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1
Tickenbrock, Lara. "Das Tumorsuppressor-Protein APC strukturelle und biochemische Aspekte /." [S.l.] : [s.n.], 2002. http://deposit.ddb.de/cgi-bin/dokserv?idn=966017064.
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2
Hankey, William C. IV. "Chromatin-associated functions of the APC tumor suppressor protein." The Ohio State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=osu1480198247672881.
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3
Cuddihy, Jane. "The non-Wnt functions of APC : unravelling the link between APC and apoptosis." Thesis, University of Dundee, 2016. https://discovery.dundee.ac.uk/en/studentTheses/bfb0d6ce-149b-4152-a591-943d61e2c714.
Повний текст джерелаАнотація:
Colorectal cancer (CRC) is the second most common cause of cancer-related death in the UK and Western world. More than 90% of sporadic CRCs harbour mutations in the multi-functional tumour suppressor gene Adenomatous polyposis coli (Apc). The most commonly studied function of APC is its role as a scaffold for the β-catenin destruction complex involved in Wnt signalling. However, APC binds many other proteins. For example, it directly binds to and stabilises microtubules and actin. These non-Wnt related functions of APC are poorly understood. My PhD examines non-Wnt functions of APC. To this end, I created degron-tagged APC in DT40 cells that allowed for the rapid, conditional degradation of endogenous APC. The aim was to identify the immediate effects on cellular processes. Then, to identify the contribution of different APC domains by measuring the ability to rescue any defects when reintroducing fragments of APC. However, creation of these degron-tagged Apc knock-in cell lines resulted in hypomorphic phenotypes and auxin-associated off-target effects. Nonetheless, I compared the response of APChigh, APClow, and APCminimal cells to DNA damaging agents and Taxol® but found no significant differences. Subsequently, I focused on the relationship between APC and apoptosis. Previous observations suggested that deficiency in Apc rendered cells less sensitive to low doses of Taxol®. However, Apc deficient cells were more readily killed when Taxol® was combined with the Bcl-2 inhibitor, ABT-737. One possible explanation is the increase in Bcl-2 protein upon Apc depletion. However, I found that ABT-737, Taxol® and Apc depletion each cause activation of the unfolded protein response. This suggests that these treatments elicit a stress response that can stimulate apoptosis. Moreover, the same treatments also cause changes in mitochondria. Importantly, all of these effects do not require an increase in the β-catenin protein. Together, my data reveal novel links between APC and apoptosis that could be exploited clinically.
4
Vijaya, Chandra Shree Harsha [Verfasser], and Jürgen [Akademischer Betreuer] Behrens. "Functional analysis of truncated APC protein in human colorectal cancers = Funktionelle Analyse von verkürztem APC Protein in humanem kolorektalen Krebs / Shree Harsha Vijaya Chandra. Betreuer: Jürgen Behrens." Erlangen : Universitätsbibliothek der Universität Erlangen-Nürnberg, 2011. http://d-nb.info/1015474802/34.
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5
Yu, Yao. "Endothelial cell signalling of APC and thrombin : the involvement of protein kinase C." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/18048.
Повний текст джерелаАнотація:
Activated protein C (APC) is a natural anticoagulant. In addition to this well-described function, APC also mediates endothelial cell (EC) cytoprotection, including anti-apoptotic, anti-inflammatory and endothelial barrier integrity stabilising effects. APC confers these effects through proteolytic activation of protease activated receptor 1 (PAR1), but only when it is bound to its receptor, endothelial protein C receptor (EPCR). Interestingly, thrombin exerts opposing cellular responses (including induction of endothelial hyperpermeability) through activation of PAR1. How activation of the same receptor can mediate such different signals remains unclear. I hypothesised that, downstream of PAR1 cleavage, activation of different protein kinase C (PKC) isoforms may account for the divergent signal transduction. The aim of my thesis was to explore the contribution of specific PKC isozyme(s) that are involved in APC and thrombin mediated signalling. To do this, I expressed, purified and characterised a panel of APC variants lacking either anticoagulant activity, EPCR binding, PAR1 binding or proteolytic activity. I demonstrated that both APC and thrombin activate Erk1/2 pathway in the endothelial cells in a dose and time-dependent manner. APC also dose-dependently stabilised endothelial monolayer integrity, whereas thrombin disrupted this. APC’s cytoprotective properties, based on this established cell assay model, were found to be PAR1 and EPCR dependent. Using peptides that inhibit specific PKC isozymes, I found that the atypical PKCζ isozyme, was involved in Erk1/2 phosphorylation triggered by thrombin and both classical PKC isozymes (PKCβ1) and PKCζ were involved in the hyperpermeability induced by thrombin. In contrast, no PKC isozyme was found to play roles in the APC-mediated Erk1/2 activation as well as EC permeability reduction. These findings might indicate that the difference in PKC involvement may contribute to the diverse intracellular signalling pathways of APC and thrombin, and hence their opposite cellular responses.
6
Shen, Ying. "Regulation of EphA4 expression through the APC-mediated ubiquitin-proteasome pathway /." View abstract or full-text, 2007. http://library.ust.hk/cgi/db/thesis.pl?BICH%202007%20SHEN.
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7
Mills, Kate May. "A novel role for Adenomatous Polyposis Coli protein in the transport of mitochondria." Thesis, The University of Sydney, 2015. http://hdl.handle.net/2123/14184.
Повний текст джерелаАнотація:
Adenomatous Polyposis Coli (APC) is a multifunctional tumour suppressor protein, contributing to pathways in normal cell growth and differentiation. APC gene mutation is one of the earliest events in the progression of colorectal cancer (CRC), and typically gives rise to a truncated protein lacking C-terminal sequences, initiating deregulation of key cellular pathways. This thesis describes a new role for APC in mitochondrial transport. Silencing of wild-type APC by siRNA induced a redistribution of mitochondria from the cell periphery to the perinuclear region. Subsequently, novel interactions for APC were identified at the mitochondria with kinesin-motor complex proteins Miro/Milton. These interactions were mapped to the C-terminus of APC, correlating with defective mitochondrial transport and loss of Miro/Milton binding in CRC cells, which were restored by reconstitution of wild-type APC. Analysis by live cell imaging showed that loss of APC slowed the frequency of mitochondrial anterograde transport towards the cell periphery. It is proposed that APC drives mitochondria to the membrane to supply energy required for directed cell migration, a process disrupted in CRC. This opens up a new route through which CRC-associated APC mutations may contribute to carcinogenesis.
8
Dieckhoff, Patrick. "Protein modification and degradation in the cell cycle of the yeast Saccharomyces cerevisiae." Doctoral thesis, [S.l. : s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972638644.
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9
Quyn, Aaron J. "The role of the APC protein in mitotic spindle orientation and tissue organisation in gut epithelium." Thesis, University of Dundee, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.505629.
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10
Zimmermann, Julia Janina [Verfasser]. "Untersuchung des Einflusses verschiedender Liganden auf die Inaktivierungskinetik von aktiviertem Protein C (APC) / Julia Janina Zimmermann." Bonn : Universitäts- und Landesbibliothek Bonn, 2015. http://d-nb.info/1080591761/34.
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11
Sumner, Evan T. "Characterizing the Oncogenic Properties of C-terminal Binding Protein." VCU Scholars Compass, 2016. http://scholarscompass.vcu.edu/etd/4153.
Повний текст джерелаАнотація:
The paralogous C-terminal binding proteins (CtBP) 1 and 2 are evolutionarily conserved transcriptional coregulators that target and disrupt the expression of several genes essential for multiple cellular processes critical to regulating tumor formation. CtBP’s ability to govern the transcription of genes necessary for apoptosis, tumor suppression, invasion/migration and EMT gives rise to its oncogenic activities. Both isoforms of CtBP are found to be overexpressed in cancers including colorectal, pancreatic, ovarian, and breast, with higher levels correlating to lower overall median survival. Although multiple lines of evidence suggest CtBP plays a role in tumorigenesis, it has never been formally characterized as an oncogene. For this reason, the goal of this dissertation was to design a set of experiments to determine the transforming ability of CtBP2 in vitro using both murine and human fibroblast and in vivo using the Apcmin/+ mouse model of cancer. Specifically, we demonstrate that overexpression of CtBP2 alone can drive transformation of NIH3T3 cells leading to loss of contact inhibition, increased x invasion/migration, and anchorage independent growth. In addition, CtBP2 was found to cooperate with the large T-antigen (LT) component of the simian virus 40 (SV40) to lead to transformation of murine embryonic fibroblasts (MEFs) and with both LT and small T-antigen (ST) to induce migration/invasion and anchorage-independent growth in BJ human foreskin fibroblasts. To confirm the role of Ctbp2 in a mouse tumor model with Ctbp overexpression, we bred Apcmin/+ mice to Ctbp2 heterozygous (Ctbp2+/-) mice, which otherwise live normal lifespans. CtBP is a known target of the APC tumor suppressor and is thus stabilized in APC mutated human colon cancers and is found in high levels in Apcmin/+ polyps. Remarkably, removing an allele of Ctbp2 doubled the median survival of Apcmin/+ mice (P <0.001) and reduced polyp formation to near undetectable levels. These data suggest the importance of CtBP2 in driving cellular transformation and identify it as a potential target for prevention or therapy in APC mutant backgrounds.
