 100-nucleotide region of the Cp 3′-UTR that was required for complex formation as well as for silencing of translation. Although transcript-specific translational control is common during development and differentiation and global translational control occurs during responses to cytokines and stress, to our knowledge, this is the first report of translational silencing of a specific transcript following cytokine activation.

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Yao, Bing, Songqing Li, Hyun Min Jung, Shang L. Lian, Grant X. Abadal, Frank Han, Marvin J. Fritzler und Edward K. L. Chan. „Divergent GW182 functional domains in the regulation of translational silencing“. Nucleic Acids Research 39, Nr. 7 (02.12.2010): 2534–47. http://dx.doi.org/10.1093/nar/gkq1099.

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Wang, Bingbing, Tara M. Love, Matthew E. Call, John G. Doench und Carl D. Novina. „Recapitulation of Short RNA-Directed Translational Gene Silencing In Vitro“. Molecular Cell 22, Nr. 4 (Mai 2006): 553–60. http://dx.doi.org/10.1016/j.molcel.2006.03.034.

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Lingenfelter, Brandon M., und Jianbo Yao. „Bos taurus microRNA-181a Promotes Translational Silencing of Nucleoplasmin 2.“ Biology of Reproduction 78, Suppl_1 (01.05.2008): 59–60. http://dx.doi.org/10.1093/biolreprod/78.s1.59c.

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Brown, Andrew S., Bidyut K. Mohanty und Philip H. Howe. „Identification and characterization of an hnRNP E1 translational silencing motif“. Nucleic Acids Research 44, Nr. 12 (11.04.2016): 5892–907. http://dx.doi.org/10.1093/nar/gkw241.

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Kuwano, Yuki, Hyeon Ho Kim, Kotb Abdelmohsen, Rudolf Pullmann, Jennifer L. Martindale, Xiaoling Yang und Myriam Gorospe. „MKP-1 mRNA Stabilization and Translational Control by RNA-Binding Proteins HuR and NF90“. Molecular and Cellular Biology 28, Nr. 14 (19.05.2008): 4562–75. http://dx.doi.org/10.1128/mcb.00165-08.

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ABSTRACT The mitogen-activated protein (MAP) kinase phosphatase 1 (MKP-1) plays a major role in dephosphorylating and thereby inactivating the MAP kinases extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. Here, we examine the posttranscriptional events underlying the robust MKP-1 induction by oxidants in HeLa cells. H2O2 treatment potently stabilized the MKP-1 mRNA and increased the association of MKP-1 mRNA with the translation machinery. Four RNA-binding proteins (RNA-BPs) that influence mRNA turnover and/or translation (HuR, NF90, TIAR, and TIA-1) were found to bind to biotinylated transcripts spanning the MKP-1 AU-rich 3′ untranslated region. By using ribonucleoprotein immunoprecipitation analysis, we showed that H2O2 treatment increased the association of MKP-1 mRNA with HuR and NF90 and decreased its association with the translational repressors TIAR and TIA-1. HuR or NF90 silencing significantly diminished the H2O2-stimulated MKP-1 mRNA stability; HuR silencing also markedly decreased MKP-1 translation. In turn, lowering MKP-1 expression in HuR-silenced cultures resulted in substantially elevated phosphorylation of JNK and p38 after H2O2 treatment. Collectively, MKP-1 upregulation by oxidative stress is potently influenced by increased mRNA stability and translation, mediated at least in part by the RNA-BPs HuR and NF90.

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Kong, Jian, Marina Sumaroka, Dawn L. Eastmond und Stephen A. Liebhaber. „Shared Stabilization Functions of Pyrimidine-Rich Determinants in the Erythroid 15-lipoxygenase and α-globin mRNAs“. Molecular and Cellular Biology 26, Nr. 15 (01.08.2006): 5603–14. http://dx.doi.org/10.1128/mcb.01845-05.

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ABSTRACT The poly(C)-binding proteins, αCPs, comprise a set of highly conserved KH-domain factors that participate in mRNA stabilization and translational controls in developmental and viral systems. Two prominent models of αCP function link these controls to late stages of erythroid differentiation: translational silencing of 15-lipoxygenase (Lox) mRNA and stabilization of α-globin mRNA. These two controls are mediated via association of αCPs with structurally related C-rich 3′-untranslated region elements: the differentiation control elements (DICE) in Lox mRNA and the pyrimidine-rich motifs in α-globin mRNA. In the present report a set of mRNA translation and stability assays are used to determine how these two αCP-containing complexes, related in structure and position, mediate distinct posttranscriptional controls. While the previously reported translational silencing by the DICE is not evident in our studies, we find that the two determinants mediate similar levels of mRNA stabilization in erythroid cells. In both cases this stabilization is sensitive to interference by a nuclear-restricted αCP decoy but not by the same decoy restricted to the cytoplasm. These data support a general role for αCPs in stabilizing a subset of erythroid mRNAs. The findings also suggest that initial binding of αCP to target mRNAs occurs in the nucleus. Assembly of stabilizing mRNP complexes in the nucleus prior to export may maximize their impact on cytoplasmic events.

