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Molecular Mechanisms of O-GlcNAcylation: Regulating Progesterone Receptor Function and Adipose Tissue Inflammation
Saunders, Harmony I.
Saunders, Harmony I.
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Abstract
O-GlcNAcylation, a dynamic post-translational modification involving the addition of N-acetylglucosamine to serine and threonine residues, is emerging as a critical regulator of diverse cellular processes, including transcription, signal transduction, and metabolism. This dissertation investigates the multifaceted roles of O-GlcNAcylation in two distinct biological contexts: breast cancer and adipose tissue homeostasis. In the first project, we examined the role of O-GlcNAcylation in modulating the activity of the progesterone receptor (PR), a key transcription factor and therapeutic target in breast cancer. Using a combination of in vitro molecular biology techniques, including site-directed mutagenesis, immunoprecipitation, and chromatin immunoprecipitation, we demonstrated that site-specific O-GlcNAcylation of PR is required for its ability to suppress the expression of interferon-stimulated genes (ISGs). This reveals a novel mechanism by which O-GlcNAcylation fine-tunes PR's transcriptional activity and implicates this modification in the regulation of the innate immune response within the breast cancer microenvironment. In the second project, we investigated the in vivo consequences of adipocyte-specific O-GlcNAc transferase (OGT) deletion using a tamoxifen-inducible mouse model (Adipocre-ERT2;Ogtfl/fl). In lean, male mice, OGT deletion led to a significant reduction in epididymal white adipose tissue (eWAT) mass, accompanied by smaller adipocytes and increased immune cell infiltration. Flow cytometric analysis revealed significant shifts in subpopulations of eWAT immune cell populations, including an increased proportion of NK cells and CD11c+ dendritic cells. In contrast, when challenged with a high-fat diet (HFD), male OGT-KD mice, while still exhibiting reduced eWAT mass, showed a blunted expansion of several immune cell populations typically associated with obesity-induced inflammation. These findings highlight a complex, context-dependent role for adipocyte OGT in regulating adipose tissue mass and immune cell composition.
Collectively, this dissertation demonstrates the broad regulatory influence of O-GlcNAcylation, from modulating the transcriptional activity of a key nuclear receptor in cancer cells to impacting whole-body metabolism and immune homeostasis. The findings reveal novel mechanisms by which O-GlcNAcylation contributes to cellular function and provides a foundation for future investigations into the therapeutic potential of targeting O-GlcNAc pathways in breast cancer and metabolic disease.
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Date
2025-01-01
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University of Kansas
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Cellular biology, Immunology, Biochemistry, adipose, breast cancer, O-GlcNAc, obesity, OGT, Progesterone receptor