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Kalibjian, J. R., T. J. Voss, J. J. Yio, and B. Hedeline. "Automated Binding of Attributes to Telemetry Data." International Foundation for Telemetering, 1993. http://hdl.handle.net/10150/608880.
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International Telemetering Conference Proceedings / October 25-28, 1993 / Riviera Hotel and Convention Center, Las Vegas, Nevada<br>An automated method is described for binding attributes to extracted data from a
telemetry stream. These attributes can be used by post processing utilities to facilitate
efficient analysis. A practical implementation of such a scheme is described.
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Wolf, Joshua Jaeger. "Post-transcriptional coordination by an RNA-binding protein." Thesis, Massachusetts Institute of Technology, 2010. http://hdl.handle.net/1721.1/57893.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2010.<br>Cataloged from PDF version of thesis.<br>Includes bibliographical references.<br>RNA-binding proteins can regulate the stability, localization, and translation of their target mRNAs. Post-transcriptional regulation can orchestrate dynamic changes in gene expression, and can coordinate multiple cellular processes in response to various stimuli. Filamentous growth in Saccharomyces cerevisiae is a morphogenetic switch that occurs in response to nitrogen starvation and requires alterations in cell growth, cell cycle, and cell wall functions. Tyl element retrotransposition is also induced under conditions of nitrogen starvation. I describe a role for the RNA-binding protein Khdl in regulating these two responses to environmental stress through its mRNA targets. I identified the RNA targets of Khdl using in vivo crosslinking and immunoprecipitation (CLIP), combined with deep sequencing. This produced a high-resolution map of Khdl binding sites across the transcriptome, and provided unprecedented insight into its biological functions. Khdl regulates multiple post-transcriptional regulatory loops to coordinate the components of filamentous growth and Tyl retrotransposition. Although similar mechanisms were known to transcriptionally regulate these processes, the posttranscriptional coordination is a novel discovery. The feed-forward regulation that Khdl confers on FLO11, which encodes a protein required for filamentous growth, enables asymmetric expression between mother and daughter cells to switch between filamentous and yeast form growth. In this thesis, I describe regulation of gene expression by RNA-binding proteins, methods to identify their target transcripts and recognition sequences, the KH domain, known functions of Khdl, and the phenotypes it coordinates. My work represents the first application of CLIP to budding yeast, and the growing understanding of RNA-binding proteins in this organism facilitated the placement of Khdl into its posttranscriptional regulatory network. While many questions remain regarding the role Khdl plays in regulating cellular activities, this thesis addresses its direct role in key processes.<br>by Joshua Jaeger Wolf.<br>Ph.D.
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Taylor, W. J. "Post-synaptic actions of opiate peptides and gamma-aminobutyrate." Thesis, University of Leeds, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.372580.
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Tierney, Marcus John 1973. "Post-transcriptional regulation of plasminogen activator inhibitor type 2." Monash University, Dept. of Medicine, 2002. http://arrow.monash.edu.au/hdl/1959.1/8496.
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Ademokun, Alexander. "Post-transcriptional regulation of BLIMP-1 by the RNA-binding protein TIS11b." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612489.
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Sawicka, Kirsty J. "Post-transcriptional regulation of gene expression by the polypyrimidine tract binding protein." Thesis, University of Nottingham, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.537674.
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Nguyen, Chi Mai. "Post-transcriptional regulation during spermatogenesis : Role of the RNA-binding protein hu." Toulouse 3, 2008. http://thesesups.ups-tlse.fr/365/.
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La spermatogenèse est un processus élaboré permettant d'une part le maintien de cellules souches par divisions mitotiques et d'autre part la production de spermatozoïdes par différenciation. Au cours des dernières étapes de la différenciation, la chromatine se compacte, ne laissant plus à la cellule la possibilité de transcrire ses gènes. Du fait de l'arrêt brutal de la transcription, bien avant la fin du processus de différenciation, la cellule germinale utilise le stock d'ARN messagers (ARNm) préexistants pour finaliser sa différenciation. Ce phénomène repose sur la régulation fine du stockage et de la traduction des ARNm au cours du temps, deux régulations post-transcriptionnelles encore très peu documentées dans les cellules germinales. Au cours de ma thèse je me suis intéressée au rôle potentiel de deux protéines de liaison à l'ARN exprimées dans le testicule de souris: HuR/ELAVL1 et AUF1/hnRNP D. Dans les cellules somatiques, ces protéines lient les séquences riches en adénines et uridines (AU-rich element ou ARE) localisées dans la région 3' non codante de certains ARNm (ARN à ARE). HuR protége de la dégradation ses ARN à ARE cibles et favorise leur traduction, alors qu'AUF1 induit leur dégradation. Afin d'étudier la contribution d'HuR et d'AUF1 aux mécanismes post-transcriptionnels indispensables au bon déroulement de la spermatogénèse, nous avons dans un premier temps examiné leur patron d'expression. Nous avons montré que l'expression d'HuR est étroitement régulée au cours de la spermatogénèse, alors que celle d'AUF1 est ubiquitaire. Dans un second temps, nous avons utilisé des lignées de souris transgéniques surexprimant HuR (HuRtg) ou AUF1 (AUF1tg) établies au laboratoire et montré que la surexpression d'HuR et non celle d'AUF1 altère la spermatogenèse, entraînant leur stérilité dans 25% des cas (Sertoli Cells Only syndrome). Par la suite, nous avons mis évidence que de nombreux ARN à ARE, naturellement abondamment exprimés dans le testicule, sont dérégulés dans les cellules germinales HuRtg et AUF1tg. Une étude approfondie des ARN cibles d'HuR et d'AUF1, a révélé que ces deux protéines ont une activité différente car elles s'associent à des ARN différents dans les cellules germinales. .<br>Spermatogenesis, the elaborate process by which sperm are produced, is marked by dramatic proliferation and differentiation. During the late steps of spermatogenesis, transcription suddenly ceases prior the end of differentiation, because of drastic epigenetic modifications that result in chromatin compaction. Thus, haploid germ cells make use of extensive temporal mRNA storage and translation regulation to ensure stage-specific protein synthesis. Factors and cellular compartments involved in these post-transcriptional controls are still poorly understood. During my PhD, I hypothesized that the two RNA binding proteins HuR/ELAVL1 and AUF1/hnRNP D, might play a role in these controls. They bind AU-rich element-containing mRNAs (ARE-mRNAs) in somatic cells and regulate their stability and translation: HuR protects ARE-mRNAs from degradation and favours their translation, whereas AUF1 usually induces their degradation. First, to investigate the contribution of HuR and AUF1 to the post-transcriptional mechanisms occurring in germ cells, I used transgenic mice derived in our laboratory overexpressing HuR (HuRtg) and AUF1 (AUF1tg) in their testes. Strikingly, whereas spermatogenesis proceeded normally in AUF1tg mice, HuR overexpression impaired spermatogenesis, revealing the importance of a regulated expression of HuR to fulfill male germ cell differentiation. The comparative analysis of AU-transcriptome of pre-pubertal wild type testes with that of HuRtg and AUF1tg testes, combined with computational analyses and RNA/Protein immunoprecipitation experiments, revealed that these two proteins regulate different targets mRNAs and thus exhibit different activities. .
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Almlöf, Tova. "Gene regulation by the glucocorticoid receptor : post-DNA binding mechanisms of transcriptional activation /." Stockholm, 1997. http://diss.kib.ki.se/1997/91-628-2675-1.
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Liu, Qingbin. "Post-translational modification on arginine and function of CCAAT/enhancer binding protein alpha." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2012. http://dx.doi.org/10.18452/16620.
