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tissue, and lymphocytes.

Skeletal actions

Stimulate increased bone turnover (resorption > formation).

Carbohydrate and lipid metabolism

Hyperthyroidism increases hepatic gluconeogenesis and glycogenolysis.

Gastrointestinal effects

T3 stimulates gut motility.

figure 6-16 Effects of hypothyroid and hyperthyroid status on oxygen consumption in various rat tissues. Oxygen consumption was determined in thyroidectomized rats before (solid bars) and after (striped bars) treatment with thyroxine for 4-6 days. Note the paradoxical response of the pituitary to thyroid hormone in relation to the other tissues of the body; the basis for this response is not presently understood. [Modified from Barker, S. B. (1964). Physiological activity of thyroid hormones and analogues. In "The Thyroid Gland", (R. Pitt-Rivers and W. R. Trotter, eds.), p. 200. Butterworths London.]

figure 6-16 Effects of hypothyroid and hyperthyroid status on oxygen consumption in various rat tissues. Oxygen consumption was determined in thyroidectomized rats before (solid bars) and after (striped bars) treatment with thyroxine for 4-6 days. Note the paradoxical response of the pituitary to thyroid hormone in relation to the other tissues of the body; the basis for this response is not presently understood. [Modified from Barker, S. B. (1964). Physiological activity of thyroid hormones and analogues. In "The Thyroid Gland", (R. Pitt-Rivers and W. R. Trotter, eds.), p. 200. Butterworths London.]

the many effects of thyroid hormone on gene expression.

The majority of effects of thyroid hormones are now believed to be mediated through interactions of thyroxine with its nuclear receptors, so as to bring about changes in gene expression.

B. Thyroid Hormone Receptor

1. Introduction

In analogy to the steroid hormones, retinoic acid, and la,25(OH)2D3, thyroid hormones are known to bind to a nuclear receptor that interacts with transcription factors to either up-regulate or down-regulate the transcription of a wide array of genes. The nuclear receptor for thyroid hormones belongs to the steroid receptor supergene family (see Figure 1-27). Since the landmark discovery in 1986 that the nuclear protein encoded by the c-erb-A gene (a cellular homologue of the v-erb-A oncogene) was structurally identified to be the thyroid nuclear protein, multiple isoforms of the thyroid receptor have been discovered. As summarized in Figure 6-17, five isoforms of the thyroid receptor are now known. Interestingly, two of these isoforms, TRa-2 and TRa-3, do not bind a ligand. There is marked tissue-specific expression of the isoforms of the thyroid receptor: TR/3-1 is expressed in most tissues, while TRa-1 and TRa-2 are present in relatively high concentrations in skeletal and cardiac muscle, brain, and brown fat. The TR/3-2 isoform is only expressed in the anterior pituitary gland and selected regions of the brain. There is also emerging evidence that the TRa gene mRNA may be alternatively spliced, so as to generate a number of distinct protein products.

2. Thyroid Hormone Receptor Structural Properties

The functional properties of the thyroid receptor have been mapped via the preparation of scanning deletion mutants (see, for example, Figure 1-44); thus, it has been possible to precisely define the DNA-binding region, nuclear localization signal, thyroxine ligand-binding domain, and heterodimerization domains (see Figure 6-18).

One hallmark of the thyroid receptor is that, even in the absence of ligand, the unoccupied receptor is always found to be associated with the nucleus and its chromatin; this is because the receptor is not cyto-plasmically anchored to heat shock proteins, and thus the nuclear localization signal is operative. This is dictated by the sequence of amino acids in the region of 176-186, the so-called nuclear localization domain (See Figure 6-18).

The ability to recognize target genes is a critical aspect of the action of all steroid receptors, including the thyroid receptor. On the basis of structural homology within the DNA-binding domain and other members of the steroid superfamily (see Table 1-10), the thyroid receptor is classified as a member of the estrogen-vitamin D receptor-thyroid subfamily. These receptors all share the same consensus sequence preference of AGGTCA in the DNA-binding domain. These receptors preferentially bind to this so-called half-site when it is present as a single or multiple copy in the promoters of genes that are subject to regulation.

3. Transcriptional Regulation by Thyroid Receptor

The three-dimensional structure of the rat a, thyroid receptor ligand binding domain with a thyroid hormone agonist has been determined at a 2.2 A resolution via X-ray crystallographic procedures. The receptor secondary structure was found to be composed of twelve a-helices and four /3-strand domains (see Figure 6-19).

The front cover of this book presents a schematic representation of the secondary structure a-helices (red for helixj >>> royal blue for helix12) and /3-strand elements (yellow color) and indicates the orientation of the ligand. The hormone (purple color) is depicted as a space-filling model. There are two notable features of this structure: (a) the ligand is completely buried within the ligand binding domain as part of the hydrophobic core; (b) the carboxy-terminal heterodimeriza-

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1 227 514

FIGURE 6-17 Isoforms of the thyroid nuclear receptor isolated from the rat. The amino acid sequences have been deduced from the cDNA. The numbering of the amino acid residues is indicated above each form. The percent homology of the DNA-binding domain of TR/3-1 (black region) is also indicated. Identical patterns indicate 100% aa sequence identity. Similar patterns (horizontal lines) indicate highly similar sequences. The TRa-2 and TRa-3 isoforms contain unique carboxyl-terminal sequences that eliminate ligand binding. [Modified with permission from Lazar, M. A. (1993). Thyroid hormone receptors: Multiple forms, multiple possibilities. Endocr. Rev. 14, 184-193.]

FIGURE 6-17 Isoforms of the thyroid nuclear receptor isolated from the rat. The amino acid sequences have been deduced from the cDNA. The numbering of the amino acid residues is indicated above each form. The percent homology of the DNA-binding domain of TR/3-1 (black region) is also indicated. Identical patterns indicate 100% aa sequence identity. Similar patterns (horizontal lines) indicate highly similar sequences. The TRa-2 and TRa-3 isoforms contain unique carboxyl-terminal sequences that eliminate ligand binding. [Modified with permission from Lazar, M. A. (1993). Thyroid hormone receptors: Multiple forms, multiple possibilities. Endocr. Rev. 14, 184-193.]

tion domain (see Figures 6-18 and 6-19) forms an am-phipathic helix with its hydrophobic face constituting part of the ligand hormone binding cavity. These two observations suggest a structural role for the ligand in determining the functionally active conformation for the receptor related to the receptor's role in the regulation of gene expression.

The functional stoichiometry of the thyroid receptor as it interacts with the promoters of regulated genes is variable. Both monomers and homodimers as well as heterodimers of the thyroid hormone receptor are

TRpi h2n-

DNA-binding specificity Nuclear localization T3 binding Heterodimerization

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