test Browse by Author Names Browse by Titles of Works Browse by Subjects of Works Browse by Issue Dates of Works

Advanced Search
& Collections
Issue Date   
Sign on to:   
Receive email
My Account
authorized users
Edit Profile   
About T-Space   

T-Space at The University of Toronto Libraries >
School of Graduate Studies - Theses >
Doctoral >

Please use this identifier to cite or link to this item: http://hdl.handle.net/1807/32019

Title: Molecular Characterization of the von Hippel-Lindau Tumour Suppressor Protein
Authors: Russell, Ryan
Advisor: Ohh, Michael
Department: Laboratory Medicine and Pathobiology
Keywords: VHL
Issue Date: 17-Jan-2012
Abstract: 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.
URI: http://hdl.handle.net/1807/32019
Appears in Collections:Doctoral

Files in This Item:

File Description SizeFormat
Russell_Ryan_C_200911_PhD_thesis.pdf6.03 MBAdobe PDF

This item is licensed under a Creative Commons License
Creative Commons

Items in T-Space are protected by copyright, with all rights reserved, unless otherwise indicated.