Дисертації: "ATP-binding cassette proteins"

1

Fischer, Jeffrey James, and University of Lethbridge Faculty of Arts and Science. "Initial characterization of the ribosome-associated ATP binding cassette (ABC) protein YHIH from E. Coli." Thesis, Lethbridge, Alta. : University of Lethbridge, Faculty of Arts and Science, 2007, 2007. http://hdl.handle.net/10133/658.

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Protein synthesis is a highly conserved process across all domains of life, both structurally and functionally. This cyclic process is catalyzed by numerous soluble protein factors that interact with the ribosome to facilitate efficient protein synthesis. Many canonical translation factors bind and hydrolyze GTP to induce conformational changes that facilitate translation. For example, GTP hydrolysis by EF-Tu is required for the release of aminoacyl-tRNA into the ribosomal A site; GTP hydrolysis by EF-G facilitates the movement of tRNA and mRNA from the A site to the P site of the ribosome. However, protein synthesis seems to also have a requirement for ATP; the essential yeast protein eEF-3 facilitates release of deacyl-tRNA from the ribosomal E site. In Escherichia coli, the protein product of the open reading frame yhih has been suggested to have a similar function. However, the role of this unique prokaryotic protein is not understood. Preliminary characterization of this protein suggests a nucleotide-dependent conformational change occurs in a truncated form of the protein, ΔP541 Yhih. Interestingly, this phenomenon is not observed in ΔL432 Yhih. Both ΔP541 Yhih, and to a lesser extent ΔL432 Yhih, exhibit a ribosome-dependent ATPase activity, suggesting the primary region for binding with the ribosome lies between Leu432 and Pro541.
x, 101 leaves : ill. ; 29 cm.

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2

Harrington, Leon E. O. "Engineering pores for stochastic sensing and single molecule studies." Thesis, University of Oxford, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.711643.

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3

Johnson, Soraya Sarah. "Control of the protein and lipid content of the plasma membrane by ATP-binding cassette transporter proteins in S. Cerevisiae." Diss., University of Iowa, 2010. https://ir.uiowa.edu/etd/825.

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Pdr5 and Yor1 are two ATP-binding cassette transporters regulated by the pleiotropic drug resistance (PDR) network in the yeast Saccharomyces cerevisiae. Recent work from another group demonstrated that a pdr5Δ yor1 strain confers remarkable resistance to a sphingolipid intermediate, phytosphingosine (PHS), which was surprising as loss of these transporters normally leads to elevated drug sensitivity. PHS is toxic to the cell at high levels due to mislocalization of nutrient permeases, such as the high affinity tryptophan transporter, Tat2. Although the above study suggested that this resistance was due to increased expression of Rsb1, a known mediator of PHS tolerance, this was not reproducible in our hands and we sought to identify other determinants for this phenotype. The work presented here demonstrates that the pdr5Δ yor1 strain exhibits delayed turnover of Tat2 and an increase in tryptophan uptake, which we postulate is due to changes membrane asymmetry resulting in decreased endocytosis. Conversely, cells lacking Rsb1 showed a decrease in tryptophan import and increased Tat2 turnover, independent of endogenous PHS levels. Rsb1 has a predicted 7 transmembrane (7TM) topology, which argues against the idea that Rsb1 functions directly in PHS transport, as there are currently no known transporters with this topology. These data suggest that Rsb1 and Pdr5/Yor1 function in regulation of endocytosis of Tat2, and possibly other membrane proteins. Ethyl methanesulfonate mutagenesis of the pdr5Δ yor1 strain and a candidate gene approach were alternative methods used to identify mediators of PHS tolerance in this strain. Inconsistent results from PHS selection led to the discovery that the pdr5Δ yor1 strain was also robustly resistant to the sphingolipid biosynthesis inhibitor, Aureobasidin A (AbA), which was subsequently used for analysis. These approaches revealed several genes, including Gda1, Mss4, and Ypk1 that are important for AbA tolerance in the pdr5Δ yor1 strain. Many of these determinants play a role in cell wall integrity, suggesting that loss of Pdr5 and Yor1 may lead to activated cell wall integrity pathways resulting in altered cell wall structure.

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4

Kennedy, Kathleen Anne. "Assembly of the maltose transport complex of Escherichia coli and the dimerization, localization, and functional domain structure of its ATP-binding subunit, MalK /." Thesis, Connect to this title online; UW restricted, 1999. http://hdl.handle.net/1773/11504.

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5

Englund, Gunilla. "Interindividual Variability of Drug Transport Proteins : Focus on Intestinal Pgp (ABCB1) and BCRP (ABCG2)." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis: Univ.-bibl. [distributör], 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6127.

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6

Brechbuhl, Heather Michelle. "ATP-cassette binding transporters : modulators of glutathione levels in normal cellular physiology and as a means for therapeutic applications /." Connect to abstract via ProQuest. Full text is not available online, 2008.

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7

Nelson, Bryn D. "Examining the role of MalG in the assembly and function of the maltose transport complex in Escherichia coli : implications for the study of integral membrane proteins /." Thesis, Connect to this title online; UW restricted, 1998. http://hdl.handle.net/1773/11508.

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8

Ibbotson, Kathryn, Joshua Yell, and Patrick T. Ronaldson. "Nrf2 signaling increases expression of ATP-binding cassette subfamily C mRNA transcripts at the blood–brain barrier following hypoxia-reoxygenation stress." BIOMED CENTRAL LTD, 2017. http://hdl.handle.net/10150/623277.

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Background: Strategies to maintain BBB integrity in diseases with a hypoxia/reoxygenation (H/R) component involve preventing glutathione (GSH) loss from endothelial cells. GSH efflux transporters include multidrug resistance proteins (Mrps). Therefore, characterization of Mrp regulation at the BBB during H/R is required to advance these transporters as therapeutic targets. Our goal was to investigate, in vivo, regulation of Abcc1, Abcc2, and Abcc4 mRNA expression (i.e., genes encoding Mrp isoforms that transport GSH) by nuclear factor E2-related factor (Nrf2) using a well-established H/R model. Methods: Female Sprague-Dawley rats (200-250 g) were subjected to normoxia (Nx, 21% O-2, 60 min), hypoxia (Hx, 6% O-2, 60 min) or H/R (6% O-2, 60 min followed by 21% O-2, 10 min, 30 min, or 1 h) or were treated with the Nrf2 activator sulforaphane (25 mg/kg, i.p.) for 3 h. Abcc mRNA expression in brain microvessels was determined using quantitative real-time PCR. Nrf2 signaling activation was examined using an electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) respectively. Data were expressed as mean +/- SD and analyzed via ANOVA followed by the post hoc Bonferroni t test. Results: We observed increased microvascular expression of Abcc1, Abcc2, and Abcc4 mRNA following H/R treatment with reoxygenation times of 10 min, 30 min, and 1 h and in animals treated with sulforaphane. Using a biotinylated Nrf2 probe, we observed an upward band shift in brain microvessels isolated from H/R animals or animals administered sulforaphane. ChIP studies showed increased Nrf2 binding to antioxidant response elements on Abcc1, Abcc2, and Abcc4 promoters following H/R or sulforaphane treatment, suggesting a role for Nrf2 signaling in Abcc gene regulation. Conclusions: Our data show increased Abcc1, Abcc2, and Abcc4 mRNA expression at the BBB in response to H/R stress and that Abcc gene expression is regulated by Nrf2 signaling. Since these Mrp isoforms transport GSH, these results may point to endogenous transporters that can be targeted for BBB protection during H/R stress. Experiments are ongoing to examine functional implications of Nrf2-mediated increases in Abcc transcript expression. Such studies will determine utility of targeting Mrp isoforms for BBB protection in diseases with an H/R component.

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9

Petri, Niclas. "Involvement of Membrane Transport Proteins in Intestinal Absorption and Hepatic Disposition of Drugs Using Fexofenadine as a Model Drug." Doctoral thesis, Uppsala University, Department of Pharmacy, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-5808.

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The aims of this thesis were to study the in vivo relevance of membrane transporters for intestinal absorption and the hepatic disposition of drugs in humans and preclinical models. Fexofenadine is a substrate for ABCB1 (P-glycoprotein) and members of the organic anion transporting polypeptide (OATP/SLCO) family. It is marginally metabolised in humans.

The influence of known inhibitors of ABCB1 and OATPs on the membrane transport and pharmacokinetics of fexofenadine was investigated in Caco-2 and porcine models and in humans. The permeability of fexofenadine remained low, even when significantly altered by the addition of an inhibitor. Using the Loc-I-Gut^® technique in vivo in humans, it was possible to see that the jejunal effective permeability of fexofenadine was unchanged when given with verapamil. However, the systemic exposure and apparent absorption rate of fexofenadine increased. This suggests that the first-pass liver extraction of fexofenadine was reduced by verapamil, probably through the inhibition of sinusoidal OATP-mediated and/or canalicular ABCB1-mediated secretion. The unchanged permeability can be explained by simultaneous inhibition of jejunal apical OATP-uptake and ABCB1-efflux, which would leave fexofenadine to be transported by passive trancellular diffusion. A Loc-I-Gut^® perfusion in the porcine model enabling blood sampling in the portal and hepatic veins and bile collection revealed increased jejunal permeability, but no subsequent verapamil-induced elevation in the systemic exposure of fexofenadine. This indicates a species-related difference in the localisation of and/or the substrate specificity of fexofenadine for the transporters involved. The absence of an effect on the first-pass liver extraction in the porcine model might be caused by the observed lower liver exposure of verapamil.

