Date Thesis Awarded
Honors Thesis -- Access Restricted On-Campus Only
Bachelors of Science (BS)
Thyroid hormone receptors (TRs), such as TRα1, TRβ1, and TRβ2, are members of the nuclear receptor superfamily which can bind both DNA and the thyroid hormone T3, controlling gene expression. However, TRs shuttle rapidly between a cell’s nucleus and cytoplasm in a manner controlled by binding interactions with import and export proteins, as well as by post-translational modification of TR itself. The localization of TR is believed to be closely tied to its function. We studied the activity of a TRα1 mutation that causes the disease Resistance to Thyroid Hormone α (RTH-α), a condition in which the body produces T3 but TRα1 does not appropriately influence gene expression. This mutation, known as C392X, causes premature truncation and eliminates one of the protein’s nuclear export signals. We thus hypothesized that the C392X mutation causes disease by preventing interactions between TRα1 and exportins 5 and 7. To test this hypothesis, we co-transfected human cells with expression plasmids for mutant or wild-type TRα1 alongside overexpressed exportin 5 (XPO5) or 7 (XPO7) and studied the resulting localization patterns. We found that wild-type TRα1 was significantly more nuclear when co-transfected with overexpressed XPO5 than when co-transfected with the control; however, localization of C392X TRα1 did not change. Neither mutant nor wild-type TRα1 displayed altered localization patterns when overexpressed with XPO7 compared to the control. As a result, it appears that the C392X may contribute to disease by reducing responsiveness to XPO5-induced localization patterns, but the way this occurs is unclear. Loss of interaction between C392X TRα1 and XPO7 does not seem to contribute to RTHα. Additionally, we tested the feasibility of using the human influenza hemagglutinin (HA) tag to visualize the localization of TRα and TRβ via fluorescent and chemiluminescent western blot. The success of these blots indicates that this tag may be a valuable tool moving forward in studying TR localization patterns.
Heaton, Helen, "Investigating Thyroid Hormone Receptor Shuttling Patterns" (2023). Undergraduate Honors Theses. William & Mary. Paper 2011.
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