Дисертації з теми "Proteasome System"
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1
Bingol, Baris Zinn Kai George. "Ubiquitin-proteasome system at the synapse /." Diss., Pasadena, Calif. : Caltech, 2006. http://resolver.caltech.edu/CaltechETD:etd-05272006-184911.
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Gupta, Nilaksh. "UBIQUITIN-PROTEASOME SYSTEM MODULATES PLATELET FUNCTION." Cleveland State University / OhioLINK, 2014. http://rave.ohiolink.edu/etdc/view?acc_num=csu1408896695.
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3
Menéndez, Benito Victoria. "The ubiquitin-proteasome system during proteotoxic stress /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-706-5/.
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4
Ghannam, Khetam [Verfasser]. "Ubiquitin proteasome system and myopathies / Khetam Ghannam." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2015. http://d-nb.info/1075493374/34.
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5
Jolly, R. S. "The ubiquitin proteasome system in Huntington's disease." Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/1444454/.
Повний текст джерелаАнотація:
Huntington's disease (HD) is an autosomally dominant, progressive movement disorder, caused by an expansion in the polyglutamine tract of huntingtin protein. HD is pathologically characterised by the presence of insoluble, proteinaceous neuronal intranuclear inclusions (NHs) and dystrophic neurite inclusions (DNIs) in affected neurons that can be immunostained for ubiquitin and other proteins involved in the ubiquitin-proteasome system (UPS). The UPS is a highly conserved mechanism for degradation of both normal and misfolded proteins in eukaryotic cells. This has led to suggestions that the UPS is inhibited in HD. This study utilises microscopy, biochemistry and fluorometric assays to examine the molecular composition of aggregates and the potential dysfunction of the UPS in the R6/2 mouse line, an established model of HD. The ultrastructure of aggregates is shown to be predominantly amorphous and granular in appearance and likely to be formed through the process of transglutamination. Immunohistochemical data shows that certain chaperones, ubiquitin-like proteins (UBLs) and proteins involved in the UPS localise to Nils and DNIs differentially. Fluorometric assays demonstrate that the proteasome exhibits a differential profile in R6/2 mice where both chymotrypsin-like and PGPH-like activities are markedly increased whilst trypsin-like activity is decreased relative to litter-mate control mice. Furthermore, these activity changes may be explained by alterations in proteasome regulation, levels and maturation. These results suggest that, in the R6/2 line, the proteasome is not inhibited by the presence of mutant huntingtin, rather that there are alterations of the catalytic activities of the proteasome. It appears that Nil's act not only as focal points of proteolysis, but also of proteasome biogenesis. This is consistent with, and extends, the concept of clastosomes.
6
Min, Mingwei. "Decoding the mitotic exit ubiquitin-proteasome system." Thesis, University of Cambridge, 2014. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708388.
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7
Rieger, Melanie. "Strukturelle und funktionelle Anpassung des Ubiquitin-Proteasomsystems an IFN-gamma." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2009. http://dx.doi.org/10.18452/15888.
Повний текст джерелаАнотація:
Das Ubiquitin-Proteasom-System ist an der Degradation cytosolischer Proteine und der Generierung von Antigenen beteiligt, die über MHC Klasse I Moleküle CD8+ T Zellen präsentiert werden. Die Antigenprozessierung wird durch Typ I und II Interferone beeinflusst, welche die Formierung des Immunoproteasoms und des Proteasomen-Aktivators PA28 induzieren und so die katalytische Aktivität des Ubiquitin-Proteasom-Systems qualitativ verändern. In der vorliegenden Arbeit wurde im Zellkulturmodell unter dem Einfluss von IFN gamma die zunehmende Inkorporation der Immunountereinheiten in de novo assemblierende 20S Proteasomen und die daraus resultierende Veränderung der proteolytische Aktivität untersucht. Die Inkorporation der Immunountereinheiten wurde mittels 2D Gelelektrophorese und Western Blots von 20S Proteasomen untersucht, die nach unterschiedlicher Stimulationsdauer mit IFN gamma aus HeLa Zellen isoliert wurden. Es konnte gezeigt werden, dass innerhalb der ersten 24h einer IFN gamma Stimulation die strukturelle Heterogenität des zellulären Proteasomenpools zunimmt, indem sowohl intermediäre als auch Immunoproteasomen assemblieren. In der Nativ-PAGE von Lysaten IFN gamma stimulierter Zellen wurde eine Zunahme des 20S Proteasoms als freier Komplex und in Assoziation mit PA28 beobachtet, während die Menge des zum ATP-abhängigen Abbau von polyubiquitinierten Proteinen notwendigen 26S Proteasoms unverändert blieb. Die Stimulation mit IFN gamma hatte eine Steigerung der gesamtproteasomalen Aktivität zur Folge, die unter Inhibition der Interaktion zwischen 20S Proteasom und PA28 verzögert erfolgte. Die katalytischen Eigenschaften isolierter Proteasomen wurden anhand der Generierung eines immunrelevanten Hepatitis C CTL Epitops des viralen Core Proteins in vitro untersucht. Im Verlauf der IFN gamma Stimulation de novo assemblierte Proteasomen wiesen jeweils unterschiedliche Präferenzen für die Generierung des untersuchten CTL Epitops auf. Eine weitere, proteasomen-spezifische Änderung der katalytischen Aktivität bewirkte die Assoziation des Proteasomen-Aktivators. Innerhalb der ersten zwölf Stunden einer IFN gamma Stimulation wurde das Epitop vermehrt mit der Unterstützung des Proteasomen-Aktivators generiert, nach 24 Stunden zunehmend durch freies 20S Proteasom. Die Ergebnisse der vorgestellten Arbeit zeigen, dass Strukturvarianten des Proteasoms zusammen mit PA28 redundant funktionieren und eine hohe proteolytische Plastizität des UPS gewährleisten.The ubiquitin proteasome system is responsible for the degradation of cytosolic proteins and the processing of MHC class I restricted antigens. The generation of these antigens is influenced by type I and II interferons which induce the expression of immunoproteasomes and the proteasome activator PA28; and thereby impact the quality of peptides processed by the proteasome system. The adoption of the proteasome system to a proinflammatory environment has been investigated in a cell culture model by isolating proteasomes after different stages of IFN gamma stimulation. The composition of isolated proteasomes was analysed by 2D PAGE and western blot approach. The presented work shows that within 24h of IFN gamma stimulation an increasing heterogeneity of the cellular proteasome pool is observed, resulting from the assembly of both intermediate type proteasomes and immunoproteasomes at the early stage of IFN gamma stimulation. It could be shown by native PAGE of HeLa cell lysates that IFN gamma induces increasing amounts of 20S proteasomes and PA28 associated proteasomes without decreasing the amount of 26S proteasomes that are necessary for the ATP dependent degradation of ubiquitinated proteins; and resulting in an enhanced total proteasomal activity in vitro. This increase in activity was delayed when the interaction of 20S proteasomes and PA28 was inhibited. A comparative analysis of the ability of isolated 20S proteasomes to generate a known hepatitis C virus derived CTL epitope in vitro proved that during early IFN gamma stimulation de novo assembled proteasomes exhibited a structure specific preference to generate the HCV CTL epitope either alone or in combination with the proteasome activator PA28. Within the first 12h of IFN gamma stimulation the epitope was generated with higher efficiency by 20S proteasomes in association with PA28, whereas after 24h the impact of PA28 on the proteasome pool was less pronounced. The presented work shows that IFN gamma induces a heterogeneity of 20S proteasomes in the early stage of stimulation, acting in combination with the proteasome activator in a redundant manner; and provides a high proteolytic placticity of the proteasome system.
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Silva, Elisabete Rodrigues do Monte. "Caracterização do repertório peptídico intracelular de células expressando o proteassomo imune." Universidade de São Paulo, 2014. http://www.teses.usp.br/teses/disponiveis/42/42134/tde-26062014-184010/.
Повний текст джерелаАнотація:
Células eucarióticas contêm vários tipos de proteassomo que regulam o processo de degradação de proteína. Proteassomos são proteases multicatalíticas que são responsáveis pela maior parte de degradação não-lisossomal de proteínas em células eucarióticas. As três subunidades catalíticas do proteassomo são β1, β2 e β5. Em condições de stress e resposta imune essas três subunidades são substituídas por β1i, β2i and β5i, respectivamente, para formar o proteassomo imune. Estas três subunidades induzíveis, parecem alterar as especificidades de peptidase do proteassoma imune em células tratadas com IFN-g. Nosso objetivo no presente trabalho foi caracterizar um modelo celular para a indução do proteassomo imune, e ainda investigar o repertório peptídeo intracelular produzido por esta forma particular do proteassoma, através da técnica de espectrometria de massas. Em resumo, os nossos dados mostraram um aumento de 3 vezes do peptídeo EL28 derivado da proteína RPT2 em células HeLa tratadas com o IFN-g. O peptídeo EL28 pode ser de relevância clínica para o tratamento de distúrbios relacionados com a apresentação de antígenos, visto que ele parece ativar a atividade quimotripsina-like quando incubado com o extrato celular de células HeLa.Eukaryotic cells contain several types of proteasome regulating the process of protein degradation. The proteasome are responsible for most non - lysosomal protein degradation in eukaryotic cells. The three catalytic subunits of the proteasome are β1, β2 and β5. Under conditions of stress and immune response these three subunits are replaced by β1i, β2i and β5i, respectively, to form the immune proteasome . These three inducible subunits, appear to alter the specificity of the immune proteasome peptidase in cells treated with IFN-g. Our aim in this study was to characterize a cellular model for the induction of the immune proteasome, and even investigate the intracellular peptide repertoire produced by this particular form of the proteasome, through the technique of mass spectrometry. In summary, our data showed an increase of 3 times the peptide derived from RPT2 EL28 protein in HeLa cells treated with IFN-g. The EL28 peptide may be of clinical relevance for the treatment of disorders related to antigen presentation, since it seems to activate the chymotrypsin-like activity when incubated with the cell extract of HeLa cells.
9
Verhoef, Lisette Gerridina Gezina Catharina. "The role of the ubiquitin-proteasome system in neurodegenerative disorders /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-743-X/.
