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Nucleocytoplasmic Shuttling of the Thyroid Hormone Receptor

Department of Biology (J.A.N., K.E.F., T.A.S., B.S.W., L.A.A.) College of William and Mary Williamsburg, Virginia, 23187
Department of Zoology (C.F.B., J. M., L.A.A.) University of Canterbury Christchurch, New Zealand 8001

The thyroid hormone receptor (TR) exhibits a dual role as an activator or repressor of gene transcription in response to thyroid hormone (T₃). Our studies show that TR, formerly thought to reside solely in the nucleus tightly bound to DNA, actually shuttles rapidly between the nucleus and cytoplasm. The finding that TR shuttles reveals an additional checkpoint in receptor control of gene expression. Using Xenopus oocyte microinjection assays, we show that there are two coexisting mechanisms for nuclear entry of TR. First, nuclear import of TR (molecular mass 46 kDa) was not sensitive to general inhibitors of signal-mediated transport, indicating that TR can enter the oocyte nucleus by passive diffusion. Second, when TR was tagged with glutathione-S-transferase, import of the fusion protein (molecular mass 73 kDa) was completely blocked by these inhibitors, demonstrating that an alternative, signal-mediated import pathway exists for TR. Nuclear retention of TR in oocytes is enhanced in the presence of T₃, suggesting that more intranuclear binding sites are available for the ligand-bound receptor. Using mammalian cells, we show that shuttling of green fluorescent protein (GFP)-tagged and untagged TR is inhibited in both chilled and energy-depleted cells, suggesting that there is an energy-requiring step in the nuclear retention/export process. Nuclear export of TR is not blocked by leptomycin B, a specific inhibitor of the export receptor CRM1, indicating that TR does not require the CRM1 pathway to exit the nucleus. Dominant negative mutants of TR with defects in DNA binding and transactivation accumulate in the cytoplasm at steady state, illustrating that even single amino acid changes in functional domains may alter the subcellular distribution of TR. In contrast to TR, nuclear export of its oncogenic homolog v-ErbA is sensitive to leptomycin B, suggesting that the oncoprotein follows a CRM1-mediated export pathway. Acquisition of altered nuclear export capabilities may contribute to the oncogenic properties of v-ErbA.

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