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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

The Role of Neu1 Sialidase in Epidermal Growth Factor Receptor Activation

Gilmour, Alanna 28 June 2011 (has links)
The epidermal growth factor receptor (EGFR) exists as a single, highly glycosylated subunit receptor on the plasma membrane of a cell. Upon ligand binding to its extracellular domain, the EGFR dimerizes with an adjacent receptor. This results in activation of the EGFR’s intracellular tyrosine kinase domain, and consequently, autophosphorylation of specific tyrosine residues on the receptor’s cytoplasmic tail. Adaptor proteins bind to these phosphorylated tyrosine residues and transduce the message internally, initiating a multitude of signalling cascades which stimulate cell growth, division, and movement. Despite all that has been elucidated regarding the activation and signalling pathways of the EGFR, the parameters controlling dimerization and activation remain unknown. Recently, Neu1 sialidase, an enzyme which cleaves α-2,3-linked sialic acids from glycosylated substrates, has been implicated as a critical mediator of TrkA receptor activation. Upon activation, the sialidase desialylates the external receptor glycosylation, removing a physical barrier which was formerly hindering receptor dimerization, and thus, receptor activation. Based on the known sialylation of EGFR glycosylation, as well as the demonstrated importance of receptor glycosylation in EGFR activation, we hypothesized that the EGFR may be activated by a similar mechanism. Here, we report an identical membrane signalling paradigm initiated by epidermal growth factor (EGF) binding to EGFR to rapidly induce Neu1 sialidase activity in live NIH3T3-EGFR cells but not in live Neu1-deficient human fibroblast cells. Furthermore, we report that Neu1 sialidase activity is required for EGFR activation, supported by the finding that tyrosine phosphorylation is inhibited in EGF-stimulated NIH3T3-hEGFR cells which have been pretreated with both broad-range (oseltamivir phosphate) and specific (anti-Neu1 neutralizing antibody) sialidase inhibitors. MMP-9 plays a role in the initiation of Neu1 sialidase post-ligand binding, as pre-treatment of NIH3T3-hEGFR cells with specific MMP-9 inhibitor prior to EGF stimulation blocks membrane sialidase activity as well as tyrosine phosphorylation. Of critical importance to this schematic is the finding that both Neu1 and MMP-9 co-immunoprecipitate with EGFR on the plasma membrane of both naïve and EGF-stimulated NIH3T3-hEGFR cells. Together, these findings reveal a novel EGFR activation mechanism in which cross-talk between Neu1 and MMP-9 plays a vital role in EGF-induced receptor activation. / Thesis (Master, Microbiology & Immunology) -- Queen's University, 2011-06-26 12:04:40.486
2

Regulation of EGFR Degradation by Ankyrin105

2012 July 1900 (has links)
Growth factors can regulate a variety of cellular processes by activating receptors on the cell surface. Many of the receptors belong to the receptor tyrosine kinase family, including the platelet-derived growth factor receptor and the epidermal growth factor receptor and its related family members, such as ErbB2. Constitutively activated receptor tyrosine kinases and their downstream signaling pathways (such as the Ras-mitogen activated protein kinase pathway and the phosphatidylinositol 3 kinase-Akt pathway) are frequently observed in cancer cells. Therefore, understanding the degradation mechanism of receptors is important and may facilitate the development of new prognostic or treatment strategies for cancer. Ankyrin105 is the smaller isoform of ankyrin3 and is localized to late endosomes and lysosomes. Our laboratory has previously shown that ankyrin105 can bind to the phosphatidylinositol 3 kinase regulatory subunit p85, stimulate lysosomal-mediated degradation of the platelet-derived growth factor receptor and differentially affect its signaling pathways in NIH 3T3 cells. To determine whether ankyrin105 can induce degradation of multiple receptor tyrosine kinases in a similar manner, we extended these studies to include the epidermal growth factor receptor and its downstream signaling in this project. Hemagglutinin-tagged ankyrin105 was introduced into COS-1, HEK293T, MCF10A, MDA-MB-231 and AU565 cells, respectively. We demonstrated that overexpression of ankyrin105 did not enhance the epidermal growth factor receptor degradation or downregulation of its signaling pathways in these selected cell lines. AU565 cells, which expressed relatively high levels of both epidermal growth factor receptor and ErbB2, were susceptible to geldanamycin or herceptin facilitated ErbB2 internalization and degradation, which subsequently promoted the epidermal growth factor receptor degradation. However, ankyrin105 did not further improve geldanamycin-induced epidermal growth factor receptor degradation or impact its downstream signaling pathways. These studies suggest that the influence of ankyrin105 may be receptor-specific (platelet-derived growth factor receptor, but not epidermal growth factor receptor) and/or cell type specific (NIH 3T3 cells, but not COS-1, HEK293T, MCF10A, MDA-MB-231 or AU565 cells).
3

