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Exploring the Role of HDAC6 in Thyroid Hormone Receptor Intracellular Localization
Lopez, Giuliana
Lopez, Giuliana
Abstract
The thyroid hormone receptor (TR) is a member of the nuclear receptor family that regulates gene expression. The thyroid hormone (TH) is the ligand responsible for activating TR and its targeted genes. Disease-associated mutations have been shown to change TR’s ligand binding ability and cellular localization. Furthermore, post-translational modifications such as acetylation may contribute to the receptor’s localization. A mutant form of TR that mimics the acetylated state has been shown to experience a shift to a more cytosolic localization. The present thesis evaluates whether histone deacetylase 6 (HDAC6) plays a role in this influential modification. In order to examine HDAC6’s potential involvement, HeLa (human) cells were exposed to the selective HDAC6 inhibitor tubastatin A (TubA) and compared to a control group. Using fluorescence microscopy, the localization of green fluorescent protein (GFP)-tagged TR was recorded. In one of the major subtypes of TR, thyroid hormone receptor alpha 1 (TRɑ1), a significant increase in cytosolic localization was observed in the cells treated with TubA. When the experiment was repeated for thyroid hormone receptor beta 1 (TRβ1), a second subtype of TR, no significant difference was shown between the cells treated with TubA and the controls. The effects of inhibiting HDAC6 and its potential function in translocating TRβ1 might have been hidden by the fact that TRβ1 already has a higher cytosolic localization relative to TRɑ1 at steady-state. The findings of the present thesis build the basis for future work to pursue further investigation of HDAC6’s mechanism in TR localization and provide insight into the nature of TR-related illnesses.
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2023-05-01
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Biology