Studies into the receptor-mediated induction of hypoxia inducible factor 1α.
type: CreativeWork
description: The transcription factor Hypoxia Inducible Factor (HIF) is pivotal to the cellular response upon exposure to low oxygen stress (hypoxia). Post-translational modification of the HIF a-subunit (HIFa) by hydroxylase enzymes has recently been identified as the key 'oxygen sensing' mechanism within the cell. Regulation of HIF is complex; during hypoxia, regulation primarily occurs through inhibition of the hydroxylase enzyrnes and facilitates dramatic up-regulation of the protein stability and transcriptional activation capabilities of the HIF a-subunits. HIF also appears to play a role in target gene transcription in a hypoxia-independent manner. This novel, hypoxia-independent function of HIF is poorly characterised but has been recently shown to involve HIFa induction by receptor-mediated factors and the phosphatidyl-inositol-3-kinase/Akt or mitogen activated protein kinase (MAPK) signalling cascades. Activation of HIFa through these pathways is more subtle than that which occurs during induction by hypoxia. Activation of Akt and MAPK is reported to increase HIFa protein synthesis and results in increased HIFa protein levels and transcriptional activity. In addition, in some cell types MAPK potentiates the transcriptional activity of HIFa via a separate mechanism that does not require protein stabilization, but instead effects the recruitment of transcriptional co-factors. Adding a further level of complexity to the mechanisms for HIFa regulation is the existence of alternatively spliced isoforms for the three characterised HIFa genes. Recent work has identified tissue-specific expression of HIF1a isoforms that have diminished or absent transcriptional activation capabilities, suggesting that the overall transcription of target genes by HIFla may be modulated by interactions between these isoforms. This thesis focuses on the role of growth factor signalling to HIFIa and the potential influence of insulin resistance and Type 2 Diabetes on this signalling. It aims to te…
abstract: The transcription factor Hypoxia Inducible Factor (HIF) is pivotal to the cellular response upon exposure to low oxygen stress (hypoxia). Post-translational modification of the HIF a-subunit (HIFa) by hydroxylase enzymes has recently been identified as the key 'oxygen sensing' mechanism within the cell. Regulation of HIF is complex; during hypoxia, regulation primarily occurs through inhibition of the hydroxylase enzyrnes and facilitates dramatic up-regulation of the protein stability and transcriptional activation capabilities of the HIF a-subunits. HIF also appears to play a role in target gene transcription in a hypoxia-independent manner. This novel, hypoxia-independent function of HIF is poorly characterised but has been recently shown to involve HIFa induction by receptor-mediated factors and the phosphatidyl-inositol-3-kinase/Akt or mitogen activated protein kinase (MAPK) signalling cascades. Activation of HIFa through these pathways is more subtle than that which occurs during induction by hypoxia. Activation of Akt and MAPK is reported to increase HIFa protein synthesis and results in increased HIFa protein levels and transcriptional activity. In addition, in some cell types MAPK potentiates the transcriptional activity of HIFa via a separate mechanism that does not require protein stabilization, but instead effects the recruitment of transcriptional co-factors. Adding a further level of complexity to the mechanisms for HIFa regulation is the existence of alternatively spliced isoforms for the three characterised HIFa genes. Recent work has identified tissue-specific expression of HIF1a isoforms that have diminished or absent transcriptional activation capabilities, suggesting that the overall transcription of target genes by HIFla may be modulated by interactions between these isoforms. This thesis focuses on the role of growth factor signalling to HIFIa and the potential influence of insulin resistance and Type 2 Diabetes on this signalling. It aims to te…
author: Bilton, Rebecca
date published: 2003
date modified: 2026-07-24T00:50:50Z
provider: University of Adelaide
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: University of Adelaide

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property ID: Handle
value: http://hdl.handle.net/2440/93637