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Der Transkriptionsfaktor CCAAT/enhancer-binding protein α (C/EBPα) kontrolliert Zellzyklusarrest und terminale Differenzierung von neutrophilen Granulozyten und Adipozyten. Mutationen von C/EBPα treten häufig im Zusammenhang mit akuter myeloischer Leukämie auf. Massenspektrometrische Untersuchungen zeigten, dass C/EBPα an mehreren konservierten Argininen citrunilliert ist, einschließlich R297 in der C-terminalen basischen Region von C/EBPα. Mutationen von C/EBPα R297 wurden bereits beschrieben, weshalb der Schwerpunkt dieser Arbeit auf die Analyse der Modifikation dieses Aminosäurerestes gelegt wurde. Die Ergebnisse zeigen, dass die Peptidyl-Arginin-Deaminase (PADI4) mit C/EBPα interagiert und an mehreren Aminosäureresten citrunilliert. Citrunillierung oder Mutation von R297 beeinflusst die Aktivität von C/EBPα, einschließlich DNA-Bindung und Interaktion mit Partnerproteinen. Mutationsanalysen legen nahe, dass die positive Ladung des Aminosäurerestes R297 für die Bindung an cis-regulatorische DNA-Elemente, Protein Interaktionen, Genaktivierung, Fettzelldifferenzierung und Zellzyklusarrest ausschlaggebend ist. Knock-down von PADI4 in der myeloischen Vorläufer-Zelllinie 32D oder in der leukämischen U937 Zelllinie induziert Granulozyten-Differenzierung, möglicherweise durch Blockierung der PADI4-vermittelten Citrunillierung und Inaktivierung von C/EBPα. Zusammengefasst ergibt sich aus den Daten, dass PADI4 die positiv-geladene Seitenkette von C/EBPα R297 in eine ungeladene, citrunillierte Form umwandelt, die die Assoziation mit DNA destabilisiert und die C/EBPα-E2F-Interaktion beeinflusst, was wiederum das Gleichgewicht zwischen Proliferation und Differenzierung bestimmt.<br>The transcription factor CCAAT/enhancer-binding protein α (C/EBPα) coordinates cell cycle arrest and terminal differentiation of neutrophil granulocytes and adipocytes. Mutations in C/EBPα are frequently associated with acute myeloid leukemia. Mass spectrometric analysis revealed that citrullination occurred on multiple conserved C/EBPα arginine residues including R297 in the C/EBPα basic region. C/EBPα R297 was previously reported to be mutated in acute myeloid leukemia and we therefore focused on the modification this residue. Data presented here show that peptidylarginine deiminase 4 (PADI4) interacts with and citrullinates C/EBPα at several sites. Citrullination or mutation of R297 dramatically changed C/EBPα activities, including DNA binding and interaction with protein partners. Mutational analysis demonstrated that the positive charge of residue R297 was critical for binding to cis-regulatory sites on DNA, gene activation, adipocytic differentiation, and cell cycle arrest. Knock down of PADI4 in the myeloid precursor cell line 32D or U937 leukemia cells induced granulocyte differentiation, potentially through relieving PADI4 mediated citrullination and inactivation of C/EBPα. Taken together, the data suggest that PADI4 converts the positive C/EBPα R297 side chain to the non-charged citrulline side chain which destabilizes the association with DNA and affects C/EBPα - E2F interaction that determines the balance between proliferation and differentiation.
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Zhou, Shanggen. "Post-translational regulation of CCAAT/enhancer binding protein [delta] (C/EBP[delta]) by ubiquitin family proteins." Columbus, Ohio : Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1195227986.
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Mason, Joanne Nicola. "Biosynthesis and post-translational processing of heparin-binding epidermal growth factor-like growth factor." Thesis, University of Cambridge, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.621007.
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Adolph, Jessie Prahlad Anand. "Time-binding in African American verbal art as a salve for post-traumatic slave syndrome." Diss., Columbia, Mo. : University of Missouri-Columbia, 2009. http://hdl.handle.net/10355/6711.
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The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file. Title from PDF of title page (University of Missouri--Columbia, viewed on January 26, 2010) Thesis advisor: Dr. Anand Prahlad. Includes bibliographical references.
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Zhou, Shanggen. "Post-translational regulation of ccaat/enhancer binding progrein δ(C/EBPδ)by ubiquitin family proteins". The Ohio State University, 2007. http://rave.ohiolink.edu/etdc/view?acc_num=osu1195227986.
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Hertlein, Erin K. "Post-translational modification of NF-kappaB regulation of stability and gene expression /." Columbus, Ohio : Ohio State University, 2006. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1167336380.
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Chi, Celestine. "Post-synaptic Density Disc Large Zo-1 (PDZ) Domains : From Folding and Binding to Drug Targeting." Doctoral thesis, Uppsala universitet, Institutionen för medicinsk biokemi och mikrobiologi, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-126129.
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Understanding how proteins fold and bind is interesting since these processes are central to most biological activity. Protein folding and protein-protein interaction are by themselves very complex but using a good and robust system to study them could ease some of the hurdles. In this thesis I have tried to answer some of the fundamental questions of protein folding and binding. I chose to work with PDZ domains, which are protein domains consisting of 90-100 amino acids. They are found in more than 400 human proteins and function mostly as protein-protein interaction units. These proteins are very stable, easy to express and purify and their folding reaction is reversible under most laboratory conditions. I have characterized the interaction of PSD-95 PDZ3 domain with its putative ligand under different experimental conditions and found out that its binding kinetics is sensitive to salt and pH. I also demonstrated that the two conserved residues R318 and H372 in PDZ3 are responsible for the salt and pH effect, respectively, on the binding reaction. Moreover, I determined that for PSD 95 PDZ3 coupling of distal residues to peptide binding was better described by a distance relationship and there was a very weak evidence of an allosteric network. Further, I showed that another PDZ domain, SAP97 PDZ2 undergoes conformational change upon ligand binding. Also, I characterized the binding mechanism of a dimeirc ligand/PDZ1-2 tandem interaction and showed that despite its apparent complexity the binding reaction is best described by a square scheme. Additionally, I determined that for the SAP 97 PDZ/HPV E6 interaction that all three PDZ domains each bind one molecule of the E6 protein and that a set of residues in the PDZ2 of SAP 97 could operate in an unexpected long-range manner during E6 interaction. Finally, I showed that perhaps all members in the PDZ family could fold via a three state folding mechanism. I characterized the folding mechanism of five different PDZ domains having similar overall fold but different primary structure and the results indicate that all five fold via an intermediate with two transition states. Transition state one is rate limiting at low denaturant concentration and vice versa for transition state two. Comparing and characterizing the structures of the transition states of two PDZ domains using phi value analysis indicated that their early transition states are less similar as compared to their late transition states.
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Gao, Enoch N. (Enoch Nuo). "Post-translational lipid modification and nucleotide binding of Myelin 2',3'-Cyclic Nucleotide 3'-Phosphodiesterase (CNP)." Thesis, McGill University, 1996. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=23889.
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The myelin protein CNP $(2 sp prime,3 sp prime$-Cyclic Nucleotide 3$ sp prime$-Phosphodiesterase) is thio-palmitoylated. Since acylation plays an important role in the protein-membrane interaction, CNP palmitoylation was further investigated. Seven cysteine residues in CNP were individually converted into serines and the palmitoylation was analyzed in either COS-7 cells or an in vitro acylation reaction. No single Cys to Ser mutation could reduce substantially the level of palmitoylation, which may indicate that the turnover of palmitate on CNP is high and that there are multiple palmitoylation sites. Immunostaining and subcellular fractionation showed that isoprenylation is the major factor to control the membrane association of CNP while palmitoylation may serve as a fine tuning mechanism. A double mutation of Cys 231 to Ser and Thr 374 to Pro greatly reduced CNPase activity and the level of palmitoylation. CNP was expressed in Sf9 cells and the mutant C397S was purified to near homogeneity. Since CNP contains several ATPase consensus motifs, we investigated in a preliminary way its ATPase/ATP-binding properties. CNP was affinity-photolabeled by $ lbrack alpha- sp{32}$P) 8-azido ATP in a specific and saturable way, although no apparent ATPase activity was detected. The binding of 8N3 ATP could be competed by ATP, GTP and CTP at different concentrations.
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Ekstrand, Gayle. "The effect of exercise intensity on post-exercise insulin-binding responses in male insulin-dependent diabetics." Thesis, University of Ottawa (Canada), 1986. http://hdl.handle.net/10393/4760.
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Vadrevu, Suryakiran. "Biochemical investigation of phosphodiesterase type IV post-translational modification, cellular localisation and interaction with associated binding proteins." Thesis, University of Glasgow, 2008. http://theses.gla.ac.uk/219/.
