Mislocalization of Cancer-associated Thyroid Hormone Receptor Mutants.

The thyroid hormone receptor (TR) is essential for the proper regulation of metabolism and development, as it regulates gene expression in response to thyroid hormone. Nuclear localization signals (NLSs) and nuclear export signals (NESs) allow for TR transport into and out of the nucleus, respectively. Previous research suggests that nuclear import, nuclear retention, and nuclear export of TR are associated with modulation of gene expression, the alteration of which can contribute to various diseases. Here, we examined the impact of cancer-associated mutations on TR localization patterns as a way of analyzing key structural components of TR and to further explore the correlation between TR trafficking, misfolding, and disease. Through mammalian cell transfection of expression plasmids for green fluorescent protein (GFP) and mCherry-tagged TRα1 and quantitative fluorescence microscopy, we examined particular groups of TRα1 mutations that were observed in patients with hepatocellular carcinoma, renal cell carcinoma, and thyroid cancer, and are associated with NLSs and NESs of TRα1. We also investigated structural alterations of the mutants by in silico modeling. Our results show striking shifts towards a more cytoplasmic localization for many of the mutants and an increased tendency to form cytosolic and nuclear aggregates.