Thesis (Ph. D.)--Oregon State University, 2010. / Printout. Includes bibliographical references (leaves 91-101). Also available on the World Wide Web.

Thesis (Ph. D.)--University of Hong Kong, 2006.

Thesis (Ph. D.)--University of Missouri-Columbia, 2005. / "December 2005" The entire dissertation/thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file (which also appears in the research.pdf); a non-technical general description, or public abstract, appears in the public.pdf file. Vita. Includes bibliographical references.

Thesis (Ph. D.)--Ohio State University, 2006. / Full text release at OhioLINK's ETD Center delayed at author's request

Neste trabalho foi realizado o estudo por docagem e simulação de dinâmica molecular de doze derivados benzazólicos fluorescentes por ESIPT, interagindo com o dodecâmero de Dickerson-Drew na forma B-DNA. Estes doze ligantes foram divididos em dois grupos (A e B), sendo o primeiro grupo composto por derivados do 2-(2’-hidroxifenil)-benzoxazol e o segundo grupo composto por três derivados do 2-(4’-amino-2’-hidroxifenil)-benzazóis, alternando entre N, S e O no anel azólico, mais três bases de Tröger derivadas dos mesmos. Na análise da docagem molecular do grupo A, os derivados com grupamento –NH2 no anel fenólico apresentaram energias de interação mais favoráveis com o DNA, verificando um favorecimento ainda maior, para os ligantes que continham –NO2 como substituinte no anel benzoxazólico. Na análise da docagem molecular para grupo B, as bases de Tröger (4ac) apresentaram interações significativamente mais favoráveis, quando comparados com seus respectivos precursores (3ac). Na análise da DM, tanto o grupo A, quanto o B, apresentaram a formação de complexos estáveis. O grupo A apresentou uma indução a alterações estruturais mínimas no DNA, sendo as maiores alterações a abertura do Rise quando os ligantes estavam intercalados, acompanhado pelo desenrolamento do parâmetro Twist. Nas interações de sulco menor, o ligante 2a foi o que formou o complexo mais estável com o DNA. Na análise da DM do grupo B, as bases de Tröger apresentaram uma preferência maior por interações do tipo intercalação que seus precursores, sendo os primeiros, os quais induziram o oligonucleotídeo a maiores alterações estruturais. Durante todas as simulações os ligantes mantiveram-se com uma forte interação com o oligonucleotídeo, sem causar a desnaturação do mesmo. Devido às interações estáveis, e também as propriedades fotofísicas peculiares dos ligantes estudados, esta classe de moléculas pode atuar como possíveis sondas biológicas. / In this work we carried out a study by docking and molecular dynamics simulations of twelve ESIPT-fluorescent benzazoles, interacting with the Dickerson-Drew dodecamer in the canonical B-DNA form. These twelve ligands were divided into two groups (A and B), with the first group consisting of derivatives of 2-(2’-hydroxphenyl)-benzoxazole and the second group consisting of three derivatives of 2-(4’-amino-2’-hydroxyphenyl)-benzazoles, alternating between N, S and O in the azole ring and three Tröger bases derived from them. In the analysis of the molecular docking of group A, the derivatives with group –NH2 in the phenolic ring presented more favorable interaction energies with the DNA, and the score was even more favorable for the ligands which contained –NO2 as substituent in the benzoxazolic ring. In the analysis of the molecular docking for group B, the Tröger bases (4ac) presented significantly more favorable interactions, when compared with their respective precursors (3ac). In the analysis of the DM, both groups A and B formed stable complexes. Group A induced only slight structural distortions in the DNA, being the largest modifications the increase of the Rise parameter when the ligands were intercalated, accompanied by the unwinding of Twist parameter. Regarding minor groove interactions, the ligand 2a formed the most stable complex with the DNA. In the analysis of the DM both groups A and B, the Tröger bases presented a greater preference for intercalation interactions than their precursors and the Tröger bases induced the largest structural changes to the oligonucleotide. During all the simulations the ligands maintained a strong interaction with the oligonucleotide, without causing the denaturation of the same. Due to the stable interactions, and also the peculiar photophysical properties of the ligands studied, this class of molecules can act as possible biological probes.