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cAMP is a secondary messenger that is involved in a variety of signalling pathways through its effectors including EPAC, PKA and ion channels. cAMP signalling regulates processes such as memory, muscle contraction and inflammatory responses. PDE enzymes offer a mechanism to negatively regulate elevated cAMP levels elicited by activators of adenylyl cyclase. Studies have shown that cAMP signalling is compartmentalised through binding of PDEs to A-kinase anchoring proteins (AKAPs) that scaffold PKA regulatory subunits. In this study post-translational-modification of PDE4 isoforms is investigated. SUMOylation is a relatively newly identified post-translational modification that is known to regulate the structure and function of its substrates. PDE4 isoforms of the PDE4A and 4D subfamilies are SUMOylated by an E3 ligase, PIASy. SUMOylation alters the rolipram sensitivity and potentiates the PKA mediated activation of the isoforms whilst it confers protection from ERK-mediated inhibition of PDE4 activity. SUMOylation alters the association of PDE4 isoforms with binding partners like β-Arrestin, AKAP18 δ and UBC9. Rolipram is an archetypal PDE4 specific inhibitor. In this study it is shown that in cells expressing a GFP tagged form of PDE4A4 undergoes redistribution into accretion foci upon chronic treatment with rolipram. Data suggests that foci formation requires protein turnover and is regulated by signalling pathways such as PI3 kinase pathway, p38 MAP kinase pathway and PKC pathways. Further, the Immunomodulatory drug Thalidomide® also inhibits foci formation. PDE4 isoforms have isoforms specific N-terminal regions, which play a crucial role in sub-cellular localisation and protein-protein interactions. It is shown here that PDE4D5 interacts with a novel RhoGAP called ARHGAP21 which has been previously reported to bind β-arrestins. This interaction is independent of GAP activity of ARHGAP as well as PDE4 activity. Previous reports have indicated a role of β-Arrestin, PDE4 and ARHGAP21 in regulation of actin cytoskeleton dynamics. Hence complex β-Arrestin-PDE4-ARHGAP21 may play a crucial role in regulating actin dynamics.
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Gouveia, Ayden. "The Atypical Protein Kinase C - Creb Binding Protein Pathway Regulates Post-Stroke Neurovascular Remodeling and Functional Recovery." Thesis, Université d'Ottawa / University of Ottawa, 2017. http://hdl.handle.net/10393/35674.
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Ischemic stroke related brain damage causes loss of multiple cell types, including neural and vascular cells. The extent of post-stroke neurogenesis and angiogenesis predicts the level of functional regeneration/recovery after stroke. In this regard, my thesis was focused on defining the molecular process that modulates post-stroke functional recovery by co-ordinating post-stroke neurovascular remodeling. Since stroke-related brain damage releases enriched local microenvironmental cues, I examined the role of a signaling-induced epigenetic pathway, an atypical protein kinase C (aPKC)-mediated phosphorylation of CREB Binding Protein (CBP), in regulating post-stroke neurovascular remodeling and functional recovery. This pathway has previously been shown to be activated by metformin, an adenosine monophosphate kinase (AMPK) activator, to promote the differentiation of neural precursors in the developing and adult brain. Here, I first developed a murine focal cortical ischemic stroke model with persistent motor function deficits by combined intra-cortical injections of endothelin-1 (ET-1) and L-NAME into the sensorimotor cortex. Second, I applied the ET-1/L-Name-induced focal cortical stroke model in a knock-in mouse CBPS436A where the aPKC-CBP pathway is deficient, and showed that the aPKC-CBP pathway is involved in post-stroke functional recovery by coordinating neurovascular remodeling. Specifically, CBPS436A-KI mice displayed reduced motor recovery, correlated with reduced vascular remodeling and impaired post-stroke angiogenesis. Intriguingly, I also observed that CBPS436A-KI mice showed a reduction in the population of stroke-induced newborn pericytes but an increase in the population of perivascularly-derived neural precursors, implying that the aPKC-CBP pathway may be involved in the process that reprograms pericytes into neural precursors. Together, this study elucidates the novel role of the aPKC-CBP pathway in modulating neurovascular remodeling and functional recovery following focal ischemic cortical stroke.
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Zagore, Leah Louise. "The Molecular Function of the RNA Binding Protein DAZL in Male Germ Cell Survival." Case Western Reserve University School of Graduate Studies / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=case1575647143675768.
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Lebedeva, Svetlana [Verfasser]. "Transcriptome-wide functional analysis of post-transcriptional regulatory interactions of the RNA-binding protein HuR/ELAVL1 / Svetlana Lebedeva." Berlin : Freie Universität Berlin, 2012. http://d-nb.info/1028496648/34.
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Hubers, Lisa. "Arginine methylation of RNA-binding protein HuD by CARM1 regulates MN-1 differentiation through a post-transcriptional mechanism." Thesis, University of Ottawa (Canada), 2010. http://hdl.handle.net/10393/28632.
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Spinal Muscular Atrophy results from loss of the survival of motor neuron (SMN) gene, leading to a deficiency in SMN protein and selective degeneration of motor neurons. We have found that coactivator-associated arginine methyltransferase 1 (CARM1) regulates the switch from proliferation to differentiation, downstream of neurotrophic signaling, in motor neuron-like cells. Here, through down-regulation of CARM1 levels, methylation of one of its substrates, HuD, is reduced, resulting in an increase in p21 mRNA. Methylation of HuD by CARM1 negatively regulates its direct interaction with p21 mRNA, the first demonstration that CARM1 can directly influence the RNA binding activity of a substrate.
We have also identified a novel interaction between HuD and SMN. In MN-1 differentiation, we propose that SMN functions as an adaptor module through arginine methylation-regulated interactions with RNA binding proteins, including HuD, and that the formation of distinct mRNP complexes on mRNA are regulated either similarly or differentially by PRMTs and/or SMN. These findings may help to elucidate the specific role of arginine methylation and SMN in regulating differentiation of motor neurons and provide crucial insights into the cell-specific pathophysiology of spinal muscular atrophy.
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Pastic, Alyssa. "LRRK2 Phosphorylates HuD to Affect the Post-Transcriptional Regulation of Parkinson's Disease-Linked mRNA Targets." Thesis, Université d'Ottawa / University of Ottawa, 2018. http://hdl.handle.net/10393/38593.
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Parkinson's Disease (PD) is a late-onset neurodegenerative disease characterized by progressive motor dysfunction caused by a loss of dopaminergic neurons for which there is no known cure. Among the most common genetic causes of PD are mutations in the leucine-rich repeat kinase 2 gene (LRRK2), encoding a multi-domain protein with kinase activity. The LRRK2 G2019S mutation causes hyperactivity of the kinase domain and is the most frequent LRRK2 mutation in patients with familial PD, though its role in PD pathology remains unclear. Preliminary data from the lab of our collaborator, Dr. David Park, demonstrated through a genetic screen in Drosophila melanogaster that the deletion of rbp9 encoding an RNA-binding protein prevented pathology induced by PD-relevant mutations in the LRRK2 kinase domain. The neuronal homolog of RBP9 in humans is HuD, a member of the Hu family of RNA-binding proteins that regulates the expression of many transcripts involved in neuronal development, plasticity, and survival. In addition, HuD has been shown to modify the age-at-onset or risk of developing PD. Here, we studied the effect of LRRK2 on the post-transcriptional regulation of mRNAs bound by HuD in the context of PD. Our findings showed that HuD is a substrate for LRRK2 phosphorylation in vitro, and that LRRK2 G2019S hyperphosphorylates HuD. We demonstrated that LRRK2 kinase activity is required for the binding of several transcripts by HuD that encode PD-relevant proteins such as α-synuclein and neuronal survival factor BDNF. Our findings in human neuroblastoma cells indicated that LRRK2 regulates the protein levels of HuD mRNA targets α-synuclein and BDNF in a mechanism that can by modified by HuD. Finally, we showed that the combination of HuD knockout with LRRK2 G2019S expression in mice rescues aberrant expression of HuD targets in mice with only the LRRK2 G2019S mutation or the knockout of HuD alone. Together, our findings demonstrate that LRRK2 affects the post-transcriptional regulation of HuD-bound mRNAs, and suggest the use of HuD as a potential therapeutic target in patients with PD caused by the LRRK2 G2019S mutation.
