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1
Basu, Shrivastava Meenakshi. "Régulation de la stabilité de NFATc3 par SUMO et les E3 ubiquitine-ligases Trim39 et Trim17." Thesis, Montpellier, 2020. http://www.theses.fr/2020MONTT043.
Texte intégralRésumé :
Les facteurs de transcription NFAT (facteur nucléaire des cellules T activées) jouent un rôle physiologique important dans le développement et le fonctionnement de nombreux organes, notamment dans le système immunitaire et le système nerveux. Par conséquent, leur dérégulation a été impliquée dans diverses maladies humaines telles que le cancer, les maladies neurodégénératives et les maladies auto-immunes. La régulation de l'activité de NFAT par translocation nucléo-cytoplasmique a été largement étudiée. En revanche, la régulation du niveau protéique de NFAT par le système ubiquitine-protéasome est encore mal comprise. Pourtant, les protéines NFAT ont une durée de vie courte et la régulation de leur stabilité est donc essentielle pour le contrôle de leur activité.Dans une étude précédente, mon groupe a montré que l'E3 ubiquitine-ligase Trim17 se lie à NFATc3 mais ne favorise pas son ubiquitination et tend plutôt à stabiliser la protéine. Les résultats préliminaires obtenus suggéraient que Trim39, un partenaire de Trim17, pourrait être une E3 ubiquitine-ligase pour NFATc3 et que la SUMOylation de NFATc3 modulait sa stabilité. L'objectif de ma thèse était donc de comprendre les mécanismes par lesquels Trim39, Trim17 et SUMO régulent la stabilité de NFATc3.Au cours de ma thèse, j'ai caractérisé Trim39 comme une E3 ubiquitine-ligase de NFATc3. En effet, mes résultats indiquent que la surexpression de Trim39, mais pas de son mutant inactif, induit l'ubiquitination de NFATc3 dans les cellules. En revanche, la déplétion de Trim39 endogène diminue le niveau d'ubiquitination de NFATc3. La protéine Trim39 recombinante induit directement l'ubiquitination de NFATc3 in vitro. De plus, la surexpression de Trim39 diminue les niveaux protéiques de NFATc3 alors que la déplétion de Trim39 les augmente. J'ai également montré que Trim17 inhibe l'ubiquitination de NFATc3 induite par Trim39, à la fois dans les cellules et in vitro. Trim17 agit à la fois en réduisant l'activité E3 ubiquitine-ligase intrinsèque de Trim39 et en empêchant l'interaction entre NFATc3 et Trim39. En outre, j'ai montré qu'un mutant de NFATc3 ne pouvant être SUMOylé est moins ubiquitiné et plus stable que la forme sauvage de NFATc3, ce qui suggère que la SUMOylation de NFATc3 est importante pour son ubiquitination et sa dégradation. En outre, j'ai identifié un motif d'interaction à SUMO (SIM) dans la séquence de Trim39, par lequel Trim39 lie les polymères de SUMO2. La mutation de ce SIM dans Trim39 ou des sites consensus de SUMOylation dans NFATc3 diminue l'interaction entre Trim39 et NFATc3, et l'ubiquitination de NFATc3 induite par Trim39. Ces résultats suggèrent fortement que Trim39 reconnaît et ubiquitine préférentiellement les formes SUMOylées de NFATc3 et agit donc comme une « E3 ubiquitine-ligase guidée par SUMO » (STUbL) pour NFATc3. Enfin, nous avons mesuré l'impact de ces mécanismes sur la fonction physiologique de NFATc3. J'ai tout d'abord montré que Trim39 diminue l'activité transcriptionnelle de NFATc3. En outre, à l'aide de cultures primaires de neurones granulaires du cervelet, nous avons montré que la mutation des sites de SUMOylation de NFATc3 et la déplétion de Trim39 endogène aggravent l'apoptose neuronale, probablement en stabilisant la protéine NFATc3. En conclusion, l’ensemble de mes données indiquent que Trim39 module l'apoptose neuronale en agissant comme une STUbL pour NFATc3 et en contrôlant sa stabilité<br>NFAT (Nuclear factor of activated T cells) transcription factors play important physiological roles in the development and function of many organs, notably in the immune system and nervous system. As a consequence, their dysregulation has been implicated in various human diseases such as cancer, neurodegenerative diseases, and auto-immune diseases. The regulation of NFAT activity by calcium-dependent nuclear-cytoplasmic shuttling has been extensively studied. In contrast, the regulation of NFAT protein level by the ubiquitin-proteasome system is still poorly understood. However, NFATs are short-lived proteins and regulation of their stability is critical for controlling their activity.In a previous study, my group has shown that the E3 ubiquitin-ligase Trim17 binds NFATc3 but does not promote its ubiquitination and rather stabilizes it. Preliminary results suggested that Trim39, a partner of Trim17, might be an E3 ubiquitin-ligase for NFATc3 and that SUMOylation of NFATc3 might modulate its stability. Therefore, the goal of my PhD was to understand the mechanisms through which Trim39, Trim17, and SUMO regulate the stability of NFATc3.During my PhD, I have characterized Trim39 as an E3 ubiquitin-ligase of NFATc3. Indeed, my results indicate that overexpression of Trim39, but not its inactive mutant, induces the ubiquitination of NFATc3 in cells. In contrast, silencing of endogenous Trim39 decreases the ubiquitination level of NFATc3. Recombinant Trim39 directly induces the ubiquitination of NFATc3 in vitro. Moreover, overexpression of Trim39 decreases the protein levels of NFATc3 whereas the silencing of Trim39 increases it. I have also shown that Trim17, which can bind Trim39, inhibits Trim39-mediated ubiquitination of NFATc3, both in cells and in vitro. Trim17 acts by both reducing the intrinsic E3 ubiquitin-ligase activity of Trim39 and by preventing the interaction between NFATc3 and Trim39. Furthermore, I found that a SUMOylation-deficient mutant of NFATc3 is less ubiquitinated and more stable than the wild type NFATc3, suggesting that SUMOylation of NFATc3 is important for its ubiquitination and degradation. Importantly, I identified one SUMO interacting motif (SIM) in the sequence of Trim39 through which Trim39 binds SUMO2 polymers via one of these SIMs. Mutation of this SIM in Trim39 or SUMOylation consensus sites in NFATc3 decreased the interaction between Trim39 and NFATc3, and the ubiquitination of NFATc3 mediated by Trim39. These results strongly suggest that Trim39 binds and ubiquitinates preferentially the SUMOylated forms of NFATc3 and therefore acts as a SUMO-targeted E3 ubiquitin-ligase (STUbL) for NFATc3. Finally, we have measured the impact of these mechanisms on the physiological function of NFATc3. I first found that Trim39 decreases the transcriptional activity of NFATc3. Furthermore, using primary cultures of cerebellar granule neurons as a model, we have shown that the mutation of the SUMOylation sites of NFATc3 and silencing of endogenous Trim39 enhances neuronal apoptosis, probably by stabilizing the NFATc3 protein. Taken together, these data indicate that Trim39 modulates neuronal apoptosis by acting as a STUbL for NFATc3 and by controlling its stability
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Buberl, Cilli Dana [Verfasser]. "Expressionsanalyse der putativen E3 Ligasen Trim23 und Trim7 in der frühen Neuralentwicklung von Xenopus laevis / Cilli Dana Buberl." Halle, 2017. http://d-nb.info/1137867698/34.
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Borle, Pawar Ankush [Verfasser], Norbert [Akademischer Betreuer] Frey, and Dennis [Gutachter] Schade. "Functional characterization of TRIM24 and TRIM32 proteins in the heart through their interaction with Dysbindin / Ankush Borle Pawar ; Gutachter: Dennis Schade ; Betreuer: Norbert Frey." Kiel : Universitätsbibliothek Kiel, 2019. http://d-nb.info/1220691259/34.
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Locke, Matthew. "TRIM32 in Genetic Disease." Thesis, University of Oxford, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.514962.
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VENUTO, SANTINA. "Dissecting the TRIM8 role in the pathogenesis of glioma." Doctoral thesis, Università degli Studi di Foggia, 2019. http://hdl.handle.net/11369/382357.