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Huntzinger, Eric, und Elisa Izaurralde. „Gene silencing by microRNAs: contributions of translational repression and mRNA decay“. Nature Reviews Genetics 12, Nr. 2 (18.01.2011): 99–110. http://dx.doi.org/10.1038/nrg2936.

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Leatherman, Judith L., und Thomas A. Jongens. „Transcriptional silencing and translational control: key features of early germline development“. BioEssays 25, Nr. 4 (19.03.2003): 326–35. http://dx.doi.org/10.1002/bies.10247.

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Jin, Hua, Mi Ra Suh, Jinju Han, Kyu-Hyeon Yeom, Yoontae Lee, Inha Heo, Minju Ha, Seogang Hyun und V. Narry Kim. „Human UPF1 Participates in Small RNA-Induced mRNA Downregulation“. Molecular and Cellular Biology 29, Nr. 21 (24.08.2009): 5789–99. http://dx.doi.org/10.1128/mcb.00653-09.

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ABSTRACT MicroRNAs (miRNAs) are endogenous antisense regulators that trigger endonucleolytic mRNA cleavage, translational repression, and/or mRNA decay. miRNA-mediated gene regulation is important for numerous biological pathways, yet the underlying mechanisms are still under rigorous investigation. Here we identify human UPF1 (hUPF1) as a protein that contributes to RNA silencing. When hUPF1 is knocked down, miRNA targets are upregulated. The depletion of hUPF1 also increases the off-target messages of small interfering RNAs (siRNAs), which are imperfectly complementary to transfected siRNAs. Conversely, when overexpressed, wild-type hUPF1 downregulates miRNA targets. The helicase domain mutant of hUPF1 fails to suppress miRNA targets. hUPF1 interacts with human Argonaute 1 (hAGO1) and hAGO2 and colocalizes with hAGO1 and hAGO2 in processing bodies, which are known to be the sites for translational repression and mRNA destruction. We further find that the amounts of target messages bound to hAGO2 are reduced when hUPF1 is depleted. Our data thus suggest that hUPF1 may participate in RNA silencing by facilitating the binding of the RNA-induced silencing complex to the target and by accelerating the decay of the mRNA.

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Nakamura, Akira, Reiko Amikura, Kazuko Hanyu und Satoru Kobayashi. „Me31B silences translation of oocyte-localizing RNAs through the formation of cytoplasmic RNP complex duringDrosophilaoogenesis“. Development 128, Nr. 17 (01.09.2001): 3233–42. http://dx.doi.org/10.1242/dev.128.17.3233.

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Embryonic patterning in Drosophila is regulated by maternal factors. Many such factors become localized as mRNAs within the oocyte during oogenesis and are translated in a spatio-temporally regulated manner. These processes are controlled by trans-acting proteins, which bind to the target RNAs to form a ribonucleoprotein (RNP) complex. We report that a DEAD-box protein, Me31B, forms a cytoplasmic RNP complex with oocyte-localizing RNAs and Exuperantia, a protein involved in RNA localization. During early oogenesis, loss of Me31B causes premature translation of oocyte-localizing RNAs within nurse cells, without affecting their transport to the oocyte. These results suggest that Me31B mediates translational silencing of RNAs during their transport to the oocyte. Our data provide evidence that RNA transport and translational control are linked through the assembly of RNP complex.

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Eulalio, Ana, Isabelle Behm-Ansmant, Daniel Schweizer und Elisa Izaurralde. „P-Body Formation Is a Consequence, Not the Cause, of RNA-Mediated Gene Silencing“. Molecular and Cellular Biology 27, Nr. 11 (02.04.2007): 3970–81. http://dx.doi.org/10.1128/mcb.00128-07.

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ABSTRACT P bodies are cytoplasmic domains that contain proteins involved in diverse posttranscriptional processes, such as mRNA degradation, nonsense-mediated mRNA decay (NMD), translational repression, and RNA-mediated gene silencing. The localization of these proteins and their targets in P bodies raises the question of whether their spatial concentration in discrete cytoplasmic domains is required for posttranscriptional gene regulation. We show that processes such as mRNA decay, NMD, and RNA-mediated gene silencing are functional in cells lacking detectable microscopic P bodies. Although P bodies are not required for silencing, blocking small interfering RNA or microRNA silencing pathways at any step prevents P-body formation, indicating that P bodies arise as a consequence of silencing. Consistently, we show that releasing mRNAs from polysomes is insufficient to trigger P-body assembly: polysome-free mRNAs must enter silencing and/or decapping pathways to nucleate P bodies. Thus, even though P-body components play crucial roles in mRNA silencing and decay, aggregation into P bodies is not required for function but is instead a consequence of their activity.