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Deveau, Laura M. "Characterizing the Disorder in Tristetraprolin and its Contribution to Post-Transcriptional Gene Regulation: A Dissertation." eScholarship@UMMS, 2016. http://escholarship.umassmed.edu/gsbs_diss/855.
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RNA-binding proteins (RBPs) are important for a wide variety of biological processes involved in gene regulation. However, the structural and dynamic contributions to their biological activity are poorly understood. The tristetraprolin (TTP) family of RBPs, including TTP, TIS11b and TIS11d, regulate the stability of mRNA transcripts encoding for key cancer-related proteins, such as tumor necrosis factor- and vascular endothelial growth factor. Biophysical studies have shown that the RNA binding domain, consisting of two CCCH zinc fingers (ZFs), is folded in the absence of RNA in TIS11d and TIS11b. In TTP, however, only ZF1 adopts a stable fold, while RNA is required to completely fold the tandem zinc finger (TZF). The focus of this research was to understand the origin and biological significance of the structural differences observed for the TZF domains of TTP and TIS11d. Three residues were shown to control the affinity for the structural Zn2+ and determine the folding of ZF2 in the absence of RNA. The partially-folded TZF domain of TTP has greater selectivity for RNA sequences than the fully folded TZF domain of TIS11d. The mRNA destabilizing activity of TTP was increased when the partially disordered RBD of TTP was replaced with the fully structured TZF domain of TIS11d. Disruption of the structure and/or dynamics of the TZF domain observed in the disease-associated mutations of TIS11d, P190L and D219E, results in aberrant cytoplasmic localization. This work demonstrates that the extent of RBD folding in the TTP family is important for differential RNA recognition, mRNA turnover, and protein localization in vivo.
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Chiari, Estelle. "Etude de modifications post-traductionnelles de la protéine Tax du virus HTLV-I." Paris 7, 2005. http://www.theses.fr/2005PA077062.
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Ström, Holst Bodil. "In vitro characterisation of cryopreserved canine spermatozoa : with special reference to post-thaw survival time and zona pellucida binding capacity /." Uppsala : Swedish Univ. of Agricultural Sciences (Sveriges lantbruksuniv.), 1999. http://epsilon.slu.se/avh/1999/91-576-5445-X.pdf.
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Ding, Shih-Torng. "Lipid Metabolism and The Ontogeny of ACYLCoA:Cholesterol Acyltransferase and Fatty Acid-Binding Protein in Developing Embryos and Post-Hatch Turkeys /." The Ohio State University, 1996. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487933648649402.
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Hallal, Samantha. "Characterisation of the zinc fingers of Erythroid Kruppel-Like Factor." University of Sydney, 2008. http://hdl.handle.net/2123/4030.
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Doctor of Philosophy (PhD)<br>Gene expression is known to be regulated at the level of transcription. Recently, however, there has been a growing realisation of the importance of gene regulation at the post-transcriptional level, namely at the level of pre-mRNA processing (5’ capping, splicing and polyadenylation), nuclear export, mRNA localisation and translation. Erythroid krüppel-like factor (Eklf) is the founding member of the Krüppel-like factor (Klf) family of transcription factors and plays an important role in erythropoiesis. In addition to its nuclear presence, Eklf was recently found to localise to the cytoplasm and this observation prompted us to examine whether this protein has a role as an RNA-binding protein, in addition to its well-characterised DNA-binding function. In this thesis we demonstrate that Eklf displays RNA-binding activity in an in vitro and in vivo context through the use of its classical zinc finger (ZF) domains. Furthermore, using two independent in vitro assays, we show that Eklf has a preference for A and U RNA homoribopolymers. These results represent the first description of RNA-binding by a member of the Klf family. We developed a dominant negative mutant of Eklf by expressing its ZF region in murine erythroleukaemia (MEL) cells. We used this to investigate the importance of this protein in haematopoietic lineage decisions by examining its effect on the multipotent K562 cell line. We provide evidence that Eklf appears to be critical not only for the promotion of erythropoiesis, but also for the inhibition of megakaryopoiesis.
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Duggimpudi, Sujitha Smruthy [Verfasser]. "Elucidating the physiological function of the RNA binding protein EWS and its role in post-transcriptional gene regulation / Sujitha Smruthy Duggimpudi." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2015. http://d-nb.info/1080298142/34.
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Westberg, Christopher Bryant. "Identification and characterization of three RNA helicase A binding proteins and their roles in the post-transcriptional regulation of simple retroviruses /." Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2002. http://wwwlib.umi.com/cr/ucsd/fullcit?p3044786.
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Liu, Qingbin [Verfasser], Achim Akademischer Betreuer] Leutz, Udo [Akademischer Betreuer] Heinemann, and Thomas [Akademischer Betreuer] [Sommer. "Post-translational modification on arginine and function of CCAAT, enhancer binding protein alpha / Qingbin Liu. Gutachter: Achim Leutz ; Udo Heinemann ; Thomas Sommer." Berlin : Humboldt Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2012. http://d-nb.info/1028566840/34.
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Alidousty, Christina [Verfasser]. "Die Regulation der CCL5-Expression in der Monozytendifferenzierung durch post-translationale Modifikation des Y-Box Binding Protein-1 (YB-1) / Christina Alidousty." Aachen : Hochschulbibliothek der Rheinisch-Westfälischen Technischen Hochschule Aachen, 2015. http://d-nb.info/107100820X/34.
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Bruzzone, Lucía. "A crosstalk between the RNA binding protein Smaug and the Hedgehog pathway links cell signaling to mRNA regulation in drosophila." Thesis, Sorbonne Paris Cité, 2018. https://theses.md.univ-paris-diderot.fr/BRUZZONE_Lucia_1_va_20180319.pdf.
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La régulation post-transcriptionnelle de l'expression génique joue un rôle essentiel dans divers processus cellulaires pendant le développement. Les protéines de liaison à l'ARN (RBP) sont des médiateurs fondamentaux des régulations post-transcriptionnelles qui contrôlent l'expression de l'ARNm en reconnaissant des séquences spécifiques dans les transcrits cibles. Smaug est une protéine de liaison à l'ARN conservée de la levure jusqu’à l’homme qui est essentielle pendant l'embryogenèse précoce de la drosophile. Smaug reconnaît et lie des éléments de reconnaissance de Smaug (SRE) dans ses ARNm cibles et recrute des facteurs supplémentaires, via des interactions protéine-protéine, qui régulent l'ARNm lié. Un concept qui émerge est celui des voies de signalisation pouvant moduler l'activité des RBP par des modifications post-traductionnelles, en ajoutant ainsi une couche supplémentaire dans le contrôle de l'expression des gènes.Au cours de mon travail de thèse, j'ai cherché à mettre en évidence que la voie de signalisation Hedgehog régule Smaug en favorisant sa phosphorylation. Mon travail montre que la signalisation HH diminue les niveaux de protéines Smaug affectant sa capacité à réprimer la traduction de l'ARNm. Cet effet négatif semble dépendre de l'interaction entre Smaug et le transducteur de signal HH, Smoothened. De plus, Smaug est constitutivement phosphorylée dans son domaine de liaison à l'ARN, ce qui semble être nécessaire pour la formation des foci cytoplasmiques de Smaug<br>Post-transcriptional regulation of gene expression plays a critical role in a variety of cellular processes during development. RNA binding proteins are fundamental mediators of post-transcriptional regulations that control mRNA expression by recognizing specific cis acting elements within the target transcripts. Smaug is a highly conserved sequence specific RNA-binding protein that is essential during Drosophila early embryogenesis. Smaug binds Smaug Recognition Elements (SRE) in the target mRNA and recruits additional factors, via protein-protein interactions, that regulate the bound mRNA. An emergent concept that signaling pathways can modulate RBP activity by post-translation modifications adds a new layer in the control of gene expression. During my thesis work, I sought to understand how the Hedgehog pathway regulates Smaug by promoting its phosphorylation. My work shows that HH signaling downregulates Smaug protein levels affecting its ability to repress mRNA translation. This negative effect seems to be dependent on the interaction between Smaug and the HH signal transducer Smoothened. Moreover, Smaug is constitutively phosphorylated in its RNA binding domain, which appears to be necessary for cytoplasmic Smaug foci formation
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Lönn, Peter. "Regulation of TGF-β Signaling by Post-Translational Modifications". Doctoral thesis, Uppsala universitet, Ludwiginstitutet för cancerforskning, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-128855.