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10
Seeger, Michael [Verfasser]. "Functional aspects of the ubiquitin-proteasome system / Michael Seeger." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2015. http://d-nb.info/1070498343/34.
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11
Glover, James S. A. "Investigation of the ubiquitin proteasome system in Schizosaccharomyces pombe." Thesis, University of Edinburgh, 2010. http://hdl.handle.net/1842/4797.
Повний текст джерелаАнотація:
Ubiquitin is an essential 76 amino acid protein which can be conjugated to lysine residues on a variety of substrates via its C-terminal diglycine motif. This conjugation allows the protein to act as a molecular tag in a range of processes, including regulation of chromatin compaction, signalling cascades and DNA repair. In addition, ubiquitin moieties are capable of forming chains through the successive conjugation to lysine residues within ubiquitin itself. One of the most well characterized functions of ubiquitin is its role in protein quality control and degradation. Tetra-ubiquitin chains, most commonly through a lysine-48 linkage, are responsible for directing proteins to the 26S proteasome for degradation. This process is of importance both in the removal of miss-folded proteins, and in the regulated destruction of specific targets, such as the cyclins. The 90kDa AAA-ATPase Cdc48/p97/VCP is an essential protein that forms a hexameric complex, which interacts with a wide variety of ubiquitinated substrates. The specificity of Cdc48 is modulated by a series of different cofactors, which together allow Cdc48 to operate in several different contexts, from removal of misfolded proteins from the ER, to regulating securin stability. The role of two Cdc48 cofactors, Ubx4 and Ubx5, was studied in an attempt to dissect their function and to determine how they may modulate the function of Cdc48. Neither protein was found to be essential, as knockouts of either were found to be viable with no major defect in growth rate. The work also describes the findings of a yeast two-hybrid screen to identify potential substrates for both cofactors. Delivery of ubiquitinated proteins to the proteasome is mediated by shuttling factors, which are able to bind to both ubiquitin and the proteasome, and hence mediate the interaction between both. The shuttling factor Dph1 binds ubiquitin via a C-terminal UBA domain, while its N-terminal UBL domain mediates its interaction with the proteasome. This work identified a novel interaction between the Sti1 domains of Dph1 and the N-terminal region of a mitochondrial localized AAA-ATPase, homologous to the Saccaromyces cerevisiae protein Msp1. In addition, cell fractionation experiments revealed the presence of Dph1 at the mitochondria. This interaction provides hints that Mlp1 may be involved in the removal of ubiquitinated proteins from the mitochondria, and their delivery to the proteasome. The thesis begins to try and attempt to identify possible substrates of this proposed mitochondria associated degradation pathway, and looks for ways in which the hypothesis may be tested.
12
Gao, Guang. "Role of the ubiquitin/proteasome system in coxsackievirus induced-myocarditis." Thesis, University of British Columbia, 2010. http://hdl.handle.net/2429/30466.
Повний текст джерелаАнотація:
Viral myocarditis, an inflammatory disease of the myocardium, can lead to the development of dilated cardiomyopathy (DCM), a common cause of heart failure. Coxsackievirus B3 (CVB3) in the family of Picornaviridae is one of the primary causative agents of viral myocarditis. The ubiquitin/proteasome system (UPS), a primary intracellular protein degradation system in eukaryotic cells, has emerged as a key modulator in viral infectivity and virus-mediated pathogenesis. Our laboratory has previously demonstrated a potential role of the UPS in CVB3 infection. However, the effect of proteasome inhibition on CVB3-induced myocarditis in vivo has not been assessed and the underlying mechanism by which the UPS regulates CVB3 replication remains unclear.
In this dissertation, my hypothesis is that the UPS plays a critical role in the pathogenesis of CVB3-induced myocarditis through promoting CVB3 replication and by regulating host protein degradation. To test this hypothesis, I proposed three aims.
In aim 1, using a myocarditis-susceptible mouse model, I demonstrated that treatment with a proteasome inhibitor MLN353 significantly attenuates CVB3-induced myocardial damage, suggesting that proteasome inhibition may provide a therapeutic means for viral myocarditis. During this study, however, the potential toxicity of general inhibition of proteasome was recognized, which prompted me to search for the specific targets within the UPS utilized by CVB3.
In aim 2, collaborating with others, I showed that protein ubiquitination is enhanced and CVB3 protein 3D is ubiquitinated during viral infection. Gene-silencing of ubiquitin significantly reduces viral titers. However, this reduction is not as potent as by proteasome inhibition, suggesting that ubiquitin-independent proteasomal degradation may also play a role during CVB3 infection.
In aim 3, I showed that REG gamma, which mediates ubiquitin-independent protein degradation, enhances CVB3 replication via facilitating p53 degradation. During CVB3 infection, REG gamma is sumoylated and translocated.
Taken together, the results suggest a therapeutic value of proteasome inhibition in the treatment of viral myocarditis. The data also demonstrate important roles of both the ubiquitin-dependent and -independent pathways in the regulation of CVB3 infection. Identification of the specific substrates within the UPS during CVB3 infection and the potential mechanisms involved allows for more precise targeting in drug therapy.
13
Sun, Faneng. "Ubiquitin-proteasome system dysfunction in experimental models of Parkinson's disease." [Ames, Iowa : Iowa State University], 2007.
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14
Lindsten, Kristina. "Functional studies of the ubiquitin-proteasome system using GFP-based reporters /." Stockholm, 2002. http://diss.kib.ki.se/2002/91-7349-398-8/.
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15
McKinnon, C. A. "The role of the ubiquitin-proteasome system in prion disease pathogenesis." Thesis, University College London (University of London), 2013. http://discovery.ucl.ac.uk/1411348/.
Повний текст джерелаАнотація:
Prion diseases are a group of fatal neurodegenerative disorders characterised by the accumulation of misfolded prion protein (PrPSc) in the brain. They are caused by the conformational rearrangement of the normal cellular protein, PrPC, to the abnormal isoform PrPSc. The critical relationship between aberrant protein misfolding and neurotoxicity currently remains unclear. The aim of this Thesis was to investigate the role of the ubiquitin-proteasome system (UPS) in prion disease pathogenesis. The UPS is a tightly regulated system for the identification and subsequent degradation of misfolded or redundant proteins by the 26S proteasome. Previous in vitro studies have identified a direct inhibitory interaction between misfolded PrP isoforms and the proteasome. To evaluate whether UPS dysfunction plays a significant role in vivo, a detailed time-course study was carried out in prion-infected UbG76V-GFP proteasome reporter mice. This work revealed a spatiotemporal correlation between the accumulation of PrPSc and the onset of UPS dysfunction in neurons and astrocytes. UPS impairment was shown to occur prior to the onset of behavioural dysfunction and neuronal loss, underlining that upregulation of the UPS may be an important therapeutic approach for the treatment of prion diseases. To test this theory, a novel recombinant adeno-associated viral vector was developed to attempt upregulation of the UPS in vivo by overexpression of the 19S regulatory particle subunit PSMD11. In parallel with in vivo studies, work in this Thesis aimed to develop a neural stem cell line expressing an epitope-tagged PrPC chimera (PrP-224AlaMYC) which can be differentiated into a mixed population of neurons and astrocytes. Since previous cell models of prion infection have utilised immortalised neuroblastoma cells which do not exhibit prion-induced cell death, the development of this post-mitotic cell system could provide important insights into how PrPSc gains access to the cytosolic compartment to interact with the UPS.
16
Lim, Hui Jun. "Dynamic regulation of histone lysine methylation via the ubiquitin-proteasome system." Thesis, Harvard University, 2013. http://dissertations.umi.com/gsas.harvard:11163.
Повний текст джерелаАнотація:
Lysine methylation is an important post-translational modification found on histones that is added and removed by histone lysine methyltransferases and demethylases, respectively. Lysine methylation occurs in a specific and well-regulated manner, and plays key roles in regulating important biological processes such as transcription, DNA damage and cell cycle. Regulation of the protein abundance of these methylation enzymes particularly by the ubiquitin-proteasome system has emerged as a key mechanism by which the histone methylation status of the cell can be regulated, allowing cells to respond rapidly to specific developmental and environmental cues. In my thesis, I focus on two histone lysine demethylases, KDM4A and PHF8, both of which appear to be regulated by E3 ligases; this regulation impacts their function in the cell. Chapter 2 shows that KDM4A is targeted for proteasomal degradation by the SCFFBXO22, and mis-regulation of KDM4A results in changes in global histone 3 lysine 9 and 36 (H3K9 and H3K36) methylation levels and impacts the transcription of a KDM4A target gene, ASCL2. Chapter 3 shows how PHF8 is targeted for proteasomal degradation by the APCCDC20 via a novel, previously unreported LxPKxLF motif on PHF8. I also found that similar to other APCCDC20 substrates like Cyclin B, PHF8 is an important G2-M regulator, loss of which results in cell cycle defects such as prolonged G2 and defective M phases. To further interrogate PHF8 biology, Chapter 4 describes the generation of a PHF8 conditional knockout mouse. PHF8 biology is interesting and relevant to human disease, as mutations are found in X-linked intellectual disability and autism. Complete loss of PHF8 by full body knockout in the mouse appears to be embryonically lethal, underscoring its key role in early development. This mouse model would allow us to extensively study the biochemistry and biology of PHF8 in the context of development and especially in brain function, where it is anticipated to play key roles. Overall, my dissertation work provides mechanistic and biological insights into how histone demethylases are dynamically regulated by the ubiquitin-proteasome system, providing an extra dimension to our understanding of how chromatin marks can be regulated.
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Watson, Morag Elspeth. "Design and synthesis of molecular tools for the ubiquitin proteasome system." Thesis, University of Strathclyde, 2016. http://digitool.lib.strath.ac.uk:80/R/?func=dbin-jump-full&object_id=27447.