Neste trabalho foi realizado o estudo por docagem e simulação de dinâmica molecular de doze derivados benzazólicos fluorescentes por ESIPT, interagindo com o dodecâmero de Dickerson-Drew na forma B-DNA. Estes doze ligantes foram divididos em dois grupos (A e B), sendo o primeiro grupo composto por derivados do 2-(2’-hidroxifenil)-benzoxazol e o segundo grupo composto por três derivados do 2-(4’-amino-2’-hidroxifenil)-benzazóis, alternando entre N, S e O no anel azólico, mais três bases de Tröger derivadas dos mesmos. Na análise da docagem molecular do grupo A, os derivados com grupamento –NH2 no anel fenólico apresentaram energias de interação mais favoráveis com o DNA, verificando um favorecimento ainda maior, para os ligantes que continham –NO2 como substituinte no anel benzoxazólico. Na análise da docagem molecular para grupo B, as bases de Tröger (4ac) apresentaram interações significativamente mais favoráveis, quando comparados com seus respectivos precursores (3ac). Na análise da DM, tanto o grupo A, quanto o B, apresentaram a formação de complexos estáveis. O grupo A apresentou uma indução a alterações estruturais mínimas no DNA, sendo as maiores alterações a abertura do Rise quando os ligantes estavam intercalados, acompanhado pelo desenrolamento do parâmetro Twist. Nas interações de sulco menor, o ligante 2a foi o que formou o complexo mais estável com o DNA. Na análise da DM do grupo B, as bases de Tröger apresentaram uma preferência maior por interações do tipo intercalação que seus precursores, sendo os primeiros, os quais induziram o oligonucleotídeo a maiores alterações estruturais. Durante todas as simulações os ligantes mantiveram-se com uma forte interação com o oligonucleotídeo, sem causar a desnaturação do mesmo. Devido às interações estáveis, e também as propriedades fotofísicas peculiares dos ligantes estudados, esta classe de moléculas pode atuar como possíveis sondas biológicas. / In this work we carried out a study by docking and molecular dynamics simulations of twelve ESIPT-fluorescent benzazoles, interacting with the Dickerson-Drew dodecamer in the canonical B-DNA form. These twelve ligands were divided into two groups (A and B), with the first group consisting of derivatives of 2-(2’-hydroxphenyl)-benzoxazole and the second group consisting of three derivatives of 2-(4’-amino-2’-hydroxyphenyl)-benzazoles, alternating between N, S and O in the azole ring and three Tröger bases derived from them. In the analysis of the molecular docking of group A, the derivatives with group –NH2 in the phenolic ring presented more favorable interaction energies with the DNA, and the score was even more favorable for the ligands which contained –NO2 as substituent in the benzoxazolic ring. In the analysis of the molecular docking for group B, the Tröger bases (4ac) presented significantly more favorable interactions, when compared with their respective precursors (3ac). In the analysis of the DM, both groups A and B formed stable complexes. Group A induced only slight structural distortions in the DNA, being the largest modifications the increase of the Rise parameter when the ligands were intercalated, accompanied by the unwinding of Twist parameter. Regarding minor groove interactions, the ligand 2a formed the most stable complex with the DNA. In the analysis of the DM both groups A and B, the Tröger bases presented a greater preference for intercalation interactions than their precursors and the Tröger bases induced the largest structural changes to the oligonucleotide. During all the simulations the ligands maintained a strong interaction with the oligonucleotide, without causing the denaturation of the same. Due to the stable interactions, and also the peculiar photophysical properties of the ligands studied, this class of molecules can act as possible biological probes.