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Brownsword, Matthew J., Nicole Doyle, Michèle Brocard, Nicolas Locker und Helena J. Maier. „Infectious Bronchitis Virus Regulates Cellular Stress Granule Signaling“. Viruses 12, Nr. 5 (14.05.2020): 536. http://dx.doi.org/10.3390/v12050536.

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Viruses must hijack cellular translation machinery to express viral genes. In many cases, this is impeded by cellular stress responses. These stress responses result in the global inhibition of translation and the storage of stalled mRNAs, into RNA-protein aggregates called stress granules. This results in the translational silencing of the majority of mRNAs excluding those beneficial for the cell to resolve the specific stress. For example, the expression of antiviral factors is maintained during viral infection. Here we investigated stress granule regulation by Gammacoronavirus infectious bronchitis virus (IBV), which causes the economically important poultry disease, infectious bronchitis. Interestingly, we found that IBV is able to inhibit multiple cellular stress granule signaling pathways, whilst at the same time, IBV replication also results in the induction of seemingly canonical stress granules in a proportion of infected cells. Moreover, IBV infection uncouples translational repression and stress granule formation and both processes are independent of eIF2α phosphorylation. These results provide novel insights into how IBV modulates cellular translation and antiviral stress signaling.

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Kakumani, Pavan Kumar, Louis-Mathieu Harvey, François Houle, Tanit Guitart, Fátima Gebauer und Martin J. Simard. „CSDE1 controls gene expression through the miRNA-mediated decay machinery“. Life Science Alliance 3, Nr. 4 (11.03.2020): e201900632. http://dx.doi.org/10.26508/lsa.201900632.

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In animals, miRNAs are the most prevalent small non-coding RNA molecules controlling posttranscriptional gene regulation. The Argonaute proteins (AGO) mediate miRNA-guided gene silencing by recruiting multiple factors involved in translational repression, deadenylation, and decapping. Here, we report that CSDE1, an RNA-binding protein linked to stem cell maintenance and metastasis in cancer, interacts with AGO2 within miRNA-induced silencing complex and mediates gene silencing through its N-terminal domains. We show that CSDE1 interacts with LSM14A, a constituent of P-body assembly and further associates to the DCP1–DCP2 decapping complex, suggesting that CSDE1 could promote the decay of miRNA-induced silencing complex-targeted mRNAs. Together, our findings uncover a hitherto unknown mechanism used by CSDE1 in the control of gene expression mediated by the miRNA pathway.

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Kamenska, Anastasiia, Wei-Ting Lu, Dorota Kubacka, Helen Broomhead, Nicola Minshall, Martin Bushell und Nancy Standart. „Human 4E-T represses translation of bound mRNAs and enhances microRNA-mediated silencing“. Nucleic Acids Research 42, Nr. 5 (13.12.2013): 3298–313. http://dx.doi.org/10.1093/nar/gkt1265.

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Abstract A key player in translation initiation is eIF4E, the mRNA 5′ cap-binding protein. 4E-Transporter (4E-T) is a recently characterized eIF4E-binding protein, which regulates specific mRNAs in several developmental model systems. Here, we first investigated the role of its enrichment in P-bodies and eIF4E-binding in translational regulation in mammalian cells. Identification of the conserved C-terminal sequences that target 4E-T to P-bodies was enabled by comparison of vertebrate proteins with homologues in Drosophila (Cup and CG32016) and Caenorhabditis elegans by sequence and cellular distribution. In tether function assays, 4E-T represses bound mRNA translation, in a manner independent of these localization sequences, or of endogenous P-bodies. Quantitative polymerase chain reaction and northern blot analysis verified that bound mRNA remained intact and polyadenylated. Ectopic 4E-T reduces translation globally in a manner dependent on eIF4E binding its consensus Y30X4Lϕ site. In contrast, tethered 4E-T continued to repress translation when eIF4E-binding was prevented by mutagenesis of YX4Lϕ, and modestly enhanced the decay of bound mRNA, compared with wild-type 4E-T, mediated by increased binding of CNOT1/7 deadenylase subunits. As depleting 4E-T from HeLa cells increased steady-state translation, in part due to relief of microRNA-mediated silencing, this work demonstrates the conserved yet unconventional mechanism of 4E-T silencing of particular subsets of mRNAs.

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Schultz, Kimberly L. W., und Paul D. Friesen. „Baculovirus DNA Replication-Specific Expression Factors Trigger Apoptosis and Shutoff of Host Protein Synthesis during Infection“. Journal of Virology 83, Nr. 21 (12.08.2009): 11123–32. http://dx.doi.org/10.1128/jvi.01199-09.