Повний текст джерелаАнотація:
Alzheimer’s disease (AD) has become one of the biggest global public health challenges, with 0.5% of the population living with dementia. The ubiquitin proteasome system (UPS), in particular the interaction between a mutant form of ubiquitin, Ubb+1, and the E2-conjugating enzyme E2-25K, has been identified as playing a possible pathophysiological role in the early and late stage progression of AD. The E2-25K/Ubb+1 protein-protein interaction (PPI) is regulated by the α-helix 9 of E2-25K. Creating a short helical peptide analogous to α-9 of E2-25K with the technique of peptide stapling could potentially block the action of Ubb+1 and provide a tool to investigate the role of the UPS in AD. Following synthesis of the requisite alkenyl amino acids for peptide stapling, an initial palette of nine peptides, containing the wild-type E2-25K sequence, and eight stapled analogues, were successfully synthesized and ring-closed on the solid phase. Circular dichroism spectroscopy was used to analyse secondary structure, revealing the peptides exhibited a range of 16 – 91% helicity. Further NMR studies demonstrated the more precise helical nature of short helical peptides in solution. Preliminary biological assays indicated that the synthesised peptides are capable of inhibiting Ubb+1 incorporation into long polyubiquitin chains. Remarkably, these antagonists proved to be selective towards Ubb+1 over ubiquitin despite the high degree of similarity in the relative binding sites of the two proteins. Further in silico design led to the development of a second generation of six stapled peptides. Further biological evaluation revealed an additional sequence potentially capable of activating E2-25K mediated Ubb+1 capped PolyUb chain formation. Overall, this preliminary study has shown that short helical analogues of E2-25K can be successfully synthesized and used to block or activate the E2-25K/Ubb+1 PPI. Further optimisation of these stapled peptides could provide valuable tool compounds into the investigation of Ubb+1 mediated inhibition of the UPS, and the downstream effects on the pathogenesis of AD.
18
Lino, Caroline Antunes. "O sistema ubiquitina-proteassoma no modelo de hipertrofia cardíaca induzida por hormônio tireoidiano." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/42/42131/tde-13032014-162752/.
Повний текст джерелаАнотація:
Disfunções da glândula tireóide são, frequentemente, associadas a manifestações cardiovasculares e, em situações de hipertireoidismo, o coração hipertrofia. A hipertrofia cardíaca (HC) consiste em uma resposta adaptativa caracterizada pelo aumento de síntese de proteínas estruturais. O Sistema Ubiquitina Proteassoma (UPS) corresponde ao principal mecanismo de proteólise intracelular e crescentes evidências sugerem seu envolvimento no desenvolvimento da HC. O objetivo do presente estudo foi avaliar a modulação do UPS no tecido cardíaco de animais submetidos ao hipertireoidismo. Os resultados referentes ao aumento da atividade e expressão do proteassoma (PT) cardíaco apresenta-se mais contundente no grupo tratado por 7 dias, período em que a HC já encontra-se estável. Ao término de 14 e 21 dias, a modulação desse sistema tende à normalização. Os resultados obtidos atestam evidências da literatura que sugerem o aumento da atividade do PT cardíaco como resposta compensatória ao aumento de síntese proteica.Thyroid gland disorders are often associated with cardiovascular events and hyperthyroidism state promotes cardiac hypertrophy (CH). CH consists in adaptive response characterized by increased synthesis of structural proteins. The Ubiquitin Proteasome System (UPS) is the major mechanism of intracellular proteolysis and increased evidences suggest its involvement in the development of CH. The aim of this study was to evaluate the modulation of UPS in cardiac tissue of animals subjected to hyperthyroidism. The results related to the increased proteasome (PT) activity and expression in the heart was more accentuated in the group treated for 7 days, when the CH process finds stable. At the end of 14 and 21 days of hyperthyroidism, the modulation of cardiac UPS achieves standard values. These results suggest an increased activity of cardiac PT as a compensatory response to protein synthesis induced by thyroid hormones.
19
Bhattarai, Salyan [Verfasser]. "Functional role of ubiquitin proteasome system in idiopathic inflammatory myopathies / Salyan Bhattarai." Berlin : Freie Universität Berlin, 2017. http://d-nb.info/1128646374/34.
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Fuchs, Adrian [Verfasser], and Lupas [Akademischer Betreuer]. "The Prokaryotic Origins of the Ubiquitin-Proteasome System / Adrian Fuchs ; Betreuer: Lupas." Tübingen : Universitätsbibliothek Tübingen, 2019. http://d-nb.info/1182985386/34.
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21
Wise, Helen Margaret. "Regulation of neural development by the Ubiquitin Proteasome System in Xenopus laevis." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612194.
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22
Ferdoush, Jannatul. "Regulation of nuclear phase of eukaryotic gene expression by ubiquitin-proteasome system." OpenSIUC, 2019. https://opensiuc.lib.siu.edu/dissertations/1751.
Повний текст джерелаАнотація:
Eukaryotic gene expression is a highly synchronized cellular process whose nuclear phase is comprised of transcription, and mRNA processing and export. Transcription can be further comprised of transcription initiation, and elongation. Regulation of transcription initiation, transcription elongation, and mRNA processing and export are crucial for normal cellular function, since misregulation of these processes are associated with various diseases including cancer. Many factors or proteins are associated with these cellular processes which are modulated by different regulatory processes to maintain normal cellular function. Ubiquitin-proteasome system (UPS) is one of the recently studied regulatory processes. Over the years, ubiquitin and 26S proteasome have emerged as important regulatory factors in coordination of transcription and coupled mRNA export. However, the mechanisms as to how the ubiquitin and 26S proteasome regulate transcription and coupled mRNA export have not been clearly elucidated. Therefore, my dissertation has focused on understanding the role of UPS in these important cellular processes: transcription initiation, transcription elongation and mRNA export. The results have shown the non-proteolytic role of 19S RP of 26S proteasome in regulation of transcriptional initiation of SAGA and TFIID-dependent PHO84 gene. It was found that 19S RP facilitates both SAGA- and NuA4-TFIID-dependent transcriptional initiations of PHO84 via increased recruitment of the coactivators SAGA and NuA4 HAT, which promote TFIID-independent and -dependent PIC formation in the presence and absence of an essential nutrient, Pi, in the growth media for transcriptional initiation, respectively. Next, our studies have uncovered the role of UPS in regulation of transcriptional elongation. It was found that E3 ubiquitin ligase, San1, mediated UPS regulation of transcription elongation factor, FACT is required for stimulating nucleosomal reassembly at the coding sequence of active genes for proper transcription elongation. We also found the interaction of FACT with another important transcription elongation factor, Paf1C via NTD (N-ter domain) of Cet1p (mRNA capping enzyme) to regulate transcription elongation.Subsequently, our results revealed a novel regulation of Paf1 component of Paf1C by UPS to regulate its abundance for proper cellular function. Transcription of genes could be blocked by DNA damage which can be repaired by transcription-coupled DNA repair (TCR) pathways. SUMOylation, another PTM (Post-translational modifications) like ubiquitination, is implicated in regulation of many DNA repair pathways including TCR, but it is not clearly understood how SUMOylation and associated enzymes are involved in regulation of such pathways. Here, we revealed the distinct role of SUMO ligases Siz1 and Siz2 in response to several DNA damaging agents such as UV, MMS (methyl methanesulfonate), HU (Hydroxyurea) and H2O2 (Hydrogen peroxide). Finally, we have extended our research works to understand the regulatory mechanisms of mRNA export by UPS. We found the interaction of TREX (Transcription/Export) component Sub2 with Mdm30 (F-box protein) for ubiquitination and proteasomal degradation of Sub2 in a transcription-dependent manner to regulate mRNA export. We also found the role CBC (Cap binding complex) in regulation of nuclear mRNA export. Collectively, the results of this study postulate a better understanding of regulation of transcription initiation, transcription elongation, and mRNA export by UPS.
23
Steffen, Janos. "Regulation des Ubiquitin-Proteasom-Systems in Säugetierzellen durch den Transkriptionsfaktor TCF11." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2010. http://dx.doi.org/10.18452/16184.
Повний текст джерелаАнотація:
Das Ubiquitin-Proteasom-System (UPS) ist das wichtigste System für den Abbau von nicht mehr benötigten oder beschädigten Proteinen innerhalb der eukaryotischen Zelle und ist somit an der Aufrechterhaltung der zellulären Homöostase beteiligt. Ein Abfall der proteasomalen Aktivität führt zu intrazellulärem Stress. Die Zelle wirkt diesem Abfall entgegen, indem sie die proteasomalen Gene verstärkt exprimiert und dadurch die Neubildung von 26S Proteasomen bewirkt. Während in der Bäckerhefe Saccharomyces cerevisiae mit Rpn4 der Transkriptionsfaktor für die verstärkte Expression identifiziert wurde, war dieser in Säugetieren noch nicht bekannt. In der vorliegenden Arbeit konnte TCF11 (transcription factor 11) als der verantwortliche Transkriptionsfaktor identifiziert werden, der in der humanen Endothelzelllinie Ea.hy926 die Transkription der proteasomalen Gene nach Proteasominhibition induziert. Unter physiologischen Bedingungen ist TCF11 ein N-glykosyliertes ER-ständiges Membranprotein, welches durch die ER-assoziierte Protein Degradation, unter der Mitwirkung des E3-Enzyms HRD1 und der AAA-ATPase p97, schnell abgebaut wird. Nach der Proteasominhibition kommt es zur Akkumulation von oxidierten Proteinen, und TCF11 wird aktiviert und in den Zellkern transportiert. Im Zellkern bindet TCF11 an AREs (antioxidant response element) in den proteasomalen Promotoren und aktiviert dadurch die Transkription der proteasomalen Gene. Darüber hinaus reguliert TCF11 auch die Expression von zahlreichen Enzymen, die die Ubiquitinierung von Proteinen katalysieren. Dadurch wird die zelluläre Homöostase wiederhergestellt und TCF11 sehr wahrscheinlich durch die neu gebildeten Proteasomen abgebaut. Die Ergebnisse der vorliegenden Arbeit zeigen auf, dass die Integrität des UPS nach Proteasominhibition in der humanen Endolthelzelllinie Ea.hy926 über einen TCF11 abhängigen Rückkopplungsmechanismus aufrechterhalten wird.The ubiquitin-proteasome-system (UPS) is the most important system for regulated protein degradation in eukaryotes. Therefore it is involved in the regulation of cellular homeostasis. Reduced proteasome activity results in proteotoxic stress. To counteract for reduced proteasome activity, eukaryotic cells enhance proteasome gene expression, which results in formation of new 26S proteasomes and recovery of physiological conditions. While in bakers yeast Saccharomyces cerevisiae the transcription factor Rpn4 is responsible for enhanced proteasome gene expression in response to proteasome inhibition, in mammals the responsible transcription factor was unknown. In this thesis, transcription factor TCF11 (transcription factor 11) was identified as a key regulator for 26S-proteasome formation in the human cell line Ea.hy926 to compensate for reduced proteolytic activity. Under non-inducing conditions N-glycosylated TCF11 resides in the endoplasmic reticulum (ER) membrane, where TCF11 is targeted to ER-associated protein degradation system requiring the E3-ubiquitin ligase HRD1 and the AAA-ATPase p97. Proteasome inhibitors trigger the accumulation of oxidant-damaged proteins, and promote the nuclear translocation of TCF11 from the ER, permitting activation of proteasome gene expression by binding of TCF11 to antioxidant response elements (ARE) in their promoter regions. Furthermore TCF11 controlls the expression of additional UPS-related genes. Thus the transcriptional feedback loop regulating human proteasome dependent protein degradation to counteract proteotoxic stress caused by proteasome inhibition was uncovered.