12
Lafargue, Mathieu. "Plasminogen Activator Inhibitor-1 (PAI-1) and Activated Protein C (aPC) Modulation Mechanisms of Pseudomonas aeruginosa Induced Pulmonary Edema." Thesis, Bordeaux 2, 2012. http://www.theses.fr/2012BOR22020/document.
Повний текст джерелаАнотація:
Une coagulopathie aigue endogène (EAC) est présente chez 25% des patients de traumatologie dès leur arrivée. Des résultats d’études récentes montrent que cette EAC est liée à l’activation de la voie de la protéine C (aPC). Quelques heures après, se développe un état pro-coagulant associant un niveau abaissé d’aPC et un taux plasmatique élevé de l’inhibiteur de l’activateur du plasminogene (PAI-1). Nous trouvons que l’incidence des pneumopathies associées à la ventilation est significativement augmentée chez ces patients sans toutefois connaître le rôle exact de ces anomalies de coagulation. Basé sur cette hypothèse central de susceptibilité augmentée a l’infection et plus particulièrement aux pneumopathie a P.aeruginosa (PA) le but de ce travail est d’identifier les mécanismes par lesquels PAI-1 et aPC peuvent moduler la perméabilité de la barrière alveolo capillaire et ceci a travers 3 objectifs spécifiques1 – Objectif 1 : déterminer les mécanismes par lequel PA augmente la perméabilité endothéliale. 2 – Objectif 2 : déterminer le rôle d’aPC dans la modulation des effets de PA sur l’œdème pulmonaire lésionnel.3 – Objectif 3 : déterminer le rôle de PAI-1 dans la modulation des effets de PA sur l’œdème pulmonaire lésionnel.En utilisant un inhibiteur spécifique des petites GTPases nous démontrons le rôle centrale joué par RhoA dans le développement de l’œdème pulmonaire induit par PA. PAI-1 et aPC sont impliquées dans le mécanisme lésionnel pulmonaire. aPC et l’inhibition de la voie du RhoA attenue le développement de l’œdème pulmonaire et diminue la dissémination systémique bactérienne. Cependant le blocage invivo de la voie de PAI-1 est associé à une surmortalité et à une augmentation de la charge bactérienne suggérant un rôle de PAI-1 dans l’activation de la réponse inflammatoire nécessaire a l’éradication de PAA clinically significant acute endogenous coagulopathy (EAC) is present in 25% of major trauma patients upon arrival in the emergency department, before any fluid resuscitation. Results from recent clinical studies indicate that EAC is primarily caused by the activation of the anticoagulant protein C pathway. Several hours later, there is the development of a systemic procoagulant activity associated with low plasma levels of activated protein C (aPC) and an inhibition of the fibrinolysis caused by elevated plasma levels of plasminogen activator inhibitor 1 (PAI-1). We have found that the incidence of ventilator-associated pneumonia (VAP) is significantly increased in trauma patients with these coagulation abnormalities [6, 9]. However, whether these coagulation abnormalities play a mechanistic role in the increased susceptibility to nosocomial lung infection observed after severe posttraumatic hemorrhage is unknown. Thus, the central hypothesis is that the increased susceptibility to P. aeruginosa (PA) pneumonia following severe trauma with tissue hypoperfusion is mediated in part by these posttraumatic coagulation abnormalities within the airspaces of the lung. Specifically, in this work, we will identify through 3 specific aims the mechanisms by which PAI-1 and aPC modulate PA–mediated increase in alveolar-capillary barrier permeability.1 - Specific Aim 1: To determine the mechanisms by which PA increases lung endothelial permeability.2 - Specific Aim 2 : To determine the Role of aPC in modulating the effect of PA on the lung endothelial barrier function3 - Specific Aim 3 : To determine the Role of PAI-1 in modulating the effect of PA on the lung endothelial barrier functionIn the present work, we demonstrated the central role small GTPases RhoA plays in the increase of permeability induced by pseudomonas infection. PAI-1 and aPC are deeply involved in the control of early lung inflammation. aPC and inhibition of the RhoA pathway attenuates the development of pulmonary edema and decrease in the systemic dissemination of P. aeruginosa. However, in vivo disruption of PAI-1 signalling is associated with higher mortality at 24 h and significant increase in the bacterial burden suggesting that PAI-1 is required for the activation of the innate immune response necessary for the eradication of PA from the distal airspaces of the lung
13
Dupasquier, Sébastien. "SOX9, un lien moléculaire entre voie Wnt/APC et PKCalpha dans l'épithélium intestinal sain et tumoral." Montpellier 1, 2008. http://www.theses.fr/2008MON1T041.
Повний текст джерелаАнотація:
Les cellules tumorales présentent des variations parfois importantes du taux de certaines protéines qui leur procurent un avantage sélectif de croissance par rapport aux cellules normales dont elles dérivent. Ces variations peuvent résulter d'altérations de l'ADN, premier support de l'information génétique, la transcription, la maturation et/ou la stabilité de l'ARN messager, ou encore la traduction et/ou la dégradation de la protéine. Les protéines kinases C (PKC) sont impliquées dans de nombreux processus cellulaires associés à la tumorigenèse, notamment le contrôle de la prolifération, de la différenciation et de l'apoptose. Or, d'importantes variations de leurs niveaux d'accumulation sont observées dans de nombreuses tumeurs humaines. Néanmoins, le lien causal entre les mécanismes régulant la transcription, la traduction ou encore la stabilité et la dégradation des PKC et ces variations est rarement établi. Nous avons pour notre part démontré que l'expression de PKCα est réprimée aussi bien in vitro qu'in vivo par le facteur de transcription SOX9 dans les cellules épithéliales intestinales. Cette répression ne nécessite pas l'interaction de SOX9 avec l'ADN via son domaine HMG mais est médiée par un nouveau mécanisme impliquant la région centrale de SOX9, très conservée entre les membres du groupe des SOXE (SOX8, 9, 10). Puisque SOX9 est une cible de la voie Wnt/APC dans les cellules épithéliales intestinales, nos résultats établissent un lien moléculaire entre voie Wnt/APC et PKCα et permettent d'expliquer pourquoi PKCα est diminuée dans les cancers colorectaux qui présentent pour 80% d'entre eux une activation constitutive de la voie Wnt/APC.
14
Arlt, Roman [Verfasser], Ralf [Akademischer Betreuer] Junker та Thorsten [Gutachter] Feldkamp. "Erstellung einer Referenzwertkohorte für Quick, D-Dimer, Faktor II, Faktor V, Faktor VII, Faktor X, Plasminogen, α2-Antiplasmin, Protein C, Protein-C-Aktivität, APC-Resistenz, freies Protein S, Protein-S-Aktivität, Fibrinogen und Prothrombinfragment 1+2 anhand eines gesunden norddeutschen Blutspenderkollektivs / Roman Arlt ; Gutachter: Thorsten Feldkamp ; Betreuer: Ralf Junker". Kiel : Universitätsbibliothek Kiel, 2019. http://d-nb.info/1220288098/34.
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15
Bolte, Melanie. "Regulation of the anaphase promoting complex (APC-C) in the mitotic and meiotic cell cycle of Saccharomyces cerevisiae." Doctoral thesis, [S.l.] : [s.n.], 2004. http://webdoc.sub.gwdg.de/diss/2004/bolte/bolte.pdf.
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16
Jordan, Sumanas W. "A mathematical model of tissue factor-induced blood coagulation: discrete sites of initiation and regulation under conditions of flow." Diss., Georgia Institute of Technology, 2010. http://hdl.handle.net/1853/33907.