Texte intégralRésumé :
I gliomi umani sono un gruppo eterogeneo di tumori cerebrali maligni primari, la cui patogenesi molecolare risulta ancora parzialmente sconosciuta. Pertanto, la comprensione dei meccanismi molecolari alla base della loro insorgenza e del loro decorso può portare a una migliore scelta di terapie appropriate e a migliori risultati prognostici, attraverso l'identificazione di nuovi geni specifici associati al glioma. Le proteine appartenenti alla famiglia “tripartite motif” (TRIM) sono coinvolte in diversi processi biologici, tra cui la regolazione trascrizionale, il controllo della progressione del ciclo cellulare, la proliferazione e il differenziamento cellulare. Alterazioni dell’espressione delle proteine TRIM sono associate a una varietà di patologie quali disturbi dello sviluppo, malattie infiammatorie e tumori. Tra le circa 80 proteine identificate appartenenti alla famiglia delle TRIM, TRIM8 è una E3 ubiquitina-ligasi coinvolta in vari processi patologici, quali ipertrofia, risposta antivirale, encefalopatia e sviluppo di diverse forme di cancro. Abbiamo recentemente identificato TRIM8 come un gene differenzialmente espresso nei gliomi, la cui espressione è correlata a un esito clinico sfavorevole nei pazienti con glioma. Per ottenere informazioni approfondite sulle funzioni di TRIM8, ne abbiamo studiato il “trascrittoma” e l' “interattoma” in cellule staminali neurali embrionali di topo, usando l’RNA-Sequencing e la spettrometria di massa, e successivamente analizzando i dati ottenuti mediante programmi bioinformatici. Sono state quindi eseguite analisi funzionali, biochimiche e cellulari, per esplorare il ruolo TRIM8 in differenti processi biologici. Il nostro studio ci ha permesso di identificare vie di segnale correlate alla neurotrasmissione e al sistema nervoso centrale (SNC), fornendo ulteriori prove dell'esistenza di una relazione funzionale tra TRIM8 e STAT3, con possibili implicazioni nello sviluppo e nella progressione del glioma. Abbiamo successivamente dimostrato che TRIM8 interagisce con KIFC1 e KIF11/Eg5, due importanti regolatori dell'assemblaggio del fuso mitotico e della riorganizzazione del citoscheletro. Approfondendo lo studio sul ruolo di TRIM8 nel processo mitotico, abbiamo verificato che TRIM8 localizza a livello del fuso mitotico durante la progressione della mitosi e svolge un ruolo chiave nella separazione dei centrosomi all’inizio della divisione mitotica, con un conseguente ritardo nella progressione della mitosi e un impatto sulla stabilità cromosomica. I nostri risultati confermano il ruolo di TRIM8 nelle funzioni cerebrali attraverso la deregolazione di geni appartenenti al pathway JAK-STAT e coinvolti in diverse funzioni del SNC. Inoltre, abbiamo identificato la funzione fisiologica di TRIM8 nello sviluppo del fuso mitotico, evidenziando un ruolo emergente di TRIM8 nella regolazione della mitosi.<br>Human gliomas are a heterogeneous group of primary malignant brain tumors, whose molecular pathogenesis is not yet solved. Therefore, understanding the molecular mechanisms underlying their aggressive behavior may lead to better management, appropriate therapies, and good outcomes through the identification of novel specific glioma-associated genes. Members of the tripartite motif (TRIM) proteins family are involved in many biological processes, including transcriptional regulation, cell proliferation and differentiation and cell cycle progression. Alterations of TRIM proteins are associated with a variety of pathologies like developmental disorders, inflammatory diseases and cancers. Among TRIMs protein family, TRIM8 encodes an E3 ubiquitin ligase involved in various pathological processes, including hypertrophy, antiviral defense, encephalopathy, and cancer development. We have identified TRIM8 as a gene aberrantly expressed in gliomas, whose expression correlates with unfavorable clinical outcome in glioma patients. To gain insights into the TRIM8 functions, we profiled the TRIM8 transcriptome and interactome in primary mouse embryonic neural stem cells using RNA-sequencing and proteomics, followed by bioinformatics analysis. Functional analysis, including biochemical and cellular assays were then performed to explore TRIM8 roles in different pathways. Our study firstly identified enriched pathways related to the neurotransmission and to the central nervous system (CNS) functions, providing additional evidence about the existence of a functional interactive crosstalk between TRIM8 and STAT3 with possible implications in the development and progression of glioma. Then, we found that TRIM8 interacts with KIFC1 and KIF11/Eg5, two master regulators of mitotic spindle assembly and cytoskeleton reorganization. Exploring the TRIM8 role in the mitotic spindle machinery, we showed that TRIM8 localizes at the mitotic spindle during mitosis and plays a role in centrosome separation at the beginning of mitosis with a subsequent delay of the mitotic progression and impact on chromosomal stability. Our results substantiate the role of TRIM8 in the brain functions through the deregulation of genes involved in different CNS-related pathways, including JAK-STAT. Moreover, we provided insights on the physiological function of TRIM8 in the mitotic spindle machinery, pointing to an emerging role for TRIM8 in the regulation of mitosis
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Crichton, Jennifer E. "The Role of the E3-ubiquitin Ligase Trim17 in the Mitochondrial Cell Death Pathway." Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/23715.
Texte intégralRésumé :
The upregulation of apoptosis is a hallmark of several neurodegenerative disorders including ischemic stroke. In neurons, as in other cell types, Bax and tBid are critical regulators of the intrinsic pathway upstream of mitochondrial outer membrane permeabilization (MOMP) and caspase activation. The characterization of the molecular events that occur during the early stages is therefore extremely important from a therapeutic standpoint. Here I show that two independent genetic pilot screens looking for novel regulators of Bax activation identified a common hit in the E3 ubiquitin ligase Trim17. Knockdown of Trim17 was found to protect against tBid-induced death in primary cortical neurons and allowed for the maintenance of mitochondrial function and oxidative phosphorylation under this apoptotic stress. The RING-domain of Trim17 was found to interact with Opa1 in mouse brain extracts. Furthermore, Opa1 co-immunoprecipitated with exogenously expressed full-length Trim17 from HEK293 cells. Knockdown of Trim17 in neurons increased Opa1 protein levels under steady-state conditions. These results suggest that Trim17 regulates Bax-dependent apoptosis in neurons via the modulation of Opa1 levels.
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Simpson, Shmona. "Genetic, structural, and functional exploration of the restrictive capacity of TRIM proteins against immunodeficiency viruses." Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:1af588ba-603a-4f39-9443-bb1a95d983f5.
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HIV-2 differs from HIV-1 in that many infected people experience normal survival, whilst only 20% progress rapidly to AIDS. Understanding mechanisms of delayed HIV-2 disease progression could provide new insights into HIV control. The Caio Community Cohort was established in Guinea-Bissau in the setting of high HIV-2 prevalence. This thesis investigates the role of polymorphic host restriction factors of the TRIM family in HIV-2 outcome. TRIM proteins are a family of E3 ubiquitin-ligases, where closely-related TRIM5α and TRIM22 are thought to inhibit HIV-1 transcription, uncoating and budding. There was an association between TRIM5α amino acid substitution R136Q and reduced HIV-2 viral load/prolonged survival. Conversely, P479L was enriched among HIV-2 infected participants and progressors with CD4+ T cell decline. TRIM22 was highly polymorphic in this cohort, revealing three novel coding variants. Although most substitutions were located in the putative virus-interacting PRYSPRY domain, two in the coiled-coil, D155N and R242T, showed significant and divergent associations with survival. R242T was enriched in HIV-2 infected participants, who progressed to death at twice the rate of wild-type controls. In silico studies predicted D282, D360, and R321 of TRIM22 to be highly conserved, exposed residues, for which polymorphisms would be deleterious. When aligned with sequences from the potent HIV-1 restriction factor, rhesus macaque TRIM5α, TRIM22 substitutions R321K, T415I, and D360Y were spatially relevant to residues involved in HIV-1 restriction. The role of TRIM22 in HIV restriction was supported by in vitro pilot studies showing that TRIM22 was upregulated by HIV-1 infection in a lymphoid cell line and co-localised with the HIV-1 capsid protein p24. Overexpression of TRIM22 resulted in the restriction of VSV-G pseudotyped HIV-1 and SIVmac. The R242T substitution diminished TRIM22's restriction of HIV-1 and SIVmac: protein analysis suggested that this may be due to the inability of the R242T mutant to fully dimerise.
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Guimarães, Dimitrius Santiago Passos Simões Fróes. "Caracterização bioquímica e celular da proteína TRIM49." Universidade de São Paulo, 2017. http://www.teses.usp.br/teses/disponiveis/17/17131/tde-10042018-112409/.
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A autofagia é o processo de degradação de estruturas celulares através do seu direcionamento ao lisossomo. As proteínas TRIMs reconhecem as -cargas? autofágicas e reúnem o complexo de nucleação do fagóforo, contudo se desconhece a função de cada domínio e a importância da atividade de E3 ligase para a sua atividade. A proteína TRIM49 clonada e expressa em E. coli ou em células humanas HEK293T não apresentou atividade de E3 ubiquitina ligase in vitro e reduziu os níveis totais de ubiquitinação in vivo, indicando que não é um E3 ubiquitina ligase. Células desafiadas com Htt74Q apresentaram menores níveis de citotoxicidade quando co-transfectadas com TRIM49 selvagem, mas não com os mutantes do domínio RING ou SPRY, indicando os dois domínios são necessários para sua atividade celular. A proteína selvagem se colocaliza com o marcador autofágico LC3, após o bloqueio da autofagia com bafilomicina A1. Os resultados indicam que a TRIM49 pode atuar na degradação intracelular de proteínas, por um mecanismo não dependente de atividade de E3 ligase.<br>Autophagy is the process of degradation of intracellular proteins through their directioning to the lysosome. TRIM proteins can directely recognize autophagic cargo and also act as a hub for the phagophore nucleation complex, however the function of each domain and the role of the E3 ligase activity in this process is unknown. The TRIM49 protein cloned and expressed in E. coli or in human cells HEK23T showed no ubiquitin E3 ligase activity in vitro and cells transfected with the wild type protein showed lower levels of polyubiquitinated proteins, indicating that TRIM49 is not a bona fide E3 ubiquitin ligase. Cells challenged with Htt74Q presented lower cytotoxicity levels when cotransfected with wild type TRIM49, when compared with the RING domain mutant or with the truncated protein lacking the SPRY domain, indicating that both domains are required for its cellular activity. The wild type protein colocalizes with the autophagic marker LC3 after treatment with the autophagy inhibitor bafilomycin A1. Taken together, these results indicate that the TRIM49 protein plays a role in protein degradation independently of a E3 ligase activity.
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Bartsch, Frederike [Verfasser], and Elke [Akademischer Betreuer] Cario. "Funktion und Regulation von TRIM58 in der myeloischen Immunabwehr / Frederike Bartsch ; Betreuer: Elke Cario." Duisburg, 2019. http://d-nb.info/1196008418/34.
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McGuire, Cy Christopher. "Evaluation of PGR properties of TRIMAX in cotton." Texas A&M University, 2005. http://hdl.handle.net/1969.1/2605.
