Date Thesis Awarded
Honors Thesis -- Open Access
Bachelors of Science (BS)
Lizabeth A. Allison
Thyroid hormone, or T3, is essential in many bodily functions, from early development to the maintenance of health in adults. It is crucial for growth and skeletal development, development of the nervous system, cell differentiation, and maintenance of metabolic balance. The thyroid hormone receptor, TR, is a major mediator of thyroid hormone action. TR is a transcription factor and able to activate or repress transcription depending on the binding of its ligand, T3. There are two isoforms of TR, encoded by different genes: TRα and TRβ. Each of these isoforms have multiple alternative splicing products.
While TR’s main function is carried out in the nucleus, multiple studies have shown that TR is shuttled rapidly between the nucleus and cytosol. Mislocalization of TR can be linked to diseases such as T3 resistance and cancer. Nuclear localization is mediated by importins, which bind to TRα by recognizing nuclear localization signals (NLSs).
Previous studies have shown the presence of two NLS in the TRα1 isoform: in the Hinge domain (NLS 1) and in the A/B transactivation domain (NLS 2). NLS 1 is a classical, bipartite NLS and is also present in the TRβ1 isoform. NLS2 is a conserved, monopartite NLS that is only present in the TRα1 isoform. It has been previously demonstrated that both NLS are individually capable of directing GFP-GST-GFP (G3)-tagged domain constructs to the nucleus, though NLS-2 is less efficient.
These same G3 domain constructs were used to investigate binding of importin α1, β1, and 7 to both TRα1 NLS. GFP-Trap co-immunoprecipitation (Chromo-Tek) and immunoblotting techniques, we have demonstrated that the importin α1/β1 heterodimer interacts with both the A/B and Hinge domains, while Importin 7 interacts only with the A/B domain. This is consistent with our findings that IPO 7 does not interact with TRβ1, which lacks NLS2.This, along with knockdown experiments, indicate that nuclear import of TRα1 involves multiple import pathways.
McGregor, Emma Lynn, "Characterizing Importin Binding to Thyroid Hormone Receptor α1" (2016). Undergraduate Honors Theses. Paper 897.
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