Inheritance of one mutant von Hippel-Lindau (VHL) allele gives rise to the development of the autosomal dominant VHL disease, which affects approximately 1 in 36 000 individuals. The VHL tumour suppressor protein plays a critical role in the E3 ubiquitin ligase-mediated destruction of hypoxia-inducible factor (HIF) and the promotion of fibronectin extracellular matrix assembly. A failure in either process is associated with oncogenic progression. Work included in this thesis provides evidence that these tumour suppressor functions are mutually exclusive. Additionally, post-translational modification of VHL by NEDD8 is shown to act as a ‘molecular switch’, altering VHL protein associations and providing a mechanism of pathway segregation. As a result of HIF stabilization, the expression of a homophilic adhesion molecule E-cadherin is significantly down-regulated in primary renal clear-cell carcinoma (RCC) upon VHL loss. E-cadherin down-regulation is shown to increase the invasive potential and is of prognostic value in RCC. Finally, VHL and SOCS1 are shown to dimerize and negatively regulate the JAK2-STAT5 signalling cascade. Defects in this dimerization are shown to underlie Chuvash polycythemia and provide a molecular understanding of the phenotypic observations associated with VHL-related polycythemias.
| Identifer | oai:union.ndltd.org:LACETR/oai:collectionscanada.gc.ca:OTU.1807/32019 |
| Date | 17 January 2012 |
| Creators | Russell, Ryan |
| Contributors | Ohh, Michael |
| Source Sets | Library and Archives Canada ETDs Repository / Centre d'archives des thèses électroniques de Bibliothèque et Archives Canada |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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