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RUSSO, ARIANNA. „Increasing Eukaryotic Initiation Factor (eIF6) gene dosage stimulates global translation and induces a transcriptional and metabolic rewiring that blocks Programmed Cell Death“. Doctoral thesis, Università del Piemonte Orientale, 2018. http://hdl.handle.net/11579/97190.
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SCAGLIOLA, ALESSANDRA. „EIF6 PHOSPHORYLATION ON SER235 IS REQUIRED FOR MAMMALIAN DEVELOPMENT AND FOR T-CELL LYMPHOMAGENESIS, ESTABLISHING A FUNCTIONAL NETWORK BETWEEN TRANSLATION AND SENESCENCE“. Doctoral thesis, Università degli Studi di Milano, 2019. http://hdl.handle.net/2434/631917.
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Deregulated translation control is a hallmark of human cancers and is critical for tumorigenesis downstream of multiple oncogenic signaling pathways. eIF6 is an oncogenic translation factor, which regulates the initiation phase of translation controlling active 80S complex formation. eIF6 depletion and dephosphorylation slow cell growth and cell transformation in vitro and protect from tumor development in mice. eIF6 activation is mTORC1-independent and driven by PKCβ mediated phosphorylation on Ser235. Intriguingly, both eIF6 overexpression and PKC hyperactivation are found in T-cell lymphomas, such as in Anaplastic Large Cell Lymphoma (ALCL). We hypothesized that eIF6 phosphorylation drives T cell lymphomagenesis and mammalian development. We used a conditional eIF6SA KI mouse model in which Ser235 is replaced by an Ala. We discovered that homozygous point mutation (eIF6SA/SA) is lethal after gastrulation. Heterozygous mice (eIF6SA/+) are viable but resistant to NPM-ALK induced lymphomagenesis. The survival of eIF6SA/SA NPM-ALK mice is significantly increased and the appearance of lymphoma is delayed up to 6 months. Surprisingly, ex vivo eIF6SA/SA NPM-ALK primary thymocytes have a striking senescence-like phenotype. Similarly, in vitro generated eIF6SA/SA MEFs show a markedly reduced proliferation and increased senescence. This phenotype is completely rescued by transducing eIF6wt, but not by eIF6SA. In eIF6SA/SA MEFs, the direct interaction between mutant eIF6SA protein with the 60S ribosomal subunit surface is extremely increased, suggesting that 60S viability, required for active translation, could be compromised.
In conclusion, our work demonstrates for the first time that eIF6 phosphorylation on Ser235 is essential for mammalian development, cell homeostasis and is rate-limiting for T-cell lymphomagenesis in vivo. Finally, we suggest that the translational control driven by eIF6 activity induces cellular premature senescence, resulting in a protective mechanism against tumor progression.
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Bertrand, Alexis. „Caractérisation fonctionnelle de mutations somatiques compensatrices d'elF6 dans le contexte du syndrome de Shwachman- Diamond“. Electronic Thesis or Diss., université Paris-Saclay, 2024. http://www.theses.fr/2024UPASL089.
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Le syndrome de Shwachman Diamond (SDS) est une ribosomopathie génétique rare entraînant une altération de la synthèse protéique associée à de nombreux symptômes, notamment une insuffisance médullaire et une neutropénie pouvant évoluer vers un syndrome de myélodysplasie ou une leucémie myéloïde aiguë. Les mutations bialléliques du gène SBDS sont responsables de plus de 90 % des cas de SDS et nous avons récemment identifié des mutations bialléliques EFL1 comme une nouvelle cause génétique de SDS. SBDS et EFL1 évincent le facteur elF6 de la sous-unité ribosomale pré60S, permettant à cette dernière d'interagir avec la sous-unité 40S pour former le ribosome mature 80S. L'acquisition naturelle d'événements génétiques somatiques au fil du temps participe au développement des maladies liées à l'âge et au développement des cancers. Cependant, dans les maladies mendéliennes, ces événements peuvent, dans de rares cas, contrer l'effet délétère de la mutation germinale et conférer un avantage sélectif aux cellules somatiquement modifiées, un phénomène appelé sauvetage génétique somatique (SGR). Nous avons récemment montré que plusieurs événements génétiques somatiques affectantl'expression ou la fonction d'elF6 sont fréquemment détectés dans les clones sanguins de patients atteints de SDS mais pas chez les individus sains, suggérant un mécanisme de SGR. Alors que la plupart de ces mutations somatiques induisent une déstabilisation de elF6 ou une haploinsuffisance d'EIF6, une mutation récurrente (N106S) n'affecte pas l'expression/stabilité d'elF6 mais réduit sa capacité à interagir avec la sous-unité 60S. Afin d'étudier plus en détail les conséquences fonctionnelles de l'haploinsuffisance de EIF6 et de la mutation N106S dans un contexte de SDS, j'ai introduit via CRISPR/Cas9 ces mutations dans des lignées fibroblastiques immortalisées de patients SDS et de contrôle. Ces modèles cellulaires originaux ont permis de déterminer l'impact de la mutation N106S sur la la localisation et la fonction d'elF6 mais aussi de préciser les effets de ces mutations sur plusieurs aspects du « fitness » cellulaire, notamment la biogenèse des ribosomes, le taux de traduction et la prolifération cellulaire. Dans l'ensemble, le développement de ce modèle a aidé à caractériser comment la mutation N106S et l'haploinsuffisance somatique de elF6 confèrent un avantage sélectif dans les cellules déficientes en SBDS ou EFL1Shwachman Diamond syndrome (SDS) is a rare genetic ribosomopathy leading to impaired protein synthesis, which causes numerous symptoms including bone marrow failure and neutropenia that can evolve to myelodysplasia syndrome or acute myeloid leukaemia. Biallelic mutations in the SBDS gene are responsible of above 90% of the SDS cases and we recently identified biallelic EFL1 mutations as a novel cause of SDS. SBDS together with EFL1 remove the anti-association factor elF6 from the pre60S ribosomal subunit, allowing its interaction with the 40S subunit to form the mature ribosome 80S. Natural acquisition of somatic genetic events over time participâtes to age-related diseases and cancer development. However, in Mendelian diseases these events can, in rare case, counteract the deleterious effect of the germline mutation and provide a sélective advantage to the somatically modified cells, a phenomenon dubbed Somatic Genetic Rescue (SGR). We recently showed that several somatic genetic events affecting the expression or function of elF6 are frequently detected in blood clones from SDS patients but not in healthy individuals, suggesting a mechanism of SGR. While most of these somatic mutations induce elF6 destabilization or EIF6 haploinsufficiency, one récurrent mutation (N106S) did not affect the expression of elF6 but rather impact its ability to interact with the 60S subunit. In order to further investigate the functional conséquences of ElF6 haploinsufficiency and N106S mutation in a context of SDS, I introduced via CRISPR/Cas9 these mutations in immortalized fibroblastic cell line from SDS patients and control. These original cellular models hâve made it possible to détermine the impact of the N106S mutation on the localisation and function of elF6 and also to clarify the effects of these mutations on several aspects of cellular fitness, in particular ribosome biogenesis, translation rate and cell prolifération. Overall, the development of these cellular models has helped to characterise how the somatic N106S mutation and elF6 haploinsufficiency confer a sélective advantage in cells déficient in SBDS or EFL1
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Crespillo, Casado Ana. „The eIF2 phosphatase : characterization and modulation“. Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/283601.
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Cellular needs are fulfilled by the combined activity of functional proteins. Consequently, cells are equipped with a complex proteostatic network that controls protein production in response to cellular requisites. Thereby, protein synthesis is induced or attenuated depending on the particular cellular conditions. One of the mechanisms to control protein synthesis is the phosphorylation of eIF2, which triggers the so-called Integrated Stress Response (ISR). Kinases that sense stresses induce the phosphorylation of eIF2, which, on the one hand, attenuates global rates of protein synthesis and, on the other hand, activates the expression of specific proteins that help to alleviate the stress. One of the proteins preferentially expressed during the ISR is PPP1R15A, a regulatory subunit of Protein Phosphatase 1 (PP1). The PP1/PPP1R15A holophosphatase dephosphorylates eIF2 and terminates the ISR once the stresses are resolved. Hence, eIF2 kinases and phosphatases work together to control levels of phosphorylated eIF2. Maintaining the right balance between the activity of these kinases and phosphatases is important, as is seen by the correlation between their perturbance and the appearance of certain cellular malfunctions or diseases. However, affecting this balance has been also suggested to have beneficial effects. For example, genetic interference with the PPP1R15A regulatory subunit is proposed to confer protection to mice and cells under ER-stress conditions. This observation led to the search for compounds with the ability to modulate the ISR, in particular, by acting on the eIF2 phosphatases. Three compounds (Salubrinal, Guanabenz and Sephin1) have been proposed as eIF2 phosphatase inhibitors with potential use as therapeutic tools in protein misfolding diseases. However, their precise mechanism of action and their direct effect on the enzyme remains an open question. This thesis focuses on the in vitro reconstitution of the eIF2 phosphatase, which served as a platform for characterizing the enzyme (in terms of its structure, activity and assembly) and for studying the proposed inhibitors. This report details key structural features of the PPP1R15/PP1 holophosphatase, the discovery of a cellular cofactor of the enzyme and the conclusions obtained after analysing the effect of its proposed inhibitors. It also includes the development of several in vitro assays, which could potentially be used to screen libraries of compounds in search for modulators of the enzyme.
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Murphy, Patrick. „Characterisation of critical interactions between translation factors eIF2 and eIF2B“. Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/characterisation-of-critical-interactions-between-translation-factors-eif2-and-eif2b(9138d7c8-34b1-4489-8048-a2ac45ef8533).html.
