The role of vitamin D and the vitamin D receptor in TCF-4 regulation and silencing of CYP24A1
Beildeck, Marcy Ellen.
Thesis (Ph.D.)--Georgetown University, 2009.; Includes bibliographical references. Vitamin D has long been associated with a protective role against cancer. Its therapeutic index in the prevention and treatment of cancer is restricted due to dose-limiting toxicity that is related to its role in calcium mobilization. In order to identify new chemotherapeutic targets in the vitamin D pathway, we are studying its downstream effects. We have identified two novel mechanisms whereby the vitamin D receptor (VDR) and its cognate ligand, 1,25(OH)2D3, may protect against aberrant gene regulation and cell cycling.; In the process of using the mouse mammary tumor cells from VDR-null animals, we observed a lack of regulation of the classic vitamin D responsive gene, CYP24A1, which is involved in the metabolism of 1,25(OH)2D3 into inactive metabolites. This gene is 'silenced' by an epigenetic DNA methylation event, as treatment with a DNA methyltransferase inhibitor restored responsiveness. In our studies, the proximal CpG island-containing promoter of CYP24A1, is not the target of this methylation event. We propose that this is either due to an indirect methylation event, a methylation event in the distal promoter or enhancer regions of CYP24A1, or a result of dynamic methylation in this region that allows demethylation and re-expression of this gene.; In this work, we identify a novel target of the vitamin D pathway that may shed light onto the mechanism whereby vitamin D prevents cancer. We also generate a new hypothesis, as well as show evidence to reinforce previously identified, but poorly supported hypotheses in the field of epigenetics.
Showing items related by title, author, creator and subject.
Janssen Schroeder, Megan Jayne. (Georgetown University, 2010)
Hussmann, Gregory Patrick (Georgetown University, 2012)Chronic nicotine administration increases the density of α4β2 neuronal nicotinic acetylcholine receptors (nAChRs) in brain. Nicotine up-regulates these receptors in numerous research models, including cultured ...
Regulation of MicroRNAs Targeting the Angiogenic Switch Molecule Fibroblast Growth Factor Binding Protein 1 by Retinoic Acid Receptor Activation Baker, Tabari (Georgetown University, 2014)This dissertation examines the role of retinoic acid receptor activation in the post-transcriptional regulation of a fibroblast growth factor binding protein. Previous work showed that all-trans retinoic acid (ATRA) reduces ...