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UBC Theses and Dissertations
Transcription regulation of two natural killer cell activating receptors, NKG2D and NCR1 Lai, Chieh Min
Natural Killer (NK) immune lymphocytes are mainly known to eliminate cancerous and virus infected cells. When they encounter another host cell, they utilize surface receptors to scan the target cell for telltale disease-associated ligands. Therefore, these receptors play a central role in regulating NK cell effector functions that include direct cytotoxicity and cytokine release. NKG2D and NCR1 are among the most studied NK receptors identified to date. NKG2D binds a range of stress induced MHC class I like ligands while NCR1 binds the viral protein, haemagglutinin, as well as unidentified tumour ligands. Knockout mouse models have highlighted the importance of these receptors in combating tumorigenesis, virus infections, and in the development of autoimmune disorders. The expression of these receptors is specific: NKG2D is expressed only on NK cells and a minority of T cell subsets while NCR1 is even more restricted to the NK lineage. Yet the basis behind the transcriptional regulation of NKG2D and NCR1 has remained a mystery. I have found genetic and epigenetic mechanisms that control the expression of the receptors, including involvement of a retrotransposon in regulation of the mouse Nkg2d gene. Luciferase assays were used to delineate crucial DNA elements such as promoters and enhancers. Bioinformatic and RNA expression techniques have led to the discovery of GABP, RUNX3 and RUNX1 as regulators of NKG2D and NCR1. The role of these transcription factors were verified using gel shift, chromatin immunoprecipitation, knockdown, dominant negative and overexpression experiments. My results shed light on transcription regulation of crucial NK receptors. At the same time, it allows me to make inferences on the NK genetic regulatory program.
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