Graber, Tyson2013-11-082013-11-0820102010Source: Dissertation Abstracts International, Volume: 72-08, Section: B, page: 4640.http://hdl.handle.net/10393/30106http://dx.doi.org/10.20381/ruor-13293This dissertation examines post-transcriptional mechanisms controlling the expression of the cellular inhibitor of apoptosis protein 1 (cIAP1) - a key negative regulator of programmed cell death. Activation of post-transcriptional control mechanisms is especially evident in the cellular response to stress and thus represent potential targets for therapeutic intervention. Post-transcriptional control is mediated by trans-acting proteins and/or non-coding RNAs that interact with a mRNA to form a messenger ribonucleoprotein particle (mRNP). Identifying components of mRNPs is therefore an important first step towards understanding how they regulate the fate of mRNAs during the response to cell stress. The cIAP1 mRNA represents an ideal model of post-transcriptional control given its regulation at the level of stability and translation following various stress stimuli. Work presented herein identifies AU-rich elements within the 3' untranslated region (UTR) that negatively affect cIAP1 mRNA stability following ultraviolet radiation (UVR) stress. Additionally, our laboratory has previously shown that the cIAP1 5'UTR contains an Internal Ribosome Entry Site (IRES) that governs translation of cIAP1 mRNA in response to endoplasmic reticulum (ER) stress. These initial observations led to the hypothesis that trans-acting protein factors associated with clAP1 mRNA play an essential role in modulating its stability and translational efficiency. Chapters 2 and 3 address this hypothesis by identifying p86 and NF45 as cIAP1 IRES trans-acting factors (ITAFs) required for IRES-mediated translation of cIAP1 following ER stress. Work presented in chapter 4 indicates that 5'UTR AU content can be reliably used to predict other NF45-dependent IRES; IRES that may function in a post-transcriptional RNA operon that maintains genomic stability, apoptotic threshold, and appropriate NF-kappaB signalling. Finally, peer-reviewed work in chapter 5 identifies hnRNP A1 as an AU-rich element binding protein that destabilizes cIAP1 mRNA following exposure of the cell to ultraviolet radiation. The work embodied in this thesis contributes significantly to our understanding of how RNA binding proteins affect changes in RNA stability and translation and identifies novel targets for therapeutic strategies that modulate cIAP1 expression and its associated cytoprotective effects.219 p.enChemistry, Biochemistry.Thesis