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Title: Regulation of HIF-l and the hypoxic response by the tumour suppressor LIMDl and LIM domains-containing proteins
Author: Bridge, Katherine S.
Awarding Body: University of Nottingham
Current Institution: University of Nottingham
Date of Award: 2013
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In order to survive in a given environment, adequate levels of oxygen are required throughout cells and tissues, as defined by cellular function and tissue type. Rapid reaction and adaption of a cell or tissue to low p02 (hypoxia) can enable it to remain viable, thus reducing potential damage to the organism. The hypoxic response signalling pathway is activated by hypoxia inducible factors (HIFs); these transcription factors activate genes whose products enable the cell to adapt to hypoxic conditions, including vascular endothelial growth factor (VEGF) and erythropoietin (EPO) . Under normal oxygen conditions (normoxia), the HIF-la subunit is rapidly degraded as a result of hydroxylation by the prolyl hydroxylase domain proteins (PHDl-3) and subsequent binding of the von Hippel-Lindau protein (VHL), which induces ubiquitination and degradation of HIF-la by the 265 proteasome. Data presented in this thesis identify the LlM domains-containing tumour suppressor gene product LlMD1, as well as other members of the ZYX class of LlM domain proteins, as regulators of HIF-l and the hypoxic response. LlMDl interacts with the PHDs and VHL at distinct sites to facilitate efficient HIF-la degradation by bringing the hydroxylase and ubiquitinase enzymes into close proximity. LlMDl enhances HIF-la degradation via the oxygen dependent degradation (ODD) domain and represses HIF-l transcriptional activity; these effects are dependent upon the ability of LlMDl to engage PHD2/VHL. In addition to LlMD1, ZYX class members Ajuba and WTIP also interact with PHD1/3 and VHL, and Ajuba confers enhanced HIF-la protein degradation. Preliminary evidence suggests Zyxin, TRIP6 and LPP, also members of the ZYX class, act as positive regulators of HIF-l, enhancing HIF-la protein stability and HIF-l transcriptional activity. This thesis therefore identifies LlMDl and implicates the ZYX class of LlM domain proteins as a unique family of protein regulators of HIF-l and the hypoxic response.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available