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Heessen, Stijn. "Regulation of the ubiquitin-proteasome system : characterization of viral and cellular stabilization signals /." Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-600-6/.
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Humbard, Matthew Adam. "Post-translational modification and the 20S proteasome system of the haloarchaeon Haloferax volcanii." [Gainesville, Fla.] : University of Florida, 2009. http://purl.fcla.edu/fcla/etd/UFE0024797.
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Reynolds, Emma. "Interactions between the ubiquitin proteasome system and mitochondria in ageing and neurological disorders." Thesis, University of Newcastle upon Tyne, 2015. http://hdl.handle.net/10443/2849.
Повний текст джерелаАнотація:
Mitochondrial dysfunction and protein aggregation (which is partly due to the decline of the ubiquitin proteasome system, UPS), are two commonly observed features of aging and age-related neurodegenerative diseases. There has been considerable recent interest in the ways in which the UPS interacts with mitochondria, particularly in the area of mitochondrial dynamics and quality control. It is not known if the age-related decline in proteasome efficiency could disrupt mitochondrial dynamics and quality control, causing mitochondrial dysfunction. In this study, I have used live-cell imaging to assess the effect of the UPS on mitochondrial dynamics in primary neurons. I found that complete disruption of the UPS greatly decreased mitochondrial motility, fission and fusion, whereas pharmacological inhibition of the deubiquitinase enzyme UCHL1 (which causes a physiologically relevant decline in the UPS) did not disrupt mitochondrial dynamics. Furthermore, I found that in UCHL1 knockout mice, mitochondria are not deficient in respiratory chain complexes I and IV; compromising the UPS does not cause mitochondrial dysfunction. UCHL1 knockout mice have a neurodegenerative phenotype characterized by impaired hind-limb function, tremor and kyphosis. Using immunohistochemistry, I demonstrated synaptic and axonal loss at the distal regions of long sensory axons that target the brainstem and cerebellum. The neuropathology of UCHL1 knockout mice is characterized by axonal spheroids, large axonal swellings containing synaptophysin, mitochondria and neurofilaments, which share some characteristics with spheroids that occur during ageing in human brains. I also studied the progression of axonal dystrophy in UCHL1 knockout mice and found that the accumulation of synaptophysin transport vesicles is central to axonal spheroid formation. Furthermore, I investigated whether the UPS is impaired in patients with mitochondrial disease, however found no evidence to suggest this. These findings indicate that the function of the UPS and mitochondria may be less tightly linked than previously thought.
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Brahemi, Ghali. "Design and synthesis of inhabitors of the ubiquitin-proteasome system as antitumour agents." Thesis, Cardiff University, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.587836.
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Louie, LeeAnn N. "Inhibition of the Ubiquitin Proteasome System Enhances Long-Term Depression in Rat Hippocampal Slices." Scholarship @ Claremont, 2013. http://scholarship.claremont.edu/scripps_theses/274.
Повний текст джерелаАнотація:
The ubiquitin proteasome system (UPS) depends on three enzymes called E1, E2, and E3 to ubiquitinate proteins and several isopeptidases to de-ubiquitinate them. Ubiquitination serves as a post-translational modification that either tags proteins for degradation by the proteasome or serves to modulate their function. This dynamic system plays a role in synaptic plasticity and dysfunction of the UPS is associated a variety of neurodegenerative diseases. In this study, three inhibitors the UPS, ziram, clasto-lactacystin β-lactone (lactacystin) and G5 were employed to illuminate involvement of the UPS in long-term and short term plasticity in area CA1 of rat hippocampal slices. Ziram, lactacystin and G5 inhibits the E1 ubiquitin-activating enzyme, the proteasome and isopeptidases, respectively. It was found that UPS inhibition enhanced long-term plasticity, by specifically increasing the magnitude of long-term depression (LTD) and altered short term plasticity, measured with paired pulse facilitation (PPF), to varying degrees. These findings establish that the UPS may play a regulatory role in LTD and PPF, and the changes in PPF further indicate that the UPS may be acting presynaptically. Overall, the results suggest ubiquitination and proteasome-mediated proteolysis are important in both long-term and short-term plasticity.
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Urbina, Armando. "Synthesis of a proteasome inhibitor containing a [Gamma]-lactam-[Beta]-lactone fused ring system." Diss., [La Jolla, Calif.] : University of California, San Diego, 2009. http://wwwlib.umi.com/cr/ucsd/fullcit?p1462105.
Повний текст джерелаАнотація:
Thesis (M.S.)--University of California, San Diego, 2009.Title from first page of PDF file (viewed March 19, 2009). Available via ProQuest Digital Dissertations. Includes bibliographical references (p. 43-44).
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Powis, Rachael Anita. "Targeting the ubiquitin proteasome system to develop novel therapeutic approaches for spinal muscular atrophy." Thesis, University of Edinburgh, 2016. http://hdl.handle.net/1842/25854.
Повний текст джерелаАнотація:
Spinal muscular atrophy (SMA) is a severe genetic neuromuscular disorder characterised by lower motor neuron degeneration and paralysis. Although it is a leading genetic cause of childhood death no approved treatment options currently exist. As SMA is caused by low levels of the survival motor neuron (SMN) protein the majority of therapeutic strategies under development are therefore aimed at trying to elevate SMN levels. However, a number of limitations with these approaches exist demonstrating a need for the investigation of SMN-independent therapeutics. Of these non-classical pathways, the ubiquitin proteasome system (UPS) is an exciting new area of SMA research. The UPS is a system which degrades unwanted or damaged proteins and alterations in the UPS (including reduced levels of ubiquitin-like modifier activating enzyme 1 [Uba1] and increased levels of ubiquitin carboxyl-terminal esterase L1 [Uchl1] and β-catenin) have been recently identified in the neuromuscular system of SMA mice, providing promising new targets for therapy development. In this thesis I demonstrate that UPS perturbations are also present in other organ systems of severe ‘Taiwanese’ SMA mice and in other SMA models including intermediate Smn2B/− mice, zebrafish and patient derived iPSC motor neurons. Given the previously demonstrated improved neuromuscular phenotype in SMA mice treated with the β-catenin inhibitor quercetin I have been establishing whether other compounds with β-catenin inhibition offer similar or even better therapeutic options. Aspirin, indomethacin and iCRT-14 trials did not improve the SMA phenotype with likely off-target adverse effects meaning that quercetin remains the most tolerable β- catenin inhibitor in SMA mice to date. Another potential target of the UPS for SMA therapeutics is the deubiquitinating enzyme Uchl1, levels of which are increased in SMA. In this thesis I show that pharmacological inhibition of Uchl1 did not improve survival or motor performance in SMA mice and instead had a detrimental impact on the disease phenotype which could be explained by worsening SMA ubiquitin defects. Histological analysis revealed that there was no improvement in lower motor neuron count numbers, neuromuscular junction deficits or muscle fibre diameters. Mimicking the UPS phenotype in primary neuronal cells suggested that targeting UPS perturbations observed in SMA that are upstream of Uchl1, particularly the loss of Uba1, may therefore offer a more effective therapeutic option. Finally, I therefore examined whether increasing Uba1 levels in SMA mice using gene therapy technology was able to improve the SMA phenotype. My initial studies indicate that delivery of AAV9-UBA1 to SMA mice may be beneficial as intraperitoneal injection of AAV9-UBA1 was found to increase the weight and improve motor performance of SMA mice. Intravenous delivery of AAV9-UBA1 was found to further improve expression levels and biodistribution of AAV9-UBA1 in the central nervous system as well as systemically in all body organs and tissues. Western blot and proteomic analysis revealed that AAV9-UBA1 gene therapy is also able to correct downstream UPS perturbations found in SMA as well as increase SMN levels. Together, these results suggest that AAV9-UBA1 gene therapy is an exciting novel therapeutic approach for SMA.
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Beaudette, Patrick Edmund. "Targeted quantitative proteomics in the NF-κB signalling pathway and the ubiquitin-proteasome system". Doctoral thesis, Humboldt-Universität zu Berlin, 2018. http://dx.doi.org/10.18452/19524.
