ALLCOCK, BENJAMIN,PHILIP (2018) The downstream response to pharmacologically induced endoplasmic reticulum stress in two human cell lines. Masters thesis, Durham University.
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Author-imposed embargo until 09 May 2021.
Endoplasmic reticulum stress and the unfolded protein response are implicated in a
number of diseases, from cancer to ankylosing spondylitis. Understanding the
mechanisms underlying this response and how these may differ between cell types
is important in beginning to address potential pharmacological therapies. This thesis
investigated the effect of the pharmacological endoplasmic reticulum stress inducer
tunicamycin, and the isoflavine tyrosine kinase inhibitor genistein on the
downstream pathways of the subsequent unfolded protein response. This was
investigated in the two human cell lines HeLa and HT1080.
The investigations in this thesis found that tunicamycin induced differential
activation of downstream unfolded protein response pathways in the two cell lines.
The first main finding was that the HT1080 cells exhibited chronic activation of stress
related phosphorylation pathways in comparison to the more transient response of
the HeLa cells. Both cell lines showed a peak expression of the pro-survival proteins
after 10 minutes of tunicamycin treatment, as well as showing longer-term responses
to stress with later induction of the phosphorylated-Stat3 protein. This indicates that
both acute and chronic effects of ER stress occur in both cell types, but that HT1080
cells had a more consistent expression of stress related proteins. From live cell
imaging data, HeLa cells were much more sensitive to tunicamycin induced motility
inhibition than the HT1080 cells, which may reflect a state of resistance to stress
induced changes in motility in the HT1080 cells. Genistein decreased the
phosphorylation of stress related phosphoproteins slightly.
These findings reveal that consideration of the cell type must be made when devising
pharmacological routes to address conditions where endoplasmic reticulum stress is
a pathological factor. The differential response of cell lines to pharmacologically
induced ER stress could be exploited to create selective therapies specific to
individual cell types.
|Item Type:||Thesis (Masters)|
|Award:||Master of Science|
|Faculty and Department:||Faculty of Science > Biological and Biomedical Sciences, School of|
|Copyright:||Copyright of this thesis is held by the author|
|Deposited On:||16 May 2018 12:31|