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Title: | The HIF system and Inhibitory PAS Domain Protein (IPAS) - a role in vascular remodelling |
Authors: | Bonello, Steve |
Keywords: | Anoxemia Proteins Blood-vessels |
Issue Date: | 2006 |
Citation: | Bonello, S. (2006). The HIF system and Inhibitory PAS Domain Protein (IPAS) - a role in vascular remodelling (Doctoral dissertation). |
Abstract: | In mammalian cells, the hypoxic response is mediated by a family of transcription factors known as hypoxia inducible factors (HI F). These are heterodimers composed of a tightly regulated alpha subunit and a constituitively expressed beta subunit (also known as aryl hydrocarbon nuclear translocator, ARNT). Three 0.- subunits have been identified so far, HIF-1 α, HIF-2 α and HIF-3 α. HIF-1 α and HIF-2 α are regulated mostly At the protein level via oxygen depedent degredation by the proteasome. Hypoxia leads to their stabilisation, binding to hypoxia responsive elements (HRE) and target gene transactivation. HIF-3 α is still poorly characterised. In mouse, a HIF- 3 α splice variant called inhibitory PAS domain protein has an inhibitory effect on HIF- 10. mediated activity. In humans a number of HII--3a splice variants have been reported. It was one aim of this study to investigate the roles of the largest isoform, HIF-3a1, and a smaller isoform resembling mouse IPAS, HIF-3a3, in the hypoxic response of endothelial cells. Both variants were expressed in vascular cells and in the vascular wall. HIF-3 α 1 but not HIF-3a3 was regulated by tile proteasome. Whilst both proteins were found to interact with HIF-1a and ARNT, HIF-3a1 was found to bind to the HRE and disturb HIF-1 α -DNA binding. A competition mechanism between HIF-3 α isoforms and HIF-1 α was found to cause downregulation of HIF-1 transcriptional activity resulting in decreased endothelial cell proliferation and angiogenesis under hypoxia. The second part of the study aimed to clarify the mechanism by which non-hypoxic stimuli can upregulate HIF-1a in pulmonary artery smooth muscle cells. HIF-1a upregulation by thrombin occurred via an ROS dependent mechanism by activation of the NADPH oxidase. This led to upregulation of NFKB activity which interacted with a novel binding site on the HIF-1a promoter and induced its transcription. |
Description: | PH.D. |
URI: | https://www.um.edu.mt/library/oar//handle/123456789/31721 |
Appears in Collections: | Dissertations - FacM&S - 2006 Dissertations - FacM&SPB - 2006 |
Files in This Item:
File | Description | Size | Format | |
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Bonello_Steve_ The HIF System and Inhibitory PAS Domain Protein.pdf Restricted Access | 12.44 MB | Adobe PDF | View/Open Request a copy |
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