Finally, a novel intubation technique enabling dosing of fexofenadine in the jejunum, ileum and the colon showed that fexofenadine was absorbed less along the length the intestine in agreement with the properties of a low permeability drug.

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10

Turner, Joel G. "Drug resistance to topoisomerase directed chemotherapy in human multiple myeloma." [Tampa, Fla] : University of South Florida, 2008. http://purl.fcla.edu/usf/dc/et/SFE0002446.

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11

Rahman, Kazi Shefaet. "Molecular modeling and simulations of the conformational changes underlying channel activity in CFTR." Diss., Georgia Institute of Technology, 2013. http://hdl.handle.net/1853/50346.

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Mutations in the gene encoding the cystic fibrosis transmembrane conductance regulator protein (CFTR) cause cystic fibrosis (CF), the most common life-shortening genetic disease among Caucasians. Although general features of the structure of CFTR have been predicted from homology models, the conformational changes that result in channel opening and closing have yet to be resolved. We created new closed- and open-state homology models of CFTR, and performed targeted molecular dynamics simulations of the conformational transitions in a channel opening event. The simulations predict a conformational wave that starts at the nucleotide binding domains and ends with the formation of an open conduction pathway. Experimentally confirmed changes in side-chain interactions are observed in all major domains of the protein. We also identified unique-to-CFTR substitutions that may have led to channel activity in CFTR. Molecular modeling and simulations are used to compare the effects of these substitutions against a canonical ABC transporter, and suggest that gain of channel function in CFTR may have risen from loss of ATPase function at its NBDs. The models and simulation add to our understanding of the mechanism of ATP-dependent gating in this disease-relevant ion channel.

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12

Pegos, Vanessa Rodrigues 1987. "Caracterização estrutural e funcional do sistema de captação de fosfato da bactéria fitopatogênica 'Xanthomonas axonopodis pv. citri'." [s.n.], 2015. http://repositorio.unicamp.br/jspui/handle/REPOSIP/316459.

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Orientador: Andrea Balan Fernandes
Tese (doutorado) - Universidade Estadual de Campinas, Instituto de Biologia
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Resumo: Xanthomonas axonopodis pv. citri (X. citri) é o causador do cancro cítrico em diversas espécies de citrus, sobretudo, laranjas. As epidemias de cancro cítrico tem causado severas perdas econômicas à citricultura mundial uma vez que não há estratégias de combate efetiva contra essa bactéria no campo. Diversos estudos demonstraram a importância de genes para a patogênese de X. citri, mas ainda não foram investigados genes envolvidos na aquisição e no metabolismo de micronutrientes tais como o fosfato. X. citri conserva o sistema de transporte do tipo ABC de fosfato inorgânico codificado pelo óperon pstSCAB. Adicionalmente a bactéria possui dois outros operons oprO/phoX e phoBR, os quais codificam, respectivamente, uma porina de membrana externa e uma proteína periplasmática ligadora e o sistema dois componentes de sinalização celular, ambos integrantes do regulon de fosfato (regulon pho). Neste trabalho, estudamos a resposta destes operons à carência de fosfato, bem como o papel da proteína ligadora periplasmática PstS, por meio de análises proteômica, metabolômica, estruturais baseadas em cristalografia de raio-X e funcionais utilizando um mutante de X. citri portador de deleção no gene pstS (Xac::pstS). Os dados obtidos foram comparados entre as linhagens selvagem e mutante. Primeiramente evidenciamos que o sistema ABC de fosfato é ativado em carência do íon, incluindo um aumento de expressão de PhoX e PstS de 49 e 33 vezes, respectivamente, e que X. citri apresenta a maioria dos genes do regulon pho. PhoX e PstS são proteínas ligadoras de fosfato que partilham 70% de identidade de aminoácidos e são originadas de uma duplicação gênica. Na ausência de PstS, PhoX parece exercer a função de captação, mas não é capaz de recuperar todos os fenótipos da bactéria selvagem. Adicionalmente, ensaios de transporte de fosfato com as bactérias selvagem e mutante mostraram diferenças no transporte e que o sistema ABC permance constitutivo na linhagem mutante. A deleção de pstS também culminou no retardamento do crescimendo da bactéria em folhas de C. sinensis, mas não interferiu na adesão bacteriana e na produção da goma, estas sim, influenciadas diretamente pela concentração de fosfato no meio. Análises de metabolômica evidenciaram que a carência de fosfato induz mudanças nas rotas bioquímicas, sobretudo na linhagem mutante que utiliza da via das pentoses e do metabolismo do piruvato para a produção de ATP. Este é o primeiro trabalho que evidencia o papel do sistema ABC de transporte de fosfato nesta bactéria e que relaciona de uma forma multidisciplinar, o papel do íon e dos componentes do regulon pho na bactéria X. citri. Adicionalmente, uma vez que o sistema é bem conservado em outras espécies, os resultados obtidos servem como modelo para o gênero Xanthomonas
Abstract: ! Xanthomonas axonopodis pv. citri (X. citri) is the cause of citrus canker in several species of citrus, especially oranges. The citrus canker epidemics have caused severe economic losses to the citrus industry worldwide since no effective combat strategies against this bacterium. Several studies have demonstrated the importance of genes related to the pathogenesis of X. citri, but there is no studies about mechanisms of micronutrients acquisition such as phosphate. X. citri has an ATP-Binding Cassete transport system for inorganic phosphate encoded by pstSCAB operon. In addition, the bacterium has two other operons oprOphoX and phoBR, which encode respectively, an outer membrane porin and a periplasmic binding protein and two-components system. The three operons and other related genes are members of the phosphate regulon (pho regulon). In this work we studied the response of these operons in phosphate deprivation, and the role of periplasmic-binding protein PstS through proteomics analysis, metabolomics, crystallography and functionally based on a X. citri mutant deleted for pstS gene (Xac::pstS). Data were compared between wild type and mutant strains. We showed that the phosphate ABC system is activated during the ion depletion, including PstS and PhoX that showed increased levels of 49 and 30 times, respectively. In addition, we showed that X. citri displays most of the genes of the pho regulon. PhoX and PstS are phosphate binding proteins that share 70% amino acid identity and have origin from a gene duplication. In the absence of PstS, PhoX seems to complement the uptake function, but it is not able to recover all phenotypes of the wild type bacteria. Additionally, phosphate transport assays with wild type and mutant bacteria showed differences in transport and constitutivity of the ABCsystem in the mutant strain. The deletion of pstS also resulted in slowing of bacteria growth in Citrus sinensis leaves, but did not interfere with bacterial adhesion and gum production, two phenomena directly influenced by the phosphate concentration in the medium. Metabolomic analyzes showed that phosphate deprivation induces changes in biochemical pathways, especially the mutant strain that uses the pentose and pyruvate metabolism for ATP production. This is the first work that highlights the role of the ABC system for phosphate in this bacterium and that reveals in a multidisciplinary way, the role of the ion and the pho regulon components in the phytopathogenic bacterium. Additionally, once the system is well preserved in other species, the results serve as a model for the genus Xanthomonas
Doutorado
Genetica de Microorganismos
Doutora em Genética e Biologia Molecular

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13

Smith, Loren E. "The Interplay Between Apolipoproteins and ATP-Binding Cassette Transporter A1." University of Cincinnati / OhioLINK, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1282575598.

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14

Pedersen, Jenny M. "ATP-Binding-Cassette Transporters in Biliary Efflux and Drug-Induced Liver Injury." Doctoral thesis, Uppsala universitet, Institutionen för farmaci, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-205355.

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Membrane transport proteins are known to influence the absorption, distribution, metabolism, excretion and toxicity (ADMET) of drugs. At the onset of this thesis work, only a few structure-activity models, in general describing P-glycoprotein (Pgp/ABCB1) interactions, were developed using small datasets with little structural diversity. In this thesis, drug-transport protein interactions were explored using large, diverse datasets representing the chemical space of orally administered registered drugs. Focus was set on the ATP-binding cassette (ABC) transport proteins expressed in the canalicular membrane of human hepatocytes. The inhibition of the ABC transport proteins multidrug-resistance associated protein 2 (MRP2/ABCC2) and bile salt export pump (BSEP/ABCB11) was experimentally investigated using membrane vesicles from cells overexpressing the investigated proteins and sandwich cultured human hepatocytes (SCHH). Several previously unknown inhibitors were identified for both of the proteins and predictive in silico models were developed. Furthermore, a clear association between BSEP inhibition and clinically reported drug induced liver injuries (DILI) was identified. For the first time, an in silico model that described combined inhibition of Pgp, MRP2 and breast cancer resistance protein (BCRP/ABCG2) was developed using a large, structurally diverse dataset. Lipophilic weak bases were more often found to be general ABC inhibitors in comparison to other drugs. In early drug discovery, in silico models can be used as predictive filters in the drug candidate selection process and membrane vesicles as a first experimental screening tool to investigate protein interactions. In summary, the present work has led to an increased understanding of molecular properties important in ABC inhibition as well as the potential influence of ABC proteins in adverse drug reactions. A number of previously unknown ABC inhibitors were identified and predictive computational models were developed.