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Eukaryotic translation initiation is a complex and highly regulated process involving the ribosome, mRNA and proteins called eukaryotic initiation factors (eIFs). The overall aim of translation initiation is to position the ribosome at the initiation codon of the mRNA. eIF2, in its GTP-bound conformation, binds the initiator tRNA (Met-tRNAiMet) and delivers it to the 40S ribosomal subunit. When the anticodon of the tRNA is bound to the initiation codon, the GTP on eIF2 is hydrolysed to GDP. The guanine nucleotide exchange factor (GEF) eIF2B regenerates eIF2-GTP. eIF2 and eIF2B are multisubunit/multidomain protein complexes. Because information regarding the interface between each complex is limited, particularly the interface on the eIF2γ subunit, which binds the guanine-nucleotides and Met-tRNAiMet, interactions between the minimal GEF domain of eIF2Bε, εGEF, and eIF2 were mapped using mutagenesis and an in vitro cysteine cross-linking approach, with the cross-linker Mts-Atf-Biotin. Site-directed mutagenesis (SDM) was used to mutate five N-terminal and five C-terminal surface-exposed εGEF residues to cysteines. The mutant alleles were analysed in Saccharomyces cerevisiae and it was found that the gcd6-R574C allele was lethal and the gcd6-T572C was Gcd-. Further gcd6-R574 mutant alleles were also found to be lethal in yeast but expressed in vivo.εGEF-R574C has dramatically reduced GEF activity in vitro and binding assays showed that this mutant has significantly reduced affinity for eIF2. The εGEF-T572C and εGEF-S576C mutants also have severe and minor eIF2-binding defects respectively, while the C-terminal εGEF-Cys mutants have slightly reduced affinity for eIF2. The N-terminal εGEF-Cys mutants cross-link specifically to eIF2γ, while the C-terminal εGEF-Cys mutants interact predominantly with eIF2β. From the data obtained in this study, we propose a new model for eIF2B-mediated guanine-nucleotide exchange that reduces the importance of eIF2β and suggests εGEF resembles other GEFs in binding primarily to its G protein partner eIF2γ.
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Guillon, Laurent. „Etude des facteurs du démarrage de la traduction eIF5B et eIF3“. Phd thesis, Ecole Polytechnique X, 2008. http://pastel.archives-ouvertes.fr/pastel-00004650.
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Le démarrage de la traduction est un processus central dans toute cellule. L'étude des protéines assistant le ribosome pour réaliser cette étape, les facteurs de démarrage (Initiation Factors Ifs), permet d'obtenir des informations sur les mécanismes moléculaires complexes assurant la fidélité et l'efficacité du démarrage. La comparaison des jeux de facteurs protéiques dans les trois règnes du monde vivant a permis de mettre en évidence la présence de trois facteurs universellement conservés. Parmi ceux-ci, le facteur eucaryotique/archéen e/aIF5B, homologue au facteur bactérien IF2, stimule l'association des sous-unités ribosomales au même titre que chez les Bactéries. Néanmoins, l'universalité du facteur est limitée par l'absence d'interaction reportée entre le facteur e/aIF5B et l'ARNt initiateur alors que cette liaison est parfaitement caractérisée chez les Bactéries. Une partie de ce travail de thèse a permis d'étendre la similitude fonctionnelle entre les facteurs en mettant en évidence une liaison de l'ARNt initiateur méthionylé par le facteur e/aIF5B. Cette liaison présente des caractéristiques identiques à celle de l'ARNt initiateur méthionylé et formylé par le facteur bactérien IF2. Une deuxième partie du travail de thèse a concerné le facteur eIF3, le plus complexe du système de démarrage chez les Eucaryotes. Ce complexe de 13 sous-unités chez l'humain et de 5 sous-unités chez la levure n'a pas d'équivalent dans les autres domaines du vivant bien qu'il joue un rôle central et essentiel chez les Eucaryotes. La compréhension de ses fonctions est néanmoins fortement limitée par le manque d'information à l'échelle moléculaire sur les interactions entre les sous-unités le composant et avec ses autres facteurs partenaires. De plus, le facteur s'avère être impliqué dans de nombreux cancers, ce qui étend l'intérêt de son étude. Mon travail a permis de développer une bibliothèque de vecteurs permettant de coexprimer les différentes sous-unités ou des formes stabilisées des sous-unités du facteur eIF3 de levure chez la Bactérie Escherichia coli. La purification des sous-unités isolées et de différents sous-complexes nous permet d'envisager la résolution de la structure du facteur et de son organisation par une approche alliant la cristallographie et la microscopie électronique.
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Wang, Xiaoshan. „Regulation of eIF3-Paip1 interaction by extracellular stimuli and phosphorylation status“. Thesis, McGill University, 2010. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=86958.
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The tertiary interaction of poly(A)-binding protein (PABP), with eukaryotic translation initiation factor 4G (eIF4G) and 3'poly(A) tail of mRNA acts to stimulate translation initiation. Subsequently, the interaction of PABP-interacting protein 1 (Paip1) with PABP and eukaryotic translation initiation factor 3 (eIF3) (via the eIF3g subunit) further stimulates translation. Here, we demonstrate that the interaction of eIF3 and Paip1 is regulated by the presence of amino acids through an mTORC1 dependent signaling pathway. This interaction is inhibited by addition of mTORC1 signaling pathway inhibitors; such as rapamycin and wortmannin. Paip1 binds to eIF3g and this subunit can be phosphorylated on either Thr41 or Ser42. However, we find that phosphorylation on these sites is not stimulated by amino acids, nor does it act to enhance eIF3-Paip1 interaction. On the other hand, we show that S6 ribosomal protein kinase (S6K) positively regulates the interaction of eIF3 and Paip1 and we propose that S6K acts as a putative kinase for eIF3. The studies of the regulation of eIF3-Paip1 interaction will lead to better understanding the translation process.L'interaction tertiaire entre la protéine PABP (poly(A)-binding protein), le facteur d'initiation de la traduction eucaryote 4G (eIF4G), et la queue poly(A) des ARN messagers, stimule l'initiation de la traduction. De plus, l'interaction entre la protéine qui interagit avec PABP, Paip1 (PABP-interacting protein 1), et le facteur d'initiation de la traduction eucaryote 3 (eIF3) (par sa sous-unité g), induit la traduction de façon plus élevée. Dans cette thèse, nous démontrons que l'interaction entre l'eIF3 et Paip1 est régulée par la présence d'acides aminées, et que cette interaction est dépendante de la voie signalétique contrôlée par mTORC1. En effet, les inhibiteurs de cette voie signalétique comme la rapamycin et la wortmannin bloquent l'interaction. Comme Paip1 s'attache directement à la sous-unité g de l'eIF3 et que cette dernière peut être phosphorylée sur la thréonine 41 ou la sérine 42, nous avons étudié le rôle la phosphorylation de eIF3g sur l'interaction entre les deux protéines. Nous démontrons que cette phosphorylation n'est pas stimulée par l'addition d'acides aminées et qu'elle n'induit pas une plus grande interaction entre eIF3 et Paip1. Par contre, nous observons que la kinase S6K (S6 ribosomal protein kinase), régule de façon positive l'interaction entre eIF3 et Paip1, et nous suggérons que cette kinase agit sur eIF3. Cette étude sur les rôles et actions de eIF3 et Paip1 aide à de plus grandes connaissances sur la régulation de l'initiation de la traduction eucaryote.
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Chamot, Danuta. „Translation initiation factor 5A (eIF-5A) in plants /“. [S.l.] : [s.n.], 1993. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Reber-Brochocka, Krystyna Barbara. „Charakterisierung genomischer Klone des Proteinsnythese-Initiationsfaktors eIF-4A /“. [S.l : s.n.], 1986. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Eshaque, Bithi. „Characterization of Eukaryotic Translation Initiation Factor 5A isoforms (eIF-5A1 & eIF-5A2) using human cell lines as a model system“. Thesis, University of Waterloo, 2006. http://hdl.handle.net/10012/1218.
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Eukaryotic translation initiation factor 5A (eIF-5A) is the only known cellular protein that contains the post-translationally derived amino acid, hypusine. Initially, eIF-5A was named as a translation initiation factor because of its capability to stimulate the formation of methionyl-puromycin, which mimics the first peptide bond formation during protein synthesis, under in vitro conditions. Subsequently, however, this proposed function of eIF-5A has been questioned because a similar effect on translation was not observed in situ. Moreover, eIF-5A appears not to be required for general protein synthesis. Rather, there is evidence that it facilitates the translation of specific subsets of mRNAs required for cell proliferation as well as apoptosis. There are two isoforms of eIF-5A in the human genome which have designated eIF-5A1 and eIF-5A2. The objective of the present study was to gain an increased understanding of the roles of eIF-5A1 and eIF-5A2 during apoptosis and cell proliferation using human cell lines as a model system. Apoptosis was induced by treating the cells with Actinomycin D or sodium nitroprusside (SNP), which initiate programmed cell death by different mechanisms. It was observed for both normal and cancer cells that eIF-5A1 protein is up-regulated during apoptosis induced by Actinomycin D or SNP, whereas eIF-5A1 mRNA is constitutively expressed and does not change in abundance during this treatment. The up regulation of eIF-5A1 protein levels in the absence of a corresponding up-regulation in eIF-5A1 mRNA suggests that eIF-5A1 may be post-transcriptionally regulated. Moreover, eIF-5A1 protein up-regulation was stronger in normal cells than in cancer cells. By contrast, eIF-5A2 protein was below detection levels during apoptosis in both normal and cancer cells, although the corresponding transcript was detectable by semi-quantitative RT-PCR. This is attributable to inefficient translation of eIF-5A2 mRNA.