Повний текст джерелаАнотація:
Die Aktivierung des NF-kB Vorläuferproteins p100 und p105 erfolgt durch eine proteasomale Trunkierung, um die aktiven p52 und p50 zu erzeugen. Zur Erforschung wurde eine Massenspektrometrie-basierende Proteomik-Strategie entwickelt, die mit der gezielten Reaktionsüberwachungstechnik plus einer Isotopenmarkierung verwendet wurde. In einem endogenen murinen embryonalen Fibroblasten-System konnte gezeigt werden, dass beide Vorläufer zu den jeweiligen Produkten in einer parallelen und sich einander bedingenden Weise in Reaktion auf einen Lymphotoxin-β-Rezeptor-Agonisten verarbeitet werden. Unsere SRM-SILAC- Methode erlaubte die Unterscheidung von Prä-Stimulationsprotein-Populationen aus Proteinen, die de novo nach der Stimulation synthetisiert wurden, und zeigte eine Tendenz für ältere Vorläufermoleküle, sich einer Degradation zu unterziehen, während die de novo-Moleküle auf die Produkte verarbeitet wurden. Die langsame und anhaltende Kinetik, die ein typisches Merkmal des nicht-kanonischen NF-κB- Weges ist. Darüber hinaus, konnten wir beobachten, dass die hydrolytische Aktivität der AAA ATPase VCP / p97 in der Bildung von de novo p52 und p50 eine Rolle spielt. Durch ein MS-basiertes Screening für strahlungsinduzierte Protein-Interaktoren eines weiteren NF-κB-Players, der die regulatorische Untereinheit des IKK-Komplexes IKKγ / NEMO bildet, konnte der Enhancer von mRNA Decapping 4 (EDC4) entdeckt werden. Durch die zusätzliche Untersuchung der E3-Ligase, Parkin, konnte eine Verbindung mit dem NF-κB-Weg durch eine lineare Ubiquitinierung hergestellt werden. Es konnte gezeigt werden, dass Parkin ist Hauptkomponenten des linearen Ubiquitin-Ketten-Assemblierungskomplexes (LUBAC). Die Proteomanalyse im Proteinkinase A (PKA) -Signalisierungsweg konnte zwei neuartige Regulationsformen identifizieren: K63-verknüpfte Polyubiquitinierung die katalytische Untereinheit von PKA, PKAC in Richtung eines lysosomalen pathways führt, und auch durch einen Pseudosubstrat-Hemmungsmechanismus.Activation of the NF-κB precursor protein p100 and p105 by a specific proteasomal truncation to yield the active products p52 and p50 is a distinct feature of the non- canonical pathway but the mechanism governing it remains elusive. A novel mass spectrometry-based proteomics strategy was developed, using the targeted selected reaction monitoring technique in conjunction with stable isotope labeling for both absolute quantitation of proteins and to mark precursor protein populations relative to the application of the lymphotoxin β stimulation. In an endogenous murine embryonic fibroblast system, we have shown that both precursors are processed to the respective products in a parallel and interdependent manner in response to a lymphotoxin β receptor agonist. Our Dynamic SRM-SILAC method allowed distinction of pre-stimulation protein populations from proteins synthesized de novo post- stimulation, and revealed a tendency for older precursor molecules to undergo degradation while the de novo molecules went on to be processed to the products, accounting for the slow and persistent kinetics that are a hallmark of the non- canonical NF-κB pathway. In addition, the hydrolytic activity of the AAA ATPase VCP/p97 was implicated in the generation of de novo p52 and p50. An MS-based proteomics screen for specific, radiation-induced protein interactors of another key NF-κB player, the regulatory subunit of the IKK complex, IKKγ/NEMO, turned up the Enhancer of mRNA Decapping 4 (EDC4). This unexpected finding has expanded the known role of NF-κB regulation of protein levels beyond transcription into mRNA stability. Separate investigations into the ubiquitin E3 ligase, parkin, connected it to the NF-κB pathway through a linear ubiquitination it helps catalyze on IKKγ/NEMO. Proteomic analysis of polyubiquitin in the protein kinase A (PKA) signalling pathway helped to identify two novel modes of regulation: a lysosomal degradation pathway; as well as a pseudosubstrate inhibition mechanism.
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Paula, Renato Graciano de. "Schistosoma mansoni: caracterização do perfil de resposta aos estresses oxidativo, térmico e químico." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/17/17131/tde-25042018-162523/.
Повний текст джерелаАнотація:
A esquistossomose mansônica é a segunda maior endemia parasitária do mundo em termos de extensão das áreas endêmicas e do número de pessoas infectadas com 200 milhões de pessoas acometidas. Esta doença é causada pelo parasito trematódeo Schistosoma mansoni, o qual apresenta adequados mecanismos de resposta ao estresse envolvendo a regulação da expressão gênica e proteica, reparo ou substituição de moléculas danificadas, recuperação do balanço redox, controle do ciclo celular e apoptose. O sistema ubiquitina- proteassoma é importante para manter a homeostase proteica durante o estresse celular. Inibidores do proteassoma podem interferir em processos como crescimento, progressão do ciclo celular e replicação, e os seus efeitos vem sendo caracterizados em muitos parasitos. Nosso laboratório demonstrou que MG132 reduz o número de esquistossômulos, a carga parasitária e a ovoposição em camundongos infectados com S. mansoni. Neste trabalho, são descritos os efeitos in vitro do estresse oxidativo, choque térmico e estresse químico em vermes adultos de S. mansoni. Observou-se alteração no perfil de expressão proteica durante estresse oxidativo e térmico, sendo identificadas dezoito proteínas upreguladas nestas condições. Estas proteínas estão envolvidas em muitas vias intracelulares como dobramento de proteínas, proteólise, ligação a íons cálcio, regulação de proteínas e resposta a estresse. Além disso, o estresse oxidativo gerou mudanças em vermes adultos de S. mansoni em processos como produção de ovos, motilidade, morfologia do tegumento, viabilidade e pareamento dos vermes. O estresse químico induzido com Curcumina, IBMX e MG132 aumentou a produção de ROS intracelular e alterou o perfil de expressão de enzimas antioxidantes em S. mansoni. As enzimas SmGPx1 e SmPGx2 tiveram a expressão aumentada no estresse com Curcumina e IBMX, enquanto que SmSOD e SmTGR foram induzidas no estresse com Curcumina. As enzimas do proteassoma SmHul5 e SmUbp6 tiveram a expressão modulada durante o estresse oxidativo, choque térmico e estresse químico. Em adição, a análise de expressão no ciclo de vida de S. mansoni revelou que estes genes apresentam um nível alto de expressão em esporocistos, esquistossômulos e miracídios. Estes resultados sugerem que estas proteínas acessórias do proteassoma participam da resposta ao estresse e desenvolvimento do parasito. O nível de expressão de SmHul5 e SmUbp6 foi cerca 9 e 16 vezes menor em relação ao controle no estresse químico induzido com IBMX, respectivamente, sugerindo a desmontagem do proteassoma. Por outro lado, Curcumina, MG132, estresse oxidativo e choque térmico aumentaram o nível de expressão de SmHul5 e SmUbp6. Além disso, o nível de expressão da proteína de maturação do proteassoma (SmPOMP) aumentou no estresse com Curcumina, MG132 e estresse oxidativo, sugerindo a síntese de novas populações de proteassoma. Em relação ao estresse oxidativo, nós demonstramos o aumento no nível proteico de proteassoma 20S e da subunidade alfa-3 do proteassoma sugerindo que em S. mansoni as proteínas oxidadas são degradadas pelo proteassoma 20S. Além do mais, nós observamos que vermes adultos de S. mansoni parecem utilizar mecanismos de resposta similares para diferentes estresses. Nossos resultados demonstraram que o estresse oxidativo, choque térmico e estresse químico modificam o perfil de expressão de genes relacionados ao sistema ubiquitina-proteassoma e sugerem que o proteassoma é importante para as respostas celulares ao estresse neste parasito.Schistosomiasis is a neglected tropical disease caused by blood flukes (genus Schistosoma) and affecting 200 million people worldwide. This disease continues to rank, following malaria, at the second position of the world\'s parasitic diseases in terms of the extent of endemic areas and the number of infected people. There are different types of stress and the organisms have many mechanisms to respond to these stressor agents. The responses involve the regulation of gene and protein expression and consist in events such as repair or substitution of damaged molecules, recovery of redox balance, cell cycle control and apoptosis. The proteasomal system is important to support the protein homeostasis during the cellular stress. Effect of proteasome inhibitors has been described in many protozoans, either inhibiting growth or cell cycle progression, or blocking replication. Our laboratory\'s results have shown that MG132 reduces the number of lung stage schistosomula, the worm burden and consequently decreases oviposition in S. mansoni-infected mice. Here, we describe the in vitro effects of oxidative stress, heat shock and chemical stress in S. mansoni adult worms. We report that the oxidative stress and heat shock cause drastic changes in the protein profile of S. mansoni adult worms, and we identified a total of eighteen upregulated proteins in these conditions. These proteins are involved with many intracellular pathways as protein folding, proteolysis, calcium ion binding, regulator proteins and stress response. In addition, oxidative stress induced with H2O2 generated significative changes in the adult worms concerning process such as egg production, motor activity, tegument morphology, viability and pairing of worms. Chemical stress induced with Curcumin, IBMX and MG132 increases ROS production and changes the gene expression profile of antioxidant enzymes of S. mansoni adult worms. The enzymes SmGPx1 and SmGPx2 were upregulated in Curcumin and IBMXinduced chemical stress, and both SmSOD and SmTGR were upregulated- Curcumin. The proteasomal enzymes SmHul5 and SmUbp6 had their gene expression modified during oxidative stress, heat shock and chemical stress. Besides of, expression analyses in the S. mansoni life cycle indicate that genes are different express in sporocyst, schistosomula and miracidia. These results suggest these accessory proteins proteasome participates of stress response and parasite development. The expression level of SmHul5 and SmUbp6 were 16 and 9 times less than the control in chemical stress induced by IBMX, and we suggest that these results are due to the proteasome disassembling. On the other hand, Curcumin, MG132, oxidative stress e heat shock increases the expression of SmHul5 and SmUbp6. Furthermore, the expression level of maturation proteasome protein (SmPOMP) increases in stress induced by Curcumin, MG132 and oxidative stress suggesting new proteasome synthesis. In addition, we demonstrate increase the both 20S level and alpha-3 subunit proteasome in the oxidative stress, suggesting that in S. mansoni oxidized protein formed due to oxidative damage are degrade by proteasome 20S. We observed that S. mansoni adult worms utilize similar mechanisms to respond different stresses. Ours results demonstrate that oxidative stress, heat shock and chemical stress modified the expression profile of genes related with the ubiquitinproteasome system and suggest that the proteasome is important to responses the cellular stresses in the parasite.
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Bhat, Kavita Purnanda. "Roles of the Ubiquitin-Proteasome System and Mono-ubiquitination in Regulating MHC class II Transcription." Digital Archive @ GSU, 2010. http://digitalarchive.gsu.edu/biology_diss/82.