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ABSTRACT Apoptosis is an important antivirus defense. To define the poorly understood pathways by which invertebrates respond to viruses by inducing apoptosis, we have identified replication events that trigger apoptosis in baculovirus-infected cells. We used RNA silencing to ablate factors required for multiplication of Autographa californica multicapsid nucleopolyhedrovirus (AcMNPV). Transfection with double-stranded RNA (dsRNA) complementary to the AcMNPV late expression factors (lefs) that are designated as replicative lefs (lef-1, lef-2, lef-3, lef-11, p143, dnapol, and ie-1/ie-0) blocked virus DNA synthesis and late gene expression in permissive Spodoptera frugiperda cells. dsRNAs specific to designated nonreplicative lefs (lef-8, lef-9, p47, and pp31) blocked late gene expression without affecting virus DNA replication. Thus, both classes of lefs functioned during infection as defined. Silencing the replicative lefs prevented AcMNPV-induced apoptosis of Spodoptera cells, whereas silencing the nonreplicative lefs did not. Thus, the activity of replicative lefs or virus DNA replication is sufficient to trigger apoptosis. Confirming this conclusion, AcMNPV-induced apoptosis was suppressed by silencing the replicative lefs in cells from a divergent species, Drosophila melanogaster. Silencing replicative but not nonreplicative lefs also abrogated AcMNPV-induced shutdown of host protein synthesis, suggesting that virus DNA replication triggers inhibition of host biosynthetic processes and that apoptosis and translational arrest are linked. Our findings suggest that baculovirus DNA replication triggers a host cell response similar to the DNA damage response in vertebrates, which causes translational arrest and apoptosis. Pathways for detecting virus invasion and triggering apoptosis may therefore be conserved between insects and mammals.

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Tan, Huijuan, Bosheng Li und Hongwei Guo. „The diversity of post-transcriptional gene silencing mediated by small silencing RNAs in plants“. Essays in Biochemistry 64, Nr. 6 (Dezember 2020): 919–30. http://dx.doi.org/10.1042/ebc20200006.

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Abstract In plants, post-transcriptional gene silencing (PTGS) tightly regulates development, maintains genome stability and protects plant against foreign genes. PTGS can be triggered by virus infection, transgene, and endogenous transcript, thus commonly serves as an RNA-based immune mechanism. Accordingly, based on the initiating factors, PTGS can be divided into viral-PTGS, transgene-PTGS, and endo-gene-PTGS. Unlike the intensely expressed invading transgenes and viral genes that frequently undergo PTGS, most endogenous genes do not trigger PTGS, except for a few that can produce endogenous small RNAs (sRNAs), including microRNA (miRNA) and small interfering RNA (siRNA). Different lengths of miRNA and siRNA, mainly 21-, 22- or 24-nucleotides (nt) exert diverse functions, ranging from target mRNA degradation, translational inhibition, or DNA methylation and chromatin modifications. The abundant 21-nt miRNA or siRNA, processed by RNase-III enzyme DICER-LIKE 1 (DCL1) and DCL4, respectively, have been well studied in the PTGS pathways. By contrast, the scarceness of endogenous 22-nt sRNAs that are primarily processed by DCL2 limits their research, although a few encouraging studies have been reported recently. Therefore, we review here our current understanding of diverse PTGS pathways triggered by a variety of sRNAs and summarize the distinct features of the 22-nt sRNA mediated PTGS.

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Azar, R., S. Najib, H. Lahlou, C. Susini und S. Pyronnet. „Phosphatidylinositol 3-kinase-dependent transcriptional silencing of the translational repressor 4E-BP1“. Cellular and Molecular Life Sciences 65, Nr. 19 (23.09.2008): 3110–17. http://dx.doi.org/10.1007/s00018-008-8418-2.

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Fonseca Cabral, Gleyce, Jhully Azevedo dos Santos Pinheiro, Amanda Ferreira Vidal, Sidney Santos und Ândrea Ribeiro-dos-Santos. „piRNAs in Gastric Cancer: A New Approach Towards Translational Research“. International Journal of Molecular Sciences 21, Nr. 6 (19.03.2020): 2126. http://dx.doi.org/10.3390/ijms21062126.

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Background: Gastric cancer is currently the third leading cause of cancer-related deaths worldwide, usually diagnosed at late stages. The development of new biomarkers to improve its prevention and patient management is critical for disease control. piRNAs are small regulatory RNAs important for gene silencing mechanisms, mainly associated with the silencing of transposable elements. piRNA pathways may also be involved in gene regulation and the deregulation of piRNAs may be an important factor in carcinogenic processes. Thus, several studies suggest piRNAs as potential cancer biomarkers. Translational studies suggest that piRNAs may regulate key genes and pathways associated with gastric cancer progression, though there is no functional annotation in piRNA databases. The impacts of genetic variants in piRNA genes and their influence in gastric cancer development remains elusive, highlighting the gap in piRNA regulatory mechanisms knowledge. Here, we discuss the current state of understanding of piRNA-mediated regulation and piRNA functions and suggest that genetic alterations in piRNA genes may affect their functionality, thus, it may be associated with gastric carcinogenesis. Conclusions: In the era of precision medicine, investigations about genetic and epigenetic mechanisms are essential to further comprehend gastric carcinogenesis and the role of piRNAs as potential biomarkers for translational research.