The effects of eIF-5A1 and eIF-5A2 on cell proliferation were examined by modulating the levels of serum in cultures of UACC-1598 cells, which are ovarian cancer cells that express high levels of both isoforms of eIF-5A. Serum starvation, which induces cell cycle arrest and ensuing apoptosis, followed by the re-addition of serum had no effect on the transcript levels of either eIF-5A1 or eIF-5A2. However, eIF-5A1 and eIF-5A2 proteins were both up-regulated within 24 hours of the initiation of serum starvation, and this coincided temporally with the onset of apoptosis as measured by TUNEL and a subsequent decline in viable cells.
The data indicate that eIF-5A1 and eIF-5A2 are both post-transcriptionally regulated and that they have functionally redundant roles in apoptosis.
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Bertorello, Juliette. „Reprogrammation traductionnelle par eIF3 liée à la résistance aux traitements des glioblastomes“. Thesis, Toulouse 3, 2020. http://www.theses.fr/2020TOU30096.
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La résistance intrinsèque aux thérapies actuelles, conduisant à une rechute quasi systématique des patients, est une caractéristique des glioblastomes multiformes (GBM), la tumeur cérébrale la plus courante et la plus agressive. Comprendre les mécanismes sous-jacents d'une telle tumeur maligne est donc un besoin médical urgent. Il a été démontré par de nombreux travaux que la dérégulation de la machinerie de traduction des ARNm, notamment pendant l'étape d'initiation, contribue à la transformation maligne et à la progression des cancers en partie via une traduction sélective des transcrits spécifiques impliqués dans le développement et la survie des cellules cancéreuses. Mes travaux de thèse se sont concentrés sur le facteur eIF3, un complexe multimérique participant à l'initiation de la traduction et fréquemment dérégulé dans les GBM. Nos travaux montrent que l'expression dérégulée d'eIF3e, la sous-unité (e) du complexe eIF3, dans des régions de GBM spécifiques, impacte la synthèse de protéines nécessaires à la survie des cellules cancéreuses. En particulier, eIF3e restreint l'expression des protéines impliquées dans la réponse au stress cellulaire et augmente l'expression des marqueurs de cellules souches. Nos résultats montrent également que les effets d'activation et de répression d'eIF3e sur la traduction pourraient s'expliquer en partie par un modèle de liaison distinct d'eIF3e, d'eIF3d et de DDX3X (une ARN hélicase) sur les ARNm cibles. Finalement, l'ensemble des données obtenues permettent de mieux appréhender comment l'hétérogénéité intratumorale de l'expression de eIF3 aboutit à l'activation de voies de signalisation propres à chaque région tumorale dans les GBM, notion essentielle à prendre en compte dans l'élaboration de futurs traitements plus ciblés et plus personnalisés pour les patientsThe intrinsic resistance to current therapies, leading to an almost systematic relapse of patients, is a characteristic of glioblastomas (GBM), the most common and aggressive brain tumor. Understanding the underlying mechanisms of such a malignant tumor is therefore an urgent medical need. Several studies support the notion of a deregulation of the translation machinery, in particular during the initiation stage, contributes to the malignant transformation and progression of cancers, in part via a selective translation of the specific transcripts involved in the development and maintenance of cancer cells. Our work focuses on the eIF3 factor, a multimeric complex participating in the initiation of translation and frequently deregulated in GBM. Our results show that the deregulated expression of eIF3e, the subunit (e) of the eIF3 complex, in specific GBM regions, could influence the synthesis of specific proteins impacting the development of the disease. In particular, eIF3e restricts the expression of proteins involved in the response to cellular stress and increases the expression of stem cell markers. Our results also show that the activation and repression effects of eIF3e on translation could be partially explained by a distinct binding model of eIF3e, eIF3d and DDX3X (a RNA helicase) on target mRNAs. Finally, the data obtained allow us to better understand how the intratumor heterogeneity of eIF3 expression results in the activation of signaling pathways specific to each tumor region in GBM, an essential concept to take into account in the development of future more targeted and personalized treatments for patient
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Hofmann, Wilma. „Die Rolle von eIF-5A und Kernaktin bei Kernexportprozessen“. Doctoral thesis, [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=96606349X.
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Tarasovičová, Alena. „Európsky investičný fond a jeho pomoc malým a stredným podnikom na Slovensku“. Master's thesis, Vysoká škola ekonomická v Praze, 2007. http://www.nusl.cz/ntk/nusl-980.
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Hayek, Hassan Alaskari. „Rôle du facteur d'initiation eIF3 dans la traduction de l'ARNm de l'histone H4“. Thesis, Strasbourg, 2019. http://www.theses.fr/2019STRAJ081.
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La traduction de l’ARNm de l’histone H4 est initiée par un mécanisme original combinant à la fois certaines caractéristiques canoniques (fixation à la coiffe) et virales (absence de scanning et entrée interne des ribosomes). Le facteur d’initiation eIF3, un complexe de 13 sous-unités (a-m), assure le recrutement sélectif d’ARNm cellulaires, dont celui de l’histone H4, afin de contrôler leur expression. Dans cette thèse nous avons démontré l’interaction entre le facteur eIF3 et les ARNm de H4 et des histones H1, H2A, H2B et H3 in vivo et identifié 4 sous-unités eIF3c, d, e et g en interaction avec l’ARNm H4. Celles-ci se lient aux ARNm d’histones in vitro indépendamment du complexe eIF3. Nous avons analysé le rôle fonctionnel d’eIF3 sur la synthèse des histones in vivo et montré que l’inhibition des 4 sous-unités par siARN augmente la traduction des histones au début de la phase S du cycle cellulaire. eIF3 semble réprimer la traduction des ARNm d’histones quand il n’est pas limitantThe translation of the histone H4 mRNA is initiated by an original mechanism that combines both canonical (binding to the cap) and viral (absence of scanning and internal entry of ribosomes) characteristics. The initiation factor eIF3, a complex of 13 subunits (a-m), selectively recruits cellular mRNAs, including histone H4, to control their expression. In this thesis we demonstrated the interaction between eIF3 and the mRNAs of H4 and histones H1, H2A, H2B and H3 in vivo and identified 4 subunits eIF3c, d, e and g in interaction with H4 mRNA. These subunits bind to histone mRNAs in vitro independently of the eIF3 complex. We analyzed the functional role of eIF3 on histone synthesis in vivo and showed that inhibition of the 4 subunits by siRNA increased histone translation at the beginning of the S phase of the cell cycle. eIF3 appears to suppress translation of histone mRNAs when it is not limiting
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Pause, Arnim. „Mutational analysis of the mammalian translation initiation factor eIF-4A“. Thesis, McGill University, 1994. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=41744.
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eIF-4A is a eukaryotic translation initiation factor and DEAD box RNA helicase that is thought to be responsible for the melting of secondary structure in the 5$ sp prime$ untranslated region of messenger RNAs to facilitate ribosome binding. A mutational analysis of eIF-4A revealed that the ATPase A motif (AXXXXGKT) is involved in ATP binding, the ATPase B motif (DEAD) is implicated in ATP hydrolysis, the SAT region is essential for RNA unwinding, and the HRIGRXXR region is required for ATP hydrolysis-dependent RNA binding. Furthermore, defective eIF-4A mutants exhibit a strong dominant negative effect on in vitro translation of several mRNAs, including those translated by a cap-independent internal initiation mechanism. It is demonstrated that eIF-4A functions primarily as a subunit of eIF-4F, and singular eIF-4A is required to recycle through the eIF-4F during translation. Accordingly, eIF-4F appears to be required for cap-dependent and internal initiation of translation.
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Chen, Lu-hua, und 陳璐華. „Evaluation of eIF-2α phosphorylation in patients with Alzheimer's disease“. Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B45011151.
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Almeida, Fahyme Costa da Silva. „Fatores de Plasmodium falciparum envolvidos na fosforilação de eIF2α em resposta a melatonina“. Universidade de São Paulo, 2016. http://www.teses.usp.br/teses/disponiveis/42/42135/tde-17082016-154439/.
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A malária é causada por parasitas Plasmodium falciparum, e embora vários aspectos ainda sejam desconhecidos, é sabido que a regulação do ciclo intraeritrocítico é crítica para a compreensão do ciclo celular e patogênese. A melatonina modula o ciclo de P. falciparum promovendo a sincronização, mas, o mecanismo de transdução de sinal é parcialmente caracterizado, envolvendo variações citosólicas de cálcio, AMPc e ativação da PKA. Modificações pós-traducionais participam na via de sinalização, e diversas proteínas quinase podem estar envolvidas na sinalização por melatonina. eIF2α fosforilado é capaz de ativar a tradução de mRNAs em resposta a situações desfavoráveis. O genoma de P. falciparum codifica três quinases cujo substrato é eIF2α: PfeIK1, PfeIK2 e PfPK4. Investigamos o papel da PfeIK1 na via de transdução de sinal de melatonina usando cepas nocaute para PfeIK1. Além disso, os efeitos de metabólitos da degradação do heme sobre a fosforilação de eIF2α. Sugerimos que o mecanismo de fosforilação e defosforilação de eIF2α possam ser relevantes para a resposta do parasita a hemina ou biliverdina. Nossos dados indicam a PfeIK1, juntamente com a PfK7 e PKA, como quinases-chaves no controle do desenvolvimento durante o ciclo intraeritrocítico.Malaria is caused by Plasmodium falciparum parasites, and although some aspects are still unknown, its established that the intraerythrocytic cycle regulation is critic for understanding the cell cycle and pathogenesis of the parasite. Melatonin modulates the cycle of P. falciparum promoting synchronization; however, the signal transduction mechanism is partially characterized, and it contains cytosolic variations of calcium, AMPc and PKA activation. Post-translational modifications participate in this signal pathway, and several kinase proteins may be involved in melatonin signaling pathway. Phosphorylated eIF2α is able to activate mRNAs translation in stress conditions. The genome of P. falciparum encodes three kinases whose substrate is eIF2α: PfeIK1, PfeIK2 e PfPK4. We investigate the role of PfeIK1 in melatonin signaling pathway by using knockout strains for PfeIK1. Furthermore, we investigate the effects of heme degradation metabolities in eIF2α phosphorylation. We suggest that the phosphorylation and dephosphorylation mechanisms of eIF2α may be relevant for parasite response to heme and billiverdin. Our data indicates PfeIK1, PfK7 and PKA as key kinases for the development control during intraerythrocytic cycle.
