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dc.contributor.authorCorbin, Emma Kim-
dc.date.accessioned2024-06-07T13:54:38Z-
dc.date.available2024-06-07T13:54:38Z-
dc.date.issued2023-
dc.identifier.urihttp://hdl.handle.net/10443/6186-
dc.descriptionPh. D. Thesis.en_US
dc.description.abstractActivation of the NF-κB transcription factor family forms one of the first lines of defence against environmental threats to the organism and helps programme an appropriate cellular response. Although best known as critical regulators of the inflammatory response, the NFκB family of transcription factors are also activated by cellular stresses such as hypoxia, DNA damage and play an important role in ageing. Aberrant activation of NF-κB is associated with many inflammatory diseases and cancer. In work leading up to this thesis, the p52 NF-κB subunit was found to interact with the ribosomal protein RPL11. RPL11 is a component of the 5S RNP, an essential ribosomal subcomplex, comprised of the 5S ribosomal (r)RNA and the ribosomal proteins RPL5 and RPL11. Under conditions of ribosomal stress, free 5S RNP accumulates, carrying out a pivotal role in the stress response by binding to MDM2 and activating p53 tumour suppressor activity. In this thesis I have further investigated the p52/RPL11 interaction and the role of p52 during ribosomal stress. I found that depletion of p52 from cancer cell lines led to increased cell death in response to ribosomal stress. A combination of in silico analysis and coimmunoprecipitation experiments indicated that the MDM2/RPL11 and p52/RPL11 interactions are mutually exclusive. I propose that competition between MDM2 and p52 contributes to the differences in p53-dependent cellular fate during ribosomal stress. Finally, residue glutamate 86 (E86) of p52 was predicted in silico to be critical within the p52/RPL11 interface. Through mutation of E86 to alanine, this was later confirmed. Interestingly, the disruption of the RPL11 interaction caused by of the p52-E86A mutation was dependent upon DNA binding. In summary, I propose that p52 plays a cell survival and tumour promoting role following ribotoxic stress through direct binding to RPL11 that facilitates the modulation of p53 target gene expression.en_US
dc.language.isoenen_US
dc.publisherNewcastle Universityen_US
dc.titleThe Role of the Nuclear Factor-kappa B Subunit, p52, in Ribosomal Stressen_US
dc.typeThesisen_US
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