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15

Bozdech, Zbynek. "Identification and characterization of PFGCN20, an ATP-binding cassette protein from Plasmodium falciparum." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape10/PQDD_0028/NQ50117.pdf.

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16

Matsson, Pär. "ATP-Binding Cassette Efflux Transporters and Passive Membrane Permeability in Drug Absorption and Disposition." Doctoral thesis, Uppsala University, Department of Pharmacy, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-8371.

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Transport into and across the cells of the human body is a prerequisite for the pharmacological action of drugs. Passive membrane permeability and active transport mechanisms are major determinants of the intestinal absorption of drugs, as well as of the distribution to target tissues and the subsequent metabolism and excretion from the body. In this thesis, the role of ATP-binding cassette (ABC) transporters and passive permeability on drug absorption and disposition was investigated. Particular emphasis was placed on defining the molecular properties important for these transport mechanisms.

The influence of different transport pathways on predictions of intestinal drug absorption was investigated using experimental models of different complexity. Experimental models that include the paracellular pathway gave improved predictions of intestinal drug absorption, especially for incompletely absorbed drugs. Further, the inhibition of the ABC transporters breast cancer resistance protein (BCRP/ABCG2) and multidrug-resistance associated protein 2 (MRP2/ABCC2) was experimentally investigated using structurally diverse datasets that were representative of orally administered drugs. A large number of previously unknown inhibitors were identified among registered drugs, but their clinical relevance for drug-drug interactions and drug-induced toxicity remains to be determined. The majority of the inhibitors affected all three major ABC transporters BCRP, MRP2 and P-glycoprotein (P gp/ABCB1), and these multi-specific inhibitors were found to be enriched in highly lipophilic weak bases.

To summarize, the present work has led to an increased knowledge of the molecular features of importance for ABC transporter inhibition and passive membrane permeability. Previously unknown ABC transporter inhibitors were identified and predictive computational models were developed for the different drug transport mechanisms. These could be valuable tools to assist in the prioritization of experimental efforts in early drug discovery.

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17

Alzahrani, Ateeq Ahmed Hassan. "Structural biology of Cystic Fibrosis Transmembrane Conductance Regulator, an ATP-binding cassette protein of medical importance." Thesis, University of Manchester, 2012. https://www.research.manchester.ac.uk/portal/en/theses/structural-biology-of-cystic-fibrosis-transmembrane-conductance-regulator-an-atpbinding-cassette-protein-of-medical-importance(b8d020d3-24d7-474a-afb5-a112e38ac027).html.

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The cystic fibrosis transmembrane conductance regulator (CFTR) is a transmembrane protein that functions as an ion channel. Mutations in this protein cause Cystic Fibrosis. For this reason, it is important to study the structure and function of CFTR. In this study, constructs of CFTR (C-terminii), a CFTR-interacting protein and full-length CFTR were cloned, expressed and purified for structural and functional studies. The purified C-terminal polypeptides of CFTR were soluble and shown to interact with NHERF1 PDZ 1 (a CFTR-interacting protein). The CFTR C-terminus and NHERF1 PDZ 1 domain were co-expressed and co-purified. The purified complex showed a strong interaction that might induces a conformational change. Site-directed mutation of the C-terminus of CFTR was performed in order to examine the effect of removing a potentially flexible amino acid (Arginine) on protein crystallization. Pull-down assay experiments with full-length CFTR demonstrated an interaction between CFTR (in DDM detergent) and NHERF1 PDZ 1(+). No interaction was observed for CFTR in LPG (a relatively denaturing detergent) and NHERF1, implying that the interaction between the PDZ motive of CFTR and NHERF1 requires a stable folded structure for both proteins. In addition, full-length CFTR in DDM has been studied by electron microscopy and Single Particle Analysis in the presence of NHERF1 PDZ 1(+). A 3D structure was generated for the CFTR-NHERF1 PDZ 1(+) complex at a resolution of ~ 18 A. This 3D structure showed a new open conformation of CFTR (V shape). In comparable studies with CFTR alone, a 3D structure was generated at a resolution of 27 A and this structure showed a closed state as previously reported. This new data suggest a possible role for NHERF1 in terms of CFTR channel gating or activation.

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18

Zhang, Yi. "Potential impact of breast cancer resistance protein on drug disposition during pregnancy /." Thesis, Connect to this title online; UW restricted, 2007. http://hdl.handle.net/1773/7970.

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19

Yung, Man-kuen, and 容文權. "Gene copy number analysis of granulin-epithelin precursor (GEP) and ATP-binding cassette subfamily F member 1 (ABCF1) in hepatocellular carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/197068.

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Hepatocellular carcinoma (HCC) is one of the most lethal cancers in Hong Kong and Southeast Asian countries. Cancer progression is often symptomless, making the early diagnosis difficult, thus leading to a high mortality rate. Treatments against HCC were often found to be less effective than other cancers. Systemic chemotherapy, which is widely used in cancer treatments, has a low response rate in HCC. New treatment regimes, such as targeted therapy, have shown partial responses in clinical trials and therefore continuous effort in searching new drug targets is warranted. Granulin-epithelin Precursor (GEP) is a pluripotent growth factor, and has been shown to be overexpressed in HCC and various cancers. Our group has demonstrated that GEP promotes tumor growth, and regulates chemoresistance in HCC. It shares a highly similar expression pattern with one of the members of ATP-binding cassette (ABC) transporter family, ABCF1. Blocking GEP, both in vitro and in vivo, showed inhibition on HCC growth. These suggest that GEP is a potential target for HCC treatment. However, there is still little information on how GEP and ABCF1 is overexpressed in HCC. This project aims to investigate the mechanisms involved. GEP and ABCF1 genes are located on chromosomes 17q and 6p, respectively, which both are frequently amplified in HCC. We used quantitative microsatellite analysis (QuMA) to detect GEP and ABCF1 amplification in HCC samples. Both GEP and ABCF1 showed about 20% of HCC cases having amplification, and their copy numbers correlated to the mRNA expression levels. The copy numbers of GEP were also found to correlate to those of ABCF1 significantly. Clinico-pathological analysis showed that GEP copy numbers correlated with gender, serum AFP levels and HBV status, while ABCF1 did not associate with any of the clinico-pathological features. Fluorescence in situ hybridization (FISH) was performed to validate the results on DNA copy number by QuMA. The cases with highest DNA copy number on GEP and ABCF1, were examined. The average difference between FISH and QuMA results ranged ± 0.3 copies, indicating QuMA and FISH results were corroborated on DNA copy number. Furthermore, the FISH results indicated that there are different degrees of aneuploidy involved in chromosome 6p and 17q in 5 out of 6 cases investigated. These suggest that the copy number variations in GEP and ABCF1 were partly caused by the abnormal number of chromosomes. In summary, we observed that GEP and ABCF1 gene copy numbers were increased in subsets of HCC cases, and the increase correlated to their respective transcript expression levels. Furthermore, these copy number variations partly could be explained by aneuploidy as demonstrated by FISH analysis. The current study may help to understand the complex genomic aberrations in HCC and allow better treatment designs in the future.
published_or_final_version
Surgery
Master
Master of Philosophy

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20

Desuzinges-Mandon, Elodie. "Rôle du domaine extracellulaire d’ABCG2 dans l’homéostasie des porphyrines." Thesis, Lyon 1, 2010. http://www.theses.fr/2010LYO10236/document.