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Transforming growth factor-β (TGF-β) signaling is initiated when the ligand binds to type II and type I serine/threonine kinase receptors at the cell surface. Activated TGF-β type I receptors phosphorylate R-Smads which relocate, together with co-Smads, to the cell nucleus and regulate transcription. Enhancement or repression of Smad-specific gene targets leads to intracellular protein compositions which organize functional complexes and thus govern cellular processes such as proliferation, migration and differentiation. TGF-β/Smad signaling relays are regulated by various post-translational modifications. From receptors to gene promoters, intricate interplays between phosphorylation, acetylation, ubiquitination and numerous other modifications, control Smad signaling initiation and duration. However, many steps in the cascade, including receptor internalization, Smad nuclear shuttling and transcriptional termination, still remain elusive. The open gaps in our understanding of these mechanisms most likely involve additional post-translational regulations. Thus, the aim of the present investigation was to identify novel modulators of TGF-β/Smad signaling. In the first part of this thesis, we show the importance of ADP-ribosylation in Smad-mediated transcription. We identified poly(ADP-ribose) polymerase 1 (PARP-1) as a Smad interacting protein. Our work revealed that PARP-1 forms direct interactions with Smad3/4, and PARylates residues in their MH1 domains. This modification restricts Smads from binding to DNA and attenuates Smad-activated transcription. PARylation is reversed by the glycohydrolase PARG. We provide evidence that PARG can de-ADP-ribosylate Smads, which enhances Smad-promoted gene regulation. In the second part, we examine a Smad-dependent gene target of TGF-β signaling, salt inducible kinase 1 (SIK). After induction, SIK cooperates with Smad7 and Smurf2 to downregulate the TGF-β type I receptor. The mechanism relies on both the kinase and UBA domain of SIK as well as the E3-ligase activity of Smurf2. In summary, we have unveiled two enzyme-dependent TGF-β/Smad modulatory mechanisms; SIK promoted receptor turnover and PARP-1/PARG-regulated Smad signaling.
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Burns, David M. "Post-Transcriptional Control of Human Cellular Senescence: A Dissertation." eScholarship@UMMS, 2010. https://escholarship.umassmed.edu/gsbs_diss/491.
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The central dogma of biology asserts that DNA is transcribed into RNA and RNA is translated into protein. However, this overtly simplistic assertion fails to portray the highly orchestrated and regulated mechanisms of transcription and translation. During the process of transcription, RNA provides the template for translation and protein synthesis as well as the structural and sequence specificity of many RNA and protein-based machines. While only 1-5% of the genome will escape the nucleus to be translated as mRNAs, complex, parallel, highly-conserved mechanisms have evolved to regulate specific mRNAs. Trans-acting factors bind cis-elements in both the 5" and 3" untranslated regions of mRNA to regulate their stability, localization, and translation. While a few salient examples have been elucidated over the last few decades, mRNA translation can be reversibly regulated by the shortening and lengthening of the 3" polyadenylate tail of mRNA. CPEB, an important factor that nucleates a complex of proteins to regulate the polyadenylate tail of mRNA, exemplifies a major paradigm of translational control during oocyte maturation and early development. CPEB function is also conserved in neurons and somatic foreskin fibroblasts where it plays an important role in protein synthesis dependent synaptic plasticity and senescence respectively. Focusing on the function of CPEB and its role in mRNA polyadenylation during human cellular senescence, the following dissertation documents the important finding that CPEB is required for the normal polyadenylation of p53 mRNA necessary for its normal translation and onset of senescence. Cells that lack CPEB have abnormal levels of mitochondria and ROS production, which are demonstrated to arise from the direct result of hypomorphic p53 levels. Finally, in an attempt to recapitulate the model of CPEB complex polyadenylation in human somatic cells, I unexpectedly find that Gld-2, a poly(A) polymerase required for CPEB-mediated polyadenylation in Xenopus laevis oocytes, is not required for p53 polyadenylation, but instead regulates the stability of a microRNA that in turn regulates CPEB mRNA translation. Furthermore, I demonstrate that CPEB requires Gld-4 for the normal polyadenylation and translation of p53 mRNA.
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Moore, Jocelyn. "Post-transcriptional control of Drosophila pole plasm component, germ cell-less." Thesis, McGill University, 2008. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=115700.
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Mechanisms of post-transcriptional control are critical to deploy RNAs and proteins asymmetrically to a discrete region of cytoplasm at the posterior of the Drosophila oocyte and embryo, called the pole plasm and thus allow differentiation of the germline. Research presented in this thesis investigates the post-transcriptional control of Drosophila pole plasm component germ cell-less (gcl ). Maternal gcl activity is required for germ cell specification and gcl RNA and protein accumulate asymmetrically in the pole plasm. gcl RNA, but not Gcl protein, is also detected in somatic regions of the embryo, and ectopic expression of Gcl in the soma causes repression of somatic patterning genes suggesting that gcl RNA is subject to translational control. I find that Gcl is expressed during oogenesis, where its expression is regulated by translational repressor Bruno (Bru). Increased levels of Gcl are observed in the oocyte when Bru is reduced (i.e., in an arrest heterozygote) and Bru overexpression reduces the amount of Gcl. Consistent with this, reduction of the maternal dosage of Bru leads to ectopic Gcl expression in the embryo, which, in turn, causes repression of anterior huckebein RNA expression. Bruno binds directly to the gcl3'UTR in vitro, but surprisingly, this binding is largely independent of a Bruno Response Element (BRE) in the gcl 3'UTR and depends upon a novel site. Furthermore, the gcl BRE-like region is not required to repress Gcl expression during oogenesis or embryogenesis. I concluded that Bru regulates gcl translation in a BRE-independent manner. In addition, I established the role of the gcl 3'UTR in gcl RNA localization and translation using transgenes that replace the endogenous 3'UTR with the alpha-tubulin 3'UTR or place it in tandem to the bicoid 3'UTR. I find that accumulation of gcl RNA in the embryonic pole plasm requires the gcl 3'UTR. Moreover, Gel is restricted to the pole plasm by translational repression mediated by the gcl 3'UTR and a limiting pool of trans-acting translational repressors. The phenotypic consequences of loss of this translational control are relatively mild, suggesting that gcl translation does not require stringent repression in the soma.
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Fradin, Aurelie. "Identification des modifications post-traductionnelles d'Ilf3 (Interleukin enhancer binding factor 3) et de NF90 (Nuclear Factor 90) et étude de leur rôle(s) fonctionnel(s)." Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066222/document.
