Thyroid hormone receptor localization in target tissues

Abstract

The thyroid hormone receptors, TRα1, TRβ1 and other subtypes, are members of the nuclear receptor superfamily that mediate the action of thyroid hormone signaling in numerous tissues to regulate important physiological and developmental processes. Their most well-characterized role is as ligand-dependent transcription factors; TRs bind thyroid hormone response elements in the presence or absence of thyroid hormone to facilitate the expression of target genes. Although primarily residing in the nucleus, TRα1 and TRβ1 shuttle rapidly between the nucleus and cytoplasm. We have identified multiple nuclear localization signals and nuclear export signals within TRα1 and TRβ1 that interact with importins and exportins, respectively, to mediate translocation across the nuclear envelope. More recently, enigmatic cytoplasmic functions have been ascribed to other TR subtypes, expanding the diversity of the cellular response to thyroid hormone. By integrating data on localization signal motifs, this review provides an overview of the complex interplay between TR's dynamic transport pathways and thyroid hormone signaling activities. We examine the variation in TR subtype response to thyroid hormone signaling, and what is currently known about regulation of the variety of tissue-specific localization patterns, including targeting to the nucleus, the mitochondria and the inner surface of the plasma membrane.

Cytoplasmic and Nuclear Forms of Thyroid Hormone Receptor β1 Are Inversely Associated with Survival in Primary Breast Cancer

“…Links between BC and expression of other NR have already been outlined by our lab and others [5][6][7][8][9][10]. Thyroid hormone receptors (THR) are members of the NR superfamily that mediate the classical genomic actions of thyroid hormone (TH) signaling in numerous tissues and regulate important physiological and developmental processes [11,12]. THR primarily act as ligand-dependent transcription factors, after heterodimerization with retinoid X receptor (RXR).…”

Mediator subunit MED1 modulates intranuclear dynamics of the thyroid hormone receptor

“…Our prior studies have shown that in HeLa cells overexpression of wild-type TR does not saturate the capacity of the nuclear import machinery, nor do fluorescent protein tags alter localization patterns. Further, wild-type TR is primarily nuclear over a wide range of expression levels in transfected cells, 31,[35][36][37]65 and supports T 3 -dependent gene transactivation in reporter assays. 69 Finally, distribution patterns of exogenous TRs in HeLa cells are the same as in cell lines that express endogenous TRs, including HepG2 (hepatocellular carcinoma) cells that express low levels of TRα1 and TRβ1, and GH4C1 (rat pituitary tumor) cells that express high levels of both TRα1 and TRβ1.…”

“…[21][22][23] Transcription factors, such as TRα1 and TRβ1, cross the nuclear envelope through the nuclear pore complexes, facilitated by transport proteins called importins and exportins. [24][25][26][27][28][29][30] Although localized primarily to the nucleus at steady-state, TRα1 and TRβ1 shuttle between the nucleus and cytosol, directed by multiple nuclear export signal (NES) and nuclear localization signal (NLS) motifs [31][32][33][34] ( Figure 1A). Along with a NLS in the hinge domain (NLS-1), TRα1 houses a NLS in the A/B domain that is absent in TRβ1 and inactive in the retroviral oncoprotein v-ErbA.…”

“…A, Domain structures of TRα1, TRβ1, and v-ErbA (not to scale). The positions of NLS and NES motifs are indicated in relation to the respective individual domains of TRα1 (31). Hinge, hinge domain; NES-CRM1, CRM1-dependent NES in the viral Gag region of v-ErbA; m-NLS, inactive NLS-2 equivalent in v-ErbA; NES-H3/H6 (predicted), based on the sequence identity with NES-H3 and NES-H6 in TRα1; V, v-ErbA-specific C-terminal sequence that lacks the NES-H12/AF-2 region.…”

Біологічна Роль Йоду Та Йодна Недостатність Як патогенетичний Фактор Виникнення Тиреоїдної Патології У Вагітних Та Її Профілактика

“…Перебіг цієї реакції відбувається у середині молекули тиреоглобуліну і призводить до утворення різних йодтиронінів, включаючи тироксин (Т 4) і трийодтиронін (Т 3 ). Значна частина тиреоглобуліну зберігається в залозі, відіграючи роль прогормона [5].…”