The importance og LRIG1 in lung cancer

Kvarnbrink, Samuel January 2012 (has links)
No description available.
4

Effect of PPARα Ligand on TNFα -Dependent Expression of EGF Receptor in Human Glioma Cell Line

SAITO, Kiyoshi, YOSHIDA, Jun, SEO, Hisao, WAKABAYASHI, Kenichi, KAMBE, Fukushi, NAGAYA, Takashi, KATO, Mihoko 12 1900 (has links)
国立情報学研究所で電子化したコンテンツを使用している。
5

New synthetic routes to nitrogen heterocycles : natural products and novel drug scaffolds

Bu, Yubai January 2017 (has links)
This thesis is divided into three main sections. The first chapter contains a brief review of nitrogen heterocyclic chemistry. The second chapter reports the results and their discussion of new heterocyclic chemistry, and the experimental details are provided in the fourth chapter.
6

Un rôle inédit de la sortiline dans le contrôle du transport rétrograde de l'EGFR pour limiter la croissance tumorale / A new role of sortilin in the control of EGFR retrograde trafficking to limittumour growth

Al-Akhrass, Hussein 04 October 2017 (has links)
Le cancer du poumon est le troisième cancer le plus fréquent chez les femmes et le deuxième chez les hommes, il est la cause principale de décès par cancer dans le monde, avec une mortalité annuelle supérieure à 1 million. Malgré des progrès remarquables dans la thérapie ciblée, la majorité des patients atteints de cancer du poumon sont diagnostiqués dans un stade avancé où ils ne connaissent pas d'amélioration significative de leur survie globale. Les récepteurs à domaine tyrosine kinase, tels que le récepteur du facteur de croissance épidermique (EGFR), traduisent les informations du microenvironnement dans la cellule en activant des voies de signalisation homéostatiques. L'internalisation et la dégradation de l'EGFR suite à la liaison du ligand limitent l'intensité de la signalisation proliférative, ce qui contribue à maintenir l'intégrité cellulaire. Dans les cellules cancéreuses, la dérégulation du trafic de l’EGFR aboutit à des effets divers sur la progression tumorale. Dans cette étude, nous avons identifié la sortiline comme un régulateur clé de l'internalisation de l'EGFR à partir de la membrane plasmique. La perte de l’expression de la sortiline dans les cellules tumorales augmente la prolifération cellulaire en soutenant la signalisation de l’EGFR à la surface de la cellule, ce qui accélère la croissance tumorale. Chez les patients atteints de cancer du poumon, l'expression de la sortiline diminue avec l’augmentation du grade pathologique et l’expression de son gène, SORT1, est fortement corrélée à une meilleure survie globale, en particulier chez les patients présentant une forte expression de l'EGFR. Ainsi, la sortiline représente un nouveau régulateur du trafic intracellulaire de l’EGFR, elle agit en contrôlant l'internalisation de ce récepteur et en limitant la croissance tumorale. / Lung cancer is the third most common cancer in women and the second in men, it is the leading cause of cancer-related death worldwide, with an annual mortality of more than 1 million. Despite remarkable advances in targeted therapy, the majority of patients with lung cancer are diagnosed at an advanced stage where they do not experience a significant improvement in overall survival. Tyrosine kinase receptors such as the epidermal growth factor receptor (EGFR) transduce information from the microenvironment into the cell and activate homeostatic signalling pathways. Internalisation and degradation of EGFR after ligand binding limits the intensity of its proliferative signalling, thereby helping to maintain cell integrity. In cancer cells, deregulation of EGFR trafficking has a variety of effects on tumour progression. Here, we report that sortilin is a key regulator of EGFR internalisation. Loss of sortilin in tumour cells promotes cell proliferation by sustaining EGFR signalling at the cell surface, ultimately accelerating tumour growth. In lung cancer patients, sortilin expression decreases with increased pathologic grade, and the expression of SORT1 (the gene encoding sortilin) is strongly correlated with a better survival, notably in patients with high EGFR expression. Thus, sortilin is a novel regulator of EGFR intracellular trafficking acting by controlling receptor internalisation and limiting tumour growth.
7

