Date Thesis Awarded
Honors Thesis -- Access Restricted On-Campus Only
Bachelors of Science (BS)
Thyroid hormone is produced by the thyroid gland through the hypothalamic-pituitary-thyroid axis. It is critical for growth, development, and homeostasis, and its action is mediated by the thyroid hormone receptor alpha1 (TRα1). TRα1 is a transcription factor that activates or represses target genes in response to thyroid hormone. Although primarily localized to the nucleus at steady state, TRα1 shuttles rapidly between the nucleus and cytosol. This thesis research focused on elucidating how post-translational modification of TRα1 modulates its nucleocytoplasmic transport. TRα1 is known to be acetylated at lysine residues 128, 132, and 134. In order to determine whether acetylation of TRα1 plays a role in regulating nucleocytoplasmic transport, expression plasmids for GFP or mCherry-tagged TRα1 mutants that mimic acetylation (lysine to glutamine substitutions) and nonacetylation (lysine to arginine substitutions) were constructed. Fluorescence microscopy was used to determine the nuclear/cytosolic (N/C) ratio of the fusion proteins in transfected cells by measuring fluorescence intensity. N/C data showed that the TRα1 nonacetylation mimic and wild-type TRα1 both have a primarily nuclear localization, and that intracellular distribution patterns of the TRα1 nonacetylation mimic and wild-type TRα1 were not hormone dependent. Furthermore, when co-transfected the presence of the TRα1 nonacetylation mimic did not change wild-type TRα1 localization. In contrast, the TRα1 acetylation mimic showed a lower N/C ratio compared to wild-type TRα1, indicating a significant decrease in nuclear localization. Taken together, these data suggest that interactions between TRα1 and transport factors may depend on electrostatic interactions. These findings will extend understanding of the role of post-translational modifications in regulating the fine balance between nuclear import, export, and nuclear retention, and how this interplays with TRα1 transcriptional regulation.
Anyetei-Anum, Cyril S., "Acetylation Controls the Subcellular Localization of Thyroid Hormone Receptor α1" (2016). Undergraduate Honors Theses. William & Mary. Paper 878.
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