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Oliveira, Vinícius Faria de. „Controle molecular dos níveis eritrocitários de GTP em Colossoma macropomum (Characiformes, Cuvier 1818) em hipóxia“. Instituto Nacional de Pesquisas da Amazônia, 2017. http://bdtd.inpa.gov.br/handle/tede/2388.
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Conselho Nacional de Pesquisa e Desenvolvimento Científico e Tecnológico - CNPq
Fundação de Amparo à Pesquisa do Estado do Amazonas - FAPEAM
Hypoxia events are common in the aquatic ecosystems of the Amazon. As a result, numerous adaptive adjustments to optimize oxygen uptake are known in the fish of this region, including, but not limited to, increased opercular beats, the release of circulating blood cells, metabolic suppression, and reduction of organic phosphate concentration in erythrocytes. This study aimed to find out how the regulation of the concentration of guanosine triphosphate ([GTP]) occurs in the red cells of tambaqui exposed to hypoxia. GTP by acting as a negative modulator of the affinity of hemoglobin with O 2 decreases oxygen uptake; thus, a reduction of [GTP] in hypoxia represents a strategy to improve the transfer of oxygen to tissues. An important cellular process that may be involved in the reduction of GTP levels in erythrocytes is the synthesis of proteins, specifically the translation stage. At this point there is an element designate eIF2α, which requires GTP to be able to recruit the RNAt Met i and continue the formation of the translation machinery. Thus, we investigated the relative expression of two eIFs (eIF2α and eIF3A) by real-time PCR and quantified the GTP in erythrocytes of tambaqui juveniles exposed to normoxia, four exposures to hypoxia (<1 mgO 2 /L) (30, 140, 200 e 260 min) and recovery from hypoxia (240 e 480 min) in >6.0 mgO 2 /L. Our results showed an increase in the relative expression of the two genes analyzed at practically all times of exposure to hypoxia. eIF2α gene was not elevated relatively to the control group at 30 min only. The concentrations of GTP were sharply reduced until the group exposed to 140 min of hypoxia, remaining practically stable until 480 min of recovery. In this way, we noticed that the decrease in the [GTP] occurred between the 30 and 140 min of hypoxia. We confirmed that Colossoma macropomum specimens were hypoxic by high plasma levels of glucose and lactate of animals subjected to low oxygen availability in water. The increase in the relative expression of the eIFs at the same time as a sharp reduction in the GTP concentration in the tambaqui erythrocytes a relationship between the intensity of the protein synthesis and the consumption of GTP molecules. However, during hypoxia, a severe metabolic suppression occurs to establish a balance between production and consumption of ATP, since the primary source of this compound is compromised. As a consequence an overall decrease in protein synthesis is observed. On the other hand, many genes linked to the mechanisms of hypoxia response are regulated positively, increasing their transcripts in the cell, which, to become functional products, depend on an elevation of the translation rate, even if only transient. This phenomenon contributes to the metabolic reorganization, essential for greater resistance of organisms to hypoxia.
Eventos de hipóxia são comuns nos ecossistemas aquáticos da Amazônia. Como resultado, inúmeros ajustes adaptativos voltados a otimizar a captação de oxigênio são conhecidos nos peixes dessa região, que incluem, entre outros, aumento dos batimentos operculares, liberação de células sanguíneas na circulação, supressão metabólica e redução da concentração dos fosfatos orgânicos nos eritrócitos. O principal objetivo deste estudo foi desvendar como ocorre a regulação da concentração do trifosfato de guanosina ([GTP]) nas células vermelhas do tambaqui em hipóxia. O GTP diminui a eficiência no transporte de oxigênio porque atua como modulador negativo da afinidade da hemoglobina com O 2 . Dessa forma, a diminuição da [GTP] em hipóxia representa uma estratégia para melhorar a transferência de oxigênio para os tecidos. Um importante processo celular que pode estar envolvido com a queda na concentração de GTP nos eritrócitos é a síntese de proteínas, especificamente a etapa de tradução. Nesse ponto atua um elemento denominado eIF2α, o qual necessita de GTP para poder recrutar o RNAt Met i e dar continuidade à formação da maquinaria de tradução. Sendo assim, investigamos a expressão relativa de dois eIFs (eIF2α e eIF3A) por meio de PCR em tempo real e quantificamos o GTP nos eritrócitos de juvenis de tambaqui expostos à normóxia, quatro exposições à hipóxia (<1 mgO 2 /L) (30, 140, 200 e 260 min) e recuperação da hipóxia (240 e 480 min) em >6.0 mgO 2 /L. Nossos resultados mostraram claro aumento da expressão relativa dos dois genes analisados em praticamente todos os tempos de exposição àhipóxia; já que apenas no tempo 30 min o gene eIF2α não apresentou-se elevado em relação ao grupo controle. As concentrações de GTP sofreram forte redução até o grupo exposto a 140 min de hipóxia, mantendo-se praticamente estável até 480 min de recuperação. Sendo assim, notamos que a queda na [GTP] ocorreu entre os tempos 30 min e 140 min de hipóxia. Confirmamos que os exemplares de Colossoma macropomum estavam em hipóxia por meio dos altos níveis de glicose e lactato plasmáticos quantificados nos animais submetidos a baixa disponibilidade de oxigênio na água. O incremento na expressão relativa dos eIFs ao mesmo tempo em que houve a brusca redução na concentração de GTP nos eritrócitos do tambaqui constitui evidência a favor da relação entre intensidade da síntese de proteínas e consumo de moléculas de GTP. No entanto, durante a hipóxia, ocorre uma séria supressão metabólica para estabelecer um equilíbrio entre a produção e o consumo de ATP, uma vez que a principal fonte geradora desse composto encontra-se comprometida. Isso resulta em uma diminuição global na síntese de proteínas. Por outro lado, inúmeros genes ligados aos mecanismos de resposta à hipóxia são regulados positivamente, aumentando seus transcritos na célula, os quais, para se tornarem produtos funcionais dependem de uma elevação da taxa de tradução, mesmo que apenas transitória. Esse fenômeno contribui para a reorganização metabólica, essencial para maior resistência dos organismos à hipóxia.
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Cattie, Douglas J. (Douglas John). „Identifying a role for nonessential elF3 subunits eif-3.K and eif-3.L in the regulation of endoplasmic reticulum homeostasis and longevity in Caenorhabditis elegans“. Thesis, Massachusetts Institute of Technology, 2016. http://hdl.handle.net/1721.1/108885.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, February 2017.Cataloged from PDF version of thesis. "October 5, 2016."
Includes bibliographical references.
The eukaryotic initiation factor 3 (elF3) is a protein complex composed of 13 subunits in mammals, and is an essential scaffold of the molecular interactions required for the formation of the 43S preinitiation complex (PIC). While these 13 subunits are broadly conserved within the eukaryotic phylogeny, both biochemical and evolutionary evidence suggests that translation initiation can proceed with a vastly reduced number of elF3 subunits, with as few as six subunits in the yeast species Saccharomyces cerevisiae. In this study, I report that homologs of eIF3 subunits elF3k and elF3I are nonessential in Caenorhabditis elegans, and that in their absence there is no defect in bulk protein translation. Surprisingly, mutants lacking these subunits exhibit both enhanced endoplasmic reticulum homeostasis and increased longevity, which implicates a potential regulatory role for these subunits in the maintenance of organismal physiology.
by Douglas J. Cattie.
Ph. D.
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Chen, Lu-hua. „Evaluation of eIF-2 alpha phosphorylation in patients with Alzheimer's disease /“. View the Table of Contents & Abstract, 2007. http://sunzi.lib.hku.hk/hkuto/record/B38284273.
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Boonyapipat, Pawika. „Dissecting the role of eIF2[alpha] phosphorylation in translational control using a transgenic plant model“. Laramie, Wyo. : University of Wyoming, 2005. http://proquest.umi.com/pqdweb?did=1095423901&sid=1&Fmt=2&clientId=18949&RQT=309&VName=PQD.
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Ladeira, costa claudio Nuno filipe. „GADD34 : Lien moléculaire entre la détection des pathogènes et les voies intégrées de réponses au stress“. Thesis, Aix-Marseille, 2012. http://www.theses.fr/2012AIXM4025/document.
