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Molecular aspects of thyroid hormone actions - PubMed

Review

Molecular aspects of thyroid hormone actions

Sheue-Yann Cheng et al. Endocr Rev. 2010 Apr.

Abstract

Cellular actions of thyroid hormone may be initiated within the cell nucleus, at the plasma membrane, in cytoplasm, and at the mitochondrion. Thyroid hormone nuclear receptors (TRs) mediate the biological activities of T(3) via transcriptional regulation. Two TR genes, alpha and beta, encode four T(3)-binding receptor isoforms (alpha1, beta1, beta2, and beta3). The transcriptional activity of TRs is regulated at multiple levels. Besides being regulated by T(3), transcriptional activity is regulated by the type of thyroid hormone response elements located on the promoters of T(3) target genes, by the developmental- and tissue-dependent expression of TR isoforms, and by a host of nuclear coregulatory proteins. These nuclear coregulatory proteins modulate the transcription activity of TRs in a T(3)-dependent manner. In the absence of T(3), corepressors act to repress the basal transcriptional activity, whereas in the presence of T(3), coactivators function to activate transcription. The critical role of TRs is evident in that mutations of the TRbeta gene cause resistance to thyroid hormones to exhibit an array of symptoms due to decreasing the sensitivity of target tissues to T(3). Genetically engineered knockin mouse models also reveal that mutations of the TRs could lead to other abnormalities beyond resistance to thyroid hormones, including thyroid cancer, pituitary tumors, dwarfism, and metabolic abnormalities. Thus, the deleterious effects of mutations of TRs are more severe than previously envisioned. These genetic-engineered mouse models provide valuable tools to ascertain further the molecular actions of unliganded TRs in vivo that could underlie the pathogenesis of hypothyroidism. Actions of thyroid hormone that are not initiated by liganding of the hormone to intranuclear TR are termed nongenomic. They may begin at the plasma membrane or in cytoplasm. Plasma membrane-initiated actions begin at a receptor on integrin alphavbeta3 that activates ERK1/2 and culminate in local membrane actions on ion transport systems, such as the Na(+)/H(+) exchanger, or complex cellular events such as cell proliferation. Concentration of the integrin on cells of the vasculature and on tumor cells explains recently described proangiogenic effects of iodothyronines and proliferative actions of thyroid hormone on certain cancer cells, including gliomas. Thus, hormonal events that begin nongenomically result in effects in DNA-dependent effects. l-T(4) is an agonist at the plasma membrane without conversion to T(3). Tetraiodothyroacetic acid is a T(4) analog that inhibits the actions of T(4) and T(3) at the integrin, including angiogenesis and tumor cell proliferation. T(3) can activate phosphatidylinositol 3-kinase by a mechanism that may be cytoplasmic in origin or may begin at integrin alphavbeta3. Downstream consequences of phosphatidylinositol 3-kinase activation by T(3) include specific gene transcription and insertion of Na, K-ATPase in the plasma membrane and modulation of the activity of the ATPase. Thyroid hormone, chiefly T(3) and diiodothyronine, has important effects on mitochondrial energetics and on the cytoskeleton. Modulation by the hormone of the basal proton leak in mitochondria accounts for heat production caused by iodothyronines and a substantial component of cellular oxygen consumption. Thyroid hormone also acts on the mitochondrial genome via imported isoforms of nuclear TRs to affect several mitochondrial transcription factors. Regulation of actin polymerization by T(4) and rT(3), but not T(3), is critical to cell migration. This effect has been prominently demonstrated in neurons and glial cells and is important to brain development. The actin-related effects in neurons include fostering neurite outgrowth. A truncated TRalpha1 isoform that resides in the extranuclear compartment mediates the action of thyroid hormone on the cytoskeleton.

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Figures

Figure 1
Figure 1

A, Schematic representation of TR isoforms. TRs are encoded by the TRβ and TRα genes located on different chromosomes. Alternative splicing of primary transcripts gives rise to four thyroid hormone binding isoforms. TRs share high sequence homology in the DNA binding domain C (solid bar) and the hormone binding domain D/E (open bar). The amino-terminal A/B domains are variable in length and amino acid sequence as indicated by different symbols. The amino acids of the truncated TRs (TRΔβ3, TRΔα1, and TRΔα2) at the amino and carboxy termini are indicated by numbers. B, The DNA sequence (a) and the arrangement (b) of the TRE half-site binding motifs. The Lys TRE was identified in the promoter of lysozyme gene. DR+4 TRE represents the direct repeat separated by four nucleotides. Pal is TRE half-site in palindromic arrangement.

Figure 2
Figure 2

A simplified molecular model for transcriptional repression by unliganded TR (A) and activation by liganded TR (B). Interaction of the unliganded TR with the complex of CoRs and its associated proteins leads to repression of transcription (A). Interaction of the liganded TR with CoAs (e.g., SRC/p160 or TRAP/DRIP complex) leads to transcriptional activation (B).

Figure 3
Figure 3

Schematic representation of SRC/p160 CoA family (A) and NCoR/SMRT CoRs (B). A, The location of the receptor interaction domain (RID) in the SRC is indicated. RID and activation domain 1 (AD1) each contains three LXXLL motifs. The specific domains for interaction with P/CAF, CBP/p300, as well as the histone acetyltransferase domain, are indicated. Located near the amino-terminal region is the highly conserved bHLH–PAS domain that functions as a DNA-binding or dimerization surface in many transcription factors. B, The nuclear receptor (NR) interaction region that contains the “CoRNR box” motifs near the C-terminal region is indicated. Near the amino-terminal region is the deacetylase activation domain (DAD) that interacts with and activates HDAC3, required for repression by TR.

Figure 4
Figure 4

Nongenomic actions of thyroid hormone that are initiated at the plasma membrane receptor on integrin αvβ3 or in cytoplasm. Via the integrin receptor, thyroid hormone from the cell surface stimulates MAPK (ERK1/2) through phospholipase C (PLC) and protein kinase C (PKC) (161). Hormone-activated ERK1/2 promotes trafficking of specific proteins resident in cytoplasm to the nuclear compartment and serine phosphorylation of nucleoproteins by activated ERK1/2 also translocated to the nucleus. Target proteins phosphorylated by hormone-directed ERK include estrogen receptor (ER)-α, TR-β1, signal transducing and activator of transcription (STAT)-1α, and CoA protein Trip230. Complex cellular events induced from the cell surface receptor include angiogenesis (endothelial and vascular smooth muscle cells) and tumor cell proliferation (160). In cytoplasm, T3 can nongenomically activate PI3K and initiate downstream transcription of specific genes. Activation of PI3K can involve TRβ1 or TRα resident in cytoplasm. A truncated form of TRα1 (TRΔα1) in cytoplasm mediates the action of T4 and rT3 on the actin cytoskeleton. T3 and T4 may also activate PI3K from the integrin αvβ3 hormone receptor site (148). GLUT1, Glucose transporter-1.

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