Повний текст джерелаАнотація:
A mathematical model of blood coagulation under defined flow conditions, initiated and modulated by spatially discrete regions of surface bound tissue factor (TF) and thrombomodulin (TM), respectively, is presented. The model incorporates fluid phase and surface-associated reactions of the extrinsic, intrinsic, and common pathways, as well as three inhibitory pathways. The spatially heterogeneous model is formulated by finite element method, and an effective prothrombotic zone, which quantifies the spatial propagation of thrombin generation is defined. Characteristic features of coagulation are simulated under physiologic conditions, and the behavior of the system in response to perturbations in TF and TM surface densities, TF site dimensions, and wall shear rate is explored. The major findings of these studies include: (i) The model system responds in an 'all-or-none', threshold-like manner to changes in model parameters. (ii) It was found that prothrombotic effects may extend significantly beyond the dimensions of the spatially discrete site of TF expression in both axial and radial directions. (iii) The relationship between the length of the effective prothrombotic zone and the interval distance between tandem sites of TF expression dictate the net response of the system. Additive prothrombotic effects of sub-clinical lesions as well as suppressive antithrombotic effects of intervening TM-containing regions were observed. Secondly, the computational model is applied to calculate an individualized, systems-based metric of clotting potential for 210 pre-menopausal women in the Leiden Thrombophilia Study (LETS). The simulated variable was found to be a highly predictive parameter for deep venous thrombosis risk.
17
Gold, Matthew. "Targeting AGC protein kinases." Thesis, Institute of Cancer Research (University Of London), 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.504788.
Повний текст джерелаАнотація:
A-kinase anchoring proteins (AKAPs) restrict the action of the broad-specificity cyclic AMP-dependent protein kinase (PKA) to discrete subcellular locations. The highresolution crystal structure of the docking and dimerisation (D/D) domain of the RIIa regulatory Bubunit of PKA in complex with the high-affinity anchoring peptide AKAP-IS explains the molecular basis of AKAP specificity for PKA regulatory subunits. AKAPIS folds into an amphipathic a-helix that engages an essentially preformed shallow groove on the surface of the RUa dimer D/D domains. Conserved AKAP aiiphatic residues dominate interactions to RUa at the predominantly hydrophobic interface, whereas polar residues are important in conferring regulatory subunit isoform specificity. Structural information for the AKAP family was previously limited to studies of the PKA-AKAP interface. To address this deficiency, a bioinformatic screen of AKAPs was performed to identify domains within AKAPs that might be suitable for structural investigation. A central domain in AKAP18 was identified, and its crystal structure was solved. The domain is structurally similar to 2H phosphoesterase enzymes, which catalyse the hydrolysis of cyclic nucleotides, with a central groove at the base of which two His-x-Thr motifs are positioned. The domain binds specifically to 5' AMP/CMP, with a dissociation constant for AMP in the physiological range, and the molecular basis for nucleotide specificity has been established. No catalytic activity was associated with the domain, so it may function as an AMP sensor. AKAP79 is a prototypical mammalian scaffold protein, which nucleates mUlti-protein kinase-phosphatase complexes, and localises at the cell membrane under the control of calmodulin. A system for expression and purification of AKAP79 has been developed enabling sufficient production of pure AKAP79 complexes for structural and biochemical investigation. Imaging of an AKAP79-PKA-calmodulin complex by negative-staining transmission electron microscopy indicates that the first three-dimen'sional reconstruction of this complex may be possible in the near future.
18
Daly, Carl S. "The roles of the Apc proteins in homeostasis and tumourigenesis." Thesis, Cardiff University, 2013. http://orca.cf.ac.uk/51008/.
Повний текст джерелаАнотація:
The adenomatous polyposis coli (APC) gene encodes a multifunctional tumour suppressor protein that is essential for normal development. The most characterised role of APC is its ability to mediate the Wnt signaling pathway, a pathway disrupted in the majority of human cancers. The identification of a second adenomatous polyposis coli gene (APC2) which possesses many shared structural characteristics with APC and potentially comparable functions raises the possibility that APC2 also functions both in development and in tumour suppression, and that some redundancy may exist between the two proteins. Analysis of these proteins in the mouse has been hampered due to the lethality of the Apc mutation and the lack of a suitable Apc2 mutation. However, to circumvent the first of these difficulties, Cre-lox technology was employed to conditionally delete Apc in adult mouse tissues and so study its function in vivo. To circumvent the second difficulty, a novel Apc2 null allele had become available from the laboratory of Professor Hans Clevers. Remarkably, constitutive deletion of Apc2 does not lead to embryonic lethality, permitting study of the effects of Apc2 deficiency within adult tissues. In this thesis I aimed to characterise the consequences of Apc2 loss alone, and in the context of tissue specific Apc loss, in a range of tissues. Apc2 deficiency led to subtle changes in Wnt signaling in the intestines and liver however, no detectable differences of this pathway were apparent within the mammary gland. Phenotypically, altered homeostasis was only observed within the intestines. Apc2 deficiency led to an increase in epithelial cell division, an increase in markers of intestinal stemness and increases in intestinal cell migration. However, loss of Apc2 failed to induce tumourigenesis in the intestines or indeed any other tissue. In the context of Apc loss, the effect was dependent upon the tissue. Within the intestines, additional loss of Apc2 altered the immediate phenotype of Apc loss but failed to modify Apc induced tumourigenesis. Within the mammary gland, whilst either Apc protein alone was dispensable, combined loss synergised to disrupt homeostasis and drive tumourigenesis. Contrary to this, in the liver the additional loss of Apc2 attenuated tumourigenesis induced by reduced levels of Apc. Together, these studies highlight the importance of these proteins and their interactions and redundancies in homeostasis and tumourigenesis.
19
Sedgwick, Garry Gray. "Identification and functional characterisation of novel APC/C interacting proteins." Thesis, University of Birmingham, 2010. http://etheses.bham.ac.uk//id/eprint/1090/.
Повний текст джерелаАнотація:
The anaphase promoting complex /cyclosome (APC/C) is a multi-protein E3 ubiquitin ligase complex that regulates cellular proliferation through its ability to target essential cell cycle regulators such as cyclin A, cyclin B, securin and S-phase kinase-associated protein 2 (SKP2) for proteasomal-dependent degradation. APC/C substrates and coactivators are aberrantly expressed in many cancers. It is thought that the APC/C can also regulate cellular proliferation by controlling p21 and cell division cycle 6 homologue (CDC6) transcription. It is therefore of great interest to study other cellular proteins that interact with the APC/C as these proteins may also be important in cell cycle regulation and hence may enhance our understanding of the molecular basis of cancer. Therefore, the aim of my study was to identify novel APC/C interacting proteins through mass spectrometric analysis of APC/C subunit 7 (APC7) immunoprecipitates and go on to examine the functional significance of these interactions. I identified six novel APC7 interacting proteins, and decided to focus on two of these interactions. Initially I examined the interaction between APC7 and transcriptional intermediary factor 1\(\gamma\) (TIF1\(\gamma\)), a transcriptional repressor previously reported to be aberrantly expressed in cancer. Data presented in this study demonstrate that the APC/C and TIF1\(\gamma\) cooperate to regulate mitotic progression. Notably TIF1\(\gamma\) displays in vivo interactions with APC/C subunits 1-8, the APC/C‟s mitotic coactivator CDC20 and mitotic substrate cyclin A. Moreover, TIF1\(\gamma\) depletion by RNAi arrests cells in a metaphase-like state characterised by elevated levels of APC/C substrates, cyclin A, cyclin B and CDC20. In support of a role for TIF1\(\gamma\) in regulating mitotic progression by directly targeting the APC/C, cells treated with TIF1\(\gamma\)-specific siRNA exhibit reduced APC/C E3 ubiquitin ligase activity. This work defines TIF1\(\gamma\) as a novel mitotic regulatory protein essential for APC/C function and suggests that loss of TIF1\(\gamma\) may compromise genomic integrity by allowing the mis-segregation of chromosomes. I also investigated the functional relationship between APC7 and the nuclear factor 90/45 heterodimer (NF90/NF45), given that all of these proteins function as transcription factors. Results obtained demonstrate that APC5 and APC7 bind directly to NF90 in vitro and also form complexes with NF90 in vivo. It appears that APC/C interaction with NF90 is important in the regulation of interleukin-2 (IL-2) and tumour neucrosis factor (TNF) transcription, as exogenous APC5 and APC7 cooperate with NF90/NF45 to transactivate IL-2 and TNF promoter constructs. Lastly endogenous APC5 and APC7 bind to the IL-2 promoter in vivo while endogenous APC5 represses TNF transcription in vivo. Given that TNF and IL-2 stimulate cellular proliferation data presented here suggests that the APC/C might control cellular proliferation by regulating TNF and IL-2 transcription.