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Ilf3 et NF90, deux protéines de liaison aux ARN localement structurés en double-brin, sont générées par épissage mutuellement exclusif à partir du gène ILF3. Pour chacune d’entre-elles, un épissage alternatif permet la synthèse de deux isoformes, une longue et une courte, qui diffèrent par la présence ou non d’une séquence de 13 acides aminés localisée à leur extrémité N-terminale et qui correspond à un signal de localisation nucléolaire. La particularité de ces deux protéines est de présenter une forte hétérogénéité avec au moins 20 isoformes produites à partir du même gène, 12 pour Ilf3 et 8 pour NF90. Elle est générée par deux mécanismes complémentaires, l’épissage alternatif et les modifications post-traductionnelles dont deux ont été mises en évidence au laboratoire, la diméthylation asymétrique de l’arginine 609/622 présente dans une séquence consensus de type RGG et catalysée par PRMT1 (« protein arginine N-methyltransferase 1 ») ainsi qu’une phosphorylation sur la sérine 190/203. Ce polymorphisme pourrait être à l’origine des différences de localisation subcellulaire observées selon l’isoforme considérée et/ou aurait comme fonction de réguler soit leurs interactions avec leurs partenaires protéiques ou nucléiques, soit leur activité biologique. Par des expériences d’immunofluorescence et de « GST pull-down », il a été montré que ces deux modifications post-traductionnelles d’Ilf3 et de NF90 ne semblent impliquées ni dans leur localisation subcellulaire, ni dans la régulation de leurs interactions avec leurs partenaires protéiques. Du fait des nombreuses fonctions associées aux protéines Ilf3 et NF90 dans la littérature, les modifications identifiées pourraient être impliquées dans la régulation de leurs interactions avec leurs partenaires nucléiques, ADN ou ARN<br>Ilf3 and NF90, two double stranded RNA-binding proteins, are generated by exclusive splicing from the ILF3 gene. For each one, a 5? alternative splicing leads to the synthesis of a long and a short isoforms that differ by the presence or not of 13 amino acid sequence at their N-terminus corresponding to a nucleolar localization signal. The characteristic of these two proteins is to exhibit a high degree of heterogeneity with at least 20 isoforms produced from the same gene, 12 for Ilf3 and 8 for NF90. It is generated by two complementary mechanisms, alternative splicing and posttranslational modifications which two have been identified in the laboratory, the arginine 609/622 asymmetric dimethylation present in a RGG consensus sequence and catalyzed by PRMT1 ("protein arginine N-methyltransferase 1") and the serine 190/203 phosphorylation. This polymorphism could explain the various cellular functions described for both proteins and could regulate their subcellular localization and the interaction with protein or nucleic partners. By immunofluorescence and GST pull-down experiments, it was shown that these two posttranslational modifications of Ilf3 and NF90 neither seem involved in their subcellular localization, nor in the regulation of interactions with their protein partners. Because of the many functions associated with Ilf3 and NF90 proteins in the literature, the identified modifications may be implicated in regulating the interactions with their nucleic partners, DNA or RNA
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Sherrard, Ryan W. [Verfasser], and Barbara [Akademischer Betreuer] Conradt. "Post-transcriptional regulation of the central apoptotic pathway by microRNAs and RNA-binding proteins during C. elegans development / Ryan W. Sherrard ; Betreuer: Barbara Conradt." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1180981820/34.
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Sherrard, Ryan William [Verfasser], and Barbara [Akademischer Betreuer] Conradt. "Post-transcriptional regulation of the central apoptotic pathway by microRNAs and RNA-binding proteins during C. elegans development / Ryan W. Sherrard ; Betreuer: Barbara Conradt." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1180981820/34.
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David, Géraldine. "Rôle de la protéine CELF1 dans la régulation post- transcriptionnelle de l'expression des gènes." Thesis, Rennes 1, 2015. http://www.theses.fr/2015REN1S094.
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Dans les cellules eucaryotes, l'expression des gènes est régulée à de multiples étapes. Les régulations post-transcriptionnelles regroupent l'ensemble des contrôles qui s'exercent sur un ARN, en particulier sa maturation nucléaire, sa stabilité et son contrôle traductionnel. Les protéines de liaison aux ARN sont des acteurs majeurs de ces régulations post-transcriptionnelles. Les protéines CELF1 et ELAVL1, abondantes et quasiment ubiquitaires, participent à ces différents niveaux de régulation et sont susceptibles de modifier le devenir des transcrits. Au cours de ces travaux, nous avons étudié l'impact de CELF1 sur l'abondance et la maturation des ARN par des approches transcriptomiques. Nous avons classé les transcrits en fonction de leurs réponses aux différentes inactivations. L'ensemble de ces données montre que i) CELF1 et ELAVL1 ont des rôles bivalents, leur déplétion étant associée à une répression ou une activation de certains gènes ; ii) dans des cellules HeLa, les effets des différentes déplétions sont majoritairement des effets indirects ; iii) CELF1 et ELAVL1 ont très majoritairement le même effet sur l'abondance des ARNm qu'elles contrôlent directement ; iv) CELF1 et ELAVL1 ont le plus souvent des effets coopératifs ou redondants sur l'abondance des transcrits liés. L'effet combinatoire de CELF1 et ELAVL1 dépend de l'ARNm considéré, révélant une complexité des régulations post-transcriptionnelles critiques pour le devenir d'une cellule<br>In eukaryotic cells, after transcription gene expression is controlled at multiple steps. These qualitative and quantitative post-transcriptional regulations are specified by RNA binding proteins (RBP). By combining transcriptomic analysis and binding site information for CELF1, we showed that CELF1 regulates both nuclear and cytoplasmic steps of gene expression. CELF1 directly controls the stability of cyclin D1 mRNA and the splicing of several RNA including KLC1 (light chain kinesin 1). Because mRNAs are in complexes consisting of multiple RBP we studied whether CELF1 and ELAVL1 would interact and control the abundance of their bound mRNAs. This analysis unravel a surprising redundancy or cooperativity of CELF1 and ELAVL1. The combinatorial effects of CELF1 and ELAVL1 were highly dependent on the considered RNA. Interestingly, we showed that both proteins cooperate and interact physically
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Brimau, Fanny. "Rôle des odorants-binding protein dans le mécanisme de transduction olfactive : implication de modifications post-traductionnelles dynamiques dans la spécificité de liaison avec les ligands." Thesis, Tours, 2010. http://www.theses.fr/2010TOUR4038/document.
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Les OBP sont des petites protéines solubles qui se lient avec des molécules odorantes et phéromonales. Le rôle des OBPs n’est pas complètement compris. Une hypothèse suggère que l’OBP solubilise et transporte les ligands aux récepteurs olfactifs et la liaison entre les molécules odorantes et l’OBP est non spécifique. Une autre hypothèse suggère que le complexe formé est une liaison spécifique entre une molécule odorante donnée et une OBP spécifique. Ce travail de thèse montre que les OBPs sont impliquées dans la première étape de la discrimination des odeurs. Dans un premier temps, nous avons montré l’implication de la Phe35 et la Tyr 82 dans la sortie du ligand par l’OBP. Dans un second temps, nous avons mis en évidence la présence de différentes isoformes d’OBP et de VEG qui diffèrent par les modifications post-traductionnelles (phosphorylation et GlcNAcylation) a la fois sur les protéines natives extraites de la muqueuse respiratoire et sur les protéines recombinantes produites par P.pastoris et CHO. Ces isoformes sont capables de discriminer des molécules odorantes et phéromonales. Les OBPs ne sont pas des transporteurs passifs car elles assurent un fin codage des molécules odorantes ou phéromonales avant l’interaction de ce complexe avec un récepteur spécifique<br>OBPs are small soluble proteins that bind with odorant molecules and pheromones. The role of OBP is not completely understood. A hypothesis suggests that OBP solubilize and transport the ligands to olfactory receptors and the binding between odorant molecule and OBP is unspecific. An other hypothesis suggest that the complex formed is the specific binding between a given odorant molecule and a specific OBP. This work of thesis show that OBP are involved in the first step of odorant discrimination. Initially, we have showed the involvement of the Phe35 and Tyr 82 in the uptake of ligands by OBP. Second, we have given rise to the presence of various isoform of OBP and VEG that differ by post-translational modifications (phosphorylation and GlcNAcylation) both on natives proteins extract of respiratory mucosa and on recombinants proteins produce by P. pastoris and CHO. These isoforms are able to discriminate of odorant molecules and pheromones. OBPs are not passives carriers because they ensure a fine coding of odorant molecules and pheromones before interaction of this complex with specific receptor
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Marchese, Domenica 1986. "Post-transcriptional regulation of Alpha-synuclein and link to Parkinson's disease." Doctoral thesis, Universitat Pompeu Fabra, 2016. http://hdl.handle.net/10803/525819.
