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Title: The unfolded protein response and HLA-B27 misfolding : implications for ankylosing spondylitis
Author: Lemin, Andrew James
ISNI:       0000 0004 2704 3449
Awarding Body: Durham University
Current Institution: Durham University
Date of Award: 2010
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The unfolded protein response (UPR) detects the presence of misfolded proteins in the endoplasmic reticulum (ER) and subsequently relieves ER stress by increasing the folding capacity of the ER. The secretory pathway substrate HLA-B27 is highly associated with the chronic inflammatory disease ankylosing spondylitis (AS) and has a tendency to misfold in the ER. Here, we show that overexpression of HLA-B27 and non-disease associated HLA-B7 in immortalised cell lines leads to heavy chain misoxidation, which is accompanied by upregulation of BiP and splicing of XBP1, a key step in the IRE1 pathway of the UPR which is increasingly being linked with intestinal inflammation. We also demonstrate that different cell lines respond to different ER stress stimuli in distinct ways. We establish that HT1080 cells inefficiently induce a UPR in response to tunicamycin and that this has consequences for cell survival. However, inefficient activation of the UPR in HT1080 cells can be overcome by secondary signals, since co-administration of the tyrosine kinase inhibitor genistein leads to activation of XBP1. Furthermore, we show that genistein can inhibit UPR induction of BiP in response to a range of ER stresses indicating that the cancer drug genistein can inhibit or activate the UPR depending on the environment and cell type. This has implications for inflammatory disease since regulation of the UPR is important in determining a cell’s tendency towards apoptosis.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available