20
Cliffe, Adam Nicholas. "The functions of the Drosophila E-APC and Axin proteins." Thesis, University of Cambridge, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.619925.
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21
He, Xuhua. "Vitamin K-dependent anticoagulant protein S biochemical and histochemical studies /." Lund : Dept. of Clinical Chemistry, Wallenberg Laboratory, University of Lund, University Hospital MAS, 1994. http://catalog.hathitrust.org/api/volumes/oclc/39693810.html.
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22
Pohl, Antje Heide. "Lipid transport by ABC proteins." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2002. http://dx.doi.org/10.18452/14784.
Повний текст джерелаАнотація:
In eukaryotischen Zellen sind die Lipidspezies häufig asymmetrisch zwischen den Hälften der Plasmamembran verteilt. Insbesondere Phosphatidylserin (PS) weist oft eine ausgeprägte transversale Asymmetrie auf, da es fast ausschliesslich auf die innere Hälfte der Plasmamembran beschränkt ist. In den letzten Jahren wurden mehrere Proteine diskutiert, die Lipide zwischen den Membranhälften transportieren und möglicherweise die transversale Lipidasymmetrie sowie damit verbundene Zelleigenschaften beeinflussen. Im Mittelpunkt der vorliegenden Promotion steht der Auswärtstransport fluoreszierender (C6-NBD-) Lipid-Analoga und endogener Lipide durch das Multidrug Resistance 1 P-Glycoprotein (MDR1 Pgp), das der ATP Binding Cassette (ABC) Transporter Superfamilie angehört. Interessanter Weise wird für MDR1 Pgp eine ungewöhnlich breite Substratspezifität angenommen. Das anionische Lipid PS war hier von besonderem Interesse, obgleich es in vorhergehenden Arbeiten nicht als MDR1 Pgp Substrat betrachtet wurde. Der Auswärtstransport von Phosphatidylcholin-, Phosphatidylethanolamin-, Glucosylceramid- und Sphingomyelin-Analoga durch MDR1 Pgp konnte in einer humanen Magenkarzinomlinie (EPG85-257), die MDR1 überexprimiert, mittels Fluoreszenzspektroskopie bestätigt werden. Zudem legt die verringerte Akkumulation von Diacylglycerol- und Ceramid-Analoga den Transport dieser Lipidspezies durch MDR1 Pgp nahe. Im Anschluß an die intrazelluläre Markierung mit C6-NBD-PS mittels eines neuen Verfahrens konnte der signifikant erhöhte Auswärtstransport dieses Analogons in MDR1 überexprimierenden Zellen durch Verwendung spezifischer Inhibitoren MDR1 Pgp zugeschrieben werden. In flusscytometrischen Versuchen war die Exponierung von endogenem PS auf der äusseren Membranhälfte von MDR1 überexprimierenden Zellen signifikant höher als in Kontrollzellen. Verringerung der PS-Exponierung durch einen Inhibitor von MDR1 Pgp deutet auf den Transport von endogenem PS durch MDR1 Pgp hin. Zusätzlich wurde hier der Transport von C6-NBD-PS in vier weiteren Zellinien mit verschiedener Spezies- und Gewebezugehörigkeit charakterisiert, die unterschiedliche Mengen an MDR1 Pgp synthetisieren. Wie Experimente in einer BCRP überexprimierenden EPG85-257-Sublinie nahelegen, ist ausser MDR1 Pgp möglicherweise ebenfalls der ABC Halb-Transporter Breast Cancer Resistance Protein (BCRP) am Transport von C6-NBD-PS und an der verstärkten Exponierung von endogenem PS beteiligt.In eukaryotic cells, the lipid species are frequently distributed asymmetrically between the plasma membrane leaflets. Phosphatidylserine (PS), in particular, often exhibits a distinct transverse asymmetry, being restricted almost exclusively to the inner leaflet. In the past years, several proteins were suggested to transport lipids between the leaflets of a membrane, and to potentially influence transverse lipid asymmetry and related cell properties. This thesis focuses on outward transport of fluorescent (C6-NBD-) lipid analogs and endogenous lipids by the Multidrug Resistance 1 P-Glycoprotein (MDR1 Pgp), a member of the ATP binding cassette (ABC) transporter superfamily. Interestingly, MDR1 Pgp has been suggested to exhibit an unusually broad substrate specificity. Here, the anionic PS was of particular concern, although previously reported not to be an MDR1 Pgp substrate. In a human gastric carcinoma cell line (EPG85-257) overexpressing MDR1, outward transport of phosphatidylcholine, phosphatidylethanolamine, glucosylceramide and sphingomyelin analogs via MDR1 Pgp was confirmed using fluorescence spectroscopy. In addition, decreased accumulation of analogs of diacylglycerol and ceramide suggest MDR1 Pgp mediated transport of these lipid species. Upon intracellular labelling with C6-NBD-PS using a novel approach, significantly increased outward transport of this analog in MDR1 overexpressing cells could be attributed to MDR1 Pgp by employing specific inhibitors. In a flow cytometry setup, the exposure of endogenous PS on the outer plasma membrane leaflet was significantly elevated in MDR1 overexpressing cells compared to controls. Reduction of PS exposure by an MDR1 Pgp inhibitor suggests transport of endogenous PS by MDR1 Pgp. Transport of C6-NBD-PS was furthermore characterized here in four additional cell lines of different species and tissue origin with varying synthesis levels of MDR1 Pgp. Besides MDR1 Pgp, the ABC half-size transporter Breast Cancer Resistance Protein (BCRP) is possibly also involved in transport of C6-NBD-PS and in increased exposure of endogenous PS, as found in a BCRP overexpressing EPG85-257 subline.
23
Rivers, Damien M. R. "Characterization of the Rhizobiaceae protein RhaK." ASM, 2013. http://hdl.handle.net/1993/30289.
Повний текст джерелаАнотація:
In Rhizobium leguminosarum the ABC transporter responsible for rhamnose transport is dependent on RhaK, a sugar kinase that is necessary for the catabolism of rhamnose. It was hypothesized that RhaK has two separate functions; phosphorylation of rhamnose, and an unknown interaction with the rhamnose ABC transporter.
To address this hypothesis a linker-scanning mutagenesis of rhaK was carried out. Two generated variants (RhaK72 and RhaK73) were found to maintain kinase activity, but were severely impaired in rhamnose transport function. Structural modelling suggested that both RhaK72 and RhaK73 affect surface exposed residues in two distinct regions localized to one face of the protein. This suggests that this proteins face may play a role in a protein-protein interaction that affects rhamnose transport.
Using a two-hybrid system, an N-terminal and a C-teminal fragment of RhaK were both shown to interact with the N-terminal fragment of RhaT. These fragments span the regions that contain the rhaK73 and rhaK72 inserts respectively. When the rhaK72 and rhaK73 insert alleles were cloned and assayed using the two-hybrid system, these they were unable to interact with the RhaT fragment, suggesting these inserts abolish transport by interfering with a physical interaction between RhaT and RhaK.
A phylogeny was generated based on the amino acid sequence of RhaK like proteins found in syntenous opereons. To gain insight into what residues may constitute a binding domain a PRALINE alignment of the orthologous kinases was combined with secondary structure analysis, known informative mutations, and functional residue predictions. A putative 12 amino acid binding site was identified using this method. An alanine scanning mutagenesis and subsequent two-hybrid analysis was carried out on this region. The substitution of any of these residues greatly affected the interaction between RhaT and RhaK.
Although heterologous complementation of RhaK is possible, cosmid complementation anomalies and phylogenetic analysis of RhaK indicates the R. leguminosarum and S. meliloti kinases are different. Through a series of heterologous complementation experiments, enzyme assays, gene fusions, and transport experiments we show that the R. leguminosarum kinase is capable of directly phosphorylating rhamnose and rhamnulose, whereas the Sinorhizobium meliloti kinase does not have rhamnose kinase activity.May 2015
24
Schröder, Markus [Verfasser]. "Interactions of the adaptor proteins AP2 and 14-3-3 with the presynaptic scaffolding protein Bassoon / Markus Schröder." Magdeburg : Universitätsbibliothek, 2015. http://d-nb.info/1075547520/34.