Neste trabalho foi realizado o estudo por docagem e simulação de dinâmica molecular de doze derivados benzazólicos fluorescentes por ESIPT, interagindo com o dodecâmero de Dickerson-Drew na forma B-DNA. Estes doze ligantes foram divididos em dois grupos (A e B), sendo o primeiro grupo composto por derivados do 2-(2’-hidroxifenil)-benzoxazol e o segundo grupo composto por três derivados do 2-(4’-amino-2’-hidroxifenil)-benzazóis, alternando entre N, S e O no anel azólico, mais três bases de Tröger derivadas dos mesmos. Na análise da docagem molecular do grupo A, os derivados com grupamento –NH2 no anel fenólico apresentaram energias de interação mais favoráveis com o DNA, verificando um favorecimento ainda maior, para os ligantes que continham –NO2 como substituinte no anel benzoxazólico. Na análise da docagem molecular para grupo B, as bases de Tröger (4ac) apresentaram interações significativamente mais favoráveis, quando comparados com seus respectivos precursores (3ac). Na análise da DM, tanto o grupo A, quanto o B, apresentaram a formação de complexos estáveis. O grupo A apresentou uma indução a alterações estruturais mínimas no DNA, sendo as maiores alterações a abertura do Rise quando os ligantes estavam intercalados, acompanhado pelo desenrolamento do parâmetro Twist. Nas interações de sulco menor, o ligante 2a foi o que formou o complexo mais estável com o DNA. Na análise da DM do grupo B, as bases de Tröger apresentaram uma preferência maior por interações do tipo intercalação que seus precursores, sendo os primeiros, os quais induziram o oligonucleotídeo a maiores alterações estruturais. Durante todas as simulações os ligantes mantiveram-se com uma forte interação com o oligonucleotídeo, sem causar a desnaturação do mesmo. Devido às interações estáveis, e também as propriedades fotofísicas peculiares dos ligantes estudados, esta classe de moléculas pode atuar como possíveis sondas biológicas. / In this work we carried out a study by docking and molecular dynamics simulations of twelve ESIPT-fluorescent benzazoles, interacting with the Dickerson-Drew dodecamer in the canonical B-DNA form. These twelve ligands were divided into two groups (A and B), with the first group consisting of derivatives of 2-(2’-hydroxphenyl)-benzoxazole and the second group consisting of three derivatives of 2-(4’-amino-2’-hydroxyphenyl)-benzazoles, alternating between N, S and O in the azole ring and three Tröger bases derived from them. In the analysis of the molecular docking of group A, the derivatives with group –NH2 in the phenolic ring presented more favorable interaction energies with the DNA, and the score was even more favorable for the ligands which contained –NO2 as substituent in the benzoxazolic ring. In the analysis of the molecular docking for group B, the Tröger bases (4ac) presented significantly more favorable interactions, when compared with their respective precursors (3ac). In the analysis of the DM, both groups A and B formed stable complexes. Group A induced only slight structural distortions in the DNA, being the largest modifications the increase of the Rise parameter when the ligands were intercalated, accompanied by the unwinding of Twist parameter. Regarding minor groove interactions, the ligand 2a formed the most stable complex with the DNA. In the analysis of the DM both groups A and B, the Tröger bases presented a greater preference for intercalation interactions than their precursors and the Tröger bases induced the largest structural changes to the oligonucleotide. During all the simulations the ligands maintained a strong interaction with the oligonucleotide, without causing the denaturation of the same. Due to the stable interactions, and also the peculiar photophysical properties of the ligands studied, this class of molecules can act as possible biological probes.