Повний текст джерелаАнотація:
Major Histocompatibility Complex (MHC) class II molecules are indispensable arms of the im-mune system that present extracellular antigens to CD4+T cells and initiate the adaptive immune response. MHC class II expression requires recruitment of a master regulator, the class II trans-activator (CIITA). How this master transcriptional regulator is recruited, stabilized and degraded is unknown. The 26S proteasome, a master regulator of protein degradation, is a multi-subunit complex composed of a 20S core particle capped on one or both ends by 19S regulatory particles. Previous findings have linked CIITA and MHC class II transcription to the ubiquitin proteasome system (UPS) as mono-ubiquitination of CIITA increases its transactivity whereas poly-ubiquitination targets CIITA for degradation. Increasing evidence indicates individual ATPase subunits of the 19S regulator play non-proteolytic roles in transcriptional regulation and histone modification. Our initial observations indicate proteasome inhibition decreases CIITA transac-tivity and MHC class II expression without affecting CIITA expression levels. Following cyto-kine stimulation, the 19S ATPase Sug1 associates with CIITA and with the MHC class II enhan-ceosome complex. Absence of Sug1 reduces promoter recruitment of CIITA and proteasome inhibition fails to restore CIITA binding, indicating Sug1 is required for CIITA mediated MHC class II expression. Furthermore, we identify a novel N-terminal 19S ATPase binding domain (ABD) within CIITA. The ABD of CIITA lies within the Proline/Serine/Threonine (P/S/T) re-gion of CIITA and encompasses a majority of the CIITA degron sequence. Absence of the ABD increases CIITA half-life, but blocks MHC class II surface expression, indicating that CIITA requires interaction with the 19S ATPases for both its deployment and destruction. Finally, we identify three degron proximal lysine residues, lysines (K): K315, K330 and K333, and a phosphorylation site, serine (S), S280, located within the CIITA degron, that regulate CIITA ubiquitination, stability and MHC class II expression. These are the first lysine residues identified as sites of CIITA ubiquitination that are essential for MHC class II expression. These observations increase our understanding of the role of the UPS in modulating CIITA mediated MHC class II transcription and will facilitate the development of novel therapies involving manipulation of MHC class II gene expression.
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Siepe, Dirk. "Role of the peptidyl-prolyl cis/trans isomerase Pin1 in the ubiquitin proteasome system (UPS)." Diss., lmu, 2009. http://nbn-resolving.de/urn:nbn:de:bvb:19-116564.
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Jänicke, Laura Annika [Verfasser], and Martin [Gutachter] Eilers. "Regulation of MYC Activity by the Ubiquitin-Proteasome System / Laura Annika Jänicke. Gutachter: Martin Eilers." Würzburg : Universität Würzburg, 2015. http://d-nb.info/1111887241/34.
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Meiners, Silke [Verfasser]. "Inhibitors of the Ubiquitin-Proteasome System as Potential Therapeutic Agents for Cardiovascular Diseases / Silke Meiners." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2008. http://d-nb.info/1023022303/34.
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Keller, Martin. "Die Modulation des Ubiquitin-Proteasom-Systems als Immunevasionsmechanismus des malignen Melanoms." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2009. http://dx.doi.org/10.18452/15960.
Повний текст джерелаАнотація:
Die effiziente Präsentation von Tumorepitopen stellt einen kritischen Faktor zur Eliminierung von Tumorzellen durch die CD8+ cytotoxische T-Lymphozyten (CTL) vermittelte Immunantwort dar. Eine wichtige Rolle spielt in diesem Zusammenhang die effiziente Generierung von Tumorepitopen durch das Ubiquitin-Proteasom-System (UPS). Veränderungen von Komponenten des UPS, die an der Degradation und Prozessierung von Antigenen beteiligt sind, können daher zur Immunevasion von Tumorzellen gegenüber CTL führen. In der vorliegenden Arbeit wurden zwei unterschiedliche UPS-assoziierte Immunevasionsmechanismen des malignen Melanoms identifiziert, die auf einer ineffizienten Präsentation des immundominanten Tumorepitops Melan-A26-35 basieren. Ein Mechanismus beruht auf den unterschiedlichen katalytischen Eigenschaften von Proteasomsubtypen, deren Expression durch INFgamma induziert wird. Proteasomen, die einerseits die Immunountereinheiten beta1i und/oder beta2i beinhalten, oder anderseits mit dem Proteasomaktivator 28 (PA28) assoziiert sind, führen zu einer drastisch reduzierten Generierung des Tumorepitops Melan-A26-35. In beiden Fällen ist dies auf eine ineffiziente Prozessierung des N-Terminus des Epitops zurückzuführen. Der andere Immunevasionsmechanismus steht im Zusammenhang mit der ER-assoziierten Degradation (ERAD), die den retrograden Transport von Proteinen aus dem Endoplasmatischen Retikulum (ER) ins Cytosol zur proteasomalen Degradation beinhaltet. Durch Immunselektion mittels Melan-A26-35-spezifischen CTL wurden cytolyseresistente Melanomzellen identifiziert, deren Resistenz auf eine defiziente ER-assoziierte Degradation zurückzuführen ist. Dieser Defekt beruht auf einer verminderten Expression von ERAD-Komponenten, deren Reduktion die Verfügbarkeit des Antigens Melan-A zur proteasomalen Degradation und Generierung des immundominanten Epitops Melan-A26-35 wesentlich limitiert.Efficient presentation of tumor epitopes by MHC class I molecules on the cell surface is a prerequisite for the elimination of tumor cells by cytotoxic CD8+ T lymphocytes. The generation of these epitopes requires the degradation and processing of proteins by the ubiquitin proteasome system (UPS). Therefore alterations of UPS components can lead to tumor escape from immune recognition as a result of decreased epitope generation. In the present thesis two different UPS connected immune escape mechanisms of melanoma cells were identified. Both are based on an impaired generation of the immunodominant epitope Melan-A26-35 derived from Melan-A/MART-1 tumor antigen. One mechanism is mediated by the expression of different INFgamma-inducible proteasome immunosubunits leading to the formation of intermediate proteasome subtypes, which differ in their cleavage site preferences. Purified proteasomes harboring the immunosubunits beta1i and/or beta2i show a dramatic decrease in the generation of the Melan-A26-35 epitope. In addition, the INFgamma induced association of proteasomes with the proteaosome activator 28 (PA28) results in a reduced epitope generation. Both mechanisms are induced by an inefficient processing of the epitope’s N-terminus. The second immune escape mechanism is caused by defects of the ER-associated degradation pathway (ERAD). ERAD mediates the transport of ER-proteins back to the cytosolic compartment for proteasomal degradation. Via immunselection of tumor cells with Melan-A26-35 specific CTL, cytolysis resistant cells were identified. Resistance to CTL mediated lysis was shown to be connected to a decreased expression of ERAD components. This defect of the ERAD pathway limits the availability of the Melan-A protein and as consequence the generation of the immunodominant Melan-A26-35 epitope by proteasomes.
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Mohamed, Hala Alhadi Ali. "Alterations in cytoskeletal proteins and microtubule stability following 26S proteasome dysfunction in mouse brain cortical neurons." Thesis, University of Nottingham, 2017. http://eprints.nottingham.ac.uk/47188/.
Повний текст джерелаАнотація:
The mechanisms involved in the cause and progression of chronic neurodegenerative diseases are still unclear. The ubiquitin proteasome system (UPS) plays an essential role in the maintenance of intracellular protein homeostasis by degrading unwanted proteins. The accumulation of ubiquitinated proteins is a hallmark of major neurodegenerative diseases, including Alzheimer’s and Parkinson’s diseases. In most cases, these diseases are also associated with changes in cytoskeletal proteins and microtubule stability. We previously reported decreased levels of microtubule destabilizing protein stathmin (STMN) following 26S proteasome dysfunction in mouse cortical neurons; associated with neurodegeneration and the formation of intraneuronal protein inclusions in surviving neurons. This suggested a role for the 26S proteasome in maintaining the neuronal cytoskeleton. This thesis investigates the levels and localisation of cytoskeletal proteins in mouse cortical neurons following 26S proteasome dysfunction (Psmc1fl/fl;CaMKIIα-Cre). This study provides new insights into the role of the UPS in maintain cytoskeletal proteins that may be important in neurodegenerative disease. We found an early increase in neurofilaments following 26S proteasome dysfunction; before obvious changes in microtubule stability. An increased free/polymerised tubulin ratio was evident at later stages indicative of microtubule instability in Psmc1fl/fl;CaMKIIα-Cre mice. In addition, we found decreased levels of microtubule proteins, microtubule-associated proteins and detyrosinated-tubulin; with increased tyrosinated-tubulin following 26S proteasome dysfunction. These changes are contrary to decreased STMN expression observed in Psmc1fl/fl;CaMKIIα-Cre mice. We suggest that decreasing STMN may be part of a negative feedback loop to stabilize MT following 26S proteasome dysfunction. STMN is known to be a downstream target of p53, p27 and the PI3K/Akt pathway. We found expression of p53 was increased in the cortex following 26S proteasome dysfunction, correlating with decreased phosphorylated-Akt expression at an early stage and may effect STMN expression. However, we did not observe any significant differences in pro- and anti-apoptotic proteins of the Bcl-2 family between control and Psmc1fl/fl;CaMKIIα-Cre mice, which may also by effected by p53 and phosphorylated-Akt. Immunohistochemical studies revealed changes in cortical neuron morphology accompanied 26S proteasome dysfunction. Cortical thickness was significantly decreased; associated with less neurons in the layers III and V. However, nuclear size of cortical neurons was increased, as well as the length and arborisation of their apical dendrites. Taken together, our novel data contributes to our understanding of molecular and cellular events underlying neurodegeneration and suggest that control of microtubule changes may help to slow or restore pathology of neurons.
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Sotzny, Franziska. "Regulation des Ubiquitin-Proteasom-Systems unter proteotoxischem Stress." Doctoral thesis, Humboldt-Universität zu Berlin, Lebenswissenschaftliche Fakultät, 2016. http://dx.doi.org/10.18452/17599.