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Schröder, Jens A., und Pauline E. Jullien. „The Diversity of Plant Small RNAs Silencing Mechanisms“. CHIMIA International Journal for Chemistry 73, Nr. 5 (29.05.2019): 362–67. http://dx.doi.org/10.2533/chimia.2019.362.

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Small RNAs gene regulation was first discovered about 20 years ago. It represents a conserve gene regulation mechanism across eukaryotes and is associated to key regulatory processes. In plants, small RNAs tightly regulate development, but also maintain genome stability and protect the plant against pathogens. Small RNA gene regulation in plants can be divided in two canonical pathways: Post-transcriptional Gene Silencing (PTGS) that results in transcript degradation and/or translational inhibition or Transcriptional Gene Silencing (TGS) that results in DNA methylation. In this review, we will focus on the model plant Arabidopsis thaliana. We will provide a brief overview of the molecular mechanisms involved in canonical small RNA pathways as well as introducing more atypical pathways recently discovered.

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Sidahmed, Abubaker, Shaza Abdalla, Salahedin Mahmud und Bruce Wilkie. „Antiviral innate immune response of RNA interference“. Journal of Infection in Developing Countries 8, Nr. 07 (14.07.2014): 804–10. http://dx.doi.org/10.3855/jidc.4187.

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RNA interference (RNAi) is an ancient, natural process conserved among species from different kingdoms. RNAi is a transcriptional and post-transcriptional gene silencing mechanism in which, double-stranded RNA or hairpin RNA is cleaved by an RNase III-type enzyme called Dicer into small interfering RNA duplex. This subsequently directs sequence-specific, homology dependent, Watson-Crick base-pairing post-transcriptional gene silencing by binding to its complementary RNA and initiating its elimination through degradation or by persuading translational inhibition. In plants, worms, and insects, RNAi is the main and strong antiviral defense mechanism. It is clear that RNAi silencing, contributes in restriction of viral infection in vertebrates. In a short period, RNAi has progressed to become a significant experimental tool for the analysis of gene function and target validation in mammalian systems. In addition, RNA silencing has then been found to be involved in translational repression, transcriptional inhibition, and DNA degradation. RNAi machinery required for robust RNAi-mediated antiviral response are conserved throughout evolution in mammals and plays a crucial role in antiviral defense of invertebrates, but despite these important functions RNAi contribution to mammalian antiviral innate immune defense has been underestimated and disputed. In this article, we review the literature concerning the roles of RNAi as components of innate immune system in mammals and how, the RNAi is currently one of the most hopeful new advances toward disease therapy. This review highlights the potential of RNAi as a therapeutic strategy for viral infection and gene regulation to modulate host immune response to viral infection.

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Ma, Xinrong, Fadia Ibrahim, Eun-Jeong Kim, Scott Shaver, James Becker, Fareha Razvi, Ronald L. Cerny und Heriberto Cerutti. „An ortholog of the Vasa intronic gene is required for small RNA-mediated translation repression inChlamydomonas reinhardtii“. Proceedings of the National Academy of Sciences 117, Nr. 1 (23.12.2019): 761–70. http://dx.doi.org/10.1073/pnas.1908356117.

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Small RNAs (sRNAs) associate with Argonaute (AGO) proteins in effector complexes, termed RNA-induced silencing complexes (RISCs), which regulate complementary transcripts by translation inhibition and/or RNA degradation. In the unicellular algaChlamydomonas, several metazoans, and land plants, emerging evidence indicates that polyribosome-associated transcripts can be translationally repressed by RISCs without substantial messenger RNA (mRNA) destabilization. However, the mechanism of translation inhibition in a polyribosomal context is not understood. Here we show thatChlamydomonasVIG1, an ortholog of theDrosophila melanogasterVasa intronic gene (VIG), is required for this process. VIG1 localizes predominantly in the cytosol and comigrates with monoribosomes and polyribosomes by sucrose density gradient sedimentation. AVIG1-deleted mutant shows hypersensitivity to the translation elongation inhibitor cycloheximide, suggesting that VIG1 may have a nonessential role in ribosome function/structure. Additionally, FLAG-tagged VIG1 copurifies with AGO3 and Dicer-like 3 (DCL3), consistent with it also being a component of the RISC. Indeed, VIG1 is necessary for the repression of sRNA-targeted transcripts at the translational level but is dispensable for cleavage-mediated RNA interference and for the association of the AGO3 effector with polyribosomes or target transcripts. Our results suggest that VIG1 is an ancillary ribosomal component and plays a role in sRNA-mediated translation repression of polyribosomal transcripts.