L'étude de la dynamique intrinsèque de l'ADN-B permet de caractériser l'espace conformationnel exploré par cette macromolécule. Cette dynamique, qui dépend de la séquence, est un facteur clé dans les mécanismes d'interaction avec les protéines, l'ADN étant plus ou moins prédisposé à s'adapter à son partenaire. Lors de cette thèse, nous avons sondé la dynamique de l'ADN à deux échelles de temps, en nous basant sur l'étude de quatre dodécamères par Résonance Magnétique Nucléaire (RMN). Nous nous sommes d'abord intéressés à la dynamique des groupements phosphates, qui correspondent à des mouvements rapides (picoseconde-nanoseconde). Nous avons ainsi confirmé l'effet de la séquence dinucléotidique sur cette dynamique, qui peut être prédit et quantifié. Nous avons également mis en lumière pour la première fois l'étroite inter-dépendance qui existe entre déplacements chimiques du phosphore, distances internucléotides et constantes de couplage dipolaire résiduel. L'interprétation de ces observables RMN en termes de conformations des phosphates, de paramètres hélicoïdaux et de taille des sillons, montre qu'en fait ces couplages reflètent la mécanique intrinsèque de l'ADN en solution. En interfaçant ces résultats avec l'effet de séquence observé sur la dynamique des phosphates, il est aussi possible de saisir de quelle façon la conformation moyenne de la double hélice et l'espace conformationnel associé sont modulés par la séquence au niveau dinucléotidique. Enfin, des dynamiques moléculaires réalisées avec les très récents champs de force CHARMM36 et Parmbsc0ezOLI, confrontées aux données expérimentales, ont permis d'apprécier le réalisme croissant des ADN simulés et ont aidé à préciser des éléments de la dynamique qui échappent à l'expérience. Le deuxième volet de cette thèse a porté sur les mouvements de l'ADN se produisant à l'échelle de la milliseconde, encore très peu étudiés. Nous avons mis au point des expériences de dispersion-relaxation qui ont apporté la preuve de l’existence d’un échange conformationnel d'un type totalement nouveau. Cet échange ne semble apparaitre que sur un type particulier de séquence, riche en A:T. Certaines régions de l’ADN, probablement spécifiques, peuvent ainsi localement évoluer vers une forme très faiblement peuplée, dont la structure détaillée reste à caractériser. L'ensemble de ces résultats offre un panorama des capacités dynamiques de l'ADN, dépendantes de la séquence, et ouvre ainsi de nombreuses perspectives vers une meilleure compréhension des mécanismes qui guident la formation des complexes ADN-protéines. / The study of B-DNA intrinsic dynamics enables to characterize the conformational landscape explored by this macromolecule. Indeed, binding of DNA to proteins is modulated by subtle sequence-dependent variations inherent to the dynamics of free DNA, which facilitate or disfavor the structural fit with cognate partners.In this thesis, the DNA dynamics was investigated at two time-scales, on the basis of the Nuclear Magnetic Resonance (NMR) study of four dodecamers. First, we examined the fast dynamics (pico-nanosecond) of phosphate linkages. We confirmed that the dinucleotide sequence modulates the backbone dynamics, an effect that can be quantified and predicted. Then, our experimental data enabled to establish that phosphorus chemical shifts, internucleotide distances and residual dipolar couplings constants are closely correlated. The translation of the NMR observables in terms of phosphate conformations, helicoidal parameters and minor groove dimension, allowed the structural interpretation of the couplings and led to the first coherent description of the intrinsic DNA mechanics in solution. Owing our knowledge of the effect of the sequence on the backbone behavior, it is now possible to understand how the DNA shape and the associated conformational landscape are modulated at the dinucleotide level. Finally, the performance of molecular dynamics (MD) simulations with the recent force-fields Parmbsc0εζOLI and CHARMM36 was tested extensively against our NMR data. We found impressive progress towards a realistic representation of DNA, despite residual shortcomings. This advance allowed to reveal new aspects of the DNA dynamics, which cannot be assessed from experiments.The second part of this thesis focused on slow motions in B-DNA, which are still largely under-investigated. Using and developing sophisticated relaxation-dispersion NMR experiments, we demonstrated the existence of a new conformational exchange at the millisecond time-scale, which seems to only occur in a particular type of sequence, A:T rich. Thus, in addition to the familiar structural patterns that are the signature of the B double helix, some short DNA regions, likely specific, are able to explore another conformational state, weakly populated, whose detailed structure still needs to be characterized.Overall, these results provide original insights on the DNA dynamic repertoire, sequence-dependent, and open the way towards a better understanding of the mechanisms underlying the formation of DNA-protein complexes.