Повний текст джерелаАнотація:
Das Ubiquitin-Proteasom-System (UPS) stellt eines der wichtigsten zellulären Abbausysteme dar. Es vermittelt die Degradation fehlgefalteter, beschädigter sowie regulatorischer Proteine. Folglich ist es essentiell für die Proteinqualitätskontrolle und für eine Vielzahl zellulärer Prozesse. Eine Störung des UPS steht im engen Zusammenhang mit neurodegenerativen Erkrankungen und malignen Tumoren. Adaptive Mechanismen ermöglichen es der Zelle das UPS an den stetig schwankenden Bedarf proteolytischer Aktivität anzupassen. So wirkt eine erhöhte Expression proteasomaler Gene einem Abfall der proteasomalen Aktivität entgegen. Der Transkriptionsfaktor TCF11/Nrf1 wurde hierbei als Hauptregulator identifiziert. Unter physiologischen Bedingungen ist TCF11/Nrf1 in der ER-Membran lokalisiert und wird über das ER-assoziierte Degradationssystem (ERAD) abgebaut. In Antwort auf Proteasominhibition wird der Transkriptionsfaktor aktiviert und in den Nukleus transferiert. Hier vermittelt er durch Bindung der regulatorischen antioxidative response elements die Genexpression proteasomaler Untereinheiten. Die Ergebnisse dieser Arbeit zeigten, dass es sich bei diesem autoregulatorischen Rückkopplungsmechanismus um einen generellen adaptiven Regulationsmechanismus in Mammalia handelt. Zudem ergaben weitere Untersuchungen, dass der durch Proteasominhibition hervorgerufene oxidative Stress, die TCF11/Nrf1-vermittelte Aktivierung der Genexpression fördert. Die induzierende Wirkung von oxidativem Stress wurde ferner unter Verwendung des Pro-Oxidans Rotenon bekräftigt. Dieses Neurotoxin induziert die TCF11/Nrf1-abhängige Transkription proteasomaler Untereinheiten und folglich die Neubildung aktiver Proteasomkomplexe. Der Transkriptionsfaktor förderte ferner die Zellviabilität Rotenon-behandelter SH-SY5Y Zellen. Diese Ergebnisse demonstrieren, dass die TCF11/Nrf1-vermittelte Genexpression proteasomaler Untereinheiten bedeutend für die Aufrechterhaltung der Redox- sowie der Protein Homöostase ist.The ubiquitin proteasome system (UPS) represents a major protein degradation machinery. It facilitates the degradation of misfolded and damaged as well as regulatory proteins, thereby ensuring protein quality control and regulation of various cellular processes. Disturbances of the UPS are strongly associated with neurodegeneration and cancer. Adaptive mechanisms enable the cell to deal with changing demand in proteolytic activity. A rise in proteasomal gene expression compensates for decreased proteasomal activity. This adaption is mainly regulated by the transcription factor TCF11/Nrf1. Under unstressed conditions TCF11/Nrf1 resides in the ER-membrane where it is degraded via the ER-associated protein degradation system (ERAD). Proteasome inhibition causes the nuclear translocation of TCF11/Nrf1. In the nucleus, it mediates the gene expression of proteasomal subunits by interacting with their regulatory antioxidant response elements. Within this thesis, it was shown, that this autoregulatory feedback loop represents a general adaptive mechanism in mammalian cells. Moreover, experiments using antioxidative compounds revealed, that the oxidative stress induced by proteasomal inhibition promotes the TCF11/Nrf1-dependent proteasomal gene expression. The inducing effect of oxidative stress was verified using the pro-oxidant rotenone. This neurotoxin activates the transcription of the proteasomal genes resulting in the formation of newly synthesised, active proteasome complexes. Thus, TCF11/Nrf1 exerts a cytoprotective function in response to oxidative and proteotoxic stress in SH-SY5Y cells. In conclusion, this thesis revealed that TCF11/Nrf1-dependent induction of the proteasome expression promotes the maintenance of the redox as well as protein homeostasis.
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Tran, Karen. "Human cytomegalovirus subverts and utilizes components of the ubiquitin-proteasome system in facilitating a productive infection." Diss., [La Jolla, Calif.] : University of California, San Diego, 2009. http://wwwlib.umi.com/cr/ucsd/fullcit?p3386843.
Повний текст джерелаАнотація:
Thesis (Ph. D.)--University of California, San Diego, 2009.Title from first page of PDF file (viewed February 10, 2010). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 129-146).
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Vosper, Jonathan Matthew David. "Regulation of neurogenin stability by the Ubiquitin Proteasome System during the early development of Xenopus laevis." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612190.
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Reyskens, Kathleen Maria Simone Elise. "The maladaptive effects of HIV protease inhibitors (Lopinavir/Ritonavir) on the rat heart." Stellenbosch : Stellenbosch University, 2013. http://hdl.handle.net/10019.1/85782.
Повний текст джерелаАнотація:
Thesis (PhD)--Stellenbosch University, 2013.ENGLISH ABSTRACT: Although antiretroviral treatment decreases HIV-AIDS morbidity/mortality, long-term effects include onset of insulin resistance and cardiovascular diseases. Increased oxidative stress and dysregulation of the ubiquitin-proteasome system (UPS) are implicated in protease-inhibitor (PI)-mediated cardio-metabolic pathophysiology. We hypothesized that PI treatment (Lopinavir/Ritonavir) elevates myocardial oxidative stress and concomitantly inhibits the UPS, thereby attenuating cardiac function. Lopinavir/Ritonavir was dissolved in 1% ethanol (vehicle) and injected into mini-osmotic pumps that were surgically implanted into Wistar rats for eight weeks vs. vehicle and sham controls. Subsequently, we evaluated metabolic parameters and heart function (ex vivo and in vivo methods) at baseline and following ischemia-reperfusion. PI-treated rats exhibited weight gain, increased serum LDL-cholesterol, higher tissue triglycerides (heart, liver), but no evidence of insulin resistance. It also upregulated hepatic gene expression of acetyl-CoA carboxylase β and 3-hydroxy-3-methylglutaryl-CoA-reductase, key regulators of fatty acid oxidation and cholesterol synthesis, respectively. Further, PI-treated hearts displayed impaired UPS, increased superoxide dismutase (SOD) activity and unaltered superoxide levels, and elevated peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC-1α) peptide levels. Perfusion data revealed contractile dysfunction at baseline and following ischemia-reperfusion, while post-ischemic hearts exhibited decreased ATPase specific activity vs. matched controls. Early changes initiated by PI treatment resemble the metabolic syndrome and reflect a pre-atherogenic profile. Moreover, the effects of PIs on cardiac contractile function may in part be triggered by impaired UPS activity together with strain on the mitochondrial energetic system. Our study alerts to cardio-metabolic side effects of PI treatment and raises the question of the most appropriate co-therapies for patients on chronic antiretroviral treatment.
AFRIKAANSE OPSOMMING: Alhoewel anti-retrovirale behandeling MIV-VIGS morbiditeit/mortaliteit verlaag, bestaan daar langtermyn effekte soos die aanvang van insulienweerstandigheid en kardiovaskulêre siektes. Verhoogde oksidatiewe stres en wanregulering van die ubikwitien-proteosoomsisteem (UPS) word geïmpliseer met protease-inhibeerder (PI) gemediëerde kardio-metaboliese patofisiologie. Ons hipotetiseer dat PI behandeling (Lopinavir/Ritonavir) miokardiale oksidatiewe stres verhoog, en gevolglik die UPS inhibeer waardeur dit kardiale funksie verander. Lopinavir/Ritonavir is in 1% etanol (draer) opgelos en in ‘n mini-osmotiese pomp ingespuit wat chirurgies in Wistar rottes ingeplant is vir agt weke vs. draer en valskontroles. Gevolglik het ons die metabolise parameters en hartfunksie (ex vivo en in vivo metodes) op basislyn en na afloop van ischemie-reperfusie ondersoek. PI-behandelde rotte het ‘n toename in massa getoon asook verhoogde serum LDL-cholesterol, hoër weefseltrigliseriede (hart, lewer), maar geen bewys van insulienweerstandigheid nie. Dit het ook hepatiese asetielko-ensiem A karboksilase β en 3-hidrokise-3-metielglutariel KoA reduktase geenuidrukking opwaarts gereguleer, wat sleutel reguleerders van vetsuuroksidasie en cholesterolsintese onderskeidelik is. Verder, het PI-behandelde harte ingeperkte UPS, verhoogde SOD aktiwiteit en onveranderde superoksiedvlakke vertoon, asook verhoogde peroksisoomproliferator-geaktiveerde reseptor-γ ko-aktiveerder 1-α (PGC-1α) peptiedvlakke. Perfusie data toon kontraktiele wanfunskionering gedurende basislyn en na afloop van ischemie-reperfussie, terwyl post-ischemiese harte verlaagde ATPase spesifieke aktiwiteit vs gepaarde kontrole vertoon. Vroeë veranderinge wat deur PI behandeling veroorsaak word, kom ooreen met die metabolise sindroom en reflekteer op ‘n pre-aterogeniese profiel. Bowendien kan die effekte van PIs op kardiale kontraktiele funksie deels veroorsaak word deur die ingeperkte UPS aktiwiteit tesame met die las op die mitochondriale energie sisteem. Ons studie waarsku teen kardio-metaboliese newe effekte met PI behandeling en rig die vraag; wat die mees gepaste ko-behandeling vir pasiënte op chroniese anti-retrovirale behandeling is.
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Ligr, Martin. "Apoptosis in the yeast Saccharomyces cerevisiae a novel cell death process regulated by the Ubiquitin-Proteasome system /." [S.l. : s.n.], 2001. http://www.bsz-bw.de/cgi-bin/xvms.cgi?SWB9203728.
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Moonga, J. "In vivo dissection of the role of the ubiquitin proteasome system in the pathogenesis of prion disease." Thesis, University College London (University of London), 2012. http://discovery.ucl.ac.uk/1348373/.