Texte intégralRésumé :
Pesticides comprise a large portion of production inputs in cotton. Reducing or
enhancing their efficacy presents an avenue to increase profit. Pesticides containing
both insecticidal and growth enhancing properties may be a viable option to increased
profitability. In cotton (Gossypium hirsutum L.), early season applications of some
insecticides have shown effects similar to those of plant growth regulators (PGRs).
TRIMAX?? (imidacloprid) is one of these purported PGR insecticides. TRIMAX?? and
Centric?? 40WG (thiamethoxam), both nitroguanidine insecticides, have properties that
may exhibit PGR activity.
A two - year field study was conducted at the Texas A&M Agricultural
Experiment Station in Burleson County, Texas to assess the physiological effects of
Centric?? 40WG and TRIMAX?? on cotton. The statistical design consisted of a
randomized complete block with four replications. Treatments consisted of each
insecticide being applied one, two, and three times at the 5- leaf stage, 5- leaf stage plus
10 days after initial treatment (DAIT), and 5-leaf stage plus 10 DAIT plus 20 DAIT.
Rates consisted of TRIMAX?? and Centric?? 40WG being applied at 0.020 and 0.017
L/ha, respectively. Data was collected for plant height, total number of nodes, biomass
partitioning, photosynthetic rate, midseason plant mapping, end of season box- mapping,
yield, and fiber quality analysis.
No significant differences in lint yield were observed among any of the
insecticide PGR treatments. There was a general trend for numeric decreases in lint
yield with each additional insecticide application for both chemistries, with the
exception of TRIMAX?? at three applications in 2004. No significant differences were
detected in any of the growth parameters that were measured (height, total nodes,
biomass partitioning, and leaf area). Numerical differences resulted in trends, but rate
responses did not follow any logical pattern. Numerous trends and rate responses were
also observed in the Absolute and Relative Growth Rates, and photosynthetic rates, but
no significant differences were evident. In general, as more insecticide was applied, the
photosynthetic rates decreased along with lint yield.
Based on the parameters investigated during the course of this two-year study,
there is no conclusive evidence that supports TRIMAX?? or Centric?? 40WG as being
growth and or yield enhancers in cotton.
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Roberts, Simon Benedict. "Investigating new genetic susceptibility loci in osteoarthritis." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/28982.
Texte intégralRésumé :
Primary osteoarthritis (OA) is a late-onset, degenerative condition of synovial joints, and is the major cause of pain and disability in older persons. OA represents a significant disease burden and focus of research, especially as no disease-modifying therapies exist to manage the condition. The genetic influence to OA is complex and polygenic. The arcOGEN study, the most powerful genome-wide association study yet to investigate OA in humans, identified the 9q33.1 locus to be significantly associated with hip OA in females. TRIM32 lies within the 9q33.1 susceptibility locus and may have strong biological relevance to OA; it encodes a protein with E3 ubiquitin ligase activity. Sanger sequencing of TRIM32 in the youngest 500 female patients with hip OA from the arcOGEN study was performed to identify rare variants in TRIM32 that are associated with OA of the hip in females. Polymorphisms were identified in the proximal promoter, and 3’untranslated regions (3’UTR) of TRIM32 that are disproportionately represented in female patients with hip OA, compared to the control population. In vitro studies identified expression of TRIM32 in human femoral head cartilage; reduced expression of TRIM32 was also demonstrated in femoral head primary articular chondrocytes from patients with hip OA compared to control patients. Trim32 knockout resulted in increased aggrecanolysis in murine femoral head explants. Murine chondrocytes deficient in Trim32 also exhibited increased expression of markers of a mature chondrocyte phenotype in response to anabolic cytokine stimulation, and increased expression of markers of a hypertrophic chondrocyte phenotype upon catabolic cytokine stimulation. In vivo studies of joint degeneration in Trim32 knockout mice demonstrated increased cartilage degradation and tibial epiphyseal bone changes after surgically induced knee joint instability, compared to wild-type mice. Increased cartilage degradation and medial knee subchondral bone changes were also identified upon ageing of Trim32 knockout mice. These results further implicate TRIM32 in the genetic predisposition to OA, and indicate a role for TRIM32 in the joint degeneration evident in OA. These results support the further study of TRIM32 in the pathophysiology of OA and development of novel therapeutic strategies to manage OA.
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Reusse, Ekaterina [Verfasser], Dimosthenis [Akademischer Betreuer] Trimis, Dimosthenis [Gutachter] Trimis, and Heiko [Gutachter] Hessenkemper. "Innovative industrielle Erdgasbeheizungssysteme auf der Basis der Porenbrennertechnologie für Hochtemperaturanwendungen / Ekaterina Reusse ; Gutachter: Dimosthenis Trimis, Heiko Hessenkemper ; Betreuer: Dimosthenis Trimis." Freiberg : Technische Universitaet Bergakademie Freiberg Universitaetsbibliothek "Georgius Agricola", 2013. http://d-nb.info/1220911461/34.
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Frenzel, Isabel [Verfasser], Dimosthenis [Akademischer Betreuer] Trimis, Dimosthenis [Gutachter] Trimis, and Sven [Gutachter] Kureti. "Flammenstruktur und Rußbildung in Verbrennungsprozessen mit ethanol- und butanolhaltigen Kraftstoffen / Isabel Frenzel ; Gutachter: Dimosthenis Trimis, Sven Kureti ; Betreuer: Dimosthenis Trimis." Freiberg : Technische Universität Bergakademie Freiberg, 2018. http://d-nb.info/1226101038/34.
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Schaller, T. "Characterisation of TRIM5α and related retroviral restriction factors". Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/18779/.
Texte intégralRésumé :
Retroviruses possess an RNA genome that is reverse transcribed into DNA and becomes integrated into the host genome during infection. Human immunodeficiency virus 1 (HIV-1) belongs to the genus lentivirus of the retroviridae family and is a major human pathogen with more than 50 million infected people worldwide to date. Lentiviruses have very narrow host ranges. Cross-species lentiviral transmissions are rare, due to the ability of mammals to counteract viral infections by the innate immune system, which includes intracellular factors that block virus replication. Of these, the murine protein Fv1 and the tripartite (RBCC) motif protein family member TRIM5α potently inhibit retroviral infections early after virus cell entry. This study presents evidence that antiviral activity exerted by TRIM5α is conserved across mammals. Rabbit cells are strongly non-permissive to infections by certain retroviruses including HIV-1. The study identifies a TRIM5α orthologue in rabbits, which possesses antiretroviral activity. Phylogenetic analysis demonstrates that rabbit TRIM5 is a true orthologue and clusters with other mammalian TRIM5 genes. Remarkably, TRIM5 fusion proteins with the prolyl-peptidyl isomerase cyclophilin A (CypA) have independently evolved twice by retrotransposition of a CypA cDNA into the TRIM5 genomic locus, generating a viral restriction factor with a CypA binding domain. This study shows that CypA fusion proteins with RBCC domains of other TRIM proteins also function as restriction factors against HIV-1. Furthermore, fusion of CypA to Fv1 enables the restriction of HIV-1 and FIV. Insights into the mechanism of TRIM5α restriction are also provided in this study. Functional analyses of TRIM5α and TRIMCyp deletion mutants, as well as fusion proteins of Fv1Cyp with the TRIM5α RING and B-box domains, indicate that the RING and B-box domains mediate the proteasome dependent block to reverse transcription during TRIM5α/TRIMCyp restriction. The results suggest that the major antiviral activity exerted by TRIM5α is a RING dependent block to reverse transcription, whereas the major activity of TRIMCyp is independent of RING function.
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Reddi, Tejaswini Satya. "TRIM22 IS A NOVEL RESTRICTION FACTOR OF HERPESVIRUSES." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17464655.
Texte intégralRésumé :
The host response to the family of nuclear replicating DNA viruses or the herpesviruses includes the intrinsic, innate and adaptive arms of the immune system. Intrinsic resistance is a constitutively active line of defense against virus infections and members of the Tripartite Motif (TRIM) superfamily of proteins; such as TRIM5 and TRIM19/PML in nuclear domain 10 (ND10) bodies are important restriction factors in this system. Nuclear intrinsic restriction against the prototypical DNA virus, herpes simplex virus 1 (HSV-1) includes interferon-inducible protein 16 (IFI16) and ND10 bodies. However, the viral E3 ubiquitin ligase, ICP0, encoded by wild-type HSV-1, targets these intrinsic immune proteins for degradation.
Previous reports on the anti-viral function of TRIM22, the human paralog of the prototypical TRIM5α protein, emphasized its role as a gene of the innate immune system, particularly its expression as a Type I and Type II interferon-stimulated gene and its antiviral function against retroviruses. This study shows that TRIM22 has an additional intrinsic immune role against DNA viruses, using the herpesviruses as an example of a family of DNA viruses.
We report that TRIM22 is a novel restriction factor of HSV-1 and limits HSV-1 ICP0-null virus replication. The TRIM22-mediated restriction of HSV-1 occurs after nuclear entry but prior to viral immediate-early gene transcription, by promoting histone occupancy and heterochromatinization to reduce immediate-early viral gene expression. The ICP0-rescued virus evades the TRIM22-specific restriction by a mechanism independent of TRIM22 degradation. We also demonstrate that TRIM22 inhibits other DNA viruses, including representative members of the β- and γ- herpesviruses. These results collectively show that TRIM22 acts in the nucleus, and provide evidence that TRIM22 restricts HSV gene expression by promoting histone occupancy on the viral genes.
