Mechanism and regulation of the von Hippel-Lindau tumour suppressor protein /
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(Published version)
Date
2009
Authors
Paltoglou, Steve,
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thesis
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Abstract
The VHL tumour suppressor gene acts as “gatekeeper” protein in the prevention of tumour growth. When the gene is mutated, tumours arise, frequently because a second sporadic mutation has occurred leading to an effective loss of pVHL function in the afflicted tissue. These tumours manifest in a number of cell types and tend to be enriched in blood vessels because of pVHL’s role in down-regulating factors that promote blood vessel formation. The primary discovery relating to the functional role of pVHL stemmed from its ability to trigger the degradation of HIF-1<, mediated by pVHL’s assembly into a larger multi-protein complex that ubiquitinates HIF-1<. This interaction is mediated by oxygen-dependent hydroxylation of a proline on HIF-1<, which initiates pVHL binding to HIF-1<. To achieve this function, pVHL interacts with Elongin C, Elongin B and Cullin-2 and Rbx1 in a complex referred to as the VBCCul- 2 complex.
This complex displays remarkable structural and modular similarity with the Skp1-Cdc53/Cul-1-F-box protein (SCF) complex. As with its SCF counterparts, the VBC-Cul-2 complex has been shown to constitute an E3 ligase, which serves to recruit protein substrates for degradation by the 26S proteasome. The identification of pVHL as an established member of the Cullin-RING Ligase (CRL) family likely represents the principal molecular format in which pVHL finds itself within the eukaryote cell. My dissertation focused on how this central paradigm might shift if novel modes of regulation, in the form of post-translational modifications, were to inhibit, enhance or alter pVHL’s action towards HIF-1. The scope of this thesis was not restricted to the pVHL/HIF-1< axis alone, and in the final chapter, other pVHL tumour pathways were explored, some of which are regulated by a key modification to pVHL, identified for the first time in this thesis.
School/Discipline
University of South Australia. School of Pharmacy and Medical Sciences
School of Pharmacy and Medical Sciences
School of Pharmacy and Medical Sciences
Dissertation Note
Thesis (PhDBiomedicalScience)--University of South Australia, 2009.
Provenance
Copyright 2009 Steve Paltoglou.
Description
xii, 192 leaves :
illustrations (chiefly colour).
Includes bibliographic references.
illustrations (chiefly colour).
Includes bibliographic references.
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506 0#$fstar $2Unrestricted online access