Повний текст джерела
25
Kunttas-Tatli, Ezgi. "Role of APC Proteins in Regulating Wnt Signaling and Cytoskeletal Organization in Drosophila." Research Showcase @ CMU, 2014. http://repository.cmu.edu/dissertations/423.
Повний текст джерелаАнотація:
Development of an embryo is a fascinating biological process that requires effective communication between neighboring cells and coordination of movement across the entire organism. At a cellular level, this is achieved by upstream signaling pathways ultimately regulating gene expression to provide cells with cues to perform certain tasks such as cell division, migration, cell rearrangements or changes in cell shape. All of these diverse tasks ultimately rely on rearrangements of the cytoskeleton. However, it is unclear what the molecular connections are between signaling and cytoskeletal dynamics. Adenomatous Polyposis Coli (APC) is a multifunctional protein that plays vital roles both in regulating the canonical Wnt signaling pathway and the cytoskeleton. Mutations of APC are associated with more than 80% of both familial and sporadic colorectal cancer cases. APC is one of few cytoskeletal proteins with direct links to cancer. However, as a multi-domain, multifunctional protein, a comprehensive understanding of APC biology has been difficult to achieve. While we have known for almost 20 years that APC proteins are essential negative regulators of Wnt signaling, the precise role they play both in regulating Wnt signaling and cytoskeletal have been unclear. In order for APC proteins to perform these diverse tasks and regulate both signaling and the cytoskeleton, it needs to be highly regulated itself. In my Ph.D. project, I approached APC proteins from many different angles, in many different developmental contexts, to gain insights into the precise role they play and how they are regulated in both the Wnt signaling and the cytoskeletal context. To better understand how APC proteins are regulated, I used Drosophila as a simpler, more tractable model. The large size of the vertebrate APCs (~300 kDa) makes it difficult to perform structure/function studies in the context of a full-length protein. Similar to vertebrates, flies have two highly conserved APC proteins (APC1 and APC2). Thus, I chose to study the fly APC homologs and mostly focused on the smaller member of the family, APC2, in my studies. To elucidate how APC proteins are regulated in the context of Wnt signaling, first we dissected the role of phosphorylation in the context of Wnt signaling. APC proteins are highly phosphorylated, and this plays a role in APCs activity in Wnt signaling. As a part of the destruction complex, APC targets the key effector of the pathway, ß-catenin for degradation. Phosphorylation of the central 20 amino acid repeats (20Rs) has received the most attention over the last decades, and has been shown to change the affinity of β-catenin binding in vitro. However, many of these in vitro models lacked an in vivo model. To test the functional significance of 20R phosphorylation in Wnt signaling, we used Drosophila APC2 and took advantage of the awesome power of genetics in this model organism. Our studies showed for the first time in an intact animal that 20R phosphorylation played an essential role. This study also suggested functional diversity among different 20Rs as well as gave us hints about the presence of macromolecular destruction complex, which we coined the term “destructosome’ (see Chapter 2). Besides the phosphorylation of the 20Rs, phosphorylation of other APC domains, such as the Axin binding SAMP repeats, had not been investigated before. Therefore, I also studied the phosphorylation of SAMP repeats and tested if it played a functionally significant role in APCs Wnt function. Similar to the 20Rs, I’ve shown that SAMP phosphorylation plays a previously uncharacterized role in APCs Wnt signaling function and proposed a novel idea of functional diversity among different SAMP repeats (see Chapter 3). As mentioned above, while studying the importance of 20R phosphorylation, I got interested in the idea of higher order destruction complex structures, or destructosome. This led me to think about the role of APC proteins in the assembly of this complex. Although it has been long appreciated that human APC can self-associate, the precise role of self-association in Wnt signaling hasn’t been explored in part due to the complexity of self-association in the vertebrate APC (vAPC) proteins. By using Drosophila APC2, I’ve identified a novel self-association domain (ASAD) and uncovered a new role for APC proteins in promoting the assembly and stability of the destructosome (see Chapter 4). I was interested in APC phosphorylation not only in the context of Wnt signaling but also in APCs cytoskeletal roles. One of the emerging themes in APCs role in regulating the actin cytoskeleton is its interaction with the formin Diaphanous (Dia). Previous work from our laboratory suggested that Drosophila APC2 and Dia cooperated during the formation of actin based structures during embryogenesis and this interaction was regulated. In order to understand this relationship further, I tested the role of phosphorylation as potential regulatory mechanism. My studies showed, in deed phosphorylation played a role in APCs activity in this context too (see Chapter 5). This study also revealed a potential cross talk between two pools of actin (linear and branched). In summary, studying APC, an exciting and highly complex protein, allowed me to think about many different biological questions from signaling to cytoskeleton in various developmental contexts. The findings from my Ph.D. research uncovered new aspects of APC biology, and showed how various regulatory mechanisms weather it’s phosphorylation or self-association, affect its functions, both during Wnt signaling and also in regulating the actin cytoskeleton. My studies will also help better understand the disease relevance of human APC proteins and provide novel insights.
26
Billsten, Peter. "Studies on the conformation of adsorbed proteins." Lund : Göteborg University, 1997. http://catalog.hathitrust.org/api/volumes/oclc/39776983.html.
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Issa, Khodr. "Effet protecteur du sulfure d'hydrogène, de la protéine C activée et de la dexamétasone dans la modulation hémodynamique et inflammatoire de l'ischémie/reperfusion." Thesis, Université de Lorraine, 2013. http://www.theses.fr/2013LORR0059/document.
Повний текст джерелаАнотація:
L'ischémie/reperfusion (I/R) est un phénomène très fréquent en clinique humaine. Ce phénomène est observé lors de la désobstruction d'une artère digestive, du traitement d'un état de choc, ainsi qu'au cours d'autres pathologies. L'interruption de la perfusion tissulaire (ischémie) et le rétablissement de celle-ci (reperfusion) sont la cause de la mise en place de troubles hémodynamiques et métaboliques. L'I/R est souvent présentée comme étant la principale source de l'hyperlactatémie et le moteur de la réponse inflammatoire lors des états de choc (cardiogénique, hypovolémique, septique). Parallèlement, elle est responsable de l'induction de la production de la libération des espèces réactives de l'oxygène, des cytokines et du monoxyde d'azote. Suite à un choc hémorragique par Ischémie/reperfusion chez le rat, nous avons montré que 1) le NaHS, donneur d'H2S limite la diminution de la pression artérielle moyenne et diminue le lactate plasmatique, témoin de la souffrance tissulaire, 2) cette amélioration hémodynamique est associée à une baisse de l'expression myocardique des ARNm d'iNOS, une diminution de la concentration des dérivés NOx plasmatiques et une diminution des concentrations aortiques et myocardiques de NO et d'anion superoxyde et 3) l'inhibition d'H2S par la DL-propargylglycine aggrave le tableau hémodynamique et les conséquences tissulaires du choc. Dans un autre modèle d'ischémie/reperfusion intestinale, les résultats obtenus, montrent que l'administration de la Protéine C activée (PCa) ou de la dexaméthaosne (Dexa) : 1) améliore la PAM et la réactivité vasculaire, 2) permet d'augmenter le pH et de diminuer la lactatémie, 3) diminue la production des cytokines pro-inflammatoires et 4) inhibe les médiateurs de l'apoptose. Ces résultats sont reliés à une down régulation d'iNOS, une restauration de la voie Akt/eNOS et à une resensibilisation des adrénorécepteurs alpha. Ces résultats ouvrent de nouvelles perspectives cliniques dans les traitements de l'I/RIschemia/reperfusion (I/R) is a very common phenomenon, observed during intestinal artery surgery, shock treatment, as well as in several other diseases. The disruption of tissue perfusion (ischemia) and recovery (reperfusion) induce hemodynamic and metabolic dysfunction. Gut ischemia/reperfusion is often presented as the main source of lactate and the motor of the inflammatory response, such as cardiogenic, hypovolemic and septic shock. In parallel, gut reperfusion produces numerous mediators such as reactive oxygen metabolites, pro-inflammatory cytokines, and high concentrations of nitric oxide. In a model of ischemia/reperfusion induced by hemorrhagic shock, we found that 1) NaHS an injectable form of H2S, limited the decrease in arterial pressure induced by shock and decreased plasmatic lactate, a witness of tissue suffering, 2) this hemodynamic improvement was associated with a fall in myocardial iNOS mRNA expression, a reduction in the concentration of plasmatic NOx and a reduction of aortic and myocardial concentrations of NO and superoxide anion and 3) the inhibition of H2S with DL-propargylglycine worsened hemodynamics and tissue consequences of shock An experimental model of intestinal I/R has been developed, we demonstrated that the administration of APC or Dexa : 1) Improves MAP and vascular reactivity, 2) increased pH and decreased lactate, 3) decreased pro-inflammatory cytokines production and 4) inhibited apoptosis mediators expression. These results are related to a down regulation of iNOS, to a restoration of the AKT/eNOS pathway, and to alpha-adrenoreceptor resensitization. These results open new perspectives in clinical treatment of I/R
28
Looman, Camilla. "The ABC of KRAB zinc finger proteins." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2003. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-3515.