Furthermore, we identified seven haplotypic variants of TRIM22 and propose that amino acid substitutions in the linker L2 domain and the coiled-coil domain of TRIM22 alter the magnitude of its restriction against the herpesviruses. Together, these results argue for the importance of the TRIM22 gene as a restriction factor against herpesviruses and offer a novel avenue for further investigation on the role of TRIM genes in host genetic variation in herpesviral susceptibility.<br>Medical Sciences
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Jerabkova, Katerina. "Les rôles de Trim15 et UCHL3 dans la régulation, médiée par l’ubiquitine, du cycle cellulaire." Thesis, Strasbourg, 2019. http://www.theses.fr/2019STRAJ034.
Texte intégralRésumé :
La mitose est précisément contrôlée par la signalisation via l'ubiquitine et est essentielle au maintien de l'intégrité du génome. Dans ce travail, j'ai étudié la fonction de l'enzyme de dé-ubiquitination, UCHL3 et de la ligase E3-ubiquitine, TRIM15. J'ai observé que TRIM15 régule l'adhésion et la mobilité des cellules. UCHL3 a été identifié par un criblage à haut contenu, en tant que facteur critique contrôlant l'alignement et la ségrégation des chromosomes. Fait intéressant, il a déjà été rapporté que les niveaux d’expression d’UCHL3 sont altérés dans divers types de cancer. En utilisant une approche protéomique, nous avons identifié la kinase Aurora B comme un médiateur potentiel de ces phénotypes. Comme l'aneuploïdie est la marque de nombreux cancers et que l'adhésion cellulaire joue un rôle important dans l'invasion des tumeurs et les métastases, mes résultats suggèrent que ces deux protéines pourraient jouer un rôle dans la carcinogenèse<br>Mitosis is tightly controlled by ubiquitin signaling and is crucial to maintain genome integrity. In this work, I investigated the function of the deubiquitinating enzyme UCHL3 and the E3 ubiquitin ligase TRIM15. I observed that TRIM15 regulates cell adhesion and motility. UCHL3 was identified in a high-content screen, as a critical factor controlling the chromosome alignment and segregation. Interestingly, it has been previously reported that UCHL3 levels are altered in various cancer types. Using a proteomic approach, we identified Aurora B kinase as a potential mediator of these phenotypes. Since aneuploidy is a hallmark of many cancers, and cell adhesion plays an important role in tumor invasion and metastasis, my results suggest that both proteins could play a role in carcinogenesis
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Anger, Stephan [Verfasser], Dimosthenis [Akademischer Betreuer] Trimis, Dimosthenis [Gutachter] Trimis, and Angelika [Gutachter] Heinzel. "Untersuchungen zur Prozessgasaufbereitung von Flüssiggas für die Dampfreformierung in Brennstoffzellen-BHKW / Stephan Anger ; Gutachter: Dimosthenis Trimis, Angelika Heinzel ; Betreuer: Dimosthenis Trimis." Freiberg : Technische Universitaet Bergakademie Freiberg Universitaetsbibliothek "Georgius Agricola", 2016. http://d-nb.info/122091231X/34.
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Rau, Florian [Verfasser], Dimosthenis [Akademischer Betreuer] Trimis, Dimosthenis [Gutachter] Trimis, and Andreas Siegfried [Gutachter] Bräuer. "Einsatz biogener Kraftstoffe zur Senkung der Emissionen von stationären Verbrennungsmotoren / Florian Rau ; Gutachter: Dimosthenis Trimis, Andreas Siegfried Bräuer ; Betreuer: Dimosthenis Trimis." Freiberg : Technische Universität Bergakademie Freiberg, 2021. http://d-nb.info/1240475837/34.
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Kim, Kyusik. "HIV-1 Evasion of Human TRIM5α via Cyclophilin A". eScholarship@UMMS, 2020. https://escholarship.umassmed.edu/gsbs_diss/1089.
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The abundant cellular protein Cyclophilin A (CypA) was found to bind to HIV-1 capsid (CA) in 1993. Since that time, several complementary methods, including disruption of the binding interface by cyclosporine A, CA mutants, and CypA mutants, have been used to demonstrate that CypA acts within human target cells to promote HIV-1 infection. In contrast, in cells from non-human primates, CypA in target cells decreases HIV-1 infectivity, and it does so by promoting TRIM5α-mediated restriction. Using human cancer cell lines and the genetic methods available at the time, attempts to obtain evidence that CypA inhibits HIV-1 restriction by the human TRIM5α ortholog, let alone that human TRIM5α restricts HIV-1, were unsuccessful.
Here we revisit the question of the mechanism by which CypA increases HIV-1 infectivity by exploiting lentiviral vectors optimized for primary human blood cells that serve as HIV-1 targets. Disruption of CA−CypA interaction is demonstrated to render HIV-1 vulnerable to endogenous human TRIM5α-mediated recognition and restriction, which occur prior to completion of reverse transcription. Identical findings were acquired with single-cycle vectors or with replication-competent viruses. Consistently, a previously identified, cyclosporine-resistant CA mutation A92E is also shown to confer resistance against restriction by human TRIM5α. Therefore, the results presented in this thesis reveal that HIV-1 exploits a host protein CypA bound to its CA to evade potent restriction by human TRIM5α. This finding not only answers a long-standing question regarding the role of CypA in HIV-1 infection, but also may reinvigorate the development of CypA inhibitors for treatment of HIV-1.
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Bouchard, Amélie. "Évolution moléculaire in vitro du facteur de restriction TRIM5α". Thèse, Université du Québec à Trois-Rivières, 2009. http://depot-e.uqtr.ca/1462/1/030123866.pdf.
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Hao, Chengcheng. "Improved Sampling-based Alpha Matting in Images and Video." Thèse, Université d'Ottawa / University of Ottawa, 2012. http://hdl.handle.net/10393/23417.
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Foreground extraction technology plays an important role in image and video processing tasks. It has been widely used in various industries. To better describe the overlap relationship between foreground and background, alpha channel is introduced. It reveals the opacity property of foreground objects. Thus, fully extracting a foreground object requires determining the alpha values for pixels, also known as extracting an alpha matte. In this thesis, we propose an improved sampling-based alpha matting algorithm, which is capable of generating high quality matting results. By analyzing the weakness of previous approaches, we optimize the sampling process and consider the cost of each sample pair to avoid missing any good samples. The good performance is demonstrated even for complex images. On the other hand, extracting foreground objects from video sequences is a more challenging task since it has higher demands on accuracy and efficiency. Previous approaches usually require a significant amount of user input and the results still suffer from inaccuracy. In this thesis, we successfully extend our algorithm to video sequences and let it run in an automatic fashion. Adaptive trimap, which is vital for matting, can be automatically generated and properly propagated in this system. Our method not only reduces the user interference but also guarantees the matting quality.
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Yeo, Richard Fraser. "The three dimensional simulation of VLF signal scattering." Thesis, University of Southampton, 1998. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286749.
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Walter, Christopher John. "Stereoselective acceleration of Diels-Alder reactions by synthetic enzymes." Thesis, University of Cambridge, 1994. https://www.repository.cam.ac.uk/handle/1810/272679.
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Schulz, Bastian [Verfasser], Dimosthenis [Akademischer Betreuer] Trimis, Dimosthenis [Gutachter] Trimis, and Jens-Uwe [Gutachter] Repke. "Entwicklung eines Reformierungssystems zur Bereitstellung von Synthesegas für den maritimen Betrieb einer MCFC-Brennstoffzelle / Bastian Schulz ; Gutachter: Dimosthenis Trimis, Jens-Uwe Repke ; Betreuer: Dimosthenis Trimis." Freiberg : Technische Universitaet Bergakademie Freiberg Universitaetsbibliothek "Georgius Agricola", 2013. http://d-nb.info/1220837377/34.
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Schank, Troy C. "Optimal aeroelastic trim for rotorcraft with constrained, non-unique trim solutions." Diss., Atlanta, Ga. : Georgia Institute of Technology, 2008. http://hdl.handle.net/1853/22654.
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Thesis (Ph. D.)--Aerospace Engineering, Georgia Institute of Technology, 2008.<br>Committee Chair: Dimitri N. Mavris; Committee Co-Chair: Daniel P Schrage; Committee Member: David A. Peters; Committee Member: Dewey H. Hodges; Committee Member: J.V.R. Prasad.
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Blaia, Junior Antonio Carlos Teixeira [UNESP]. "Geração automática de Trimap para Matting Digital de Imagens e Vídeo." Universidade Estadual Paulista (UNESP), 2013. http://hdl.handle.net/11449/89346.
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blaiajunior_act_me_sjrp.pdf: 2879763 bytes, checksum: eed492b07eec826c96bf8194c8560a7c (MD5)<br>Técnicas de composição de imagens, com extração de objetos em primeiro plano para serem combinados com um novo plano de fundo, são muito utilizadas em aplicações que vão desde simples montagens em fotos até produções cinematográficas. Estas técnicas são chamadas demattingdigital. Com elas é possível minimizar custos das produções, uma vez que o ator não precisa estar realmente no local onde a cena irá acontecer. Esta característica também viabiliza sua utilização em programas realizados para a televisão digital, que demandam uma alta qualidade da imagem. Diversas abordagens demattingdigital utilizam marcações feitas nas imagens (como informações extras), para determinar o que é o primeiro plano, o plano de fundo e as áreas de incerteza. O conjunto destas informações extras é chamado detrimap, definida por um mapa triplo representando a segmentação da imagem de entrada. Otrimap é feito, geralmente, a partir de marcações manuais realizadas pelo usuário. Levando em consideração este contexto, o presente trabalho objetivou o desenvolvimento de dois métodos para a geração detrimaps de maneira automática (sem interação do usuário), baseando-se, para isto, em informações de profundidade e/ou cores dospixels das imagens de entrada. Os métodos desenvolvidos foram implementados e comparados com suas versões manuais, tendo apresentado resultados quantitativamente semelhantes, para imagens. Os métodos revelaram, também, potencial para serem aplicados em vídeos<br>Techniques of composing images with extracting objects in the foreground to be combined with a new background, are widely used in applications ranging from simple assemblies on photos to filmmaking. these techniques are called digital matting. With them you can minimize costs of production, since the actor does not need to be really where the scene will happen. this feature also enables its use in programs made for television digital, which demand a high quality image. Several approaches utilize digital matting marks made on images (such as extra informa-tion), to determine what is the foreground, the background and areas of uncertainty. All these extra information is called a trimap, defined for a triple map representing the seg-mentation of the input image. The trimap is made, generally, from markings made by the user manuals. Considering this context, this study aimed to develop Two methods for generating trimaps either automatically (without interaction user), relying, for this, in depth information and / or colors of the pixels the input images. The developed methods were implemented and compared with their manual versions and tested quantitatively similar for images. The methods also revealed the potential to be applied in videos
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Port, Yasmine [Verfasser]. "The Role of TRIM71 in Male Germ Cell Development / Yasmine Port." Bonn : Universitäts- und Landesbibliothek Bonn, 2020. http://d-nb.info/1240761260/34.