Molecular recognition, particularly as it applies to strong binding interactions between complementary ligand/receptor molecules in solution, is important in such varied areas as molecular biology, pharmacology, synthetic chemistry, and chemical detection. Strong binding is the additive result of a number of specific, weak, non-covalent interactions occurring between complementary molecules. This dissertation reports on the energetics of forming complexes between small molecules and model DNA constructs. Ligands included cationic and metallated cationic porphyrins and polyheterocyclic ruthenium compounds. DNA receptors included double stranded B-DNAs (hairpin and short linear sequences) as well G-quadruplex DNAs. Thermodynamic data were collected using isothermal titration calorimetry, circular dichroism spectropolarimetry, ultraviolet-visible spectroscopy, and mass spectrometry. The measured thermodynamic parameters included the changes in free energy, enthalpy and entropy for ligand/receptor complex formation as well as the stoichiometry of the stable complexes. The first section of this dissertation reports that the binding of cationic porphyrins to model G-quadruplex DNA may proceed through two pathways, end stacking and intercalation. Modulating the number of pyridinium groups on a pyridinium substituted porphyrin yielded differing binding thermodynamics leading to the understanding that a balance of surface area, charge, and geometry affect the ability of a porphyrin to bind to G-quadruplex DNA. Further investigations into the binding of metallated porphyrins developed the understanding that the geometry of the central metal ion affected not only the thermodynamics but could also inhibit the intercalative mode. It was previously shown that the high affinity binding for binuclear polyheterocyclic ruthenium compounds proceeds through an intercalative mode. To further understand the binding process and the structureunction relationship of the ligand components, the binding of smaller mononuclear complexes that were representative of portions of the binuclear complex was examined in this dissertation. While limiting the intercalative ability lowered the binding affinity, the mononuclear complex with the full intercalating bridge was able bind to DNA with a higher affinity than the binuclear complex. These studies have been successful in part in determining the contributions of numerous weak interactions including: charge (Coulombic interactions), H-bonding, hydrophobic interactions, and solvent structure (solvation changes), to the overall energetics of this molecular recognition process. The first section of this dissertation reports that the binding of cationic porphyrins to model G-quadruplex DNA may proceed through two pathways, end stacking and intercalation. Modulating the number of pyridinium groups on a pyridinium substituted porphyrin yielded differing binding thermodynamics leading to the understanding that a balance of surface area, charge, and geometry affect the ability of a porphyrin to bind to G-quadruplex DNA. Further investigations into the binding of metallated porphyrins developed the understanding that the geometry of the central metal ion affected not only the thermodynamics but could also inhibit the intercalative mode. It was previously shown that the high affinity binding for binuclear polyheterocyclic ruthenium compounds proceeds through intercalation. To further understand the binding process and the structureunction relationship of the ligand components, the binding of smaller mononuclear complexes that were representative of portions of the binuclear complex was examined in this dissertation. While limiting the intercalative ability lowered the binding affinity, the mononuclear complex with the full intercalating bridge was able bind to DNA with a higher affinity than the binuclear complex. These studies have been successful in part in determining the contributions of numerous weak interactions including: charge (Coulombic interactions), H-bonding, hydrophobic interactions, and solvent structure (solvation changes), to the overall energetics of this molecular recognition process.