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ABCG2 est un transporteur de la famille ABC impliqué dans le phénotype de résistance aux drogues développé par certaines cellules, par exemple les cellules cancéreuses. Ce transporteur a aussi un rôle physiologique de détoxication de composés endogènes, notamment les porphyrines, molécules indispensables mais qui présentent une toxicité potentielle. Cette toxicité nécessite une prise en charge particulière, évitant à ces composés d’être libres en solution. Dans ce contexte, nous avons fait l’hypothèse qu’ABCG2 pourrait participer à cette détoxication en limitant l’accumulation des porphyrines dans les cellules en les présentant à un partenaire extracellulaire. Nous montrons qu’ABCG2 transporte de l’hème ainsi que certains de ses dérivés et précurseurs et que ces porphyrines, contrairement aux autres substrats d’ABCG2, se fixent sur un domaine extracellulaire spécifique d’ABCG2, ECL3, composé d’environ 70 acides aminés. L’affinité d’ECL3 pour les porphyrines est de 0,5 à 3,5 μM, suffisamment affine pour permettre leur fixation après transport.Nous montrons aussi que l’albumine sérique humaine, impliquée dans la détoxication de l’hème, récupère les porphyrines fixées sur ECL3 par une interaction directe avec ABCG2. L’ensemble de ce travail a donc permis d’une part de mieux comprendre le rôle d’ABCG2 dans la régulation de l’homéostasie des porphyrines, notamment l’hème, et d’autre part, de façon originale, d’identifier le mécanisme moléculaire par lequel cette détoxication s’effectue
ABCG2 belongs to the ABC-transporter family, involved in drug resistance developed by cells, notably cancer cells. This transporter has also a physiological role of endobiotic detoxification, in particular porphyrins that are essential but potentially toxic molecules. This toxicity implies a specific handle, to avoid them to remain free in solution. In that context, we hypothesized that ABCG2 participate to this detoxification, limiting the intracellular porphyrin accumulation by presenting them to an extracellular partner. We show that ABCG2 transports heme and some of its derivatives and precursors. Interestingly, these porphyrins, unlike other ABCG2 (non-porphyric) substrates, can bind to an extracellular domain, specific of ABCG2, ECL3, 70 residues-long. ECL3 displays affinities for porphyrins in the range of 0.5 to 3.5 μM, high enough to allow their binding after transport. We also show that human serum albumin, implicated in heme detoxification, releases porphyrins bound to ECL3 by a direct interaction with ABCG2. This work established a better comprehension of ABCG2 role in porphyrin and in particular heme homeostasis regulation. In addition, our results contribute to elucidate part of the molecular mechanism by which such regulation is carried out

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21

Thibodeau, Patrick Harlan. "Transmembrane protein folding effects of disease-causing mutations on CFTR folding and assembly /." Access to abstract only; dissertation is embargoed until after 5/16/2007, 2006. http://www4.utsouthwestern.edu/library/ETD/etdDetails.cfm?etdID=171.

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22

Wang, Fen. "In silico and in vitro determination of substrate specificity for Breast Cancer Resistance Protein (BCRP) transporter at the blood-brain barrier." Thesis, Uppsala universitet, Institutionen för farmaci, 2021. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-444527.

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Background The Breast Cancer Resistance Protein (BCRP) drug transporter is important for drug disposition and plays a critical role in regulating drug entry into the brain. Its substrate spectrum overlaps with substrates of Multi Drug Resistance Protein 1 (MDR1, P-gp), which influences and complicates the interpretation of data on drug distribution into tissues (e.g. brain). Distinguishing BCRP mediated transport from the transport by the MDR1 is often problematic. However, with new in vitro tools, this is now possible. In this project, two drug compounds, i.e. Dantrolene and Ritonavir, were investigated using these new in vitro models. The results from the experimental in vitro assay were matched with molecular dynamics (MD) simulations. Using coarse-grained (CG) simulations, a model of the BCRP transporter in a lipid bilayer was built, this model is based on the human BCRP structure revealed by Taylor et al (2017). Simulations were run for Dantrolene (a known substrate of BCRP) independently three times, and another with Ritonavir (a non-substrate) three times. Aim To determine substrate specificity for the BCRP transporter for two compounds, and to construct a CG model of BCRP transporter to see whether in silico methods can be used as an alternative for assessing substrate specificity. Methods Madin-Darby canine kidney (MDCK) II cell line with no endogenous canine MDR1 (cMDR1) expression (MDCKcMDR1-KO), overexpressing human MDR1 (hMDR1) (MDCK-hMDR1cMDR1-KO) and stable expression of human BCRP (hBCRP) (MDCK-hBCRPcMDR1-KO) cells were cultured and used in Transwell experiments. Samples were analyzed using LC-MS/MS to determine the substrate concentrations. Apparent permeability and efflux ratio was calculated and evaluated. MD simulations used the Martini 3 CG force field, and were run with Gromacs (version 2020.4). Tools including MODELLER, INSANE and others were used to construct the initial model (Webster, 2000; Wassenaar et al., 2015), for parameterization of substrate and non-substrate molecules. And visual inspection was done with the visual molecular dynamics (VMD) program and PyMOL. Results In vitro transport experiment confirmed that Dantrolene is a BCRP specific substrate, and Ritonavir is MDR1 specific substrate. Following simulations of these two compounds, Dantrolene is observed to stay in the transmembrane domains (TMD) for a certain period (on average several hundreds of nanoseconds), while Ritonavir is not found to bind in the TMD, which provides a proof of concept for future studies.

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23

Leonhardt, Nathalie. "Caracterisation de proteines de la famille atp-binding cassette impliquees dans le controle de l'osmoregulation et de l'activite des canaux ioniques chez la cellule de garde." Aix-Marseille 2, 1999. http://www.theses.fr/1999AIX22037.

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Les proteines de la famille des atp-binding cassette (abc) sont presentes dans de nombreuses especes et impliquees dans le transport actif de divers substrats. Chez les vegetaux, lorsque ce travail a commence, seule une proteine abc avait ete identifiee son role dans la plante etait inconnu. Par ailleurs, d'autres experiences suggeraient l'intervention de proteines abc dans les mecanismes de detoxication vacuolaire. Parmi les proteines abc animales, deux d'entre elles presentent des proprietes intrinseques de canaux ioniques et/ou regulent d'autres canaux. C'est le cas du cftr (cystic fibrosis transmembrane conductance regulator) qui est un canal chlorure, et du recepteur aux sulfonylurees qui associe a un canal potassique rectifiant entrant forme le canal k + sensible a l'atp, le k a t p. Ces deux proteines abc possedent un site de fixation pour les sulfonylurees. A l'aide d'approches pharmacologiques, electrophysiologiques et moleculaires, ce travail decrit la mise en evidence du role d'au moins une proteine abc capable de lier les sulfonylurees et intervenant dans la regulation des mouvements stomatiques via le controle du canal k + sortant du plasmalemme des cellules de garde. Par ailleurs, il a ete demontre dans le systeme animal que le cftr est capable de conferer la sensibilite aux sulfonylurees a differents types de canaux. En utilisant des inhibiteurs du cftr, nous demontrons que le canal anionique de type s de cellule de garde presente des proprietes biophysiques et pharmacologiques analogues a celles du cftr. De plus, les sulfonylurees interferent avec les voies de signalisation du ca 2 + et de l'aba. Ainsi, nos resultats demontrent pour la premiere fois l'intervention de proteines abc dans la regulation de l'activite de canaux ioniques et dans la transduction du signal chez les vegetaux.

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24

Dartier, Julie. "Etude du métabolisme énergétique mitochondrial et des cardiolipines dans la résistance des cellules cancéreuses mammaires à la doxorubicine." Thesis, Tours, 2016. http://www.theses.fr/2016TOUR3810/document.

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La résistance des cellules cancéreuses à la chimiothérapie est une cause majeure de l’échec thérapeutique. Des études suggèrent qu’une adaptation du métabolisme énergétique pourrait jouer un rôle dans cette résistance. Ce travail de thèse montre que la résistance des cellules cancéreuses mammaires MCF-7dox à la doxorubicine est associée à une diminution de l’activité du complexe I de la chaîne respiratoire mitochondriale et à un métabolisme des cardiolipines (CL) particulier (diminution de la quantité de CL et augmentation de la quantité de MLCL, la forme immature des CL). Nos résultats montrent aussi que les mitochondries des cellules MCF-7dox expriment deux pompes d’efflux ATP-dépendantes (BCRP et MRP1) qui participent à limiter la quantité de doxorubicine accumulée dans ces mitochondries. De plus, l’activité de ces deux transporteurs dépend partiellement de l’ATP mitochondrial dont l’efficacité de synthèse est améliorée dans les cellules MCF-7dox. D’autre part, nous montrons que l’effet sensibilisant du DHA à la doxorubicine dans les cellules MCF-7dox implique un stress oxydant mitochondrial et s’accompagne d’une diminution de l’efficacité de la synthèse d’ATP
Resistance of cancer cells to chemotherapy is a major cause of treatment failure. Studies have suggested that an adaptation of energy metabolism may play a role in the development of this resistance. The present work shows that resistance of the breast cancer cell line MCF-7dox to doxorubicin is associated with decreased activity of the mitochondrial respiratory chain complex I and particularly altered cardiolipin (CL) metabolism, (decreased CL levels and increased MLCL levels, the immature form of the CL). Our results also show that mitochondria from MCF-7dox cells express two ATP-dependent efflux pumps (BCRP and MRP1) limiting the accumulation of doxorubicin in these mitochondria. In addition, the activity of these two transporters is partially dependent on mitochondrial ATP synthesis which efficiency is improved in MCF-7dox cells. Moreover, we show that the sensitizing effect of DHA to doxorubicin in MCF-7dox cells is regulated by mitochondrial oxidative stress and is accompanied by a decrease in ATP synthesis efficiency

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25

Yang, Tianyu. "Two novel mechanisms of MHC class I down-regulation in human cancer accelerated degradation of TAP-1 mRNA and disruption of TAP-1 protein function /." Connect to this title online, 2004. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1078192113.