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Les cellules dendritiques (DCs) sont les plus efficaces cellules présentatrices d'antigène. La détection de motifs pathogènes, tel que lipopolysaccharides bactériens et ARNs double-brins (ARNdb) viraux, par les DCs provoque leur maturation et induit de nombreux changements morphologiques et biochimiques permettant aux DCs d'acquérir leurs puissants fonctions activatrices des cellules T. Dans ce travail, les réponses des DCs à l'ARNdb ont été analysées. Nous avons montré que, en réponse à au poly I:C, un analogue synthétique des ARNdb, les DCs montent une réponse de stress intégré spécifique au cours de laquelle le facteur de transcription ATF4 et le cofacteur de la phosphatase 1, GADD34, sont exprimés. Les DCs activées par le poly I:C présentent un profil de transcrits similaire à ce qui est produit au cours d'une ‘unfolded protein response'. GADD34 est important pour contrebalancer la phosphorylation du facteur d'initiation de la synthèse protéique eIF2α par la kinase PKR au cours de l'activation des DCs. Contrairement aux fibroblastes embryonnaires murins, les DCs résistent à l'inhibition de la synthèse des protéines induite en réponse à la stimulation avec poly I:C. Néanmoins, l'expression de GADD34 n'a pas un impact majeur sur la synthèse protéique globale. Par contre, GADD34 a été démontré être absolument nécessaire à la production d'interféron du type I et d'IL-6 par les fibroblastes et les DCs en réponse à l'ARNdb. Cette observation a des implications importantes en liant la détection des pathogènes avec les voies intégrés de réponse au stressDendritic cells (DCs) are the most important antigen presenting cells. In response to inflammatory stimulation, DCs display a distinct pattern of differentiation that exhibits specific mechanisms to control the immune response. In this work the responses to dsRNA were analyzed. We have shown that in response to a mimic of dsRNA, polyriboinosinic:polyribocytidylic acid (poly I:C), DCs mount a specific integrated stress response during which the transcription factor ATF4 and the growth arrest and DNA damage-inducible protein 34 (GADD34), a phosphatase 1 (PP1) cofactor, are expressed. GADD34 is important to counteract phosphorylation of eIF2α by PKR. In contrast to murine embryonic fibroblasts (MEFs), DCs resist to protein synthesis inhibition induced in response to cytosolic dsRNA. Nevertheless, GADD34 expression does not have a major impact on global protein synthesis. Importantly, GADD34 was shown to be absolutely required for type I-IFN and IL-6 production by MEFs and DCs in response to dsRNA. This observation has important implications in linking pathogen detection with the integrated stress response pathways. The importance of this link is further underlined by the extreme susceptibility of GADD34-deficient fibroblasts and neonate mice to Chikungunya virus infection
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Craddock, B. L. „The structure and function of mammalian protein synthesis initiation factor eIF-2B“. Thesis, University of Bristol, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.294126.
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Su, Qiaozhu 1965. „Control of eIF2 alpha kinases by tyrosine phosphorylation : implications for gene translation and anti-viral signaling“. Thesis, McGill University, 2006. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=103184.
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Control of mRNA translation is one of the major regulatory events in eukaryotic gene expression. Recent research has established the existence of a protein kinase family in mammalian cells, whose members phosphorylate the alpha (alpha) subunit of the eukaryotic initiation factor eIF2 (eIF2alpha) at serine 51 and regulate mRNA translation under various stress conditions. The interferon (IFN)-inducible double-stranded (ds) RNA-activated protein kinase PKR is the prototype of this family. Stress conditions activate PKR by autophosphorylation which leads to inhibition of global protein (including viral protein) synthesis and the apoptosis of infected cells. PKR has been well-characterized as a serine/threonine kinase. However, the tyrosine kinase property of PKR and its functional activity remains undetermined. This study demonstrates that human PKR possesses tyrosine kinase activity and undergoes autophosphorylation at tyrosine (Tyr) residues 101, 162 and 293 in vitro and in vivo. Phosphorylation at these tyrosine residues enhances dsRNA binding-efficiency as well as the dimerization of PKR, which in turn favours the full-scale kinase activation and its substrate phosphorylation. Biologically, tyrosine phosphorylated PKR mediates the anti-viral and cellular anti-proliferation activity of the enzyme through its ability to regulate protein synthesis. In addition, the IFNs modulate PKR at both the transcriptional and posttranslational level. Specifically, tyrosine phosphorylation of PKR is inducible in response to stimulations with IFNs. The Janus kinases (Jaks), a group of cytoplasmic tyrosine kinases, are the upstream enzymes which phosphorylate PKR at Tyr101 and Tyr293 in vitro and in vivo. Moreover, induction of PKR tyrosine phosphorylation by IFNs presents a critical missing link between IFN signaling and the translational machinery which contributes to the early effect of IFNs in inhibiting viral protein synthesis. Such a prompt reaction might allow cells to induce IFN responsive-genes and further fortify the antiviral state of the host.
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Jansen, Daniel Verfasser], und Wilfried von [Akademischer Betreuer] [Eiff. „Funktionale Sonderausstattungen in der Premium-Automobilindustrie : Eine empirische Kausalanalyse des Kaufentscheidungsverhaltens / Daniel Jansen ; Betreuer: Wilfried von Eiff“. Münster : readbox unipress in der readbox publishing GmbH, 2020. http://d-nb.info/1222106302/34.
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Jansen, Daniel [Verfasser], und Wilfried von [Akademischer Betreuer] Eiff. „Funktionale Sonderausstattungen in der Premium-Automobilindustrie : Eine empirische Kausalanalyse des Kaufentscheidungsverhaltens / Daniel Jansen ; Betreuer: Wilfried von Eiff“. Münster : readbox unipress in der readbox publishing GmbH, 2020. http://d-nb.info/1222106302/34.
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Brander, Karl. „Pollen-specific expression of a gene related to translation initiation factor eIF-4A /“. [S.l.] : [s.n.], 1993. http://www.ub.unibe.ch/content/bibliotheken_sammlungen/sondersammlungen/dissen_bestellformular/index_ger.html.
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Wu, Jianqing. „Structural Study of eIF Complexes by H/D Exchange FT-ICR Mass Spectrometry“. Palaiseau, Ecole polytechnique, 2013. https://pastel.hal.science/docs/00/91/40/13/PDF/thesis-print-WU.pdf.
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Le complexe d'initiation de la traduction 3 des eucaryotes (eIF3) joue un role central dans le réseau d'interaction des divers facteurs d'initiation de la traduction qui s'assemblent sur les ribosomes 40S, et participent aux différentes réactions au cours de la voie d'initiation de la traduction. Chez Saccharomyces cerevisiaea, ce complexe est composé de cinq sous-unités, qui sont toutes homologues avec les sous-unités de cœur du complexe eIF3 des mammifères, composé de 13 sous-unités. Un objectif majeur actuellement est d'obtenir une structure tridimensionnelle de ce complexe. Dans une première étape vers la résolution de cette structure, les efforts portent sur la détermination des régions de liaisons entre sous-unités, dont assez peu sont actuellement connues. La région d'interaction entre la sous-unité 3i et le domaine C-terminal extrémal de 3b a récemment été résolu par RMN et structure cristallographique. D'un autre côté, la région d'interaction entre 3i et 3g, bien que localisée à l'extrémité N-terminale de 3g, doit encore être précisée. Les échanges hydrogène/deutérium (HDX) se sont développés depuis les années 1990 comme outil d'analyse structurale de protéines et de complexes multiprotéiques. La spectrométrie de masse est couramment utilisée pour réaliser la mesure de l'échange. L'approche HDX la plus usuelle repose sur une mesure de masse de peptide marqués issus d'une digestion enzymatique des protéines d'intérêt afin de déterminer le contenu en deutérium ainsi que leur vitesse d'incorporation. Pour ce travail, un spectromètre de masse à ultra-haute résolution, de type FT-ICR 7T, a été utilisé conjointement avec une séparation nano-LC pour générer des données HDX-MS de haute qualité. La précision de mesure de masse d'un spectromètre de masse FT-ICR n'est pas suffisante en elle-même pour identifier de façon certaine les peptides issus d'une digestion à la pepsine, du fait de l'absence de spécificité de la pepsine. Nous avons en conséquence développé une approche statistique pour l'identification des peptides, en se basant sur la définition d'une valeur de probabilité d'occurrence pour un peptide donné dans une digestion à la pepsine. En combinaison avec la précision élevée sur la mesure de masse, ce seul critère permet une identification efficace des peptides, sans devoir recourir à une validation par MS/MS systématique. Cette méthode a été mise en application pour l'étude des régions de liaison dans les complexes eIF3i :b et eIF3i :g. Dans les deux cas, 3i a été surexprimée sous sa forme complète. Au contraire, pour 3b et 3g, seul un segment partiel de la protéine native, contenant le domaine présumé d'interaction a été surexprimé. La liste de référence des peptides présents permet une excellente couverture de séquence et une forte superposition entre séquences adjacentes, ce qui assure une élucidation de la structure avec une bonne résolution spatiale. Pour la liaison entre 3i et 3b, les régions d'interactions qui sont apparues dans des conditions en solution proches des conditions physiologiques sont cohérentes avec la structure proposée par une autre équipe au cours de la thèse, apportant des informations complémentaires à celles issues de la structure cristallographique dérivée de la phase solide. Pour la liaison entre 3i et 3g, la région d'interaction a été étudiée en l'absence de toute donnée structurale à l'échelle atomique pour 3g. Les résultats apportent une vision nouvelle sur la formation du complexe entre 3g et 3i, et pour la première fois les régions de liaisons exacts ont été mis en évidenceThe eukaryotic initiation factor 3 (eIF3) complex plays a core role in the interaction network among several eIFs that assemble on the 40S ribosomes and participate in the different reactions throughout the translation initiation pathway. The Saccharomyces cerevisiaea eIF3 complex comprises five subunits, all of which are the core subunits of the mammalian eIF3 complex consisting of 13 subunits. Attempts to decipher its tridimensionnal structure are under way. A first path to study the structure of this complex is to complete the identification of binding regions, few of which are currently known. Recently, the interaction region between eIF3i and extreme C-terminal domain of eIF3b has been obtained through NMR and crystal structure. On the other hand, the interaction region between 3i and 3g, although located to the N-terminal domain of 3g still remains to be defined. Hydrogen/deuterium exchanges (HDX) have been developed for a long time and are widely used for structural studies of proteins and multiprotein complexes. It is commonly analyzed using mass spectrometry. The most classic standard HDX-MS approach consists in making a mass measurement of deuterium-labelled peptides from an enzymatic digestion of the protein of interest to determine the level and rate of deuterium incorporation. In this study, a high performance 7 T FT-ICR mass spectrometer was used in combination with nanoLC separation to acquire highly accurate HDX-MS data. The precision on the mass measurement of FT-ICR MS is by itself not sufficient to unambiguously identify peptides from a pepsin digest due to the lack of pepsin specificity. We therefore developed a statistical approach for peptide identification, based on a probability of occurrence value of a given peptide within a pepsin digest. In combination with high mass accuracy, this method allows efficient identification of the peptides, without additional need of MS/MS verification. This method has been applied on the study of the binding regions in the complexes of eIF3i:bC3 and eIF3i:gC1ΔC. Peptide reference lists with high sequence coverage and rich sequence superposition ensured structure elucidation with high spatial resolution. For the binding of 3i and 3b, the detailed interaction regions were unveiled for proteins in the solution phase which resembled the physiological condition and were coherent with the reported protein structure, thus provided complimentary information to the crystallographic structure in solid phase. For the binding of 3i and 3g, the interaction regions were studied with the absence of any atomic structural information of 3g. This provides significant insights of the complex formation of 3i and 3g, and for the first time the precise binding regions were successfully revealed
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Elsby, Rachel Jane. „The Alpha Subunit of Eukaryotic Initiation Factor 2B Is Requisite for EIF2-Mediated Transitional Suppression of Vesicular Stomatitis Virus“. Scholarly Repository, 2008. http://scholarlyrepository.miami.edu/oa_dissertations/33.