Повний текст джерелаАнотація:
Prion diseases comprise a group of fatal neurodegenerative disorders caused by the conformational re-arrangement of a normal host-encoded prion protein, PrPC, to an abnormal infectious isoform, PrPSc. Currently, the precise cellular mechanism(s) of prion-mediated neurodegeneration remain unclear. However, increasing evidence suggests a role for the ubiquitin proteasome system (UPS) in prion disease pathogenesis, with a direct functional impairment of the 26S proteasome leading to the accumulation of UPS substrates in the brains of prion-infected mice. The UPS functions to regulate the targeted degradation of intracellular proteins and maintain cellular proteostasis. Alterations in proteasome proteolysis have been shown to contribute to the build up of proteins associated with aging and dysregulation of the UPS has been linked to several neurodegenerative diseases. The principal aim of this thesis was to characterise the progression of UPS dysfunction in vivo in the brains of prion-infected mice using a ubiquitin-GFP reporter mouse model. Using the UbG76V-GFP transgenic mouse model, UPS dysfunction was observed in the brain early in the prion disease incubation period, before key hallmarks of disease pathology were observed. The accumulation of Ub-GFP reporter coincided with markers of prion disease neuropathology, such as PrPSc deposition and extensive astrogliosis. The majority of cells in which the Ub-GFP reporter was observed in the thalamus appeared to be astrocytes, suggesting that altered proteolysis and reactive astrocyte pathology may be linked. Ubiquitin levels were increased significantly in the brains of prion infected mice, while 26S proteasome peptidase activity was reduced. Behavioural abnormalities and motor skills deficits were also observed in prion-infected UbG76V-GFP mice, which may correlate to neuronal loss and/or synaptic dysfunction associated with impairment of the UPS machinery. Collectively, the data presented in this thesis provide evidence of an early and potentially important role for UPS dysfunction in prion disease pathogenesis.
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Schormann, Eileen Josephine [Verfasser]. "Perturbations of proteostasis networks in Alzheimer´s disease: Focus on the ubiquitin proteasome system / Eileen Josephine Schormann." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2019. http://d-nb.info/1180388089/34.
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Kumar, Lalit. "DEVELOPMENT OF NOVEL CHEMICAL TOOLS FOR PROTEASOME BIOLOGY & A NEW APPROACH TO 1-AZASPIROCYCLIC RING SYSTEM." UKnowledge, 2012. http://uknowledge.uky.edu/chemistry_etds/14.
Повний текст джерелаАнотація:
The proteasome, a multiprotease complex, is clinically validated as an anticancer target by the FDA approval of bortezomib and carfilzomib for the treatment of multiple myeloma. The emergence of resistance to proteasome inhibitors however remains a major clinical challenge. Recently, distinct types of proteasomes termed ‘intermediate proteasomes’, which contain unconventional mixtures of catalytic subunits, have been implicated with drug resistance of tumor cells. In elucidating the role of intermediate proteasomes in drug resistance, a crucial step is to unequivocally determine the subunit composition of intermediate proteasomes in cells. With this in mind, the goal of the studies reported in this dissertation is to develop novel chemical tools which can facilitate the investigation of intermediate proteasomes via two complementary approaches: a FRET-based approach and a bifunctional cross-linking approach.
Chapter 2 describes the structure-based design, synthesis, and characterization of a peptide epoxyketone-based fluorescent probe, named as LKS01-B650, which selectively targets the immunoproteasome subunit β5i/LMP7. In addition to its utility in determining the identity of intermediate proteasomes as FRET-based probe, this imaging agent may also serve as a valuable tool in visualizing the immunoproteasome in living cells.
Chapter 3 describes the design and synthesis of various epoxyketone-based bifunctional agents. The ability of these bifunctional agents to cross-link different catalytic subunits within a proteasome complex is shown by mobility shift assays.These bifunctional agents may provide important information in determining the subunit composition of proteasomes.
Chapter 4 describes a systematic study of the relationship between the proteasome inhibitor structure and the inhibitory activity against critical subunits of the proteasome. Given the reported role of β5i/LMP7 in autoimmune diseases, this study may provide useful insights in developing therapeutic agents for autoimmune diseases as well as other diseases.
Chapter 5 describes a separate study which is not related to proteasome biology. A concise approach to synthesize 1-azaspirocyclic ring systems is developed by utilizing a novel semi-pinacol/Beckmann rearrangement. Additionally, an environmentally benign, microwave-assisted, and solvent-free self-condensation of carbonyl compounds is reported.
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Hope, Andrew Donald. "A molecular and cellular investigation of the role of the ubiquitin-proteasome system and tau in neurodegeneration." Thesis, University College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.408079.
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Willeumier, Kristen Carol. "The role of parkin and the ubiquitin proteasome system in the regulation of the synaptic vesicle cycle." Diss., Restricted to subscribing institutions, 2007. http://proquest.umi.com/pqdweb?did=1456284581&sid=2&Fmt=2&clientId=1564&RQT=309&VName=PQD.
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Biquand, Elise. "Delineating the interplay between the PB2 protein of influenza A viruses and the host Ubiquitin Proteasome System." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC258/document.
Повний текст джерелаАнотація:
On estime que 10%-20% de la population mondiale est infectée chaque année par des virus influenza A (IAV) saisonniers, causant 250 à 500 000 morts. De plus ces virus présentent des risques de pandémie, et sont à ce titre un problème de santé publique majeur. Le cycle viral est dépendant de la capacité du virus à manipuler le protéome cellulaire. Par ailleurs, le système ubiquitine-protéasome (SUP) cellulaire est impliqué dans de nombreux processus de régulation cellulaires par l'induction de la dégradation de protéines, ou par la modification de leur activation ou de leur localisation sub-cellulaire. Le SUP est une cible privilégiée des virus lors de l'infection. Des études récentes indiquent qu'un réseau d'interactions entre les protéines virales des IAV et les protéines du SUP pourrait contribuer à la réplication virale et l’échappement du virus face au système immunitaire. Cependant ces interactions restent encore mal connues. Nous avons construit une banque contenant 570 facteurs du SUP, ce qui représente environ 60% des facteurs SUP humains connus. Puis nous avons mis au point une méthodologie permettant de réaliser un crible comparatif des interactions entre cette banque SUP et cinq PB2 provenant de souches de virus influenza A de virulence différentes chez l’homme : deux souches saisonnières circulant actuellement dans la population humaine (H1N1pdm09 et H3N2), deux souches hautement pathogènes chez l’homme (H7N9 et H1N1-1918) et une souche de laboratoire (H1N1-WSN). Cette première phase de cartographie a permis de sélectionner 42 facteurs du SUP interagissant avec au moins une des protéines PB2 étudiées. Par ailleurs, l’analyse des similarités de profils d’interaction PB2/UPS des souches étudiées a permis de mettre en évidence une corrélation avec le temps de circulation de chaque souche dans la population humaine. Nous avons ensuite caractérisé le rôle fonctionnel des partenaires de PB2 dans le cycle viral par des expériences de déplétion transitoire de l’expression des facteurs cellulaires par siARN, et validé 36 des 42 facteurs testés. La très grande quantité de facteurs identifiés impliqués dans le cycle viral démontre la qualité de la méthodologie développée pour l’identification de ces interacteurs. Parmi ces facteurs, nous avons étudié plus en détail le rôle de trois deubiquitinases (DUBs) dans l’infection. Nous avons montré que les DUBs sont impliquées dans les phases précoces et tardives du cycle viral. De plus, avec des collègues de Hong Kong nous avons mis en évidence que la DUB OTUB1 est impliquée dans la réponse cellulaire à l’infection produisant des cytokines, et probablement dans l’assemblage des nouveaux virions. Nous avons identifié que la DUB OTUD6A est également impliquée dans les phases tardives du cycle viral. A l’inverse PAN2 qui fait partie des complexes de poly-d’adénylation est impliqué dans les phases précoces. Nous poursuivons nos études afin d’élucider le rôle de ces DUBs dans l’infection par IAVAn estimated 10%-20% of the world's population is affected each year by seasonal epidemic influenza, causing about 250,000 to 500,000 fatal cases. The pandemic risk reinforces the trait of influenza A virus (IAV) infection as a public health issue. The virus life cycle critically relies on its ability to manipulate the host proteome. Besides, the ubiquitin-proteasome system (UPS) is involved in many regulatory processes in mammalian cells by inducing protein degradation, mediating protein activation or shaping their sub-cellular localisation. Therefore, UPS is a prime target hijacked by viruses. Recent evidence indicates that an intricate regulatory network involving viral proteins and the cellular UPS is likely to contribute to viral replication and immune evasion of influenza A viruses. However, usurpation of the host UPS by IAV is far from being comprehensively deciphered. To gain better understanding, we assessed the interplay between the human UPS and the PB2 subunit of the influenza A virus polymerase through a global proteomic profiling approach. For that purpose, an UPS-dedicated library of 590 human cDNAs, comprising 63% of the whole human UPS, was constituted and characterised. In an initial screen, UPS factors were challenged using a high-throughput split luciferase assay for interaction with the PB2 protein from 5 influenza A strains of different pathogenicity in human. A total of 80 UPS factors emerged as potential PB2 partners, of which 42 were validated as high-confidence PB2 partners for at least one of the strains. Further comparison of interaction profiles of the 5 PB2 with the UPS by hierarchical clustering revealed an interaction dendrogram fitting with the circulation time in the human population.Functional importance of interactors was tested by siRNA-mediated knock down experiments using luciferase tagged recombinant IAV viruses. Depletion of 36 out of the 42 tested UPS factors showed an effect on the infection with all or a subset of IAV strains, underlying the strong functional output of the developed methodology. Among these factors three deubiquitinases (DUBs) were further studied to decipher their involvement in IAV viral cycle. We have shown that they are involved in early and late stage of the infection and began to draw their function in viral cycle. We demonstrated with our colleagues in Hong-Kong that OTUB1 is involved in the host cytokine response and most probably in virus assembly. OTUD6A was also shown to be implicated in late stages of the infection but we still don't know its exact role. Contrariwise, the inactive DUB PAN2, which is part of poly-deadenylation complexes, is implicated in early phase of IAV infection, but surprisingly apparently not through viral mRNA regulation. More work is on-going to precise by which mechanisms these DUBs are implicated in IAV infection
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Schormann, Eileen [Verfasser]. "Perturbations of proteostasis networks in Alzheimer´s disease: Focus on the ubiquitin proteasome system / Eileen Josephine Schormann." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2019. http://d-nb.info/1180388089/34.
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