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The role of RNA processing in the pathogenesis of neurodegenerative diseases is still poorly understood. α-synuclein (SNCA) is a presynaptic neuronal protein known as the major component of Lewy bodies, the pathological hallmark of Parkinson’s disease (PD). Recent evidence suggests a link between the pathogenesis of PD and the expression of SNCA mRNA isoforms with 3’ untranslated region (3’UTR) of different lengths. The purpose of my doctoral studies was the discovery of RNA-binding proteins (RBPs) regulating SNCA at the post-transcriptional level. Using computational and experimental approaches, I identified a number of trans-acting elements that physically interact with SNCA and potentially control its metabolism. I especially focused on the characterization of two RBPs, ELAVL1 and TIAR, and showed their implication in SNCA mRNA stability and translation efficiency. These two factors might play important roles in the maintenance of α-synuclein level and functionality in physiological and pathological conditions.<br>Se sap ben poc sobre el paper del processament del RNA en la patogènesi de les malalties neurodegeneratives. L’α-sinucleïna (SNCA) és una proteïna neuronal presinàptica i el principal component dels cossos de Lewy, que al seu torn són la troballa patològica característica en la malaltia de Parkinson (MP). Recentment s’ha suggerit un lligam entre la patogènesi de la MP i l’expressió d’isoformes del mRNA de SNCA amb diferents longituds de les regions de 3’ no traduïdes (en anglès conegudes com a untranslated regions UTRs). El propòsit dels meus estudis de doctorat és descobrir les proteïnes que uneixen el RNA de SNCA i el regulen a nivell posttranscripcional. Gràcies a una combinació d’estratègies computacionals i experimentals he identificat elements que interaccionen físicament amb SNCA i potencialment en regulen el metabolisme actuant en trans. M’he centrat en la caracterització de dues proteïnes que uneixen RNA, ELAVL1 i TIAR, i mostro la seva implicació en la regulació de l’estabilitat del mRNA i l’eficiència en la seva traducció. Aquestes dues proteïnes podrien tenir un paper clau en el manteniment dels nivells de α-sinucleïna i la seva funció en condicions fisiològiques i patològiques.
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Mnatsakanyan, Tatevik. "Contesting security and the binding effect in the US and the UK discourse and policy of 'war on terror' : a theoretical and empirical exploration through a dialogical-relational framework." Thesis, University of Exeter, 2014. http://hdl.handle.net/10871/17103.
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Post-structuralist IR has often treated foreign policy/security discourses and their effects on policy through a “representational model”, i.e. how one dominant representation makes possible particular policy outcomes. However, in a longitudinal analysis, where the concern with “outcome” is already about continuity/change, this model is restricting and must be replaced by a model integrating multiple voices and contestations, and looking for non-linear mechanisms of long-term constraints. Thus, the purpose of this thesis is, first, to develop a theoretical-analytical framework suitable for an explicit interest in contestations and tracing constraints; and second, in an illustrative-explorative study, to apply such relational-dialogical framework to “war on terror” in the US and the UK (2001-2012). Bakhtinian Dialogism occupies an important status in the framework; therefore, a broader aim is to demonstrate how a “dialogical turn” inspired by the philosophy of Mikhail Bakhtin and his circle would enrich debate. Developments of the past decade – increased anti-war critique, change of governments in the US and the UK, and protracted withdrawal – provide new grounds for a longitudinal inquiry into “war on terror”. Moving beyond the question how “war on terror” was initially constructed and legitimised, scholarly attention must focus on a longitudinal inquiry into why “war on terror” endured. In this respect, the formidable deconstructions of official discourses by anti-war critique have received marginal attention in IR. The empirical part explores how critical discourses have contested the official narratives; how the latter have engaged with them as well as with moderate deliberative critique, and to what effect for continuity/change, to understand whether and how successive governments in the US and the UK have been discursively constrained (bound) in their attempts to change policy. Without claiming to be a comprehensive explanation, it locates and interprets patterns and logics within the discursive exchanges, delineating potential routes contributing to constraints and hence continuation. Thus, on the one hand, destabilising critique was shattering the foundations of the official “war on terror” narratives without fully re-inscribing the dislocated space with new imaginings, thus inviting official representatives to re-claim such space. On the other hand, deliberative voices were pushing for the realisation of the promises inherent in the official discourse, demanding “winning” the (albeit “mistaken”) war, thus inviting for continued engagement.
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Tarenzi, Thomas [Verfasser], Paolo [Akademischer Betreuer] Carloni, Jörg Ludwig [Akademischer Betreuer] Fitter, and Paolo [Akademischer Betreuer] Ruggerone. "Hybrid multiscale simulation scheme to accurately predict binding poses and potency in low-resolution membrane receptors of pharmaceutical relevance / Thomas Tarenzi ; Paolo Carloni, Jörg Ludwig Fitter, Paolo Ruggerone." Aachen : Universitätsbibliothek der RWTH Aachen, 2019. http://d-nb.info/119325602X/34.
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Gerbracht, Jennifer Victoria [Verfasser], Niels [Gutachter] Gehring, Kay [Gutachter] Hofmann, and Elmar [Gutachter] Wahle. "Analysis of post-transcriptional gene expression modulated by mRNA stability and RNA-binding proteins in human cells / Jennifer Victoria Gerbracht ; Gutachter: Niels Gehring, Kay Hofmann, Elmar Wahle." Köln : Universitäts- und Stadtbibliothek Köln, 2020. http://d-nb.info/1208830554/34.
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Gerbracht, Jennifer V. [Verfasser], Niels [Gutachter] Gehring, Kay [Gutachter] Hofmann, and Elmar [Gutachter] Wahle. "Analysis of post-transcriptional gene expression modulated by mRNA stability and RNA-binding proteins in human cells / Jennifer Victoria Gerbracht ; Gutachter: Niels Gehring, Kay Hofmann, Elmar Wahle." Köln : Universitäts- und Stadtbibliothek Köln, 2020. http://d-nb.info/1208830554/34.
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Willis, William L. "YB-1 Stress-Response Protein Conformation Implicated in Post-transcriptional Control of Myofibroblast Differentiation." The Ohio State University, 2013. http://rave.ohiolink.edu/etdc/view?acc_num=osu1376593223.
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Lema, Ingrid. "Contrôle post-transcriptionnel de l'expression rénale du récepteur minéralocorticoide par les variations de tonicité extracellulaire : conséquences physiopathologiques." Thesis, Université Paris-Saclay (ComUE), 2016. http://www.theses.fr/2016SACLS290.
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L’aldostérone et le Récepteur Minéralocorticoïde (MR) participent au contrôle de la balance hydrosodée et de la pression artérielle. Les altérations de l’expression du MR ou de la signalisation minéralocorticoïde sont associées à de nombreuses pathologies chez l’Homme. Dans ce travail, nous avons démontré, le rôle majeur de protéines de liaison à l’ARN, Tis11b et HuR, dans le contrôle post-transcriptionnel de l’expression du MR en réponse aux variations de tonicité extracellulaire dans un modèle de cellules principales rénales et chez la souris. L’hypertonicité (500 mOsmol/L) induit l’expression de la protéine Tis11b, qui lie la région 3’-non traduite du transcrit MR afin d’accélérer sa dégradation, diminuant ainsi l’expression rénale de la protéine MR et de la signalisation minéralocorticoïde. A l’opposé, l’hypotonicité (150 mOsmol/L) stimule la translocation nucléo-cytoplasmique de HuR, qui stabilise le transcrit MR, augmentant ainsi l’expression du MR et la sensibilité rénale à l’aldostérone. De plus, HuR est responsable de l’édition d’un nouveau variant d’épissage du MR, le variant MR Δ6, obtenu par l’exclusion de l’exon 6.Ce variant d’épissage exerce un effet dominant négatif sur la signalisation minéralocorticoïde. Enfin, l’identification de microARN modulés par l’hypertonicité suggère leur rôle potentiel dans le contrôle de la signalisation minéralocorticoïde rénale. La caractérisation de ces mécanismes inédits modulant l’action du MR améliore notre compréhension de la physiopathologie de la signalisation minéralocorticoïde, et pourrait aboutir, à terme, à de nouvelles stratégies thérapeutiques<br>Aldosterone and the Mineralocorticoid Receptor (MR) participate to the control of salt and water balance and the arterial pressure. Alteration of renal MR expression or mineralocorticoid signaling pathway contributes to the development of numerous human disorders. In this work, we have demonstrated the major role played by the RNA-Binding Proteins, Tis11b and HuR, in the control of MR expression in response to variations of extracellular tonicity in a model of principal tubular cells and in vivo. Hypertonicity (500 mOsmol/L) increases the expression ofTis11b, which binds the 3’-untranslated region of MR transcript and accelerates the degradation of MR transcript, leading to the reduction of the mineralocorticoid signaling. Conversely, hypotonicity (150 mOsmol/L) stimulates nuclear-cytoplasmic shuttling of HuR protein, which stabilizes MR transcript increasing its expression and renal sensitivity to aldosterone action. Furthermore, HuR participates to the editing of the novel MR Δ6 splice variant, which lacks exon 6, and exerts a dominant negative effect on mineralocorticoid signaling. Finally, we have provided evidence that hypertonicity modulates expression of microRNA, which may control mineralocorticoid signaling pathway. Characterization of these original mechanisms modulating MR action is pivotal for a better understanding of mineralocorticoid-related pathophysiology, and should ultimately lead to the development of new therapeutic strategies
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Surappa-Narayanappa, Ananth Prakash. "The evolution, modifications and interactions of proteins and RNAs." Thesis, University of Cambridge, 2017. https://www.repository.cam.ac.uk/handle/1810/269851.