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Анотація:

Thesis (Ph. D.)--Ohio State University, 2004.
Title from first page of PDF file. Document formatted into pages; contains x, 117 p.; also includes graphics (some col.) Includes bibliographical references (p. 99-117). Available online via OhioLINK's ETD Center

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26

Nardinelli, Luciana. "Acompanhamento molecular de pacientes com leucemia mielóide crônica tratados com mesilato de imatinibe e avaliação dos mecanismos de resistência ao tratamento: mutação do gene BCR-ABL e expressão dos genes MDR1 e BCRP." Universidade de São Paulo, 2009. http://www.teses.usp.br/teses/disponiveis/5/5136/tde-02062009-092027/.

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A leucemia mielóide crônica (LMC) é caracterizada pela translocação (9;22) que dá origem ao gene quimérico BCR-ABL. Este gene codifica uma proteína com atividade tirosina quinase, p210, constitutivamente ativa. O três mecanismos envolvidos na patogênese da LMC são o aumento da proliferação celular, alteração da adesão celular ao estroma e matriz medular e inibição da apoptose. A introdução do mesilato de imatinibe (MI), um inibidor de tirosina quinase, revolucionou o tratamento da LMC levando pacientes em fase crônica a remissões duráveis, porém uma parcela destes não responde ou perde a resposta ao longo do tratamento. Os mecanismos de resistência ao MI podem ser classificados como independentes de BCR-ABL (a1- glicoproteína ácida e genes de resistência a múltiplas drogas) ou dependentes de BCR-ABL (superexpressão de BCR-ABL e mutações do domínio quinase do gene ABL). Objetivo: avaliar a presença de mutações no domínio quinase do gene ABL e a expressão dos genes de resistência a múltiplas drogas MDR1 e BCRP em amostras pré-tratamento com MI, acompanhar estes pacientes mensalmente através da quantificação de transcritos BCR-ABL e quando ocorrer resistência reavaliar a presença de mutações do domínio quinase do ABL e a expressão dos genes de resistência a múltiplas drogas. Material e Métodos: Foram avaliados 61 pacientes com LMC em fase crônica. A pesquisa de mutações do domínio quinase foi realizada pela técnica de seqüenciamento direto e a expressão relativa dos genes de resistência a múltiplas drogas foi avaliada por PCR em tempo real. A quantificação absoluta do número de transcritos BCR-ABL foi realizada pela técnica de PCR em tempo real utilizando-se o sistema Taqman de sondas de hibridização. Resultados: Nas amostras pré-tratamento dos 61 pacientes estudados não foram detectadas mutações. Quando relacionamos o aumento da expressão dos genes MDR1 e BCRP à resposta citogenética completa aos 12 meses de tratamento não houve diferença estatística significativa (p>0,05). Quanto ao número de transcritos BCR-ABL, observamos que os pacientes que apresentaram menos de 1% pela escala internacional aos 3 meses de tratamento atingiram a RMM em período menor (7 meses) do que os que apresentaram mais de 1% (12 meses) com diferença estatística significativa (p = 0,03). Conclusões: As mutações do domínio quinase do gene BCR-ABL nas amostras pré-tratamento não foram detectadas ou pela sensibilidade da técnica de seqüenciamento direto (10%) ou porque tais mutações são mais freqüentes nas fases acelerada e blástica. A expressão dos genes de resistência a múltiplas drogas (MDR1) e BCRP) em pacientes com LMC-FC ao diagnóstico não apresentou correlação com o aparecimento de resistência secundária ao MI. Além disso a quantificação mensal dos transcritos BCR-ABL aos 3 meses pode ser considerada um marcador com valor prognóstico.
Chronic myeloid leukemia is characterized by t(9;22) translocation. The chimeric gene BCR-ABL encodes a p210BCRABL protein with constitutive tyrosine kinase activity which is directly related to CML pathogenesis. The imatinib mesylate, a tyrosine kinase inhibitor, is the first-choice treatment for patients in chronic phase but some patients show primary resistance or relapse after initial response. The mechanisms of resistance to the imatinib mesylate treatment are BCR-ABL dependent (amplification of BCR-ABL and mutation of kinase domain of BCR-ABL) or independent of BCR-ABL (1-acid glycoprotein and expression of multidrug resistance genes). Objective: The objective of this work was to evaluate the mechanisms of resistance (kinase domain mutation and MDR1 and BCRP genes expression) to imatinib mesylate in pretreatment samples, quantify of BCR-ABL transcript on a monthly follow up plan, and to re-evaluate the mechanisms of resistance in the absence or loss of treatment response. Patients and Methods: We have evaluated 61 pretreatment samples derived from chronic phase CML patients. The number of BCR-ABL transcripts was quantified by RTQ-PCR with taqman probes and MDR1 and BCRP expression were evaluated by RTQ-PCR with Syber Green. Mutations within the BCR-ABL kinase domain were screened by direct sequencing and we also have screened the T315I mutation in pretreatment samples by allele-specific PCR. Results:We detected no mutations in the 61 pretreatment samples. The correlation analysis between the expression of MDR1/BCRP genes and the cytogenetic response at 12 months of treatment revealed no significant statistical difference (p = > 0.05). The results of BCR-ABL quantification in the follow up of our cohort indicated that patients who had transcripts <1% by the international scale at 3 months of therapy are more likely to achieve rapid MMR (median of 7 months) than those who had >1% (median of 12 months) (p = 0,03). Conclusions: As expected, the kinase domain mutations of BCR-ABL in pretreatment samples of CML chronic phase patients are not detectable by direct sequencing because of the sensitivity of the assay (10%) and also because these mutations are more common in accelerated phase and blast crisis. About the expression of multidrug resistance genes MDR1 and BCRP, they showed no correlation with secondary resistance to imatinib mesylate. And finally the number of BCR-ABL transcripts at 3 months of treatment can be considered a marker with prognostic value.

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27

Sook, Brian R. "I. Characterization of Sulfonated Phthalocyanines by Mass Spectrometry. II. Characterization of SIAA, a Streptococcal Heme-Binding Protein Associated with a Heme ABC Transport System." unrestricted, 2008. http://etd.gsu.edu/theses/available/etd-04212008-140556/.

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Thesis (Ph. D.)--Georgia State University, 2008.
Title from file title page. Dabney W. Dixon, committee chair; Kathryn B. Grant, Jerry Smith, committee members. Electronic text (171 p. ; ill. (some col.)) : digital, PDF file. Description based on contents viewed June 23, 2008. Includes bibliographical references.

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28

Mir, Mushtaq Ahmad. "Molecular Characterisation Of The ATP Binding Cassette (ABC) Transporter Type FtsE And FtsX Proteins Of Mycobacterium Tuberculosis." Thesis, 2006. http://hdl.handle.net/2005/363.