Determination of matriptase-prostasin cleavage sites in the extracellular domain of the epidermal growth factor receptor (EGFR)

Weaver, Sarah Elizabeth 01 January 2008 (has links)
This year the American Cancer Society predicts that 565,650 individuals will lose their life as a result of their battle with cancer. Due to its established roles in cancer and extracellular presentation, the Epidermal Growth Factor Receptor (EGFR) is an excellent target for anti-cancer drugs. It has been determined that matriptase and prostasin serine proteases are proteolytic regulators of EGFR membrane presentation, and downstream signaling. Currently, there are several drugs that target EGFR, but research continues in order to further understand drug-resistant EGFR. In cancer cell lines that exhibit both EGFR signaling and these proteases, proteolytic cleavage may be a mechanism of resistance to drugs that target the EGFR extracellular domain (ECD). The specific aim of this project was to determine which protease was direct! y responsible for EGFR cleavage and establish the precise cleavage site within the EGFR ECD. DNA corresponding to amino acid residues 336-505 of the EGFR ECD was cloned into the p-GEX-6P-I vector and expressed as a GST-fusion protein in E.coli cells. This fusion protein was isolated and purified by affinity chromatography. Purified GSTEGFR BCD fusion protein was mixed with prostasin and matriptase and evaluated for cleavage. No cleavage was detected using this method. Trypsin serine protease was used to ensure the cleavability of the GST-EGFR ECD. The GST-EGFR ECD fusion protein was found to be inappropriate for determining matriptase or prostasin cleavage sites, which are now being pursued by other means.
8

Rôle de Calnuc dans l'endocytose du récepteur à l'EGF

Gagnon, Hugo January 2009 (has links)
EGFR est un récepteur tyrosine kinase important dans la survie cellulaire et souvent impliqué dans différents cancers. Il a été montré que le calcium pouvait jouer un rôle dans la régulation de l'endocytose d'EGFR via la protéine à mains EF calmoduline. Calnuc est une protéine ubiquitaire possédant des mains EF et qui pourrait agir comme senseur de calcium. De plus, Calnuc pourrait être impliquée dans le cancer. Le but de l'étude était donc de déterminer si Calnuc joue un rôle dans l'endocytose d'EGFR. Le niveau d'expression de Calnuc a donc été modulé par surexpression ou par ARN interférence afin d'observer ses effets sur la dégradation et le triage intracellulaire d'EGFR. Des études d'immunobuvardage et d'immunofluorescence ont démontré que Calnuc module la dégradation d'EGFR suite à son endocytose. La diminution d'expression de Calnuc accélère le trafic intracellulaire d'EGFR vers les lysosomes, alors que la surexpression de Calnuc retarde EGFR au niveau des endosomes précoces. Des études de co-immunoprécipitation ont démontré que Calnuc interagit avec GGA2 et GGA3 et que l'interaction avec GGA3, une protéine clé dans la régulation d'EGFR, est inhibée par le calcium. Une étude d'immunofluorescence démontre que Calnuc régule le recrutement de GGA3 à EGFR aux endosomes précoces. Ces résultats démontrent que Calnuc est impliquée dans l'endocytose d'EGFR via une modulation de GGA3.
9

The pathophysiological and clinical significance of TP53 in bladder cancer

Griffiths, T. R. Leyshon January 1999 (has links)
No description available.
10

NUMB and Syncytiotrophoblast Development and Function: Investigation Using BeWo Choriocarcinoma Cells

Carey, Julie 09 May 2012 (has links)
The role of NUMB, a protein important for cellular differentiation and endocytosis in non-placental cells, was investigated in syncytiotrophoblast development and function in the human placenta. The BeWo choriocarcinoma cell line was used as a model for villous cytotrophoblast cells and syncytiotrophoblast to investigate NUMB’s involvement in differentiation and epidermal growth factor receptor (EGFR) endocytosis. NUMB isoforms 1 and 3 were found to be the predominant isoforms and were upregulated following forskolin-induced differentiation. Overexpression of NUMB isoforms 1 and 3 did not mediate differentiation or EGFR signaling. Immunofluorescence analysis revealed that NUMB colocalized with EGFR at perinuclear late endosomes and lysosomes following EGF stimulation. We have demonstrated for the first time that NUMB isoforms 1 and 3 are expressed in BeWo cells, are upregulated in forskolin-differentiated BeWo cells and are involved in ligand-dependent EGFR endocytosis in BeWo cells.

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