Poly(A)-binding proteins (PABPs) are important regulators of mRNA translation and stability. In mammals four cytoplasmic PABPs with a similar domain structure have been described - PABP1, tPABP, PABP4 and ePABP. The vast majority of research on PABP mechanism, function and sub-cellular localisation is however limited to PABP1 and little published work has explored the expression of PABP proteins. Here, I examine the tissue distribution of PABP1 and PABP4 in mouse and show that both proteins differ markedly in their expression at both the tissue and cellular level, contradicting the widespread perception that PABP1 is ubiquitously expressed. PABP4 is shown to be widely expressed though with an expression pattern distinct from PABP1, and thus may have a biological function in many tissues. I have shown that PABP4 associates with polysomes and described interactions between PABP4 and proteins important for PABP1-mediated translational activation suggesting that PABP4 plays a similar role in translational regulation. Translational inhibition is a common response to cell stress. Following certain cellular stresses e.g. arsenite, PABP1 localises to cytoplasmic stress granules, sites of mRNA storage. Here, I show that PABP4 is also a component of stress granules and have investigated the role of PABPs in stress granule formation. In contrast, I have shown that both PABP1 and PABP4 relocalise to the nucleus following UV irradiation in both human and mouse cell lines. In order to understand the how the UV-induced change in PABP localisation may be regulated, I have investigated the regulation of PABP nuclear export. I have found that accumulation of PABP proteins in the nucleus after UV coincides with an accumulation of poly(A)+ RNA, indicative of a block in mRNA export, an effect which has not been previously characterized. My working model is that nuclear export of PABPs may be dependent on mRNA export, inhibition of which leads to nuclear accumulation of PABPs after UV, which may in turn augment translational inhibition.
| Identifer | oai:union.ndltd.org:bl.uk/oai:ethos.bl.uk:563204 |
| Date | January 2010 |
| Creators | Burgess, Hannah |
| Contributors | Gray, Nicola. ; Cooke, Howard |
| Publisher | University of Edinburgh |
| Source Sets | Ethos UK |
| Detected Language | English |
| Type | Electronic Thesis or Dissertation |
| Source | http://hdl.handle.net/1842/5939 |
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