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Mycobacterium tuberculosis, the principal causative agent of tuberculosis (TB) in humans, is considered to be a successful pathogen owing to the elicitation of multidrug resistance, ability to survive inside macrophage phagosomes by taking nutrients from host cell cytoplasm, and the capacity to alternate between proliferating and dormant (nonproliferating) conditions of growth. Thus, whether one looks at tubercle bacillus from the standpoint of regulation of cell division in the host system, or uptake of nutrients from the host cell cytoplasm or elicitation of drug resistance, the requirement for ATP Binding Cassette (ABC) transporter type protein complexes, which might be involved in the transport of drugs, nutrients or proteins, could be of critical importance to the pathogen. Therefore the present study was initiated to characterize ABC transporter type proteins, FtsE and FtsX of M. tuberculosis (MtFtsE and MtFtsX), and their interaction with FtsZ and FtsQ, which are the septation proteins that are recruited respectively before and after the localization of FtsE and FtsX proteins. The study was carried out in 3 parts. 1. Cloning, overexpression and purification of MtFtsE and MtFtsX proteins and elucidation of ATP binding activity of MtFtsE There exists considerable extent of homology between the FtsE and FtsX proteins of M. tuberculosis and E. coli. Therefore, in order to verify whether the structural homology is reflected in functional homology, complementation of growth defect of E. coli ftsE (Ts) by MtFtsE and MtFtsX was carried out. The MtFtsE protein could partially complement growth defect of E. coli ftsE temperature sensitive strain MFT1181, whereas co-expression of MtFtsE and MtFtsX efficiently complemented growth defect, indicating that the MtFtsE and MtFtsX proteins functionally complement E. coli FtsE and FtsX and that the two proteins together might be performing an associated function. Subsequently, in order to biochemically characterize MtFtsE and MtFtsX proteins of M. tuberculosis, MtftsE gene was cloned in pQE30, overexpressed, purified by Ni2+-NTA agarose affinity chromatography under denaturing conditions and refolded. MtFtsX protein, being toxic to E. coli cells, could not be expressed to sufficient amounts. Western blotting with anti-MtFtsE antibody showed that the recombinant 6xHis-MtFtsE protein and the native MtFtsE protein were localized to the membrane of E. coli and M. tuberculosis cells respectively. 6xHis-MtFtsE protein showed ATP binding in vitro, whereas K42R mutation abolished ATP binding. Thus, like in the case of E. coli FtsE, the K42 residue, which is positionally equivalent to K41 in EcFtsE in Walker A motif, was found to be essential for ATP binding. At 1.3 nM concentration of [α32P] ATP,70 molar excess of ATP, ADP, AMP, and GTP competed out respectively 97%, 87%, 73% and 57% of the [α32P] ATP bound to 6xHis-MtFtsE. 2. Biochemical characterization of MtFtsE protein The functional architecture of an ABC transporter consists of two each of nucleotide binding domain (NBD) and transmembrane domain (TMD), which are either part of a single polypeptide chain or individual subunits. The functional NBD is a ‘nucleotide-sandwich dimer’ with ATP flanked by the Walker A and B motifs of one NBD and the signature motif and D-loop of the other. NBD, through ATPase activity, is involved in energizing the transport of substrates namely drugs, proteins, ions, and solutes across the membrane. Since MtFtsE possesses Walker A and Walker B motifs that constitute NBD, and MtFtsX possesses TMD (four transmembrane segments), the two proteins together might constitute an ABC transporter type complex. Therefore, we wanted to know whether MtFtsE could hydrolyze ATP. MtFtsE not only could bind ATP with high affinity but could hydrolyse it also (Km, 1.5 µM; Vmax, 0.87 nmole/mg/min). It could bind and hydrolyse GTP as well, but not CTP, albeit with lower affinity and rate (Km, 25 µM; Vmax, 0.54 nmole/mg/min). The ATPase activity is strongly dependent on Mg2+ or Mn2+, with a pH optimum of 6.5 – 8.0 and temperature range of 27oC - 40oC. Kinetic analysis of ATPase and GTPase activities indicated nucleotide- dependent cooperativity (Hill coefficient for ATP is 1.7 and for GTP, 2.1). Inhibition of ATPase activity, to almost similar extent, in the presence of 10-fold excess of ATPγS, ADP, AMP, GTP, and CTP, but not TTP, indicated that nucleotide binding is through nitrogenous base of the nucleotide. Inhibition of MtFtsE by orthovanadate classified the enzyme as a P-type ATPase. Partially purified MtFtsE in soluble fraction also showed ATPase activity. The ATPase-active form of MtFtsE is a dimer with the sole cysteine (C84) at the dimer interface. Homology modeling of MtFtsE, using MalK (the NBD component of an ABC transporter for maltose) as the template, supported this observation. Stabilization of the dimer through cys-cys disulphide bond increased ATPase activity by 3.7-fold, although C84 does not have any role in ATPase activity. 3. Identification and elucidation of interaction among cell division proteins FtsE, FtsX, FtsQ and FtsZ of Mycobacterium tuberculosis Septum synthesis in E. coli is mediated by a dozen of proteins, among which the bacterial cytoskeletal protein FtsZ is the first molecule to localise to the mid-cell site, where it forms a scaffold for the localization of downstream cell division proteins namely, FtsA /ZipA < FtsE / FtsX < FtsK < FtsQ < FtsL < FtsB < FtsW < FtsI < FtsN and AmiC. If the above order of recruitment of proteins holds true for M. tuberculosis as well, the immediate proteins recruited to the mid-cell site after MtFtsZ in M. tuberculosis would be MtFtsE and MtFtsX, followed with MtFtsK and MtFtsQ. Thus it is possible that MtFtsE and MtFtsX could be interacting with MtFtsZ and MtFtsQ. Therefore attempts were made to delineate the interaction network among MtFtsE, MtFtsX, MtFtsQ and MtFtsZ of M. tuberculosis. Ni2+-NTA agarose pulldown, co-immunoprecipitation and bacterial two-hybrid assays using wild type and deletion mutants of the proteins showed that MtFtsE interacts with MtFtsQ and MtFtsX through its C-terminus. In addition, MtFtsX could interact with MtFtsZ and MtFtsQ. MtFtsX was found to homodimerise and interact with MtFtsQ in vivo. The ATPase-active of MtFtsE in vivo being a dimer, a hypothetical model for the translocation of MtFtsQ into the membrane at mid-cell site was proposed. According to this model, MtFtsQ might be inserted into the membrane at the mid-cell site by (MtFtsX)2 functioning as the membrane channel for the transport, which could be energized by the ATPase subunit (MtFtsE)2 of the (MtFtsE)2(MtFtsX)2 complex. MtFtsX might have a role in tethering the FtsZ-ring with the membrane at the mid-cell site. An altogether different possibility could be that the (FtsE)2(FtsX)2 complex might have a role in the stabilization or constriction of FtsZ-ring during the inward growth of septum.

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29

Pinto, Bárbara Palma de Abreu Caldeira. "Studies on the function and substrate permeation in ABC transporters by biomolecular simulations." Doctoral thesis, 2021. http://hdl.handle.net/10362/121941.

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"The translocation of molecules across cell membranes often requires the participation of transmembrane proteins. The ATP Binding Cassette (ABC) transporters are one of the major class of proteins dedicated to the translocation of molecules across membranes. ABC transporters make use of ATP hydrolysis and undergo a series of large-scale conformational changes in order to carry out their function. Despite being extensively studied, some molecular details regarding their function remain undisclosed. In this thesis, the function of three relevant ABC systems, CFTR, MsbA and the Escherichia coli MalFGK2E importer, was investigated using computational methods, such as molecular dynamics simulations. The effect of the CFTR mutation F508del, responsible for cystic fibrosis, was studied in the nucleotide binding domains of the CFTR receptor. In the MsbA protein, the molecular details of nucleotide binding during the adenylate kinase cycle were investigated in collaboration with experimental groups with expertise in solid state NMR and EPR. Finally, the details of substrate translocation in the MalFGK2E importer were also researched.(...)"

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30

Richards, Robert Ian. "Genes: Multigene Families, Control of Gene Expression, Genetic contributions to Human Diseases, including Chromosomal Fragile Sites and ‘Dynamic’ and ‘Non-self’ Mutations." Thesis, 2020. http://hdl.handle.net/2440/123986.

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The early work in this thesis utilizes the general approach of comparative analysis. In order to find out the relationship between entities (either functional or genetic) my colleagues and I have attempted to identify the important elements by detecting similarity between those entities that act in a similar manner. The philosophy behind this approach is simply that when two distinct objects perform a similar process then the requirements essential for that process will be revealed as similarities between those objects above a noise of difference between them. The use of comparative analysis in biological systems is an attempt to identify natural order from apparent chaos. This work includes but is not limited to :- 1. discovery of the family of kallikrein genes and exploration of their roles in biology, 2. identification of the DNA sequence elements required for hormonal and heavy metal control of metallothionein gene expression 3. discovery of at least some of the necessary and sufficient conditions for the appearance of fragile sites on chromosomes, and their consequent contributions to disease, 4. the molecular properties of repeat DNA sequence expansion that lead to dynamic mutation and consequent fragile site expression and / or disease pathogenesis. In a sense the use of genetic animal models in order to study gene function and pathogenesis follows similar logic of comparative analysis – the mutation of a single endogenous gene or the expression of a single introduced mutated gene in a (presumed) constant genetic background to enable the biological consequences of the genetic mutation or aberrant gene expression by comparing animals from the ‘wild-type’ or parent line with those that now carry the mutation or altered gene. This approach has been utilized in the most recent work contained herein as a means to determine gene function and / or to model human genetic disease pathogenesis, specifically pathogenic mechanisms of the protein WWOX in cancer and expanded repeat RNAs in neurodegenerative diseases. The culmination of this recent work is the development of an hypothesis – 4. that expanded repeat double-stranded RNA leads to neurodegeneration through its recognition by the RNA-binding pattern recognition receptors as a ‘non-self’ or foreign nucleic acid due to a paucity of RNA modification. The resultant pathogenic mechanism is therefore autoinflammatory disease. Given the wide range and variety of evidence of inflammatory activation in neurodegenerative diseases in general, this mechanism is therefore hypothesized to be the general causal mechanism for most (or all) of these diseases. A specific Introduction - highlighting the nature and significance of the work, and a Conclusion – of how this work has contributed to knowledge, are given at the start of each chapter, while the impact of the various components of this work is indicated by the number of citations for each of the included publications. Authorship contributions to each of the included publications in this work are also indicated with each specific reference.
Thesis (DSc) -- University of Adelaide, School of Biological Sciences, 2020

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31

Ronaldson, Patrick Thomas. "Functional expression of ATP-binding cassette (ABC) transporters in brain cellular compartments and in glial cells exposed to HIV-1 viral proteins." 2007. http://link.library.utoronto.ca/eir/EIRdetail.cfm?Resources__ID=742526&T=F.