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Eukaryotic initiation factor 2B (eIF2B) is a heteropentameric guanine nucleotide exchange factor (GEF) that converts inactive eIF2 GDP-bound binary complexes into active eIF2 GTP-bound complexes that can bind initiator t-RNA molecules and ribosomes to begin translation. eIF2B is functionally divided into two subcomplexes: the catalytic core comprised of eIF2B epsilon and eIF2B gamma, and the regulatory core comprised of eIF2B alpha, eIF2B beta and eIF2B delta. While the catalytic subunits are responsible for exerting GEF activity, the regulatory subunits recognize eIF2 and respond to eIF2 alpha phosphorylation. Cellular stress, such as virus infection, inhibits host protein synthesis by activating specific kinases that are capable of phosphorylating the alpha subunit of eIF2, which can then sequester eIF2B to stall guanine nucleotide exchange by a currently unresolved mechanism. Importantly, we demonstrate that loss of eIF2B alpha or expression of a variant of the human eIF2B alpha subunit harboring a single point mutation (T41A) is sufficient to neutralize the consequences of eIF2 alpha phosphorylation, and render primary MEFs significantly more susceptible to vesicular stomatitis virus infection. To extend this analysis, we further exhibit the vital function of eIF2B alpha in protein synthesis through phenotypic studies in yeast. Here, we report that this subunit can sufficiently substitute for its yeast counterpart, GCN3, and reproduce similar growth phenotypes under normal and amino acid deprived conditions. In addition, the human eIF2B alpha-T41A variant was unable derepress GCN4 translation in response to an inhibitor of amino acid biosynthesis in yeast, an activity that requires sensitivity to phosphorylation of the yeast eIF2 alpha homolog, SUI2. Previously, we have demonstrated that vesicular stomatitis virus can infect and replicate to high levels in tumor cells. Moreover, these cells appear to contain defects in eIF2 alpha-mediated translational control, plausibly due to disregulation of eIF2B activity, which overcomes the inhibitory effects of eIF2 alpha phosphorylation. Our data suggest a role for eIF2B, specifically eIF2B alpha, in suppression of translation following virus infection, and imply that this complex may contribute to oncogenic transformation. These results emphasize the importance of eIF2B alpha in mediating eIF2 kinase translation inhibitory activity and may provide insight into the complex nature of viral oncolysis and cellular transformation.
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Ndum, Ogechukwu S. „The Role of IFRD1 during the Integrated Stress Response“. Case Western Reserve University School of Graduate Studies / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=case1270751192.
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Liu, Yan. „The Roles of Two Different Pathways in Hypoxia: p53/HDM2 and PERK/GCN2/eIF2α“. Ohio University / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1249582516.
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Qin, Qingsong. „Characterization of mammalian orthoreovirus (MRV) induced stress granules (SGs) and implications of eIF2[alpha] phosphorylation on viral translation“. [Ames, Iowa : Iowa State University], 2010. http://gateway.proquest.com/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:3403826.
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Costa, Celisa Caldana. „Caracterização da proteina Tif34p e do sub-complexo Tif34p/Tif35p do fator de tradução eIF3 de Saccharomyces cerevisiae“. [s.n.], 2004. http://repositorio.unicamp.br/jspui/handle/REPOSIP/317182.
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Orientador: Nilson Ivo Tonin ZanchinDissertação (mestrado) - Universidade Estadual de Campinas, Instituto de Biologia
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Mestrado
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Metz, Anneke Maria. „Function of the wheat eukaryotic initiation factors eIF(ISO)4G and eIF4B in translation /“. Digital version accessible at:, 1998. http://wwwlib.umi.com/cr/utexas/main.
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Zyryanova, Alisa. „A molecule-inhibitor of the integrated stress response regulates activity of mammalian eukaryotic translation initiation factor 2B“. Thesis, University of Cambridge, 2018. https://www.repository.cam.ac.uk/handle/1810/284208.
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The Integrated Stress Response (ISR) is a conserved eukaryotic translational and transcriptional program implicated in mammalian metabolism, memory and immunity. Although mainly considered to be a protective mechanism, prolonged and severe ISR can result in cell death. The ISR is activated by diverse stress pathways converged on phosphorylation of the alpha subunit of eukaryotic translation initiation factor 2 (eIF2) that inhibits the guanine nucleotide exchange activity of its partner eIF2B and attenuates overall rates of protein synthesis. Numerous mutations in eIF2B are linked to a fatal neurodegenerative disease of vanishing white matter. A new chemical inhibitor of the ISR (ISRIB), a bis-O-arylglycolamide, can reverse the attenuation of mRNA translation by phosphorylated eIF2 protecting mice from prion-induced neurodegeneration and traumatic brain injury. The work presented in this dissertation describes identification of mammalian eIF2B as a cellular target of ISRIB by implementing biochemical, biophysical, structural and chemogenetic methods. The herein reported cryo-electron microscopy-based structure of eIF2B uncovers a novel allosteric site on the translation factor capturing the ISRIB-binding pocket at the interface between its β and δ regulatory subunits. The extensive CRISPR/ Cas9-based screen for ISRIB-resistant and analogue-sensitive phenotypes revealed residues on the eIF2B dimer interface important for ISRIB binding. Based on the results reported in this dissertation along with the similar findings of others the potential molecular basis of ISRIB action, and its implication for the regulation of eIF2B's activity is broadly discussed. The identification of the ISRIB binding pocket away from the known interaction sites between eIF2B and eIF2 is also put into the context of a possible molecular mechanism of eIF2B's guanine exchange inhibition by phosphorylated eIF2. The work described in this dissertation provides new insight into the translational regulation and points to the importance of fine-tuning the activity of translation factors by small chemical molecules.
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Castrillo, Katia. „Implication du facteur de terminaison de la traduction eRF3a dans la régulation de la voie mTOR“. Paris 6, 2009. http://www.theses.fr/2009PA066377.
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Outre le rôle de facteur de terminaison de la traduction, eRF3a intervient dans la voie de régulation de la synthèse protéique mTOR. Dépléter eRF3a dans les cellules HCT116 induit une diminution de la synthèse protéique et un arrêt du cycle cellulaire. De plus l’un des allèles d’eRF3a est associé à une augmentation de développer certains types de cancers. Existe-t-il un lien entre l’effet d’eRF3a dans la voie mTOR et l’augmentation du risque de développer un cancer ? Nous avons confirmé que l’effet d’eRF3a sur la voie mTOR est retrouvé dans d’autres types cellulaires, comme les Hela et les HEK293. Nous avons montré que les cellules déplétées en eRF3a ont une voie mTOR sensible à l’insuline, mais moins que les contrôles, et insensible aux acides aminés. L’étude du profil d’expression par puces des cellules dont l’expression en eRF3a est inhibée a mis en évidence que l’inhibition de la traduction induite par la déplétion en eRF3a n’est pas globale. Elle touche en particulier les gènes du métabolisme des stéroïdes. L’expression des gènes impliqués dans le métabolisme des acides aminés, des ARN est augmentée, et plus particulièrement, les gènes codant pour les effecteurs de la voie eIF2?, voie régulant le métabolisme des acides aminés et inhibant la synthèse protéique. Nous avons pu conclure que le facteur eRF3a agit sur la voie mTOR par l’intermédiaire de la voie eIF2?. La déplétion en eRF3a induit une augmentation de l’expression du facteur ATF4 et de ses effecteurs, dont REDD1 et TRIB3. Ces derniers inhibent le complexe mTORC1 par l’intermédiaire de TSC1-TSC2. La façon dont eRF3a agit sur la voie eIF2? reste à étudier.
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Réal, Eléonore. „Etude du complexe de transcription et réplication des lyssavirus“. Paris 7, 2004. http://www.theses.fr/2004PA077223.
