Molecular and Cellular Endocrinology
The thyroid hormone receptor (TR) undergoes nucleocytoplasmic shuttling and regulates target genes involved in metabolism and development. Previously, we showed that TR follows a CRM1/calreticulinmediated nuclear export pathway. However, two lines of evidence suggest TR also follows another pathway: export is only partially blocked by leptomycin B (LMB), a CRM1-specific inhibitor; and we identified nuclear export signals in TR that are LMB-resistant. To determine whether other exportins are involved in TR shuttling, we used RNA interference and fluorescence recovery after photobleaching shuttling assays in transfected cells. Knockdown of exportins 4, 5, and 7 altered TR shuttling dynamics, and when exportins 5 and 7 were overexpressed, TR distribution shifted towards the cytosol. To further assess the effects of exportin overexpression, we examined transactivation of a TR-responsive reporter gene. Our data indicate that multiple exportins influence TR localization, highlighting a fine balance of nuclear import, retention, and export that modulates TR function.
Subramanian, Kelly; Dziedzic, Rose C.; Nelson, Hallie N.; Stern, Mary E.; Roggero, Vincent R.; Bondzi, Cornelius; and Allison, Lizabeth A., Multiple Exportins Influence Thyroid Hormone Receptor Localization (2015). Molecular and Cellular Endocrinology, 411, 86-96.