β-cell dysfunction is a major feature of the development of type 2 diabetes (T2D). Endoplasmic reticulum (ER) stress has been shown to play an important role in β-cell survival and death, and has been shown to be an important factior in the development of diabetes and many other diseases. The unfolded protein response (UPR) is a unique adaptive pathway which can improve cell survival during ER stress through the activation of three ER stress transducers: PERK, IRE1 and ATF6. However, if ER stress remains unresolved, UPR signalling triggers the apoptotic pathway through, for example, expression of the pro-apoptotic protein CHOP, which is a downstream target of ATF4. In addition, eukaryotic initiation factor 5 (eIF5) has been reported to play a role in the regulation of ATF4. Therefore, this thesis aimed at investigating the expression of eIF5, ATF4 (activating transcriptional factor 4) and CHOP (C/EBP homolog protein) in response to ER stress. The studies outlined in this thesis demonstrate that the URP is induced in response to thapsigargin-induced ER stress. In MIN6 cells, the up-regulation of ATF4 and CHOP in response to ER stress is independent of the PERK-eIF2α pathway. However, IRE1 activation is required for the up-regulation of ATF4 and CHOP in response to ER stress in a variety of cell lines. Surprisingly, IRE1-mediated ATF4 and CHOP expression is independent of translation and transcription. In addition, mRNA polyadenylation appears to be required for the up-regulation of ATF4 and CHOP. Preliminary evidence also suggests that inhibition of the IRE1 pathway results in inhibition of miR214 expression. This could lower the miRNA214-mediated up-regulation of ATF4.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:631513 |
| Date | January 2014 |
| Creators | Zhao, Xuechan |
| Contributors | Herbert, Terence |
| Publisher | University of Leicester |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/2381/29312 |
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