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Pantaleo, Vitantonio, György Szittya und József Burgyán. „Molecular Bases of Viral RNA Targeting by Viral Small Interfering RNA-Programmed RISC“. Journal of Virology 81, Nr. 8 (31.01.2007): 3797–806. http://dx.doi.org/10.1128/jvi.02383-06.

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ABSTRACT RNA silencing is conserved in a broad range of eukaryotes and operates in the development and maintenance of genome integrity in many organisms. Plants have adapted this system for antiviral defense, and plant viruses have in turn developed mechanisms to suppress RNA silencing. RNA silencing-related RNA inactivation is likely based on target RNA cleavage or translational arrest. Although it is widely assumed that virus-induced gene silencing (VIGS) promotes the endonucleolytic cleavage of the viral RNA genome, this popular assumption has never been tested experimentally. Here we analyzed the viral RNA targeting by VIGS in tombusvirus-infected plants, and we show evidence that antiviral response of VIGS is based on viral RNA cleavage by RNA-induced silencing effector complex (RISC) programmed by virus-specific small interfering RNAs (siRNAs). In addition, we found that the RISC-mediated cleavages do not occur randomly on the viral genome. Indeed, sequence analysis of cloned cleavage products identified hot spots for target RNA cleavage, and the regions of specific RISC-mediated cleavages are asymmetrically distributed along the positive- and negative-sense viral RNA strands. In addition, we identified viral siRNAs containing high-molecular-mass protein complexes purified from the recovery leaves of the silencing suppressor mutant virus-infected plants. Strikingly, these large nucleoproteins cofractionated with microRNA-containing complexes, suggesting that these nucleoproteins are silencing related effector complexes.

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Chirichella, Michele, Simonetta Lisi, Marco Fantini, Martina Goracci, Mariantonietta Calvello, Rossella Brandi, Ivan Arisi, Mara D'Onofrio, Cristina Di Primio und Antonino Cattaneo. „Post-translational selective intracellular silencing of acetylated proteins with de novo selected intrabodies“. Nature Methods 14, Nr. 3 (16.01.2017): 279–82. http://dx.doi.org/10.1038/nmeth.4144.

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Djuranovic, S., A. Nahvi und R. Green. „miRNA-Mediated Gene Silencing by Translational Repression Followed by mRNA Deadenylation and Decay“. Science 336, Nr. 6078 (12.04.2012): 237–40. http://dx.doi.org/10.1126/science.1215691.

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Kenesi, Erzsébet, Juan-Jose Lopez-Moya, László Orosz, József Burgyán und Lóránt Lakatos. „Argonaute 2 Controls Antiviral Activity against Sweet Potato Mild Mottle Virus in Nicotiana benthamiana“. Plants 10, Nr. 5 (26.04.2021): 867. http://dx.doi.org/10.3390/plants10050867.

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RNA silencing is a sequence specific post-transcriptional mechanism regulating important biological processes including antiviral defense in plants. Argonaute (AGO) proteins, the catalytic subunits of the silencing complexes, are loaded with small RNAs to execute the sequence specific RNA cleavage or translational inhibition. Plants encode several AGO proteins and a few of them, especially AGO1 and AGO2, have been shown to be required for antiviral silencing. Previously, we have shown that the P1 protein of the sweet potato mild mottle virus (SPMMV) suppresses the primary RNA silencing response by inhibiting AGO1. To analyze the role of AGO2 in antiviral defense against the SPMMV, we performed a comparative study using a wild type and ago2−/− mutant Nicotiana benthamiana. Here we show that the AGO2 of N. benthamiana attenuates the symptoms of SPMMV infection. Upon SPMMV infection the levels of AGO2 mRNA and protein are greatly increased. Moreover, we found that AGO2 proteins are loaded with SPMMV derived viral small RNAs as well as with miRNAs. Our results indicate that AGO2 protein takes over the place of AGO1 to confer antiviral silencing. Finally, we provide a plausible explanation for the AGO2 mediated recovery of an SPMMV-infected sweet potato.

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Mayya, Vinay K., Mathieu N. Flamand, Alice M. Lambert, Seyed Mehdi Jafarnejad, James A. Wohlschlegel, Nahum Sonenberg und Thomas F. Duchaine. „microRNA-mediated translation repression through GYF-1 and IFE-4 in C. elegans development“. Nucleic Acids Research 49, Nr. 9 (24.03.2021): 4803–15. http://dx.doi.org/10.1093/nar/gkab162.