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Yanez, Adrienne Gail. „Regulation of microRNA activity by translation initiation factors in melanoma“. Thesis, Harvard University, 2014. http://dissertations.umi.com/gsas.harvard:11578.
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microRNAs (miRNAs) are small, noncoding RNAs that may regulate more than half of human genes, yet the molecular mechanism of miRNA-mediated repression remains obscure. Using a cell-free assay of miRNA activity, we show that miRNA-targeted mRNAs are enriched for components of the 40S, but not 60S ribosomal subunit. Additionally, a molecular toeprint of 18 nucleotides 3' relative to the start codon, consistent with nucleotide protection by 40S ribosomal subunits, is enriched on miRNA-targeted mRNAs. Our results suggest that miRNAs repress translation initiation in a cell-free system by preventing 60S ribosomal subunit joining to 40S subunits positioned at the start codon.
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Limousin, Taran. „Effet des microARNs sur la traduction cellulaire et virale“. Thesis, Lyon 1, 2013. http://www.theses.fr/2013LYO10312.
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Les microARN jouent un grand rôle dans la régulation de l'expression des gènes bien que leur mécanisme d'action soit encore sujet à débat. Des premières études chez le vers C. elegans aux différents systèmes in vitro qui ont ensuite été développés, plusieurs modèles ont été proposés, comme l'inhibition de la traduction au niveau de l'initiation ou de l'élongation, et la déstabilisation du transcrit par déadénylation. Cependant, à la lumière des découvertes récentes, un consensus semble apparaître et indique que les miARN inhiberaient d'abord la traduction avant d'induire la déadénylation du transcrit, provoquant ainsi sa dégradation prématurée. D'autre part, le blocage traductionnel semble impliquer à la fois la coiffe en 5' et la queue poly(A) en 3' de l'ARNm ainsi que les facteurs qui s'y lient, c'est à dire le facteur d'initiation de la traduction eIF4F et la Poly(A) Binding Protein (PABP). Ces résultats ont conduit au modèle selon lequel, les miARN seraient capables d'empêcher la liaison entre ces deux facteurs et donc la circularisation du transcrit qui est essentielle à la fois au recrutement de la machinerie traductionnelle et à la stabilité de l'ARNm. Afin de mieux comprendre ce mécanisme, notre laboratoire a développé un système in vitro basé sur l'utilisation du lysat de réticulocytes de lapin qui permet d'étudier l'effet traductionnel des miARN en s'affranchissant de dégradation du transcrit. L'étude de l'effet de drogues et d'enzymes virales, capables de bloquer spécifiquement la fonction de chaque facteur d'initiation dans ce système, a permis de déterminer le rôle clé de eIF4G et PABP dans l'inhibition traductionnelle par les miARN. Cependant, leur interaction n'est pas requise et le blocage s'effectue plutôt au cours de l'étape de balayage de la région 5' non codante par la petite sous-unité ribosomique. En parallèle de cette étude in vitro, un travail sur des lignées cellulaires a permis de déterminer l'influence de la queue poly(A) sur l'effet miARN. De façon très surprenante, l'expression des transcrits non polyadénylés n'est plus inhibée et est même stimulée par les miARN. Cet effet est dépendant de l'association du domaine MIF4G du facteur eIF4G avec le facteur eIF3, ce qui suggère qu'en l'absence de queue poly(A), les miARN seraient capables de stimuler le recrutement de la petite sous-unité ribosomique sur l'ARNm. L'ensemble de ces résultats révèle la complexité de l'effet miARN sur la traduction et ouvre de nouvelles voiesThe mechanism by which microRNAs (miRNAs) can control gene expression has been a great matter of debate. From the first studies in worm to the in vitro systems that are used today, many models have been proposed that include regulation at the level of translation or at the level of mRNA stability by controlling 3' deadenylation and decay. Recent studies provided a consensus model of all these discrepancies and suggested that translation inhibition occured first and is followed by deadenylation and further degradation of the target transcript. Moreover, translation silencing seems to occur at the initiation level, and requires eIF4F and PABP initiation factors. This led to the hypothesis that miRNAs could interfere with the interaction between these two factors thus affecting the circularisation of the mRNA, which is essential for translation efficiency. In order to gain insight into this mechanism, we have used an in vitro system based on the rabbit reticulocyte lysate that fully recapitulates miRNA effects on translation with virtually no effect on deadenylation and decay. Using this system and a wide spectrum of translational inhibitors, we have narrowed down the step of initiation at which repression is exerted and we found that miRNAs affect mainly ribosomal scanning. This effect requires the presence of both eIF4G and PABP but does not rely on their physical interaction. Further analysis of miRNA repression in cells revealed that the poly(A) tail was an absolute requirement for miRNA action. To most of our surprise, we observed that removal of the poly(A) resulted in a shift from repression to stimulation of mRNA expression. This effect seems to require the middle domain of eIF4G and the presence of the Ago proteins. Altogether, these results reveal the complexity of miRNA effect and open new prospects on translation regulation
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Staschke, Kirk A. „Integration of general amino acid control and TOR regulatory pathways in yeast“. Connect to resource online, 2010. http://hdl.handle.net/1805/2211.
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Thesis (Ph.D.)--Indiana University, 2010.Title from screen (viewed on July 21, 2010). Department of Biochemistry and Molecular Biology, Indiana University-Purdue University Indianapolis (IUPUI). Advisor(s): Ronald C. Wek, Howard J. Edenberg, Peter J. Roach, Martin Bard. Includes vitae. Includes bibliographical references (leaves 125-132).
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Chou, Marie-Noëlle. „Caractérisation du complexe protéique eIF2[alpha] impliqué dans la régulation de l'initiation de la traduction chez le parasite protozoaire Leishmania“. Québec : Université Laval, 2005. http://www.theses.ulaval.ca/2005/22822/22822.pdf.
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NASCIMENTO, Larissa Mélo do. „Complexo eIF2 em Leishmania sp.: expressão proteica, função biológica, interações moleculares e descrição de novo fator de iniciação da tradução“. Universidade Federal de Pernambuco, 2016. https://repositorio.ufpe.br/handle/123456789/24444.
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As leishmanioses são um conjunto de doenças causadas por protozoários do gênero Leishmania da família Trypanosomatidae. Tais enfermidades atingem populações pobres de países subdesenvolvidos e sua incidência está associada, em parte, à ausência de quimioterápicos efetivos, o que enfatiza a importância de estudos focados na biologia desses patógenos. Nos tripanossomatídeos o controle da expressão gênica ocorre, predominantemente, a nível pós-transcricional, envolvendo a regulação da síntese proteica através dos fatores de iniciação da tradução eucarióticos (eIFs). Em mamíferos, a regulação global da tradução ocorre majoritariamente através do complexo heterotrimérico eIF2 (constituído de eIF2α, eIF2β e eIF2γ), o qual é responsável pela interação com o tRNA iniciador, GTP e a subunidade ribossomal 40S. No presente trabalho, objetivou-se contribuir na caracterização do complexo eIF2 em L infantum. Inicialmente, confirmou-se a expressão constitutiva da subunidade eIF2α durante o crescimento e diferenciação do parasito, bem como, sua associação funcional com a subunidade menor ribossomal. Mais ainda, demonstrou-se sua associação com as subunidades eIF2β e eIF2γ e com os parceiros diretos eIF2B e eIF5, nesse momento confirmando a identificação do complexo eIF2B em Leishmania. Nos tripanossomatídeos, a subunidade eIF2α apresenta uma extensão N-terminal característica, a qual se mostrou importante nas interações com eIF2B, eIF5 e ribonucleoproteínas. Interessantemente, identificou-se um novo parálogo da subunidade eIF2γ, sendo denominado aqui eIF2γ-2. Evolutivamente, o eIF2γ-2 surgiu após provável evento de duplicação exclusivo na família Trypanosomatidae e derivou acumulando características singulares em sua sequência gênica. O eIF2γ-2 é capaz de interagir com eIF2α, eIF2β, na formação de um segundo complexo eIF2 exclusivo de tripanossomatídeos, assim como, com o eIF2B e eIF5. Através de ensaios de deleção e complementação gênica, confirmou-se a essencialidade de eIF2γ e se demonstrou a incapacidade de substituição deste pelo seu parálogo eIF2γ-2. Estes resultados demonstram novos aspectos inéditos na identificação e função do eIF2 dos tripanossomatídeos, não observados em outros organismos.
Leishmaniasis is a group of diseases caused by protozoa from the genus Leishmania of the Trypanosomatidae family. These diseases affect poor people in developing countries and its incidence is associated, in part, to the absence of effective chemotherapy, which emphasizes the importance of studies focused on the biology of these pathogens. In trypanosomatids the control of gene expression occurs predominantly at post-transcriptional level involving the regulation of protein synthesis through the eukaryotic initiation factors (eIFs). In mammals, the global translation regulation is mostly controlled by the heterotrimeric complex eIF2 (formed by eIF2α, eIF2β and eIF2γ), which is responsible for the interaction with the initiator tRNA, GTP and 40S ribosomal subunit. In the present study, by characterizing the eIF2 complex in L infantum, we confirmed the constitutive expression of the eIF2α subunit during the growth and differentiation of the parasite, as well as, their functional association with the minor ribosomal subunit. Furthermore, while demonstrating the association of eIF2α with eIF2β and eIF2γ subunits and with the direct partners eIF2B and eIF5, we confirmed the identification of Leishmania eIF2B complex. Herein, we also showed that eIF2α subunit in trypanosomatids has a unique N-terminal extension that is important for interaction with eIF2B, eIF5 and ribonucleoproteins. Interestingly, a paralog of eIF2γ subunit, named here eIF2γ-2, was identified for the first time. Evolutionarily, the eIF2γ-2 gene arose most likely after a duplication event in the Trypanosomatidae family and further accumulated singular characteristics in its coding sequence. The eIF2γ-2 is able to interact with eIF2α and eIF2β, acting during the formation of a second eIF2 complex exclusive to trypanosomatids, as well as with eIF2B and eIF5. By gene deletion and complementation assays, we confirmed the essentiality of eIF2γ and demonstrated the inability to replace it by eIF2γ-2. Altogether, our data demonstrate novel features of eIF2 function of trypanosomes, not seen in other organisms.