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32

Lin, Chun-Jung, and 林均蓉. "The green tea extract, EGCG, prevents foam cell formation through down-regulation of scavenger receptor A and up-regulation of ATP-binding cassette proteins." Thesis, 2008. http://ndltd.ncl.edu.tw/handle/64956934448275846176.

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碩士
國立陽明大學
生理學研究所
96
Macrophage-derived foam cells play a critical role in the development of atherosclerosis. The foam cell formation is due to excessive intracellular accumulation of cholesterol derived from modified low-density lipoprotein (LDL). In macrophages, scavenger receptors (SRs), such as class A scavenger receptor (SR-A) and CD36, are responsible for internalization of oxidized LDL (oxLDL). On the other hand, the efflux of intracellular cholesterol is mainly mediated through reverse cholesterol transporters (RCTs) such as ATP-binding cassette (ABC) transporters (ABCA1 and ABCG1) and SR-B1. Thus, therapeutic targeting of regulation of these SRs and RCTs and the cholesterol level in foam cells is recognized to be beneficial in the prevention and therapy of atherosclerosis. To this end, recent animal studies demonstrate that epigallocatechin-3-gallate (EGCG), the major and active component of green tea polyphenols, can alleviate the progression of atherosclerosis. The cellular mechanism underlying this beneficial effect of EGCG, however, is still unclear. The aim of this study was to investigate whether EGCG can alter the expressions of SRs and RCTs leading to prevention of foam cell formation in J774 cell, a mouse macrophage cell line. We found that co-incubation with EGCG indeed alleviated the lipid accumulation in oxLDL-treated J774 cell, as evidenced by the Oil Red O stain. Western blot analysis demonstrated that EGCG also decreased the protein level of SR-A and increased the protein levels of ABCA1 and ABCG1, while having no effect on CD36 and SR-BI in oxLDL-untreated macrophages. RT-PCR analysis revealed that EGCG did not affect the mRNA level of SR-A, but increased the mRNA levels of ABCA1 and ABCG1. Additionally, in the presence of cycloheximide (an inhibitor of protein biosynthesis), EGCG promoted the protein degradation of SR-A, whereas it did not influence the protein degradation of ABCA1 and ABCG1. Furthermore, pretreatment with chloroquine (an inhibitor of the lysosome pathway) totally prevented the EGCG-induced enhancement of SR-A protein degradation, whereas pretreatment with MG132 (an inhibitor of the proteasome pathway) failed to do so. In the end, EGCG also improved the protein levels of liver X receptor (LXR) and retinoid X receptor (RXR) (nuclear receptors which are responsible for the up-regulation of ABCA1 and ABCG1) by 6 hours, whereas having no effect on peroxisome proliferators-activated receptor-gamma (PPAR-��) in cell nuclear. These preliminary results suggest that EGCG prevents foam cell formation possibly through down-regulation of SR-A and up-regulation of ABCA1 and ABCG1. The down-regulation of SR-A by EGCG is a result from an enhancement of protein degradation via the lysosome pathway, while the up-regulation of ABCA1 and ABCG1 by EGCG is mediated through transcriptional regulation. Our findings thus provide a novel mechanism to, at least partly, explain the beneficial effect of EGCG in the prevention and therapy of atherosclerosis.

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33

Tseng, Pin Jung, and 曾品榕. "Investigating the interactions of MY-5445, a PDE5 inhibitor, and LY3023414, a PI3K/mTOR dual inhibitor, with MDR-linked ATP-binding cassette proteins ABCB1 and ABCG2." Thesis, 2019. http://ndltd.ncl.edu.tw/cgi-bin/gs32/gsweb.cgi/login?o=dnclcdr&s=id=%22107CGU05114084%22.&searchmode=basic.

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34

Tuo, Wei Cherng, and 脫惟程. "A fluorescent cell-based high-throughput functional screening platform for the identification of drug substrates and inhibitors of multidrug resistance-associated ATP-binding cassette proteins ABCB1 and ABCG2." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/434gng.

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35

Chang, Yen Fu, and 張晏輔. "Investigating the interactions of Citarinostat, a histone deacetylase (HDAC) inhibitor, and PDGFR inhibitor 1, a platelet-derived growth factor (PDGFR) inhibitor, with ATP-binding cassette proteins ABCB1 and ABCG2." Thesis, 2019. http://ndltd.ncl.edu.tw/cgi-bin/gs32/gsweb.cgi/login?o=dnclcdr&s=id=%22107CGU05114088%22.&searchmode=basic.

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36

Mo, Wei. "CONTRIBUTIONS OF TM5, ECL3 AND TM6 OF HUMAN BCRP TO ITS OLIGOMERIZATION ACTIVITIES AND TRANSPORT FUNCTIONS." Thesis, 2012. http://hdl.handle.net/1805/2744.

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Indiana University-Purdue University Indianapolis (IUPUI)
Human BCRP is one of the major ATP-binding cassette transporters involved in the development of multidrug resistance in cancer chemotherapy. Overexpression of BCRP in the tumor cell plasma membrane and apical membrane of the gastrointestinal tract leads to decreased intracellular accumulation of various anticancer drugs as well as reduced drug bioavailability. BCRP has been shown to exist on the plasma membrane as higher forms of homo-oligomers. In addition, the oligomerization domain of BCRP has been mapped to the carboxyl-terminal TM5-ECL3-TM6 and this truncated domain, when co-expressed with the full-length BCRP, displays a dominant inhibitory activity on BCRP function. Thus, the oligomerization of BCRP could be a promising target in reversing multidrug resistance mediated by BCRP. To further dissect the oligomerization domains of human BCRP and test the hypothesis that TM5, ECL3, and TM6 each plays a role in BCRP oligomerization and function, we engineered a series of BCRP domain-swapping constructs with alterations at TM5-ECL3-TM6 and further generated HEK293 cells stably expressing wild-type or each domain-swapping construct of BCRP. Using co-immunoprecipitation and chemical cross-linking, we found that TM5, ECL3, and TM6 all appear to partially contribute to BCRP oligomerization, which are responsible for the formation of oligomeric BCRP. However, only TM5 appears to be a major contributor to the transport activity and drug resistance mediated by BCRP, while ECL3 or TM6 is insufficient for BCRP functions. Taken together, these findings suggest that homo-oligomeric human BCRP may be formed by the interactions among TM5, ECL3 and TM6, and TM5 is a crucial domain for BCRP functions and BCRP-mediated drug resistance. These findings may further be used to explore targets for therapeutic development to reverse BCRP-mediated drug resistance and increase the bioavailability of anti-cancer drugs for better treatment of multidrug resistant cancers.

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37

Tan, Kah Poh. "Nuclear Factor (Erythroid 2-like) Factor 2 (Nrf2) as Cellular Protector in Bile Acid and Retinoid Toxicities." Thesis, 2008. http://hdl.handle.net/1807/17287.

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Exposure to toxic bile acids (BA) and retinoic acids (RA) is implicated in toxicities related to excessive oxidative stress. This thesis examined roles and mechanisms of the oxidative stress-responsive nuclear factor (erythroid 2-like) factor 2 (Nrf2) in adaptive cell defense against BA and RA toxicities. Using liver cells and mouse models, many antioxidant proteins known to be Nrf2 target genes, particularly the rate-limiting enzyme for glutathione (GSH) biosynthesis, i.e., glutamate-cysteine ligase subunits (GCLM/GCLC), were induced by BA [lithocholic acid (LCA)] or RA (all-trans, 9-cis and 13-cis) treatment. Evidence for increased Nrf2 transactivation by LCA and all-trans-RA was exemplified in HepG2 by: (1) reduced constitutive and inducible expression of GCLM/GCLC upon Nrf2 silencing via small-interfering RNA; (2) increased inducible expression of GCLM/GCLC genes by Nrf2 overexpression, but overexpression of dominant-negative Nrf2 decreased it; (3) increased nuclear accumulation of Nrf2 as signature event of receptor activation; (4) enhanced Nrf2-dependent antioxidant-response-element (ARE) reporter activity as indicative of increased Nrf2 transactivation; and (5) increased Nrf2 occupancy to AREs of GCLM and GCLC. Additionally, in BA-treated HepG2 cells, we observed concomitant increases of many ATP-binding cassette (ABC) transporters (MRPs 1-5, MDR1 and BCRP) in parallel with increased cellular efflux. Nrf2 silencing in HepG2 cells decreased constitutive and inducible expression of MRP2, MRP3 and ABCG2. However, Nrf2-silenced mouse hepatoma cells, Hepa1c1c7, and Nrf2-/- mice had decreased constitutive and/or inducible expression of Mrps 1-4, suggesting species differences in Nrf2-dependent regulation of hepatic ABC transporters. Protection by Nrf2 against BA and RA toxicities was confirmed by observations that Nrf2 silencing increased cell susceptibility to BA- and RA-induced cell death. Moreover, Nrf2-/- mice suffered more severe liver injury than the wildtype. Increased GSH and efflux activity following increased GCLM/GCLC and ABC transporters, respectively, can mitigate LCA toxicity. Activation of MEK1-ERK1/2 MAPK was shown to primarily mediate Nrf2 transactivation and LCA-induced expression of antioxidant proteins and Nrf2-dependent and -independent ABC transporters. In conclusion, Nrf2 activation by BA and RA led to coordinated induction of antioxidant and ABC proteins, thereby counteracting resultant oxidative cytotoxicity. The potential of targeting Nrf2 in management of BA and RA toxicities merits further investigation.

