Phosphorylation of substrates by kinase proteins is one of the most prominent mechanisms by which signal transduction occurs and dysregulation of this activity is implicated as a major underlying cause of a number of diseases including cancer. Much of the current work focuses on developing inhibitors for various kinases in an effort to restore normal function in pathways where this deregulation occurs. However the vast majority of kinases remain uncharacterized and the roles they play in many of these signaling pathways are still unclear. This study examines the role of the non-receptor tyrosine kinase Fer in two malignant cells lines, MDA-MB-231 (breast cancer) and PC3 (prostate cancer). Using a lentiviral based RNA interference approach, the level of Fer was reduced to 6% in MDA-MB-231 and 10% in PC3 cells relative to WT levels. Fer knockdown correlated with enhanced migration in MDA-MB-231 cells, but impaired migration in PC3 cells, suggesting opposing roles for Fer in regulating migration in each cell type. Fer knockdown correlated with enhanced proliferation in MDA-MB-231 cells, but was slightly reduced in the PC3 cells, again suggesting opposing roles for Fer in regulating proliferation between these two cell lines. In Fer knockdown PC3 cells, N-cadherin expression was increased, while E-cadherin levels were decreased; and in a fraction of cells E-cadherin relocalized from a predominantly intracellular vesicular compartment to a plasma membrane localization. In xenografting experiments, Fer knockdown MDA-MB-231 cells showed reduced tumor growth rates compared with tumors established with WT cells, suggesting that Fer may influence tumorgenesis on a tumor cell intrinsic basis. Separate xenografting studies showed that MDA-MB-231 derived tumors grew slower in fer-knockout compared to fer-wild type nude mice. This trend failed to show any statistical significance however it may still suggest an additional tumor promoting role for Fer in the stroma. / Thesis (Master, Pathology & Molecular Medicine) -- Queen's University, 2009-09-17 22:23:35.451
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OKQ.1974/5326 |
| Date | 18 November 2009 |
| Creators | Golbourn, BRIAN |
| Contributors | Queen's University (Kingston, Ont.). Theses (Queen's University (Kingston, Ont.)) |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | English, English |
| Detected Language | English |
| Type | Thesis |
| Format | 1841551 bytes, application/pdf |
| Rights | This publication is made available by the authority of the copyright owner solely for the purpose of private study and research and may not be copied or reproduced except as permitted by the copyright laws without written authority from the copyright owner. |
| Relation | Canadian theses |
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