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Abstract microRNA (miRNA)-mediated gene silencing is enacted through the recruitment of effector proteins that direct translational repression or degradation of mRNA targets, but the relative importance of their activities for animal development remains unknown. Our concerted proteomic surveys identified the uncharacterized GYF-domain encoding protein GYF-1 and its direct interaction with IFE-4, the ortholog of the mammalian translation repressor 4EHP, as key miRNA effector proteins in Caenorhabditis elegans. Recruitment of GYF-1 protein to mRNA reporters in vitro or in vivo leads to potent translation repression without affecting the poly(A) tail or impinging on mRNA stability. Loss of gyf-1 is synthetic lethal with hypomorphic alleles of embryonic miR-35–42 and larval (L4) let-7 miRNAs, which is phenocopied through engineered mutations in gyf-1 that abolish interaction with IFE-4. GYF-1/4EHP function is cascade-specific, as loss of gyf-1 had no noticeable impact on the functions of other miRNAs, including lin-4 and lsy-6. Overall, our findings reveal the first direct effector of miRNA-mediated translational repression in C. elegans and its physiological importance for the function of several, but likely not all miRNAs.

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Geng, Zhe, Ping Li, Li Tan und Houyan Song. „Targeted Knockdown of RNA-Binding Protein TIAR for Promoting Self-Renewal and Attenuating Differentiation of Mouse Embryonic Stem Cells“. Stem Cells International 2015 (2015): 1–10. http://dx.doi.org/10.1155/2015/657325.

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RNA-binding protein TIAR has been suggested to mediate the translational silencing of ARE-containing mRNAs. To analyze the functions of TIAR, we established RNAi and genetic rescue assays. We evaluated the expression of neuroectoderm markers Pax6 and nestin, mesoderm markers brachyury and Flk1, and hypoblast and definitive endoderm markers Sox17 and Gata6 during EB differentiation and found that knockdown TIAR expression restrained the differentiation of E14 cells. We assessed gene expression levels of Flk-1 and VE-cadherin and observed attenuated differentiation of E14 cells into endothelial cells upon downregulation of TIAR gene expression. As such, we hypothesized an essential role of TIAR related to EB differentiation. As TIAR inhibits the translation of c-myc, we proposed that downregulation of TIAR results in restrained differentiation of E14 cells, due in part to the function of c-myc. We found that TIAR inhibited c-myc expression at the translational level in E14 cells; accordingly, a reduction of TIAR expression promoted self-renewal of pluripotent cells and attenuated differentiation. Additionally, we established that TIAR inhibited TIA-1 expression at the translational level in E14 cells. Taken together, we have contributed to the understanding of the regulatory relationships between TIAR and both c-myc and TIA-1.

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Sakuma, Toshie, Michael A. Barry und Yasuhiro Ikeda. „Lentiviral vectors: basic to translational“. Biochemical Journal 443, Nr. 3 (16.04.2012): 603–18. http://dx.doi.org/10.1042/bj20120146.

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More than two decades have passed since genetically modified HIV was used for gene delivery. Through continuous improvements these early marker gene-carrying HIVs have evolved into safer and more effective lentiviral vectors. Lentiviral vectors offer several attractive properties as gene-delivery vehicles, including: (i) sustained gene delivery through stable vector integration into host genome; (ii) the capability of infecting both dividing and non-dividing cells; (iii) broad tissue tropisms, including important gene- and cell-therapy-target cell types; (iv) no expression of viral proteins after vector transduction; (v) the ability to deliver complex genetic elements, such as polycistronic or intron-containing sequences; (vi) potentially safer integration site profile; and (vii) a relatively easy system for vector manipulation and production. Accordingly, lentivector technologies now have widespread use in basic biology and translational studies for stable transgene overexpression, persistent gene silencing, immunization, in vivo imaging, generating transgenic animals, induction of pluripotent cells, stem cell modification and lineage tracking, or site-directed gene editing. Moreover, in the present high-throughput ‘-omics’ era, the commercial availability of premade lentiviral vectors, which are engineered to express or silence genome-wide genes, accelerates the rapid expansion of this vector technology. In the present review, we assess the advances in lentiviral vector technology, including basic lentivirology, vector designs for improved efficiency and biosafety, protocols for vector production and infection, targeted gene delivery, advanced lentiviral applications and issues associated with the vector system.

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Melnick, Ari M., Kerin Adelson und Jonathan D. Licht. „The Theoretical Basis of Transcriptional Therapy of Cancer: Can It Be Put Into Practice?“ Journal of Clinical Oncology 23, Nr. 17 (10.06.2005): 3957–70. http://dx.doi.org/10.1200/jco.2005.14.498.