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Blaia, Junior Antonio Carlos Teixeira. "Geração automática de Trimap para Matting Digital de Imagens e Vídeo /." São José do Rio Preto, 2013. http://hdl.handle.net/11449/89346.
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Orientador: Antonio Carlos Sementille<br>Banca: João Fernando Marar<br>Banca: Ildeberto Aparecido Rodello<br>Resumo: Técnicas de composição de imagens, com extração de objetos em primeiro plano para serem combinados com um novo plano de fundo, são muito utilizadas em aplicações que vão desde simples montagens em fotos até produções cinematográficas. Estas técnicas são chamadas demattingdigital. Com elas é possível minimizar custos das produções, uma vez que o ator não precisa estar realmente no local onde a cena irá acontecer. Esta característica também viabiliza sua utilização em programas realizados para a televisão digital, que demandam uma alta qualidade da imagem. Diversas abordagens demattingdigital utilizam marcações feitas nas imagens (como informações extras), para determinar o que é o primeiro plano, o plano de fundo e as áreas de incerteza. O conjunto destas informações extras é chamado detrimap, definida por um mapa triplo representando a segmentação da imagem de entrada. Otrimap é feito, geralmente, a partir de marcações manuais realizadas pelo usuário. Levando em consideração este contexto, o presente trabalho objetivou o desenvolvimento de dois métodos para a geração detrimaps de maneira automática (sem interação do usuário), baseando-se, para isto, em informações de profundidade e/ou cores dospixels das imagens de entrada. Os métodos desenvolvidos foram implementados e comparados com suas versões manuais, tendo apresentado resultados quantitativamente semelhantes, para imagens. Os métodos revelaram, também, potencial para serem aplicados em vídeos<br>Abstract: Techniques of composing images with extracting objects in the foreground to be combined with a new background, are widely used in applications ranging from simple assemblies on photos to filmmaking. these techniques are called digital matting. With them you can minimize costs of production, since the actor does not need to be really where the scene will happen. this feature also enables its use in programs made for television digital, which demand a high quality image. Several approaches utilize digital matting marks made on images (such as extra informa-tion), to determine what is the foreground, the background and areas of uncertainty. All these extra information is called a trimap, defined for a triple map representing the seg-mentation of the input image. The trimap is made, generally, from markings made by the user manuals. Considering this context, this study aimed to develop Two methods for generating trimaps either automatically (without interaction user), relying, for this, in depth information and / or colors of the pixels the input images. The developed methods were implemented and compared with their manual versions and tested quantitatively similar for images. The methods also revealed the potential to be applied in videos<br>Mestre
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Zhang, Xuzhe. "Eutherian-specific gene TRIML2 attenuates inflammation in the evolution of placentation." University of Cincinnati / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1573576401238203.
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Watkinson, Ruth Elizabeth. "Intracellular antibody receptor TRIM21 in viral neutralisation and innate immune signalling." Thesis, University of Cambridge, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708305.
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Conwell, Sara. "TRIM27 in HSV-1 Infection: A Story of Loss and Death." Thesis, Harvard University, 2015. http://nrs.harvard.edu/urn-3:HUL.InstRepos:17463971.
Texte intégralRésumé :
During viral infection, the host subjects the virus to an array of protective mechanisms. Viruses have evolved evasion strategies to thwart these defenses, and must simultaneously regulate multiple cellular pathways and resources to achieve successful replication. To orchestrate such complex regulation, viruses, including herpes simplex virus 1 (HSV-1), rely on multifunctional proteins such as the E3 ubiquitin ligase ICP0. This protein counteracts various host defenses by targeting cellular factors for degradation. We undertook a proteomic screen to identify binding partners of ICP0, and identified the Tripartite Motif 27 (TRIM27) protein, a cellular transcriptional repressor, as a novel interacting protein of ICP0. This interaction resulted in rapid loss of TRIM27 during HSV-1 infection. However, replication of an ICP0-null mutant virus required TRIM27, suggesting a complex interaction between TRIM27 and viral infection.
To further characterize regulation of TRIM27 by HSV-1, we evaluated whether infection affected TRIM27 levels independently of ICP0. Infection with an ICP0-null virus resulted in TRIM27 protein loss, but at a greatly reduced rate. TRIM27 protein exhibited a short half-life in uninfected cells, indicating that viral regulation of transcript levels could affect protein levels during infection. HSV-1 reduced TRIM27 transcripts through the virion host shutoff (VHS) function and a global inhibition of host transcription. The compound regulation of TRIM27 levels during infection demonstrated the redundant mechanisms by which HSV-1 regulates the cellular proteome.
Because degradation targets of ICP0 often function to restrict viral infection, we hypothesized that TRIM27 could contribute to an antiviral pathway. Based on the involvement of TRIM27 in programmed cell death resulting from Tumor Necrosis Factor (TNF) signaling, we evaluated the role of TRIM27 in cells treated with TNF. TRIM27 was required for TNF-dependent programmed necrosis, or necroptosis, in mouse cells. HSV-1 infection of these cells induced TNF-dependent necroptosis, reducing viral yield. This pathway required mouse TRIM27, and cells expressing human TRIM27 in place of mouse TRIM27 did not exhibit necroptosis. The differing capacities of mouse and human TRIM27 to support necroptosis during HSV-1 infection suggested that TRIM27 contributes to species-specific restriction of HSV-1 and to the selective pressure driving viral evasion of this protective host response.<br>Medical Sciences
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Veillette, Maxime. "TRIM5α : spécificité d'action, résistance virale et implications pour la thérapie génique". Thèse, Université du Québec à Trois-Rivières, 2013. http://depot-e.uqtr.ca/6956/1/030596123.pdf.
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Tag, Andrew George. "Characterization of the Tri10 gene from Fusarium sporotrichioides." [College Station, Tex. : Texas A&M University, 2003. http://hdl.handle.net/1969.1/64.
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Thesis (Ph.D.)--Texas A&M University, 2003.<br>"Major Subject: Plant Pathology" Title from author supplied metadata (record created on Jul. 18, 2005.) Vita. Abstract. Includes bibliographical references.
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Demasi, João Otavio Benevides. "Os investimentos internacionais e a reforma das TRIMs." Universidade de São Paulo, 2012. http://www.teses.usp.br/teses/disponiveis/2/2135/tde-03122012-160404/.