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Chou, Marie-Noëlle. „Caractérisation du complexe protéique eIF2[alpha] impliqué dans la régulation de l'initiation de la traduction chez le parasite protozoaire Leishmania“. Master's thesis, Université Laval, 2005. http://hdl.handle.net/20.500.11794/18072.
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Leishmania est un parasite protozoaire dimorphique causant la leishmaniose à travers le monde. Puisque aucune régulation transcriptionnelle n'a été décrite chez ce parasite, l'étude de la régulation de la traduction est devenue essentielle. Il a été décrit chez les eucaryotes supérieurs que le facteur d'initiation de la traduction, eIF2[alpha], lorsqu'il est phosphorylé en condition de stress, est capable d'inhiber la traduction. Les objectifs de ce travail étaient de 1) déterminer si le facteur eIF2[alpha] est phosphorylé chez Leishmania au cours de la différenciation ou à la suite de certains stress et 2) de caractériser une des eIF2[alpha] kinases, la PKR. Cette kinase est activée, entres autres par la présence d'ARN double brins et s'autophosphoryle. Par des expériences d'immunoprécipitation, de précipitation à l'aide d'ARNdb et d'immunobuvardage, il semble que, dans les deux cas (le facteur eIF2[alpha] et la kinase PKR), soit majoritairement phosphorylés au stade amastigote intracellulaire du parasite. Les stress de pH et de température, qui mimiqueraient l'environnement du macrophage, et de la drogue thapsigargine, qui induit un stress du RE, ne semblent pas affecter l'expression de ces facteurs mais auraient un effet sur leur phosphorylation. De plus, ces protéines sont aussi associées particulièrement aux monosomes suggérant un rôle dans l'initiation de la traduction.
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Paskvalin, Mario. „Species differences in cardiovascular effects of a novel endogenous inotropic factor (EIF) isolated from porcine heart“. Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape17/PQDD_0026/NQ32886.pdf.
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Lecampion, Cecile. „Rôle respectifs des facteurs d'initiation de la traduction eIF4E ET eIF (ISO) 4E chez Arabidopsis thaliana“. Thesis, Aix-Marseille, 2013. http://www.theses.fr/2013AIXM4096/document.
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L’initiation de la traduction est un processus complexe qui fait intervenir une douzaine de facteurs d’initiation. L’élément clef de ce mécanisme est le facteur eIF4E qui grâce à sa liaison avec la coiffe, recrute l’ensemble du complexe d’initiation au niveau de l’ARNm et permet l’assemblage du ribosome au voisinage du codon d’initiation. Chez Arabidopsis thaliana, il existe à coté de la protéine eIF4E, une isoforme : eIF(iso)4E. Ces deux protéines participent à l’initiation de la traduction. L’existence de ces deux protéines évoque un phénomène de redondance fonctionnelle qui est attestée par la létalité du double mutant alors que les simples mutants sont viables. Cependant, l’étude phénotypique de mutants pour les gènes eIF4E et eIF(iso)4E a permis de montrer que cette redondance est partielle et inégale. En effet, les mutants pour le gène eIF4E présentent un retard de croissance, un retard de floraison, une baisse de la fertilité, une sénescence précoce et une activité traductionnelle réduite. Inversement, le phénotype des plantes mutantes pour le gène eIF(iso)4E est comparable à celui du sauvage. Les mutations dans les gènes eIF4E et eIF(iso)4E induisent une hypersensibilité à la lumière Enfin, en présence d’un inhibiteur de TOR la croissance de la racine des plantes de la lignée mutante pour le gène eIF(iso)4E est moins inhibée que celle des plantes de la lignée sauvageMore than 12 initiation factors are involved in eukaryotic translation initiation. The key step of this mechanism is the binding of eIF4E with the cap of the mRNA. This step allows the recruitment of the initiation complex and the assembly of the ribosome close to the start codon. Arabidopsis thaliana encodes a second eIF4E protein: eIF(iso)4E. Those two proteins perform translation initiation. The existence of those two proteins suggests that they may be functionally redundant. Double mutant lethality testifies for functional redundancy. However, phenotypic studies of mutant lines for gene eIF4E and eIF(iso)4E showed that redundancy is partial and unequal. Indeed, the eIF4E mutant lines exhibit growth delay in rosette and roots, bolting delay, impaired fertility and early senescence in leaves. Translational activity is also largely impaired. On the contrary, a mutant line for the eIF(iso)4E gene has the same phenotype as wild type line. Mutant lines for eIF4E and eIF(iso)4E are more sensitive to light and accumulate anthocyanins even in normal light. On the molecular level, the amounts of mRNA of genes that are involved in high light response and their association to polysomes increase. When plants are grown on media containing a TOR inhibitor, AZD-8055, plants of the eIF(iso)4E mutant line show less root growth inhibition compared to wild type and eIF4E mutant lines. This result suggests that eIF(iso)4E could be targeted by the TOR pathway
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ASSIS, Ludmila Arruda de. „Caracterização do complexo de iniciação da tradução eIF3 e investigação de sua associação a complexos do tipo eIF4F em Leishmania infantum“. Universidade Federal de Pernambuco, 2015. https://repositorio.ufpe.br/handle/123456789/16832.
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CNPQ
A iniciação da síntese protéica em eucariotos depende da ação dos chamados fatores de iniciação da tradução ou eIFs. Dentre esses, destacam-se dois complexos: eIF4F, formado pelos eIF4A, eIF4E e eIF4G; e eIF3, que em mamíferos compreende 13 subunidades (eIF3a até eIF3m). Suas ações permitem o reconhecimento dos mRNAs, via eIF4E, e o recrutamento do ribosomo, mediado pelo eIF3 que por sua vez interage com o eIF4F. Em espécies de Leishmania seis homólogos de eIF4E foram identificados (EIF4E1 a 6) que parecem divergir funcionalmente enquanto o complexo eIF3 ainda é pouco caracterizado. Este trabalho buscou avaliar a presença, composição e função do eIF3 em Leishmania. Um total de 11 subunidades do complexo foram confirmadas a partir de ensaios de imunoprecipitação (IP) e espectrometria de massa utilizando soro direcionado a subunidade EIF3E. Visando uma melhor caracterização, seis dessas subunidades tiveram seus genes clonados e foram expressas em L. infantum, fusionadas ao peptídeo HA. Quatro destas proteínas heterólogas foram utilizados em novas IPs, com soro anti-HA, onde se avaliou sua capacidade de copurificar com o EIF3E. Todas mostraram essa interação, confirmando sua presença em complexos eIF3 íntegros. Homólogos de eIF4E de L. infantum também foram expressos fusionados a HA e utilizados em IPs semelhantes. Dois destes, EIF4E2 e EIF4E3, mostraram uma associação, direta ou indireta, com a subunidade EIF3E do complexo eIF3, indicando um papel relevante na tradução.
The initiation of protein synthesis in eukaryotes depends on the action of the translation initiation factors or eIFs. Among these, two major complexes are: eIF4F, formed by eIF4A, eIF4E and eIF4G; and eIF3, which comprises 13 subunits in mammals (eIF3a to eIF3m). Their actions allow the recognition of mRNAs via eIF4E, and the recruitment of the ribosome, mediated by eIF3 which interacts with eIF4F. In Leishmania species, six eIF4E homologues have been identified (EIF4E1 to 6) that seem to differ functionally, and the eIF3 complex is not well characterized. This study aimed to evaluate the presence, composition and function of eIF3 in Leishmania. A total of 11 subunits from the complex were confirmed through immunoprecipitation assays (IP) and mass spectrometry using serum directed to the EIF3E subunit. For a better characterization, six of these subunits had their genes cloned and expressed in L. infantum, fusioned to a HA peptide. Four of the resulting heterologous proteins have been used in new IPs with anti-HA serum, which were evaluated for their ability to copurify with EIF3E. All showed this interaction, confirming their presence in intact eIF3 complexes. L. infantum eIF4E homologues were also expressed fusioned to HA and used in similar IPs. Two of these, EIF4E2 and EIF4E3 showed an association, direct or indirect, with the EIF3E subunit of eIF3 complex, indicating a relevant role during translation initiation.
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Hoareau, Alves Karine. „Etude fonctionnelle de la protéine Int-6 et caractérisation de ses interactions avec eIF3, le protéasome 26S et le COP9 Signalosome“. Lyon, École normale supérieure (sciences), 2003. http://www.theses.fr/2003ENSL0262.
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Tang, Norina Mei Ngon. „Regulation of protein synthesis and induction of oncogenesis by a cellular protein kinase inhibitor /“. Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/11501.
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László, Csaba F. „Translation Regulation of UV-induced Transcription Factor NF-κB and Oncogene COX-2“. Ohio University / OhioLINK, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=ohiou1229961185.
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Kolodzik, Adrian [Verfasser], und Matthias [Akademischer Betreuer] Rarey. „In silico modeling of small molecules and design of eIF-5A activation inhibitors / Adrian Kolodzik. Betreuer: Matthias Rarey“. Hamburg : Staats- und Universitätsbibliothek Hamburg, 2014. http://d-nb.info/1064076947/34.
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