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Type: Thesis
Title: Regulation of the Rgs4 gene by the hypoxia inducible factors.
Author: Olechnowicz, Sam
Issue Date: 2012
School/Discipline: School of Molecular and Biomedical Science
Abstract: The transcriptional response to hypoxia is critically dependent on the Hypoxia Inducible Factors HIF-1 and HIF-2, which have roles not only in development and cellular adaptation to low oxygen levels, but also in diseases such as cancer. Although many HIF target genes have been well-characterised, there is strong evidence that the complete set of HIF responsive genes have not been described. This thesis describes the characterisation of a novel hypoxia responsive gene, Rgs4, found by a previous microarray study. Rgs4 encodes the Regulator of G-protein Signalling 4 (RGS4 protein), which directly inhibits signalling from various G-protein coupled receptors. Hypoxic regulation of Rgs4 mRNA is observed in neuroblastoma and pheochromocytoma cells derived from rat, mouse and human samples. This response is found to be mimicked by HIF pathway activating chemicals, and occurs in a manner consistent with direct HIF regulation of Rgs4 transcription. However, hypoxic regulation of this gene is not observed in all cell types that Rgs4 is expressed in. Reporter gene assays testing 32.9kb of the locus encompassing the Rgs4 gene failed to detect a hypoxia responsive element, though bioinformatics analysis indicates that Rgs4 is under the control of distant enhancers outside of the region tested. Further characterisation of the Rgs4 hypoxic response could help to explain functions of HIF that are currently poorly characterised, such as its effect on catecholamine release and signalling, while the atypical nature of Rgs4 regulation by HIF may provide a model to discover other as-yet unknown HIF interacting proteins and cell type specific HIF target genes.
Advisor: Peet, Daniel John
Whitelaw, Murray Leslie
Dissertation Note: Thesis (Ph.D.) -- University of Adelaide, School of Molecular & Biomedical Science, 2012
Keywords: hypoxia inducible factors; hypoxia; Rgs4; neuroblastoma; transcription
Appears in Collections:Research Theses

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