Texte intégralRésumé :
Devido ao colapso da economia americana, em 2009, os Fluxos de Capitais foram somente da Ordem Econômica de US$ 1.8 trilhões, 82% menos do que em 2007 (US$ 10.5 trilhões). Em 2009, o volume de comércio diário de ativos foi de US$ 1.5 trilhões, com US$ 178 trilhões como ativos financeiros. Os Investimentos Internacionais produtivos são uma das bases da internacionalização de empresas e do capital. Ao estabelecer uma planta industrial e/ou adquirir ações de empresas, este fluxo transfronteiriço de capital aporta bens, tecnologia, novas práticas administrativas, inter alios actos, e se distingue do investimento bursátil de carácter meramente especulativo e apátrida do hot money. Escrito em 3 (três) capítulos, este trabalho prescruta, no plano internacional, as regras jurídicas dos fluxos produtivos e as Medidas de Comércio Relacionadas aos Investimentos (TRIMs) da Organização Mundial de Comércio (OMC). Estas contêm cláusulas de Restrições as Práticas de Negócios que impedem os Estados-Membros da OMC a realizarem políticas públicas de desenvolvimento nacional. Não se olvidando do diálogo das fontes normativas internacionais, uma vez que a OMC não está em isolamento clínico do direito internacional, assim, verifica-se um claro embate entre a Soberania Permanente aos Recursos Naturais e o Direito ao Desenvolvimento. Entre mais de 140 (cento e quarenta) casos julgados pelo ICSID, excepcionalemente, e somente em 1 (um), o Estado-hospedeiro venceu, feito o exame dos 2 (dois) grandes sistemas jurídicos de investimentos. A tríade (EUA, UE, Japão) mais Coreia do Sul querem um modelo ainda mais liberal de regras de investimentos na OMC. Discorre este trabalho sobre os mais de 2.500 (dois mil e quinhentos) Bilateral Investments Treaties (BITs) e os Regional Trade Agreements (RTAs), como o do NAFTA, draft do MAI, e as Instituições de Bretton Woods ligadas ao IED, e a interação com a Doutrina, Jurisprudência e tendências. A UNCTAD critica veementemente este conjunto de regras liberais, sejam os BITs, sejam as TRIMs. O núcleo irradiador deste trabalho é a Declaração Conjunta indo-brasileira, que propõe a Reforma das TRIMs (G/TRIMS/W/25) para permitir, por meio de compras locais e requisitos de performance, o manejo de políticas públicas de desenvolvimento nacional hoje proibidas. Este trabalho conclui ser a Reforma das TRIMs uma impraticabilidade diplomática, de modo que o direito ao desenvolvimento dar-se-ia como improvável exceção.<br>Due to the US economic downturn, the Capital Flows in 2009 were only from the economic order of U.S.$ 1.8 trillion, 82% less than 2007 (US$ 10.5 trillion). In 2009 the daily trading volume of assets were U.S.$ 1.5 trillion with US$ 178 trillion as financial assets. The productive International Investments are one of the bases from the internationalization enterprises and of the capital. By establishing an industrial plant and/or acquire assets of companies, this cross-border flow of capital brings goods, technology, new management practices, inter alios acts. Distinguishing itself, by this way, from the stock market investment of purely speculative character and stateless, from the hot money. Written in 3 (three) chapters, this work search, in the international field, the legal rules from productive flows and the Trade Related Investment Measures (TRIMs) of the World Trade Organization (WTO). These clauses contains Restrictive Business Practices (RBP) that prevents States-Members from the WTO to carry out public policies of national development. Not forgetting the dialogue of sources from international rules, once the WTO is not in clinical isolation from the international law there is a clear clash between the Permanent Sovereignty on Natural Resources and the Right to Development. Between more than 140 (one hundred and forty) cases tried by ICSID, exceptionally and only one (one) the host-State won. Made the examination of the 2 (two) major legal systems of investments. The Triad (USA, EU and Japan) plus South Korea wants a model with more liberal investment rules in the WTO. Discusses this work on the more than 2500 (two thousand and five hundred) Bilateral Investments Treaties (BITs) and Regional Trade Agreements (RTAs) such as NAFTA, the MAI draft, and the Bretton Woods institutions related to FDI and the interaction with doctrine, jurisprudence and trends. UNCTAD strongly criticizes this liberal set of rules, not only the BITs, but also the TRIMs. The core matter from this work is the Indo-Brazilian Joint Statement on the Reform of the TRIMs (G/TRIMS/W/25), that proposes through local purchases and performance requirements the right of management of public policies for national development currently forbidden. This work concludes that the Reform of the TRIMs is a diplomatic impractibility, in a mode that the Right to development can be achieved as an improbable exception
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Gil, Mir Maria Eugenia. "Expanding the MDM2 interactome." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/25781.
Texte intégralRésumé :
p53 is a key component of the protein network that regulates cell cycle progression and prevents cancer. Under non-stressed conditions, its activity is controlled by an autoregulatory feedback loop with MDM2 that maintains low levels of the p53 protein. However, in response to stress signals, p53 is triggered to become active. MDM2 has been reported to regulate p53 by a combination of mechanisms: ubiquitination using its E3-ligase capability, chaperone activity in an ATP-dependent manner and directly transrepressing p53. Because of MDM2's central role in the control of p53, it has been the target of intense drug development efforts. A family of small molecules, the Nutlins, can bind to an MDM2 pocket modulating the p53: MDM2 complex. This leads to p53 activation and growth inhibitory effects. The aim of our study was to analyse the interactome of endogenous MDM2 and to determine whether anti-cancer drugs, such as Nutlin-3, could stabilise or disrupt sets of MDM2 interactions in order to better understand the p53- dependent and independent functions of MDM2 as a signalling hub, as well as the p53-independent activity of Nutlin-3. Results show a remarkable difference in the sets of proteins found in MDM2 complexes in control and Nutlin-3 treated cells. Two proteins, TRIM25 and OTUB2, were selected from the output list for validation based on their known functions in the ubiquitin signalling network. Binding has been studied in detail and confirmed using both in cell and in vitro techniques. The data highlight potentially novel functions for MDM2 and provides insight into the on-target p53-independent activities of Nutlin-3. Additionally, and with the aim of blocking p53 ubiquitination by MDM2, I have developed probes that are able to inhibit the ubiquitylation of p53 in vitro.
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Eder, Robert [Verfasser], Dimosthenis [Akademischer Betreuer] Trimis, Dimosthenis [Gutachter] Trimis, and Eckehard [Gutachter] Specht. "Ein Beitrag zur Entwicklung neuartiger keramischer Wärmeübertrager für Rekuperatorbrenner : Ein Beitrag zur Entwicklung neuartiger keramischer Wärmeübertrager für Rekuperatorbrenner / Robert Eder ; Gutachter: Dimosthenis Trimis, Eckehard Specht ; Betreuer: Dimosthenis Trimis." Freiberg : Technische Universitaet Bergakademie Freiberg Universitaetsbibliothek "Georgius Agricola", 2015. http://d-nb.info/1220911976/34.
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Schneider, Karin [Verfasser]. "Untersuchung der molekularen Funktion des Stammzellfaktors Trim71 in der Karzinogenese / Karin Schneider." Bonn : Universitäts- und Landesbibliothek Bonn, 2015. http://d-nb.info/1109879881/34.
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Hennig, Janosch. "Structure-function studies on TRIM21/Ro52, a protein involved in autoimmune diseases /." Linköping : Department of of Physics, Chemistry and Biology, Linköping University, 2009. http://www.bibl.liu.se/liupubl/disp/disp2009/tek1272s.pdf.
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Bérubé, Julie. "Influence de l'environnement cellulaire sur l'activité des protéines antirétrovirales TRIM5α et TRIMCyp". Thèse, Université du Québec à Trois-Rivières, 2011. http://depot-e.uqtr.ca/2264/1/030276729.pdf.
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Mielnicka, Monika. "Study of the biological function of TRIM66 protein in spermatogenesis and reproduction." Thesis, Strasbourg, 2022. http://www.theses.fr/2022STRAJ077.
Texte intégralRésumé :
TRIM66 est un membre de la famille de protéines TIF1 composée de TRIM24, TRIM28 et TRIM33, qui ont un domaine tandem PHD-bromodomaine en C-terminal. TRIM66 est le membre le moins étudié de cette famille et montre une haute spécificité vers l'expression dans la lignée germinale mâle, spécifiquement dans la population de cellules testiculaires haploïdes appelées spermatides. Le processus de maturation des spermatozoïdes dans les cellules haploïdes est appelé spermiogenèse et au cours de ce processus, un remodelage majeur de la chromatine a lieu avec le remplacement des histones canoniques par des protamines, ce qui se produit également au moment du pic d'expression de TRIM66 dans le testicule. L'impact de TRIM66 sur la maturation des spermatozoïdes pendant la spermiogenèse dans le testicule est inconnu. Dans ce travail, j'ai caractérisé la fonction possible du TRIM66 en utilisant deux modèles de souris. J'ai découvert que TRIM66, bien qu'il soit exprimé dans les spermatides, n'a pas d'impact sur les capacités de fertilisation des spermatozoïdes, mais qu'il affecte le poids de la progéniture à la naissance. L'analyse du transcriptome a révélé que les gènes régulés à la hausse dans la population de spermatides isolées appartiennent aux gènes principalement impliqués dans la voie de méthylation de la lysine 4 de l'histone 3. De plus, les essais de liaison in vitro montrent que le bromodomaine PHD se lie à l'histone H3 uniquement lorsque la lysine 4 est non méthylée. Dans l'ensemble, mes résultats ont révélé un effet paternel pour la perte de fonction de Trim66 qui est probablement causé par le rôle de TRIM66 dans la régulation de H3K4me3 dans les spermatides<br>TRIM66 is a member of the TIF1 protein family composed of TRIM24, TRIM28 and TRIM33, that have a C-terminus tandem domain PHD-bromodomain. TRIM66 is the least studied member of this family and shows high specificity towards expression in the male germline, specifically in the haploid testis cell population called spermatids. The process of sperm maturation in haploid cells is called spermiogenesis and during this process a major chromatin remodeling takes place with replacement of canonical histones to protamines which happens also during the peak of the expression of TRIM66 in the testis. The impact of TRIM66 on the sperm maturation during spermiogenesis in the testis is unknown. In this work, I characterized the possible function of the TRIM66 by using two mouse models. I found that TRIM66 despite being expressed in spermatids does not impact the sperm fertilization capabilities, however it affects the weight of progeny. The analysis of transcriptome revealed that the upregulated genes in the isolated spermatids population belong to the genes predominantly involved in histone 3 lysine 4 methylation pathway. Furthermore, in vitro binding assays show that the PHD-bromodomain binds to histone H3 only when lysine 4 is unmethylated. All together, my results revealed a paternal effect for Trim66 loss-of-function that is likely caused by TRIM66’s role in H3K4me3 regulation in spermatids
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Balastik, Martin. "Trim2 mutant mice as a model for cerebellar ataxia." Doctoral thesis, [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=975117025.
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Boutanquoi, Pierre-Marie. "Traitement de la fibrose pulmonaire idiopathique : Rôle de TRIM33 et de l’inhibition d’HSPB5." Electronic Thesis or Diss., Bourgogne Franche-Comté, 2019. http://www.theses.fr/2019UBFCI016.