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38

Gulati, Sonia. "Characterizing the Interaction of the ATP Binding Cassette Transporters (G subfamily) with the Intracellular Protein Lipid Environment." Thesis, 2011. https://doi.org/10.7916/D8ZW1SW7.

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Cholesterol is an essential molecule that mediates a myriad of critical cellular processes, such as signal transduction in eukaryotes, membrane fluidity, and steroidogenesis. As such it is not surprising that cholesterol homeostasis is tightly regulated, striking a precise balance between endogenous synthesis and regulated uptake/efflux to and from extracellular acceptors. In mammalian cells, sterol efflux is a key component of the homeostatic equation and is mediated by members of the ATP binding cassette (ABC) transporter superfamily. ATP-binding cassette (ABC) transporters represent a group of evolutionarily highly conserved cellular transmembrane proteins that mediate the ATP-dependent translocation of substrates across membranes. Members of this superfamily, ABCA1 and ABCG1, are key components of the reverse cholesterol transport pathway. ABCG1 acts in concert with ABCA1 to maximize the removal of excess cholesterol from cells by promoting cholesterol efflux onto mature and nascent HDL particles, respectively. To date, mammalian ABC transporters are exclusively associated with efflux of cholesterol. In Saccharomyces cerevisiae, we have demonstrated that the opposite (i.e inward) transport of sterol in yeast is also dependent on two ABC transporters (Aus1p and Pdr11p). This prompts the question what dictates directionality of sterol transport by ABC transporters. The main focus of this study is to define the parameters that result in sterol movement across membranes. The comparison between these contrasting states (outward v. inward transport of the same substrate) will allow us to dissect whether sterol transport across the plasma membrane is defined by the molecule (i.e. the ABC transporter) or by microenvironment (i.e. the status of other proteins and lipids) in which it resides. We have developed the model eukaryote Saccharomyces cerevisiae as a tool to understand the mechanisms that influence ABC-transporter mediated movement of sterols. Specifically, we expressed murine ABCG1 (mABCG1) in yeast and assessed how changes in the intracellular sterol environment affect movement of sterols by this transporter. We found that expression of mABCG1 is able to vary (both increase and decrease) the concentration of exogenous sterols in the cell in response to intracellular sterol changes. We also found that yeast members of the ABCG subfamily, Aus1p and Pdr11p are able to promote either influx of cholesterol or efflux of a cholesterol derivative depending on the sterol context of the cell. This is the first example of an ABC transporter mediating bi-directional transport. These data suggest that direction of transport is not a static property of the transporter but rather can adapt in response to changes in the intracellular microenvironment. In addition to sterols we also found that proteins in the microenvironment may also influence direction of transport. Specifically, we found that the yeast sterol esterifying enzyme Are2p, physically interacts with the ABC transporters Aus1p and Pdr11p. Furthermore, all three proteins were found to co-localize to detergent resistant membrane microdomains. Deletion of either ABC transporter resulted in Are2p re-localization from DRMs to a detergent soluble fraction as well as a significant decrease in the percent of sterol esterified. This phenomenon is evolutionarily conserved in the murine lung where ABCG1 and ACAT1 were observed to co-localize with flotillin-1, a marker of DRMs. We propose that co-localization and complex formation of sterol esterification enzymes and ABC transporters in DRMs reflects a novel mechanism that directs membrane sterols to the esterification reaction. The studies presented in this thesis provide evidence that direction of transport is not a static inherent property of the transporter, but rather that it is mutable and influenced by surrounding sterols and proteins. The data provided here offers further insight as to how ABC transporters move cholesterol from the membrane and therefore may provide a platform for innovative strategies to combat atherosclerosis.

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39

Liu, Minjing. "Structural studies of apolipoprotein A-I and ATP-binding cassette A1 and their roles in nascent high density lipoprotein biogenesis." Thesis, 2017. https://hdl.handle.net/2144/20807.

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Apolipoprotein A-I (apoA-I) and ATP-Binding Cassette A1 (ABCA1) transporter play important roles in nascent high density lipoprotein (nHDL) biogenesis – the first step in the reverse cholesterol transport pathway. Based on the crystal structure of a C-terminally truncated form of apoA-I (apoA-I(1-184)) determined in the laboratory, structurally designed and naturally occurring mutants of apoA-I were conformationally characterized in solution. The function of these mutants in nHDL formation was assessed in ABCA1-transfected HEK293 cells. An apoA-I mutant designed to destabilize the N-terminal helical bundle at the first hinge region, 38/40G, exhibited a locally reduced α-helical content, destabilized overall structure, and increased lipid binding ability in solution, indicating a destabilized N-terminal helical bundle. In the cellular system, 38/40G showed significantly enhanced nHDL forming ability, suggesting that a destabilized N-terminal bundle will facilitate nHDL formation. Other designed N-terminal mutants (Q41A, P66G, G65A, V67P, T68P, 65/67/68P) and the naturally occurring mutants (R153P, L178P, and insertion mutant apoA-INashua) all showed either unchanged or destabilized overall structure, unchanged lipid binding abilities in solution and unchanged nHDL formation and cholesterol efflux promotion from the cells. Mutants designed to progressively extend the C-terminus (1-184, 1-198, 1-209, 1-220, 1-231) yielded progressively increased nHDL formation and cholesterol efflux, suggesting that the C-terminus of apoA-I is critical for these two activities. Central Helix 5 triple glycine mutation (H5 3xG) designed to lock the monomer conformation of apoA-I resulted in reduced nHDL formation but unaffected cholesterol efflux, suggesting that hindering apoA-I monomer to dimer conversion could retard nHDL formation. Remarkably, studies of cholesterol efflux and nHDL particle formation indicated that the two processes might be two uncoupled events. Analysis of the nHDL particles revealed the presence of ganglioside (GM1) in the complexes. Cross-linking data demonstrated binding of apoA-I to ABCA1-expressing cells. The binding level of apoA-I mutants to ABCA1-expressing cells was positively correlated with nHDL forming ability of these mutants. ABCA1 was isolated from FreeStyle™ HEK293-F cells in suspension by detergent solubilization and was shown to have ATPase activity. A direct interaction between apoA-I and amphipol solubilized- ABCA1 in solution was detected for the first time. Furthermore, the successful purification of ABCA1 has laid the foundation of structure determination of this protein in the future.

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40

Hilpert, Johannes [Verfasser]. "Interaktion des ROMK-Kaliumkanals mit dem ABCB1- (ATP-Binding Cassete Typ B1) Protein / vorgelegt von Johannes Hilpert." 2010. http://d-nb.info/1009325612/34.

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41

Cogbill, Jolene Noelani Tarnay. "The Drosophila ATP-Binding Cassette transporter gene dMRP is related to the human Multidrug Resistance-associated Protein (MRP) family and functions as a xenobiotic transporter." Thesis, 2008. http://hdl.handle.net/10125/20463.

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Thesis (Ph.D.)--University of Hawaii at Manoa, 2008.
Transport proteins provide essential cellular functions for archaea, bacteria and eukaryotes. Of the over 550 classified transporter families the ATP-Binding Cassette (ABC) Superfamily is one of the largest. The ABC Transporter Superfamily is divided into eight subfamilies designated A thru H. Members of this superfamily are involved in the transport of a variety of physiologically important substrates including ions, sugars, amino acids, vitamins, peptides, lipids and hormones. ABC transporters are also involved in diverse cellular processes such as lipid trafficking, antigen processing, nutrient uptake, and xenobiotic detoxification. Mutations in several ABC transporters result in various genetic diseases, while overexpression of certain key members of the ABCB/Multidrug Resistance (MDR) and ABCC/Multidrug Resistance-associated Protein (MRP) subfamilies can lead to the development of cellular multixenobiotic resistance. Phylogenetic analysis of the Drosophila genome has identified the Drosophila MRP (dMRP) gene as orthologous to three human genes capable of conferring xenobiotic resistance, the human ABCC1/MRP1, ABCC2/MRP2 and ABCC3/MRP3 genes. In vivo and in vitro experiments have shown that the dMRP gene is ubiquitously expressed throughout Drosophila development and established the dMRP gene as a functional ABC transporter. In vivo and in vitro pesticide assays indicated that dMRP is a pesticide-inducible xenobiotic transporter involved in pesticide metabolism.
Includes bibliographical references (leaves 209-240).
Also available by subscription via World Wide Web
240 leaves, bound 29 cm

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