Повний текст джерела
29
Olesen, Lene Elsnab. "AP2 binding proteins in clathrin-mediated endocytosis." Thesis, University of Cambridge, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.613672.
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30
Hansen, Maureen Elizabeth Kieber Joseph J. "Regulation of ethylene biosynthesis via ACC synthase protein stability." Chapel Hill, N.C. : University of North Carolina at Chapel Hill, 2008. http://dc.lib.unc.edu/u?/etd,1865.
Повний текст джерелаАнотація:
Thesis (Ph. D.)--University of North Carolina at Chapel Hill, 2008.Title from electronic title page (viewed Dec. 11, 2008). "... in partial fulfillment of the requirements for the degree of Doctor of Philosophy in the Curriculum of Genetics and Molecular Biology." Discipline: Genetics and Molecular Biology; Department/School: Medicine.
31
Libkind, Marianna. "SiaA: A Heme Protein." Digital Archive @ GSU, 2007. http://digitalarchive.gsu.edu/chemistry_hontheses/2.
Повний текст джерелаАнотація:
The protein SiaA (Streptococcal iron acquisition) is involved in heme uptake in the bacterium Streptococcus pyogenes. It is difficult to obtain this protein in its fully holo form (completely loaded with heme). To increase the concentration of heme in the growing cell, we added ä-aminolevulinic acid (ALA) and ferrous sulfate (FeSO4), precursors of heme, to the growth media. Neither increasing the concentration of heme in vivo, nor growth at lower temperature for longer times, increased the production of holoprotein. The classical method of measuring the concentration of heme in a newly discovered heme protein is cumbersome. We have developed an improved method, which gives a solution that is more stable and has a cleaner spectrum. With further development, this new technique may replace the classical assay. Background information on S. pyogenes, SiaA, ABC transporters, heme biosynthesis, and the pyridine hemochrome assay are described.
32
Marek, Magdalena. "Characterization of Aus1 protein." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2012. http://dx.doi.org/10.18452/16591.
Повний текст джерелаАнотація:
Sterine sind essentielle Komponenten der Zellmembran, deren Konzentration und Lokalisierung genau kontrolliert wird. Die Hefe Saccharomyces cerevisiae ist ein fakultativ anaerober Organismus, der in Abwesenheit von Sauerstoff auxotroph für Sterine wird. Die Proteine Aus1p und Pdr11p gehören zur Familie der ABC Proteine und spielen eine wichtige Rolle in diesem Prozess, da die gleichzeitige Deletion beider Protein die Aufnahme von Sterinen unter anaeroben Wachstumsbedingungen blockiert.In dieser Arbeit wurde das Gen AUS1 in voller Länge kloniert. Methoden für die Extraktion und Reinigung dieses Transporters wurden entwickelt, damit dieser detailliert charakterisiert werden kann. Mit Hilfe von Detergenzien wurde das Protein löslich gemacht und zeigte ATP-Bindung und -Hydrolyse. Die ATP-Hydrolyse konnte durch die Mutation eines konservierten Lysins zu Methionin im Walker A Motif verhindert. Genauso konnte die ATP-Hydrolyse auch durch klassische Inhibitoren von ABC Transportern inhibiert werden. Nach der Rekonstitution von Aus1p in Proteoliposomen wurde die ATPase Aktivität spezifisch durch Phosphatidylserin in einer stereoselektiven Weise stimuliert.Zusätzlich konnte gezeigt werden, dass Änderungen im zellulären PS Spiegel die Aus1p-abhängige Aufnahme von Sterin an die Membran beeinflussen. Diese Ergebnisse schlagen eine für die Aktivität des Transporters wichtige, direkte Interaktion zwischen Aus1p und PS vor.Da es sich bei der Aufnahme von Sterin um einen komplexen Prozess handelt, könnten Komponenten exisitieren, die mit Aus1p interagieren. Der Hefestamm, der die Immunpräzipitation von Aus1p mit seinem Interaktionspartner ermöglicht, wurde erzeugt und der Einfluß von Mannoproteinen auf Sterinaufnahme wurde getestet. Außerdem wurde eine Methode entwickelt, mit der Aus1p in Giant Unilamellar Vesicles rekonstituiert werden kann. Mit diesen Liposomen kann das Verhalten und die Aktivität von Aus1p in Membranen mit einer komplexen Lipidzusammensetzung untersucht werden.Sterols are essential components of cellular membranes and their concentration and localization are tightly controlled. Saccharomyces cerevisiae is a facultative anaerobic organism which becomes auxotrophic for sterols in the absence of oxygen. However, the precise mechanism of sterol uptake remains to be revealed. Two proteins belonging to ABC protein family, Aus1p and Pdr11p were proposed to play a critical role in this process as simultaneous deletion of both of them blocks sterol uptake under anaerobiosis. In the present work, the full length AUS1 gene was cloned. An extraction and purification procedures were then developed to allow for detailed characterization of the transporter. The detergent solubilized protein was shown to bind and hydrolyse ATP. Mutagenesis of the conserved lysine to methionine in the Walker A motif abolished ATP hydrolysis. Likewise, ATP hydrolysis was inhibited by classical inhibitors of ABC transporters. Upon reconstitution into proteoliposomes, the ATPase activity of Aus1p was specifically stimulated by phosphatidylserine (PS) in a stereoselective manner. Furthermore, it was demonstrated that Aus1p-dependent sterol uptake, but not Aus1p expression and trafficking to the plasma membrane, was affected by changes in cellular PS levels. These results suggest a direct interaction between Aus1p and PS which is critical for the activity of the transporter. Because of the complexity of sterol incorporation process efforts were made to identify additional components of the sterol uptake machinery that interact with Aus1p protein. The yeast strain allowing for immunopercipitation of Aus1p with its interaction partners was generated and previously proposed influence of mannoproteins on the sterol uptake was tested. Additionally, method was developed to reconstitute Aus1p protein into Giant Unilamellar Vesicles. These liposomes can be used further for testing of the behaviour and activity of Aus1p in the membranes with complex lipid composition.
33
Aittoniemi, Jussi Tapio. "ABC proteins : from bacterial structures to human disease." Thesis, University of Oxford, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.547442.
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34
Kobayashi, Aya. "Mechanism of membrane lipid efflux by ABC proteins." Kyoto University, 2007. http://hdl.handle.net/2433/136565.
Повний текст джерелаАнотація:
Kyoto University (京都大学)0048
新制・課程博士
博士(農学)
甲第13311号
農博第1653号
新制||農||947(附属図書館)
学位論文||H19||N4290(農学部図書室)
UT51-2007-H676
京都大学大学院農学研究科応用生命科学専攻
(主査)教授 植田 和光, 教授 阪井 康能, 教授 植田 充美
学位規則第4条第1項該当
35
Mohamed, Noha-Ehssan. "Characterizing the roles of APC2 protein in ovarian homeostasis and tumourigenesis." Thesis, Cardiff University, 2017. http://orca.cf.ac.uk/105634/.