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Proteins and RNAs are two of the most versatile macromolecules that carry out almost all functions within living organisms. In this thesis I have explored evolutionary and regulatory aspects of proteins and RNAs by studying their structures, modifications and interactions. In the first chapter of my thesis I investigate domain atrophy, a term I coined to describe large-scale deletions of core structural elements within protein domains. By looking into truncated domain boundaries across several domain families using Pfam, I was able to identify rare cases of domains that showed atrophy. Given that even point mutations can be deleterious, it is surprising that proteins can tolerate such large-scale deletions. Some of the structures of atrophied domains show novel protein-protein interaction interfaces that appear to compensate and stabilise their folds. Protein-protein interactions are largely influenced by the surface and charge complementarity, while RNA-RNA interactions are governed by base-pair complementarity; both interaction types are inherently different and these differences might be observed in their interaction networks. Based on this hypothesis I have explored the protein-protein, RNA-protein and the RNA-RNA interaction networks of yeast in the second chapter. By analysing the three networks I found no major differences in their network properties, which indicates an underlying uniformity in their interactomes despite their individual differences. In the third chapter I focus on RNA-protein interactions by investigating post-translational modifications (PTMs) in RNA-binding proteins (RBPs). By comparing occurrences of PTMs, I observe that RBPs significantly undergo more PTMs than non-RBPs. I also found that within RBPs, PTMs are more frequently targeted at regions that directly interact with RNA compared to regions that do not. Moreover disorderedness and amino acid composition were not observed to significantly influence the differential PTMs observed between RBPs and nonRBPs. The results point to a direct regulatory role of PTMs in RNA-protein interactions of RBPs. In the last chapter, I explore regulatory RNA-RNA interactions. Using differential expression data of mRNAs and lncRNAs from mouse models of hereditary hemochromatosis, I investigated competing regulatory interactions between mRNA, lncRNA and miRNA. A mutual interaction network was created from the predicted miRNA interaction sites on mRNAs and lncRNAs to identify regulatory RNAs in the disease. I also observed interesting relations between the sense-antisense mRNA-lncRNA pairs that indicate mutual regulation of expression levels through a yet unknown mechanism.
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Bardou, Florian. "Les AtNSRs, protéines régulatrices de l’épissage alternatif et du silencing post transcriptionnel." Thesis, Paris 11, 2013. http://www.theses.fr/2013PA112054/document.
Full textAbstract:
Chez les eucaryotes, plusieurs protéines liant l'ARN ou RBPs agissent sur l'ARNm à différents niveaux, de l'épissage à la traduction. Récemment, un grand nombre d’ARN non-codant des protéines (npcRNAs) ont été identifiés chez les eucaryotes et ont été montré comme interagissant avec une variété de ribonucléoprotéines (RNP) pour contrôler l'expression des gènes au niveau post-transcriptionnel. Nous avons identifié une Nuclear-Speckle RBP (ou NSR) qui interagit avec le npcRNA, ENOD40, un lncARN qui s'accumule au cours de la formation des racines latérales et des nodules chez les légumineuses. Durant cette thèse nous avons analysé le rôle des NSR d’Arabidopsis thaliana ainsi que leur lien avec les npcARN.Deux gènes AtNSRs homologues existent chez Arabidopsis nommés NSRa et NSRb, ces gènes codent des protéines localisées dans des speckles nucléaires avec certaines protéines apparentées à l’épissage. Fait intéressant, les fusions AtNSR-GFP sont relocalisées dans des granules cytoplasmiques dans certaines cellules des racines différenciées ainsi que lors d’une co-expression éctopique de ENOD40. Le gène AtNSRb est régulé par l'auxine alors AtNSRa est constitutif. Les simples mutants Atnsr ne montrent pas de phénotype, mais la croissance des racines des doubles mutants est partiellement insensible à l'auxine, ce qui suggère une fonction redondante de ces protéines dans les racines. La localisation observée pour ces protéines nous a mené à explorer un rôle des NSRs dans l’épissage, nous avons donc analysé le profil d'épissage de 288 gènes en réponse à l'auxine chez Arabidopsis et comparé ces profils entre le WT et les mutants nsra/nsrb. Tout d’abord nous avons remarqué que l’épissage général ne variait pas, en revanche, l’analyse de 288 gènes alternativement épissés montre que le profil d'épissage de 77 gènes semble être modifié durant la réponse à l'auxine et 51 gènes nécessitent les protéines AtNSR pour ce changement. Afin de vérifier l’interaction des NSRs avec les cibles d’AS et avec les npcARN nous avons co-immunoprécipité les NSRs et nous avons identifié au moins 5 cible d’AS et 2 npcARN. L’expression de l’ARN ENOD40 ainsi que du partenaire npcARN module L’AS chez Arabidopsis. Dans un deuxième chapitre, nous avons exploré le rôle des NSRs dans le PTGS déclenché par un transgène contenant un intron ce qui nous a permis de lier l’épissage alternatif et le silencing. Nous proposons donc que les NSRs pourraient lier l’épissage alternatif et l’action des ARN non codants, notamment lors de la croissance de la racine<br>In eukaryotes, several RNA binding proteins (RBPs) act on mRNA at various levels from splicing to translation. Recently a large number of non-protein coding RNAs (npcRNAs) have been identified in eukaryotes and shown to integrate into a variety of ribonucleoproteins (RNP) to control posttranscriptional gene expression. Our laboratory has identified a plant Nuclear-Speckle RBP (or NSR) that interacts with an npcRNA, ENOD40 that accumulates during lateral root and nodule formation in legumes. NSR is relocalised into a cytoplasmic RNP in the ENOD40-expressing cells. During this PhD, we have analysed the role of NSRs in Arabidopsis thaliana and its link with npcRNAs. Two AtNSR homologs from Arabidopsis thaliana, named AtNSRa and AtNSRb, code for proteins also localised in nuclear speckles together with certain splicing-related proteins. Interestingly, AtNSR-GFP fusions are relocalised into cytoplasmic granules in certain differentiated root cells and by ectopic expression of the ENOD40 RNA. The AtNSRb gene is regulated by auxin whereas AtNSRa is constitutive. Root growth and lateral root formation of double nsra/nsrb mutants is partially insensitive to auxin. The localisation of these proteins prompted us to explore roles in splicing. No defects in general splicing were observed however analysis of 288 alternatively spliced genes in WT and nsra/nsrb roots in response to auxin revealed 77 changes in splicing profiles in response to auxin from which 51 required AtNSRs. In order to validate the interaction of NSRs with alternatively spliced mRNAs and npcRNAs, we have co-immunoprecipitated NSRs and identified at least 5 interacting alternatively spliced mRNAs and 2 npcRNAs. Expression of the ENOD40 RNA or one interacting ncRNA modulate alternatively splicing in Arabidopsis. In a second chapter, we explored the role of NSRs in the modulation of PTGS triggered by intron-containing transgenes allowing us to link alternatively splicing and silencing. We propose that NSRs may link alternative splicing and the action of non-coding RNA, notably during root growth and development