Texte intégralRésumé :
La fibrose pulmonaire idiopathique (FPI) est une maladie dévastatrice caractérisée par l’accumulation de matrice extracellulaire dans les poumons. Le transforming-growth-factor (TGF)-β1 est une cytokine pro-fibrosante qui active la voie des Smads. Nous avons déjà montré que la protéine de choc thermique HSPB5 a un rôle activateur sur cette voie dans la fibrogenèse. TRIpartite Motif-containing 33 (TRIM33) est un régulateur négatif de la voie TGF-β1/Smads mais son rôle dans la fibrogenèse est inconnu. Nous avons étudié, le rôle de TRIM33 dans la FPI dans des modèles in vivo et ex-vivo, ainsi que le potentiel thérapeutique d’inhibiteurs chimiques d’HSPB5 dans des modèles de fibrose pulmonaire.Nous avons montré que TRIM33 est surexprimé dans les foyers fibroblastiques (myofibroblastes) ainsi que dans les macrophages alvéolaires de patients FPI. L’inhibition de cette protéine aggrave la différenciation mésenchymateuse, in vitro et in vivo, mais augmente également la sécrétion de TGF-β1 par les macrophages. En parallèle, nous avons mis en évidence l’efficacité de plusieurs inhibiteurs spécifiques de HSPB5, dans des modèles cellulaires de fibrose. Ces inhibiteurs ont été capables de diminuer l’augmentation des marqueurs de la différenciation mésanchymateuse induite dans le TGF-β1. Un de ces inhibiteurs s’est déjà révélé efficace pour traiter la fibrose pulmonaire induite par la bléomycine chez la souris.En conclusion, ce travail de thèse a permis de mettre en évidence le rôle de TRIM33 dans le développement de la FPI ainsi que l’efficacité d'inhibiteurs spécifiques de HSPB5 qui permettront peut-être un jour le traitement de la fibrose pulmonaire idiopathique<br>Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by myofibroblast proliferation and extracellular-matrix (ECM) accumulation in the lungs. Transforming-growth-factor (TGF)-β1 is a key profibrotic growth factor involving Smads signaling pathway. We have already shown that the heat shock protein HSPB5 has a positive role on Smads pathway activation in lung fibrogenic processes. TRIpartite Motif-containing 33 (TRIM33) has previously been reported to exert a negative control on TGF-β/Smads signaling but its role in pulmonary fibrogenesis remains unknown.We aimed to study the role of TRIM33 in IPF using ex vivo and in vivo models and to characterize the therapeutic potential of specific HSPB5 inhibitors.TRIM33 was overexpressed in alveolar macrophages and fibroblasts in IPF patients. Its inhibition led to increased TGF-β1 downstream gene expression. In addition TRIM33 depletion worsened TGF-β1 secretion by the macrophages. Moreover, we demonstrated that several specific HSPB5 inhibitors were able to downregulate the up- regulation of mesenchymal differenciation induced by TGF-β1 in in vitro models. Moreover, one of these inhibitors proved to be effective in BLM-induced fibrosis models.In conclusion, this work has allowed to demonstrate the importance of TRIM33 in the development of IPF as well as to characterize efficient HSPB5 specific inhibitors that may be used one day as treatment for IPF
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Larrieu, Dorian. "Régulation et fonctions de l'E3 ubiquitine ligase TRIP12 au cours du cycle cellulaire." Thesis, Toulouse 3, 2019. http://www.theses.fr/2019TOU30144.
Texte intégralRésumé :
TRIP12 est une E3 ubiquitine ligase de la famille HECT (Homologous to the E6-AP Carboxyl Terminus). TRIP12 a plusieurs cibles connues qu'elle adresse au protéasome par polyubiquitination. Parmi ces cibles, plusieurs protéines ont des rôles importants dans la réponse aux dommages à l'ADN, le remodelage de la chromatine et la voie d'activation de p53. Des résultats non publiés de mon équipe d'accueil ont montré une surexpression de la protéine TRIP12 dans le cancer du pancréas et les lésions pré-néoplasiques. Le groupe a mis en évidence que TRIP12 polyubiquitine et provoque la dégradation du facteur de transcription PTF1a (Pancreas Transcription Factor 1a), décrivant pour la première fois un mécanisme de régulation post-traductionnelle de PTF1a. PTF1a est essentiel au développement et à l'homéostasie du pancréas. Il est capable d'inhiber la prolifération de cellules cancéreuses pancréatiques et est considéré comme un gène suppresseur de tumeur. Bien qu'ayant pour substrats des protéines intervenant dans des processus finement régulés au cours du cycle cellulaire et altérés dans les cancers, la régulation de l'expression et les fonctions de TRIP12 au cours du cycle cellulaire n'étaient pas connues au début de mes travaux de thèse. J'ai démontré que l'expression et la localisation nucléaire de TRIP12 varient au cours du cycle cellulaire. J'ai identifié un domaine intrinsèquement désordonné dans la partie N-terminale de TRIP12 qui lui permet d'interagir avec l'euchromatine. J'ai montré que TRIP12 est impliqué dans l'entrée en mitose en contrôlant la durée de la réplication de l'ADN indépendamment de son activité catalytique. TRIP12 est également indispensable pour une bonne progression en mitose et la stabilité chromosomique. Mes résultats proposent TRIP12 comme une nouvelle protéine associée à la chromatine, essentielle à la progression dans le cycle cellulaire et au maintien de l'intégrité du génome. A terme, ce travail de thèse servira de base pour comprendre la surexpression de TRIP12 dans le cancer du pancréas et son impact dans la carcinogénèse<br>TRIP12 is an E3 ubiquitin ligase that belongs to the HECT (Homologous to the E6-AP Carboxyl Terminus) family. Several proteins are targeted by TRIP12 polyubiquitination which triggers their proteasomal degradation. Among its targets, several proteins are involved in DNA damage responses, chromatin remodelling and p53 pathway activation. Unpublished results of my team showed an increased expression of TRIP12 in pancreatic cancer and pre-neoplastic lesions. My group revealed that TRIP12 polyubiquitinates and provokes the degradation of the transcription factor PTF1a (Pancreas Transcription Factor 1a) stability. Describing for the first time a post-translational regulation of PTF1a. PTF1a is essential in pancreatic development and homeostasis. It inhibits the proliferation of pancreatic cells and is considered as a tumour suppressor gene and. Even if several TRIP12 targets are involved in cellular processes that are tightly cell cycle regulated, the regulation of TRIP12 expression and its functions during the cell cycle was unknown at the beginning of my thesis. I showed that TRIP12 expression and nuclear localization are regulated throughout the cell cycle. I identified an intrinsically disordered domain within the N-terminal region of TRIP12 that permits its interaction to euchromatin. I demonstrated TRIP12 implication in mitosis entry by controlling DNA replication timing Independently of its catalytic activity. TRIP12 is also required for maintaining a correct mitotic progression and chromosomes stability. My results propose TRIP12 as a new chromatin-associated protein that is essential for cell cycle progression and to preserve genome integrity. In the end, my studies will be fundamental to explain the increased expression of TRIP12 protein observed in pancreatic cancer and its impact in carcinogenesis
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Haubrich, Kevin [Verfasser], and Carsten [Akademischer Betreuer] Sachse. "RNA binding regulates TRIM25-mediated RIG-I ubiquitination / Kevin Haubrich ; Betreuer: Carsten Sachse." Heidelberg : Universitätsbibliothek Heidelberg, 2021. http://d-nb.info/1235674649/34.
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Falcón, Beas Felipe Ernesto. "¿Pueden las células dendríticas maduradas con trimel activar células INKT contra melanoma humano?" Tesis, Universidad de Chile, 2017. http://repositorio.uchile.cl/handle/2250/168208.
