Abstract
Thyroid hormone receptor alpha (TRα) and beta (TRβ) are critical in many aspects of metabolic control and development. TRα can use a CRM1‐dependent or a CRM1‐independent pathway for nuclear export. To determine if exportin 5 mediates TR's export by the latter pathway, Myc‐tagged exportin 5 was over‐expressed in HeLa cells. The distribution and transcriptional activity of GFP‐TRα or TRβ was analyzed by fluorescence microscopy and CAT‐ELISA, respectively. TR is primarily nuclear at steady‐state, but TR had a more cytoplasmic distribution when exportin 5 was overexpressed. In addition, CAT reporter gene expression under control of a thyroid hormone response element was markedly decreased when exportin 5 was over‐expressed, indicating less TR was present in the nucleus. TR has multiple nuclear export sequences (NESs) in the ligand‐binding domain. We tested the helix 12 NES (NES‐H12) and the NES located in the 3rd and 6th helices (NESH3/ H6) on their direct interactions with exportin 5. TR with a NES‐H12‐disrupting mutation had a more cytoplasmic distribution when exportin 5 was over‐expressed, suggesting that exportin 5 utilizes NES‐H3/H6 during export. By determining the nuclear export mechanism of TR by exportin 5 and other exportins, further knowledge into regulation of thyroid hormone‐responsive gene expression will be gained. This work was funded in part by NSF MCB 10144844 and NIH 2R15DKO58028–03 to L.A.A.
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