Date Thesis Awarded
5-2018
Access Type
Honors Thesis -- Access Restricted On-Campus Only
Degree Name
Bachelors of Science (BS)
Department
Biology
Advisor
Lizabeth Allison
Committee Members
Kurt Williamson
Lisa Landino
Shantá Hinton
Abstract
Thyroid hormone receptor a1 (TRa1) mediates the expression of thyroid hormone-responsive genes, and is vital for normal human metabolic function and development. Wild-type TRa1 resides primarily in the nucleus, but undergoes rapid shuttling between the nucleus and cytoplasm. Mutated TRa1 has been found in a number of different cancers, including renal clear cell carcinoma (rc) and thyroid papillary carcinoma (tc). To test the hypothesis that receptor mislocalization is associated with oncogenesis, the intracellular distribution patterns of two cancer-associated mutants were characterized by transient transfection in HeLa cells (human cells) of expression plasmids for fluorescent protein-tagged rc6-TRα1 (I116N, A225T, M388I) and tc15-TRα1 (S183N, H184Q, R228H). rc6-TRα1 was found to have a significantly increased cytoplasmic localization compared to wild-type TRα1, and a phenotype characterized by aggregate formation. In cotransfection assays, rc6-TRα1 also colocalized with v-ErbA, a highly mutated, retroviral oncogenic form of TR. rc6-TRα1 was also found to colocalize with GFP-170 and GFP-250, bona fide markers for nuclear and cytoplasmic aggresomes, respectively. Aggresomes are highly organized protein aggregates that serve as a defense mechanism from cellular stress, in order to minimize the damage of misfolded proteins. Taken together, these results suggest that rc6-TRα1 may follow similar cellular pathways to v-ErbA and have similar effects on the cell. tc15-TRα1 was found to have no significant shift in nucleocytoplasmic localization and lacked aggregate and aggresome formation, suggesting an alternate pathway by which this mutant contributes to oncogenesis.
Recommended Citation
Salomon, Michael, "Mutant Thyroid Hormone Receptors and the Potential Effects on Cancer" (2018). Undergraduate Honors Theses. William & Mary. Paper 1222.
https://scholarworks.wm.edu/honorstheses/1222