Lou, Pak Kin. / Thesis (M.D.)--Chinese University of Hong Kong, 2011. / Includes bibliographical references (leaves 136-170). / Abstracts in English and Chinese. / Abstract --- p.i / Acknowledgements --- p.v / Table of Contents --- p.vi / List of Figures --- p.x / List of Tables --- p.xiii / List of Publications --- p.xv / Chapter Chapter 1 --- Introduction --- p.1 / Chapter 1.1. --- Aims of Study --- p.1 / Chapter 1.2. --- Literature Review --- p.2 / Chapter 1.2.1. --- Nasopharyngeal Carcinoma --- p.2 / Chapter 1.2.1.1. --- Overview --- p.2 / Chapter 1.2.1.2. --- Histopathology --- p.2 / Chapter 1.2.1.3. --- Epidemiology --- p.3 / Chapter 1.2.1.4. --- Etiology --- p.5 / Chapter 1.2.1.4.1. --- Epstein-Barr Virus (EBV) Latent Infection --- p.5 / Chapter 1.2.1.4.2. --- Environmental Factors --- p.5 / Chapter 1.2.1.4.3. --- Genetic Factors --- p.6 / Chapter 1.2.1.5. --- Molecular Pathogenesis --- p.7 / Chapter 1.2.1.5.1. --- Chromosomal Alterations --- p.7 / Chapter 1.2.1.5.2. --- NPC-associated Tumour Suppressor Genes --- p.7 / Chapter 1.2.1.5.3. --- NPC-associated Oncogenes --- p.8 / Chapter 1.2.2. --- Epstein-Barr Virus --- p.9 / Chapter 1.2.2.1. --- Overview --- p.9 / Chapter 1.2.2.2. --- Lytic and Latent Infection of EBV --- p.9 / Chapter 1.2.2.3. --- EBV Latency Programs and Associated --- p.10 / Malignancies --- p.11 / Chapter 1.2.2.4. --- The Role of EBV in NPC --- p.12 / Chapter 1.2.3. --- NF-kB Signalling Pathways --- p.12 / Chapter 1.2.3.1. --- Overview --- p.12 / Chapter 1.2.3.2. --- Pathway Components --- p.12 / Chapter 1.2.3.2.1. --- NF-kB Subunits --- p.16 / Chapter 1.2.3.2.2. --- Inhibitors of kB (IkBs) --- p.16 / Chapter 1.2.3.2.3. --- IkB Kinases (IKKs) --- p.17 / Chapter 1.2.3.3. --- NF-kB Activation and Signalling --- p.17 / Chapter 1.2.3.3.1. --- The Canonical Pathway --- p.18 / Chapter 1.2.3.3.2. --- The Non-canonical Pathway --- p.18 / Chapter 1.2.3.3.3. --- Physiological Functions of NF-kB --- p.19 / Chapter 1.2.3.4. --- NF-kB Signalling and Tumourigenesis --- p.20 / Chapter 1.2.3.4.1. --- Oncogenic Activation of NF-kB in Hematological Malignancies --- p.20 / Chapter 1.2.3.4.2. --- Oncogenic Activation of NF-kB in Solid and Epithelial Tumours --- p.22 / Chapter Chapter 2 --- Material and Methods --- p.22 / Chapter 2.1. --- Tumour Specimens --- p.24 / Chapter 2.2. --- NPC Tumour Lines and Immortalized NP Cell Lines --- p.24 / Chapter 2.2.1. --- Cell Lines --- p.24 / Chapter 2.2.2. --- Xenografts --- p.27 / Chapter 2.3. --- DNA Sequence Analysis --- p.27 / Chapter 2.3.1. --- Genomic DNA Extraction --- p.27 / Chapter 2.3.2. --- Polymerase Chain Reaction (PCR) --- p.28 / Chapter 2.3.3. --- DNA Sequencing --- p.32 / Chapter 2.4. --- RNA Expression Analysis --- p.32 / Chapter 2.4.1. --- Total RNA Extraction and Reverse Transcription --- p.33 / Chapter 2.4.2. --- Quantitative Real-time Polymerase Chain Reaction (QRT-PCR) --- p.35 / Chapter 2.5. --- Protein Expression Analysis --- p.35 / Chapter 2.5.1. --- Total Protein Extraction --- p.35 / Chapter 2.5.2. --- Nuclear and Cytoplasmic Protein Isolation --- p.36 / Chapter 2.5.3. --- Western Blotting --- p.39 / Chapter 2.6. --- Immunohistochemical Staining --- p.41 / Chapter 2.7. --- Statistical Analysis --- p.41 / Chapter 2.8. --- Immunoprecipitation --- p.43 / Chapter 2.9. --- Electrophoretic Mobility Shift Assay (EMSA) and Supershift Assay --- p.44 / Chapter 2.10. --- Enzyme-Linked Immunosorbent Assay (ELISA) --- p.45 / Chapter 2.11. --- Plasmid Preparation --- p.45 / Chapter 2.11.1. --- Plasmids --- p.45 / Chapter 2.11.2. --- Bacterial Transformation and Plasmid DNA Extraction --- p.46 / Chapter 2.12. --- Transfections --- p.46 / Chapter 2.12.1. --- Transient Transfection --- p.46 / Chapter 2.12.2. --- Stable Transfection --- p.47 / Chapter 2.13. --- Immunofluorescence --- p.47 / Chapter 2.14. --- Cell Proliferation and Viability Analysis --- p.47 / Chapter 2.15. --- Small Interfering RNA (siRNA) Knockdown --- p.49 / Chapter 2.16. --- Expression Microarray --- p.49 / Chapter 2.16.1. --- Agilent Oligonucleotide Microarray --- p.50 / Chapter 2.16.2. --- Data Analysis --- p.51 / Chapter Chapter 3 --- Activation of NF-kB Signals in NPC --- p.51 / Chapter 3.1. --- Introduction --- p.52 / Chapter 3.2. --- Results --- p.52 / Chapter 3.2.1. --- Expression Pattern of NF-kB Subunits in NPC Tumour Lines --- p.55 / Chapter 3.2.2. --- Distinct NF-kB Complexes in NPC Tumour Lines --- p.60 / Chapter 3.2.3. --- Expression of NF-kB Subunits in NPC Primary Tumours --- p.67 / Chapter 3.3. --- Discussion / Chapter Chapter 4 --- Alterations of NF-kB Components in NPC --- p.71 / Chapter 4.1. --- Introduction --- p.72 / Chapter 4.2. --- Results --- p.72 / Chapter 4.2.1. --- Homozygous Deletion of IicBa and TRAF3 in NPC Tumour Lines --- p.76 / Chapter 4.2.2. --- Mutation of TRAF2 and A20 in NPC Tumour Lines / Chapter 4.2.3. --- Aberrant Expression of Multiple NF-kB Signalling Components in NPC Tumour Lines --- p.80 / Chapter 4.2.4. --- Expression of NF-kB Signalling Components in NPC --- p.85 / Primary Tumour --- p.92 / Chapter 4.3. --- Discussion --- p.99 / Chapter Chapter 5 --- Identification of Downstream Targets for NPC-associated NF-kB Signalling --- p.99 / Chapter 0.1. --- Introduction --- p.99 / Chapter 0.2. --- Results --- p.100 / Chapter 0.2.1. --- Target Genes Modulated by p50 --- p.100 / Chapter 0.2.2. --- Functional Annotation of p50 Target Genes --- p.105 / Chapter 0.2.3. --- Target Genes Modulated by RelB --- p.105 / Chapter 0.2.4. --- Functional Annotation of RelB Target Genes --- p.105 / Chapter 0.2.5. --- Functional Annotation of Genes Modulated by both p50 and RelB --- p.111 / Chapter 0.3. --- Discussion --- p.118 / Chapter Chapter 6 --- Functional Role of TRAF3 Inactivation in NPC --- p.118 / Chapter 0.1. --- Introduction --- p.118 / Chapter 0.2. --- Results --- p.118 / Chapter 0.2.1. --- Effect of TRAF3 Restoration on NF-kB Activity --- p.119 / Chapter 0.2.2. --- Effect of TRAF3 Expression on Cell Proliferation --- p.123 / Chapter 0.2.3. --- TRAF3 Expression Modulates Interferon Transcription in NPC Cells --- p.128 / Chapter 0.3. --- Discussion / Chapter Chapter 7 --- General Discussion --- p.132 / Chapter Chapter 8 --- Conclusion / Chapter Chapter 9 --- References / Appendix --- p.136