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Aberrant gene silencing is a frequent event in cancer and plays a critical role in the molecular pathogenesis of malignant transformation. The two major mechanisms of silencing in cancer include transcriptional repression by mutated or aberrantly expressed transcription factors, and aberrant epigenetic silencing by hypermethylation of tumor suppressor or DNA repair–related genes. Both of these mechanisms require the activities of multiprotein chromatin remodeling and modifying machines, several of which may be mutated in cancer. The end result is genetic reprogramming of cells to express combinations of genes that confer the neoplastic phenotype. Recent discoveries in transcriptional biochemistry and gene regulation indicate that therapeutic agents can be engineered to specifically target these mechanisms. We provide a framework for the clinical or translational scientist to consider how such drugs might be developed and what their impact might be on restoring cells to normal genetic programming.

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Munakata, Fusako, Masataka Suzawa und Kumiko Ui-Tei. „Identification of Phosphorylated Amino Acids in Human TNRC6A C-Terminal Region and Their Effects on the Interaction with the CCR4-NOT Complex“. Genes 12, Nr. 2 (13.02.2021): 271. http://dx.doi.org/10.3390/genes12020271.

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Human GW182 family proteins have Argonaute (AGO)-binding domains in their N-terminal regions and silencing domains, which interact with RNA silencing-related proteins, in their C-terminal regions. Thus, they function as scaffold proteins between the AGO protein and RNA silencing-related proteins, such as carbon catabolite repressor4-negative on TATA (CCR4-NOT) or poly(A)-binding protein (PABP). Our mass spectrometry analysis and the phosphorylation data registered in PhosphoSitePlus, a post-translational modification database, suggested that the C-terminal region of a human GW182 family protein, TNRC6A, has at least four possible phosphorylation sites, which are located near the region interacting with the CCR4-NOT complex. Among them, two serine residues at amino acid positions 1332 and 1346 (S1332 and S1346) were certainly phosphorylated in human HeLa cells, but other two serine residues (S1616 and S1691) were not phosphorylated. Furthermore, it was revealed that the phosphorylation patterns of TNRC6A affect the interaction with the CCR4-NOT complex. When S1332 and S1346 were dephosphorylated, the interactions of TNRC6A with the CCR4-NOT complex were enhanced, and when S1616 and S1691 were phosphorylated, such interaction was suppressed. Thus, phosphorylation of TNRC6A was considered to regulate the interaction with RNA silencing-related factors that may affect RNA silencing activity.

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Schamberger, Anita, György Várady, Ábel Fóthi und Tamás I. Orbán. „Posttranscriptional Regulation of the Human ABCG2 Multidrug Transporter Protein by Artificial Mirtrons“. Genes 12, Nr. 7 (13.07.2021): 1068. http://dx.doi.org/10.3390/genes12071068.

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ABCG2 is a membrane transporter protein that has been associated with multidrug resistance phenotype and tumor development. Additionally, it is expressed in various stem cells, providing cellular protection against endobiotics and xenobiotics. In this study, we designed artificial mirtrons to regulate ABCG2 expression posttranscriptionally. Applying EGFP as a host gene, we could achieve efficient silencing not only in luciferase reporter systems but also at the ABCG2 protein level. Moreover, we observed important new sequential-functional features of the designed mirtrons. Mismatch at the first position of the mirtron-derived small RNA resulted in better silencing than full complementarity, while the investigated middle and 3′ mismatches did not enhance silencing. These latter small RNAs operated most probably via non-seed specific translational inhibition in luciferase assays. Additionally, we found that a mismatch in the first position has not, but a second mismatch in the third position has abolished target mRNA decay. Besides, one nucleotide mismatch in the seed region did not impair efficient silencing at the protein level, providing the possibility to silence targets carrying single nucleotide polymorphisms or mutations. Taken together, we believe that apart from establishing an efficient ABCG2 silencing system, our designing pipeline and results on sequential-functional features are beneficial for developing artificial mirtrons for other targets.

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Nowak, Iwona, und Aishe A. Sarshad. „Argonaute Proteins Take Center Stage in Cancers“. Cancers 13, Nr. 4 (13.02.2021): 788. http://dx.doi.org/10.3390/cancers13040788.

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Argonaute proteins (AGOs) play crucial roles in RNA-induced silencing complex (RISC) formation and activity. AGOs loaded with small RNA molecules (miRNA or siRNA) either catalyze endoribonucleolytic cleavage of target RNAs or recruit factors responsible for translational silencing and target destabilization. miRNAs are well characterized and broadly studied in tumorigenesis; nevertheless, the functions of the AGOs in cancers have lagged behind. Here, we discuss the current state of knowledge on the role of AGOs in tumorigenesis, highlighting canonical and non-canonical functions of AGOs in cancer cells, as well as the biomarker potential of AGO expression in different of tumor types. Furthermore, we point to the possible application of the AGOs in development of novel therapeutic approaches.

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