Повний текст джерелаАнотація:
Canonical WNT signalling plays a critical role in the regulation of ovarian development during embryogenesis; dysregulation of this pathway in adult ovary is associated with subfertility and tumourigenesis. The aim of the current study was to elucidate the previously unexplored roles of Adenomatous polyposis coli 2 (APC2), a WNT signalling pathway regulator, in the ovary using an Apc2 constitutive knockout mouse. For the first time, the current work demonstrated essential roles of APC2 in regulating ovarian WNT signalling and ovarian homeostasis. In early adulthood, APC2-deficiency resulted in WNT signalling activation and sub-fertility driven by intra-ovarian defects. Follicular growth was perturbed, resulting in a reduced rate of ovulation and corpora lutea formation, which was not rescued by administration of gonadotrophins. The current study provides fundamental new knowledge on the role of APC2 in ovarian tumourigenesis. APC2-deficiency (on the background of a hypomorph Apc- allele) resulted in a predisposition to granulosa cell tumour (GCT) formation, accompanied by acute tumour-associated WNT-signalling activation and expression of a histologic pattern and molecular signature seen in human adult GCTs. Hence, APC2 has an important tumour-suppressor activity within ovarian granulosa cells. However, APC2 is dispensable for ovarian surface epithelium (OSE) homeostasis. APC2 loss on its own, or combined with PTEN or APC loss in the OSE, failed to cause tumour development. Introducing APC2-deficiency to an ovarian endometrioid adenocarcinoma (OEA) mouse model, driven by loss of PTEN and APC in the OSE, resulted in early initiation of tumourigenesis, but attenuated tumour growth. This attenuation was accompanied by squamous metaplasia, decreased mitosis, decreased p-ERK1/2 expression and disrupted immune/inflammatory signalling. Thus, for the first time, an APC2 functional dualism in initiation and progression of WNT-driven OEA in mice is reported. RNA sequence analysis unraveled 2 transcripts (HAL and HUNK) associated with OEA progression and should be considered for future research.
36
Johns, Kristine Dawn. "Evidences for Protein-Protein Interactions Between PstB and PhoU in the Phosphate Signaling Complex of Escherichia coli." BYU ScholarsArchive, 2013. https://scholarsarchive.byu.edu/etd/3932.
Повний текст джерелаАнотація:
The PstSCAB2 complex serves the dual function of being a phosphate transporter as well as the primary sensor of phosphate for the Pho regulon. PhoU is an integral protein required for the signal from PstSCAB2 to be transmitted to PhoR. Our hypothesis is that conformational changes of PstSCAB2 during the phosphate transport process are the mechanism by which information about environmental phosphate levels are transduced to the cell. Additionally, we propose that direct protein-protein interactions between PhoU and the alternating conformations of PstSCAB2 mediate PhoU interactions with PhoR. By means of genetic and biochemical approaches, we have found substantial evidence supporting both these hypotheses.
37
Rusch, André. "Molekularbiologische Analysen zur Funktion des hnRN-Proteins E1B-AP5." [S.l.] : [s.n.], 2003. http://deposit.ddb.de/cgi-bin/dokserv?idn=971837147.
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38
Matsuda, Akihiro. "(24S)-Hydroxycholesterol efflux from neuronal cells by ABC proteins." Kyoto University, 2014. http://hdl.handle.net/2433/185211.
Повний текст джерелаАнотація:
Kyoto University (京都大学)0048
新制・課程博士
博士(農学)
甲第17986号
農博第2033号
新制||農||1019(附属図書館)
学位論文||H26||N4811(農学部図書室)
80830
京都大学大学院農学研究科応用生命科学専攻
(主査)教授 植田 和光, 教授 植田 充美, 教授 三芳 秀人
学位規則第4条第1項該当
39
Tydén, Eva. "Cytochrome P450 3A and ABC-transport proteins in horse /." Uppsala : Department of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences, 2008. http://epsilon.slu.se/200893.pdf.
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40
Ousalem, Farès. "Rôles physiologiques et fonctionnels des facteurs de traduction appartenant à la famille ABC-F et leur implication dans la résistance aux antibiotiques." Thesis, Université de Paris (2019-....), 2020. http://www.theses.fr/2020UNIP7015.
Повний текст джерелаАнотація:
Les protéines de la famille ABC-F, universellement retrouvées chez les procaryotes et les eucaryotes, interagissent avec le ribosome. La souche Escherichia coli (MG1655) possède 4 ABC-F paralogues nommés EttA, YheS, YbiT et Uup. J’ai étudié ici le rôle physiologiques et fonctionnels des protéines ABC-F d’E. coli et la protéine MsrD de Streptococcus pneumoniae qui est synthétisée dans E. coli. Mes travaux ont montré que les protéines ABC-F sont importantes pour les bactéries dans des conditions de stress spécifiques. Les bactéries délétées du gène ettA sont plus sensibles au stress salin, les bactéries délétées du gène uup sont plus sensibles au stress acide tandis que la surexpression de la protéine YheS ou MsrD dans les bactéries leurs confèrent une résistance aux macrolides. J’ai également démontré que le gène ettA est important pour la croissance d’E. coli dans des conditions de stress salin et de faible concentration en phosphate quand les acides aminés, le malate ou fumarate sont utilisés comme seule source de carbone. La délétion du gène ettA rend les bactéries plus sensibles au stress salin et engendre une dérégulation de certains gènes liés au métabolisme du malate / glyoxylate ainsi que des gènes impliqués dans l'activité ribosomique. La souche délétée du gène ettA sous-exprime le gène de la malate synthase aceB par une régulation post-transcriptionnelle. La sous-expression de la malate synthase dans des bactéries favorise leurs croissances dans le milieu glyoxylate. La délétion du gène ettA a aussi induit une surexpression de facteur de modulation des ribosomes (RMF) dans le milieu LB, ce qui a provoqué une augmentation de la formation des ribosomes 100SProteins belonging to the ABC-F family are found in prokaryotes as well as eukaryotes. They interact with the ribosome and are considered as translation factors. The Escherichia coli strain (MG1655) has 4 ABC-F paralogs named: EttA, YheS, YbiT and Uup. Here I present a study of the physiological and functional role of E. coli ABC-F proteins and the Streptococcus pneumoniae MsrD protein. My work has shown that the ABC-F proteins studied are important for bacteria adaptation to stress conditions. Bacteria deleted from the ettA gene are more sensitive to salt stress, bacteria deleted from the uup gene are more sensitive to acid stress while the overexpression of the protein YheS or MsrD in bacteria provide resistance to macrolides. I also demonstrated that the ettA gene is important for the growth of E. coli under conditions of saline stress at low phosphate concentration when the amino acids, malate or fumarate are used as the only carbon source. The deletion of the ettA gene makes bacteria more sensitive to salt stress and causes dysregulation of certain genes linked to the malate / glyoxylate metabolism and genes involved in ribosomal activity. The deleted strain of the ettA gene under-expresses the malate synthase aceB gene by post-transcriptional regulation. The under- expression of malate synthase in bacteria promotes their growth in the glyoxylate medium. The deletion of the ettA gene also induced overexpression of ribosome modulation factor (RMF) in LB medium, which caused an increase in the formation of 100S ribosomes
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Turner, Mark Stephen. "A basic surface protein of lactobacillus fermentum BR11." Thesis, Queensland University of Technology, 1999.
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42
Thonghin, Nopnithi. "Structural studies of the multi-drug resistance protein P-glycoprotein (ABCB1)." Thesis, University of Manchester, 2018. https://www.research.manchester.ac.uk/portal/en/theses/structural-studies-of-the-multidrug-resistance-protein-pglycoprotein-abcb1(9f3d4a87-4d43-4984-9e41-3db5fc2be66a).html.
Повний текст джерелаАнотація:
P-glycoprotein (P-gp or ABCB1) is a membrane-bound active transporter belonging to the ABC protein superfamily. It is responsible for xenobioIc efflux and also contributes to multidrug resistance in diverse diseases including cancer and epilepsy. P-gp has been increasingly recognised as a potential target for future therapeutics. Although the protein has been studied for decades, understanding of the P-gp transport mechanism is still incomplete. Two P-gp orthologues, mouse (m) and human (h), were therefore expressed in yeasts and purified in the presence of the detergent, n-Dodecyl-β-D- Maltoside (DDM). Purified proteins were examined for aggregation and monodispersity via dynamic light scattering (DLS) and their thermal stability was determined by an assay using a thiol-specific dye (CPM). ATPase activity, measured in a detergent environment, showed that the proteins were active with a basal activity of 60 ± 4 and 35 ± 3 nmol/min/mg for mP-gp and hP-gp, respectively. Crystallisation trials were conducted in the presence of nucleotide. In meso crystallisation using commercial monoolein pre- dispensed plates yielded hexagonal crystal-like objects however they failed to diffract X- rays. P-gp samples were also subjected to cryo-EM where mP-gp in the post-hydrolytic (ADP-bound, vanadate-trapped) state provided the highest resolution dataset that led to a reconstruction of 3D density map at the resolution of 7.9 Ã
which showed an inward- facing conformation. Rigid-body model fitting unveiled densities that were not accounted for by the fitted model illustrating new features such as bound ADP, extended NBD1- TMD2 linker and alternative allocrite-binding sites. Ultimately, the knowledge of P-gp conformation alteration was enhanced and a refined alternating access mechanism of P- gp was proposed based upon information derived from this study.
