1,720,966 research outputs found
A cunning stunt: an alternative mechanism of eukaryotic translation initiation
No full textCell stress activates signaling pathways, allowing cells to choose between survival and apoptosis. Translation plays a critical role in balancing this choice by allowing for rapid and physiologically responsive changes in de novo gene expression. The steady-state abundance of cellular inhibitor of apoptosis 2 (cIAP2) is increased in response to various cell stresses. This modular protein contains baculoviral IAP repeat (BIR) motifs and ubiquitin protein ligase (E3) activity, which allows it to bind directly to caspases and to modulate activation of the transcription factor, nuclear factor kappaB (NF-kappaB). The messenger RNA (mRNA) encoding cIAP2 is a large 5.5-kb transcript, with a highly structured 5' untranslated region (5'UTR) also containing 64 upstream initiation codons ahead of the true start codon. cIAP2 employs an unusual cap-dependent mechanism of ribosome shunting to bypass the majority of the inhibitory elements in the 5'UTR, a mechanism first described for plant pararetroviruses. Furthermore, in mammalian cells, this poorly understood mechanism of translation for cIAP2 is enhanced during mild stress in the absence of pararetrovirus-encoded proteins known to be essential for this process in plant cells. Here, we discuss how cIAP2 might utilize the stress-mediated shunt process in the absence of viral proteins, which suggests a more widespread role for canonical initiation factors, internal ribosome entry sequence-specific trans-acting factors, and mRNA structure in translational control during stress
Cytoplasmic mRNA: move it, use it or lose it!
No full textOnce an mRNA is synthesized and processed, the immediate translation and later destruction of the transcript is not as inevitable as the central molecular biology dogma suggests. Interest in the field of post-transcriptional control continues to grow rapidly, as regulation of these multiple steps in gene expression is implicated in diverse aspects of biology such as metabolism, neurology, reproduction and viral lifecycle regulation. Researchers who utilize various combinations of human studies, animal models, cellular, genetic, biochemical and molecular techniques were brought together at the University of Edinburgh to discuss their latest findings. In this article, we introduce the content of the related reviews presented in this issue of Biochemical Society Transactions which together illustrate a major theme of the meeting content: namely the need to understand how dynamic changes in mRNP (messenger ribonucleoprotein) complexes modulate the multifunctionality of regulatory proteins which link different post-transcriptional regulatory events
ABC50 mutants modify translation start codon selection
No full textABC50 (also known as ABCF1) binds to eukaryotic initiation factor eIF2 and is required for efficient translation initiation. An essential step of this process is accurate recognition and selection of the initiation codon. It is widely accepted that the presence and movement of eIF1, eIF1A and eIF5 are key factors in modulating the stringency of start site selection, which normally requires an AUG in an appropriate sequence context. Here we show that expression of ABC50 mutants, which cannot hydrolyse ATP, decreases general translation and relaxes the discrimination against the use of non-AUG codons at translation start sites. These mutants do not appear to alter the association of key initiation factors to 40S subunits. The stringency of start site selection can be restored through overexpression of eIF1, consistent with the role of that factor in enhancing stringency. This study indicates that interfering with the function of ABC50 influences the accuracy of initiation codon selectio
Regulation of the Elongation Phase of Protein Synthesis Enhances Translation Accuracy and Modulates Lifespan.
No full textMaintaining accuracy during protein synthesis is crucial to avoid producing misfolded and/or non-functional proteins. The target of rapamycin complex 1 (TORC1) pathway and the activity of the protein synthesis machinery are known to negatively regulate lifespan in many organisms, although the precise mechanisms involved remain unclear. Mammalian TORC1 signaling accelerates the elongation stage of protein synthesis by inactivating eukaryotic elongation factor 2 kinase (eEF2K), which, when active, phosphorylates and inhibits eEF2, which mediates the movement of ribosomes along mRNAs, thereby slowing down the rate of elongation. We show that eEF2K enhances the accuracy of protein synthesis under a range of conditions and in several cell types. For example, our data reveal it links mammalian (m)TORC1 signaling to the accuracy of translation. Activation of eEF2K decreases misreading or termination readthrough errors during elongation, whereas knocking down or knocking out eEF2K increases their frequency. eEF2K also promotes the correct recognition of start codons in mRNAs. Reduced translational fidelity is known to correlate with shorter lifespan. Consistent with this, deletion of the eEF2K ortholog or other factors implicated in translation fidelity in Caenorhabditis elegans decreases lifespan, and eEF2K is required for lifespan extension induced by nutrient restriction. Our data uncover a novel mechanism linking nutrient supply, mTORC1 signaling, and the elongation stage of protein synthesis, which enhances the accuracy of protein synthesis. Our data also indicate that modulating translation elongation and its fidelity affects lifespan
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Full text linkWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
Inhibition of mammalian target of rapamycin (mTOR) signalling in C2C12 myoblasts prevents myogenic differentiation without affecting the hyperphosphorylation of 4E-BP1
No full textCurrent accepted models suggest that hypophosphorylated 4E-binding protein (4E-BP1) binds to initiationfactor 4E (eIF4E) to inhibit cap-dependent translation, a process readily reversed by its phosphorylationfollowing activation of mammalian target of rapamycin (mTORC1) signalling. Myogenic differentiation in theC2C12 myoblast model system reflects a concerted and controlled activation of transcription and translationfollowing the exit of cells from the cell cycle. Here we show that myogenic differentiation is associated withincreased rates of translation, the up-regulation of both 4E-BP1 mRNA and protein levels and enhanced levelsof eIF4E/4E-BP1 complex. Paradoxically, treatment of C2C12 myoblasts with an inhibitor of mTOR signalling(RAD001) which inhibits translation, promotes the hyperphosphorylation of 4E-BP1 on novel sites andprevents the increase in 4E-BP1 levels. In contrast, eIF4E appears to be under translational control with asignificant delay between induction of mRNA and subsequent protein expression
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