Texte intégralRésumé :
Grado de doctor en ciencias biomédicas.<br>Melanoma es la neoplasia cutánea más agresiva, con una incidencia ascendente a pesar de numerosos esfuerzos de prevención. En la actualidad existen diversas estrategias de tratamiento, sin embargo, no todos los pacientes responden a ellas. En nuestro laboratorio se ha ensayado una inmunoterapia basada en células dendríticas (DCs) maduradas con un lisado de líneas celulares de melanoma (TRIMEL), que ha incrementado hasta 3 veces la sobrevida en pacientes que desarrollan una respuesta inmunológica de hipersensibilidad retardada (DTH+). Hasta la fecha no se han desarrollado avances en el estudio de la fracción no peptídica de este lisado ni de su capacidad de activar células iNKT, capaces de reconocer antígenos glicolipídicas en contexto CD1d. Hipótesis: Células iNKT infiltran tumores de pacientes con melanoma avanzado y son capaces de ser activadas in vitro por células dendríticas utilizadas en inmunoterapia antitumoral. Objetivo General: Determinar el rol en pacientes con melanoma de células iNKT infiltrantes de tumor y activadas por células dendríticas maduradas ex vivo utilizadas en inmunoterapia antimelanoma. Métodos: Se determinaron células iNKT infiltrantes de tumor mediante inmunofluorescencia y se correlacionó su presencia en lesiones de melanoma primario en todos los estadios según Breslow con la sobrevida de la enfermedad. Se evaluó la capacidad de las fracciones glicolipídica y proteica de TRIMEL para inducir maduración en células dendríticas. Para este fin, las fracciones se obtuvieron mediante gradiente de densidad con MTBE (Metil-terbutil-éter) y se usaron para estimular DCs generadas en base a rhIL-4 y GM-CSF. En estas condiciones se evaluó la presencia de diversas moléculas de superficie y la producción de citoquinas. Para evaluar la capacidad de estas DCs de activar células iNKT, desde PBMC se aisló la población CD3+ mediante cell-sorting y cultivadas con distintas DCs generadas. Se analizó la proliferación celular utilizando el ensayo CFSE. También se evaluó la presencia de células iNKT mediante inmunofluorescencia en tacos de parafina de las DTH realizadas a pacientes de inmunoterapia. Resultados: Encontramos infiltración por células iNKT en todos los estadíos de la enfermedad, siendo mayor en Breslow avanzados, sin una correlación con la sobrevida global. Al evaluar la maduración de DCs, esta fue mayor en el grupo estimulada con la fracción peptídica de TRIMEL. DCs estimuladas con la fracción glicolipídica de TRIMEL no mostraron diferencias con la condición no tratada. Al evaluar mediante ensayo de proliferación realizado con CFSE, se evidenció mayor proliferación en la condición tratada con la fracción peptídica. Finalmente, sólo en 1 de 3 pacientes en los que se analizó la presencia de iNKT en las DTH se encontraron estas células. Conclusiones: unificando todos los hallazgos discutidos previamente, células iNKT infiltran tumores de melanoma, las que podrían ser inducidas a proliferar por DCs estimuladas con la fracción peptídica de TRIMEL y de esa forma migrar a sitios inflamados como representan las lesiones DTH.<br>Melanoma is the most aggressive skin tumor, with a growing incidence worldwide, despite of prevention strategies. Nowadays, there are several new therapies to treat it, however the overall survival continues to be low. Our lab has been studying a Dendritic Cell (DC) based immunotherapy maturated with a melanoma cell lines lysate (TRIMEL), which has increased survival up to 3 times in patients that developed a delayed type hypersensitivity response (DTH+). To this date no studies have been made regarding the non peptidic fraction of this lysate or its capability to activate a subpopulation of T Cells called iNKT cells, characterized by their ability to recognize glycolipids in a CD1d manner. Hypothesis: iNKT Cells infiltrate melanoma patient’s tumors and are capable to be activated in vitro by Dendritic cells Main Objective: To determinate the role of tumor infiltrating iNKT cells activated by matured Dendritic Cells ex vivo used in antimelanoma immunotherapy in melanoma patients Methods: The presence of tumor infiltrating iNKT Cells in primary melanoma in all of Breslow stages was evaluated by expression of TCR Vα24Jα18 by Immunofluorescence microscopy. To evaluate the capability of glycolipid and peptidic TRIMEL fraction to induce DCs maturation, they were isolated from TRIMEL using a MTBE (Metil-terbutil-ether) density gradient. Afterwards, these fractions were used to stimulate DCs generated with a rhIL-4 and GM-CSF protocol and surface molecules expression were assessed, as well as cytokine secretion. To evaluate DCs effectiveness to activate iNKT Cells’ proliferation, CD3+ population was isolated from Buffy Coats using cell-sorting technology and they were cultured with DCs. Proliferation was accessed with CFSE dye assay. Finally, DTH infiltrating iNKT cells were asessed in paraffined embedded samples by immunofluorescence microscopy. Results: We found that iNKT cells infiltrated melanoma tumors in every Breslow stage, with higher infiltration on advanced stages,with no correlation with overall survival. The peptidic fraction of TRIMEL induced higher expression of maturation related surface molecules in addition to cytokine secretion, whereas glycolipidic fraction showed no difference with the untreated condition. iNKT cell had a higher proliferation rate when cultured with DCs treated with the peptidic fraction of TRIMEL. And finally, we found the infiltration of iNKT in 1 of the 3 patients DTH. Conclusions: Taking together all the previous results, iNKT cells infiltrate melanoma Tumors, and they could be induced to proliferate by DCs stimulated with the peptidic fraction of TRIMEL and as well supporting their migration to inflamed tissues like the DTH samples.<br>2022
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Pillera, Giuseppe Carmelo. "Trimap: social networked learning e social mapping per il terzo settore in Sicilia." Doctoral thesis, Università di Catania, 2012. http://hdl.handle.net/10761/1147.
Texte intégralRésumé :
La tesi illustra le basi teoriche, il contesto sociale dell'operazione, i percorsi progettuali e i primi risultati relativi alla creazione e sperimentazione di Trimap (www.trimap.it), un progetto (nato all'interno di questo dottorato) di mappatura dal basso e di social learning per il mondo del no-profit.
Gli obiettivi principali sono:
1) costruire in maniera partecipativa un sistema informativo geografico (GIS) sul noprofit attraverso un sistema di mappe interattive;
2) fornire alle organizzazioni partecipanti uno spazio di autorappresentazione, comunicazione, confronto, cooperazione, collaborazione, promozione, formazione (e-portfolio dei progetti, co-progettazione, scrittura collettiva, condivisione informazioni, banca delle competenze, calendari...).
Attualmente stiamo testando la piattaforma (basata su Drupal 6.x) con la partecipazione di 250 organizzazioni noprofit
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Reinius, Leif. "Trim optimization of reefer vessels." Thesis, KTH, Marina system, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:kth:diva-162058.
Texte intégralRésumé :
The influence of trim on the fuel consumption of reefer ships have been investigated. The project have been carried out at NYKCool AB, a ship operator of reefer vessels. In the speed range 17-19 knots and deadweight percentage of approximately 70% the smallest calculated resistance is obtained for bow trims which are between -1 m and -2 m depending on the speed. Stored voyage data from the reefer ships shows that the majority of the voyages are made with positive trims. The data also shows that the mean fuel consumption in ton per hour is smallest for the even keel condition in comparison with aft (positive) trims. The conclusions have been made for deadweight conditions of 70-80 % DWT. Savings of bunker are in the order of magnitude of 3-4% and have been seen from the data analysis. The average fuel consumption in traffic is approximately 37 tons of heavy fuel oil per day. Due to factors such as different docking schedules the ships have different performance. The tests shows a correlation between the fuel consumption and optimal trims. Bow trims are always more favorable from a saving perspective. The largest bow trim that was possible and which ensured proper propeller immersion was approximately -1 m and was achieved by planning the stowage together with burning bunker from the fuel tanks in the right order. The stability is affected due to less buoyancy in the bow area compared to the mid ship sections, but always above the minimum criteria of GM0 <o 0.15 m with enough margins. GM0 remains in the interval of 2-3 m depending on the deadweight percentage and trim condition. Economical savings will be seen over longer periods of time by operating the reefer vessels with the optimal trims.
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Schimmanz, Klaus. "Konzipieren und Bewerten von Hochpräzisions-Hybridwiderständen durch Laser-Trimm-Simulation." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=966338146.
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Douvris, Adrianna. "Functional Analysis of the TRIB1 Locus in Coronary Artery Disease." Thèse, Université d'Ottawa / University of Ottawa, 2011. http://hdl.handle.net/10393/20115.
Texte intégralRésumé :
The TRIB1 locus (8q24.13) is a novel locus associated with plasma TGs and CAD risk. Trib1 is a regulator of MAPK activity, and has been shown to regulate hepatic lipogenesis and VLDL production in mice. However, the functional relationship between common SNPs at the TRIB1 locus and plasma lipid traits is unknown; TRIB1 has not been identified as an eQTL. This cluster of SNPs falls within an intergenic region 25kb to 50kb downstream of the TRIB1 coding region. By phylogenetic footprinting analysis and DNA genotyping, we identified an evolutionarily conserved region (CNS1) within the risk locus that harbours two common SNPs in tight LD with GWAS risk SNPs and significantly associated with CAD. We investigated the regulatory function of CNS1 by luciferase reporter assays in HepG2 cells and demonstrate that this region has promoter activity. In addition, the rs2001844 risk allele significantly reduces luciferase activity, suggesting that altered expression of the EST-based gene may be associated with plasma TGs. We identified an EST within the risk locus directly downstream of CNS1. We performed 5'/3' RACE using HepG2 RNA, identified multiple variants of this EST-based gene, and confirmed its transcription start site within CNS1. We hypothesize that this EST is a long noncoding RNA due to low abundance, poor conservation, and absence of significant ORF. Over-expression of a short variant implicates its function in the regulation of target gene transcription, although the mechanism of action remains unknown. We conclude that the risk locus at 8q24.13 harbours a novel EST-based gene that may explain the relationship between GWAS SNPs at this locus and plasma lipid traits.
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Marafie, Sulaiman. "TRIM7, a novel binding protein of the mTORC2 component Sin1." Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/trim7-a-novel-binding-protein-of-the-mtorc2-component-sin1(c344b542-0706-4ec0-be06-ce6683cee52e).html.
Texte intégralRésumé :
TRIM7 is a member of the TRIM (tripartite motif-containing) protein superfamily. This family has been implicated in many disorders such as genetic diseases, neurological diseases, and cancers. Little is known about the function of TRIM7 except that it interacts with glycogenin and may regulate glycogen biosynthesis. Recently, a yeast two-hybrid protein-protein interaction screen revealed the binding of TRIM7 to Sin1, a protein found in a complex with the mammalian target of rapamycin (mTOR) protein kinase. mTOR can form two complexes, mTORC1 and mTORC2, which are important for cell growth, differentiation, and survival. Sin1 is a core component of mTORC2 and is critical for mTORC2 stability and activity. It was confirmed by co-immunoprecipitation that TRIM7 associates with Sin1 and mTOR in cultured mammalian cells. Furthermore, it was demonstrated that TRIM7 is a phosphoprotein, although it was not directly targeted by mTOR in vitro. Similar to some other TRIM family proteins, it was demonstrated that TRIM7 has a ubiquitin E3 ligase function allowing it to autoubiquitinate both in vitro and in cells. The autoubiquitination of TRIM7 was dependent on its RING domain. Further characterization of TRIM7 indicated that it can both homo-oligomerise as well as hetero-oligomerise with other members of its sub-class of TRIM proteins and that it co-localises with them into discrete cytoplasmic loci. To determine the cellular function of TRIM7, a stable cell line expressing an shRNA directed against TRIM7 was generated. Successful knock down of TRIM7 was achieved and this led to an increase in the protein levels of components of the mTORC2 complex, including Sin1. This coincided with an increase in cell proliferation. In conclusion, this research identifies a novel role for TRIM7 as a ubiquitin ligase involved in regulating cell proliferation and provides a potential link between TRIM7 and the mTOR pathway, a major transducer of proliferative and cell survival signals.