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Aburima, Ahmed A. "Regulation of blood platelet function by the AGC family of protein kinases." Thesis, University of Hull, 2010. http://hydra.hull.ac.uk/resources/hull:5740.
Повний текст джерелаАнотація:
Upon vascular injury, platelets aggregate at the site of blood vessel injury to form a hemostatic plug maintaining the physiological integrity of the vascular system. Platelets respond to a variety of extracellular stimuli to undergo a rapid aggregation response, releasing active granule contents and leading to a rapidly growing thrombus. During the adhesion, activation, and aggregation of platelets at an injured site, the endothelium responds by limiting the size and growth of the hemostatic plug or thrombus, or even reversing platelet reactivity. These responses are defined as endothelial thromboregulation. There are three primary (and functionally independent) pathways during the early stages of thromboregulation by which the endothelium controls platelet reactivity (1) nitric oxide (NO); (2) prostacyclin (PGI2 ); and (3) the ectonucleotidase CD39. NO and PGI2 stimulate signalling cascades that result in the activation of the AGC family of Ser/Thr protein kinases (PKA, PKG and PKC). Once activated these kinase blunt platelet function through the phosphorylation of signalling proteins requested for activation. In this study, the role of AGC family kinases and their signaling cascades in regulating platelet function was assessed. The experimental data produced during this study demonstrate new insights in to the regulation of these kinases in platelets. More specifically it was found that 1. Peroxynitrite, a derivative of NO, regulated platelet function and particularly cytoskeletal rearrangement through PKC-dependent phosphorylation of VASPSer239/157 2. NO-mediated signalling in platelets had a requirement for PKC. 3. Multiple forms of PKA are present in platelets, which are differentially localised. 4. The potential regulation of platelet function by PKA is mediated through Akinase anchoring proteins. 5. Lipid rafts may play an important role in platelet regulation by NO and PKG. In summary, this studies present insights of the factors regulating AGC kinases in blood platelets.
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Lundgren, Andreas. "The ABC of the cell cycle: roles of the mammalian Cdc25 isoforms /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-639-5/.
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Adamska, Aleksandra. "ABC transporters and G protein-coupled receptors: perspectives for novel anti-cancer drugs." Thesis, Curtin University, 2019. http://hdl.handle.net/20.500.11937/77548.
Повний текст джерелаАнотація:
Pancreatic Ductal Adenocarcinoma (PDAC) is a very aggressive disease with high mortality rates and lacking effective therapeutic approach. Therefore, it is pivotal to develop novel treatments to improve the grim prognosis of patients. In my PhD project, I demonstrated the existence of an ABCC3-LPI-GPR55 loop in PDAC which activation boosts PDAC progression. Importantly, the pharmacological potential of this loop was demonstrated both in vitro and in vivo PDAC models paving a way to clinical trials.
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Gally, Fabienne. "Etude structure/fonction d'une proteine ABC : SUR, le récepteur des sulfonylurées." Phd thesis, Grenoble 1, 2005. http://tel.archives-ouvertes.fr/tel-00011848.
Повний текст джерелаАнотація:
Le canal KATP résulte de l'assemblage d'un canal potassique inhibé par l'ATP intracellulaire (Kir6.2) et d'un transporteurABC, le récepteur des sulfonylurées (SUR) de la famille MRP/ABCC. SUR a un rôle régulateur essentiel : il confère au
canal une sensibilité accrue à l'inhibition par l'ATP, provoque son activation lorsque l'ADP augmente, et est la cible des
activateurs et bloqueurs pharmacologiques du canal.
Nous nous sommes intéressés à divers aspects structure/fonction de SUR en tant que modèle de transporteur ABC
eucaryote. Son couplage naturel à un canal ionique en facilite grandement l'étude grâce à la technique
électrophysiologique du patch-clamp.
La poursuite des travaux pour déterminer la nature moléculaire de la sélectivité des isoformes de SUR aux ouvreurs
pharmacologiques nous a permis de conclure que seul le faible encombrement de la Thr1253 de SUR2A, contre la Met
1290 de SUR1, serait le critère important pour l'activation pharmacologique des canaux KATP.
Nos travaux ont ensuite porté sur un domaine de la sous-unité SUR riche en acides aminés chargés négativement
(succession de 15 résidus glutamates ou aspartates) qui s'est avéré ne pas être impliquée dans la fonction du canal dans
notre système d'expression.
Nous avons étudié l'effet des ions Zn2+ et Cd2+ intracellulaires sur les canaux KATP et montré que ces ions peuvent activer
les canaux via leur liaison à SUR. Ce site de liaison reste encore à déterminer.
Nous avons enfin essayé de comprendre le rôle de chacun des domaines de liaison des nucléotides et nous avons pour cela
conçu des protéines SUR2A possédant des NBD identiques (NBD1-NBD1 et NBD2-NBD2) ou inversés (NBD2-NBD1).
Nos résultats suggèrent que (1) les NBD sont interchangeables (2) l'activation pas le Mg-ADP requiert les deux NBD (3)
l'action des ouvreurs est indépendante du NBD2.
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Davidson, Ruth Elizabeth. "Cloning and expression studies on two novel ABC half-transporter proteins." Thesis, University of Sheffield, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.434532.
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Tanaka, Aro. "Studies on ABC proteins associated with lipid homeostasis in mammalian cells." Kyoto University, 2004. http://hdl.handle.net/2433/147745.
Повний текст джерелаАнотація:
Kyoto University (京都大学)0048
新制・課程博士
博士(農学)
甲第10895号
農博第1401号
新制||農||889(附属図書館)
学位論文||H16||N3906(農学部図書室)
UT51-2004-G742
京都大学大学院農学研究科応用生命科学専攻
(主査)教授 植田 和光, 教授 加藤 暢夫, 教授 矢崎 一史
学位規則第4条第1項該当
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Reynolds, Elizabeth A. "Studies on the evolution of the ethylene forming enzyme : 1-aminocyclopropane-1-carboxylate (ACC) oxidase." Thesis, University of Reading, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.343225.
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RUSSO, CLAUDIA. "STRUCTURAL AND FUNCTIONAL CONSEQUENCES OF P63 MUTATIONS CAUSATIVE OF AEC SYNDROME." Doctoral thesis, Università degli Studi di Milano, 2019. http://hdl.handle.net/2434/606802.
Повний текст джерелаАнотація:
p63, a p53 family member, is a tetrameric transcription factor required for the development and differentiation of stratified epithelia. Heterozygous mutations in p63 are causative of a group of autosomal dominant human disorders characterized by ectodermal dysplasia, orofacial clefting and limb malformations. More specifically, mutations clustering in the C-terminal domain of p63 cause Ankyloblepharon-Ectodermal defects-Cleft lip/palate (AEC) syndrome, a life-threatening disorder characterized by severe extended skin erosions.
Here we show that multiple AEC-associated p63 mutations lead to protein misfolding and aggregation, as observed also in human keratinocytes isolated from an AEC patient and in mouse keratinocytes obtained from a conditional knock-in mouse model for AEC syndrome, recently generated in our laboratory, that phenocopies the skin clinical features found in human patients. In AEC mice the aggregated p63 mutant protein causes an impaired expression of endogenous p63 target genes, among which are keratins and desmosomal proteins involved in cell adhesion and in mechanical resistance, leading to severe skin fragility and erosions. Importantly, we found that abolishing the aggregation of p63, by introducing mutations that drastically reduce the aggregation propensity of AEC mutants, allowed to rescue p63 transcriptional functions, thus suggesting that impaired p63 transactivation activity is uniquely associated in AEC syndrome with exposure of aggregation-prone sequences. In addition, our studies focused on the therapeutic potential of these findings and suggested possible approaches to treat the AEC syndrome based on targeting and strengthening the endogenous protein disaggregation machinery or using drugs designed to chemically assist the correct folding of the mutant protein.