Abstract
The thyroid hormone receptor (TR)—a nuclear receptor that is essential for the proper regulation of metabolism and development, as it regulates gene expression in response to thyroid hormone—contains nuclear localization signals (NLSs) and nuclear export signals (NESs) that allow for TR transport into and out of the nucleus, respectively. Previous research has shown 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, including Resistance to Thyroid Hormone (RTH) Syndrome, type II diabetes mellitus, and several types of cancer. There are three main subtypes of TR: TRα1, TRβ1, and TRβ2. Here, through mammalian cell transfection of expression plasmids for green fluorescent protein (GFP)‐tagged TR and fluorescence microscopy, we examined particular groups of TRα1 mutations that were observed in patients with hepatocellular carcinoma and renal carcinoma and are associated with NLSs and NESs of TRα1. More specifically, we calculated the nuclear‐to‐cytoplasmic ratios of TRα1 variants to determine the impact of TRα1 mutations on receptor localization within HeLa cells. We found that, while wild‐type TR has a primarily nuclear localization with a smooth distribution in human cells grown in culture, the TRα1 mutations S40T, K136R, L251P, V390A and A225G, D246N, G350K lead to significantly decreased nuclear‐to‐cytoplasmic TRα1 ratios (greater cytoplasmic distribution) and formation of TRα1 aggregates. We observed that the distribution of a TRα1 mutant with just one of the four mutations (L251P) is very similar to the distribution of the TRα1 mutant with all four mutations (S40T, K136R, L251P, V390A), suggesting that L251P plays a major role in the mislocalization of TRα1. In addition, we found that TRα1 with a G24E mutation had a significantly greater cytoplasmic distribution, compared to wild‐type TRα1. In conclusion, our findings suggest that certain TRα1 mutations that are associated with carcinoma lead to TRα1 mislocalization, which may alter the expression of thyroid hormone‐dependent genes. These results contribute to an improved understanding of TR structure and function, which could lead to novel strategies for discovering therapies for TR‐related illnesses.Support or Funding InformationNIH #2R15DK058028‐04This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.
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