Thyroid receptor family

Evans RM (1988) The steroid and thyroid receptor family. Science 240 889... 

Figure 17.3 The nuclear receptor superfamily. Steroid receptor family members and thyroid receptor family members differ in several structural and functional properties. The estrogen receptors share properties with both steroid and thyroid receptor families and are likely an evolutionary precursor to both families.

Table 17.2 DNA Recognition Sequences Utilized by Steroid, Estrogen, and Thyroid Receptor Family Members...

In contrast to the steroid receptor family, members of the thyroid receptor family typically do not associate with accessory proteins and are not localized to the extranucleus matrix. Rather, these receptors exist in the basal state associated with chromatin in the cell nucleus. When bound by hormone ligand, thyroid receptor family members dissociate from the chromatin and typically form heterodimeric combinations with the retinoid-X receptor (RXR). RXR also is capable of homodimerization in association with its ligand 9-cis retinoic acid. Thus high 9-cis retinoic acid levels apparently promote homodimerization, and low levels are permissive of heterodimerization of RXR with activation by the partner ligand. 

The class III cytokine receptor family includes two TNE receptors, the low affinity NGE receptor and 7-ceU surface recognition sites that appear to play a role in proliferation, apoptosis, and immunodeficiency. TNE-a (- 17, 000 protein) is produced by astrocytes and microglia and can induce fever, induce slow-wave sleep, reduce feeding, stimulate prostaglandin synthesis, stimulate corticotrophin-releasing factor and prolactin secretion, and reduce thyroid hormone secretion. TNE-a stimulates IL-1 release, is cytotoxic to oligodendrocytes, and reduces myelination this has been impHcated in multiple sclerosis and encephalomyelitis. Astrocyte TNE-a receptors mediate effects on IL-6 expression and augment astrocytic expression of MHC in response to other stimulants such as lEN-y. 

Increased P450 synthesis requires enhanced transcription and translation. A cytoplasmic receptor (termed AhR) for polycyclic aromatic hydrocarbons (eg, benzo[a]pyrene, dioxin) has been identified, and the translocation of the inducer-receptor complex into the nucleus and subsequent activation of regulatory elements of genes have been documented. A pregnane X receptor (PXR), a member of the steroid-retinoid-thyroid hormone receptor family, has recently been shown to mediate CYP3 A induction by various chemicals (dexamethasone, rifampin) in the liver and intestinal mucosa. A similar receptor, the constitutive androstane receptor (CAR) has been identified for the phenobarbital class of inducers (Sueyoshi, 2001 Willson, 2002). 

The CaR is expressed in many cells such as parathyroid cells and C cells in the thyroid gland. It is also expressed in the kidneys, osteoblasts, in the gastrointestinal mucosa, and hematopoietic cells in bone marrow. It has been found that CaR is expressed in different amounts on the cell face of many cell types and in diverse species. CaR is a member of the G protein-coupled receptor family with seven hydrophobic transmembrane helices in the plasma membrane. It has a large N-terminal domain with about 600 amino acids located in the extracellular environment and is essential for sensing extracellular calcium concentration. CaR has a large cytosolic C-terminal domain with about 200 amino acids that is subjected to phosphorylation. A dimeric structure has been proposed based on the known crystal structure of the metabotropic glutamate receptor type 1. 

Another forefront technique to improve the function of the stratum corneum and enhance barrier repair in dry skin is the use of epidermal differentiation. A number of hormone receptors for epidermal differentiation have been identified. This family of receptors includes retinoic acid receptors, the steroid receptors, the thyroid receptors, the Vitamin D receptors, the peroxisome proliferator-activated receptors, the farnesol-activated receptors, and the liver-activated receptors. It is reported that these transcription factors bind their respective ligands and regulate many of the aspects of cellular proliferation and differentiation. Examples of ligands for the last three transcription factors are fatty acids for the peroxisome proliferator-activated receptor, famesol for the farnesol-activated receptor, and hydroxylated cholesterol derivatives for the liver-activated receptor. The stimulation of epidermal differentiation stimulated the synthesis of involucrin, filaggrin, and the enzymes of the ceramide synthesis pathway (74). 

Retinoic X receptors (RXR, a, (3 and " (), also termed rexinoid receptors, are usually classified among orphan receptors, but belong to the thyroid/retinoid family. RXR is an obligatory partner dimerizing with other thyroid/retinoid receptors. RXR selectively bind the 9-cis isomer of retinoic acid, whereas RAR bind aU-tran retinoic acid as well as its 9-cis isomer. RXR selective agonists are termed rexi-noids, like bexarotene used as an antineoplastic in the treatment of cutaneous T-cell lymphoma and the cutaneous lesions of T-cell lymphomas and Kaposi s sarcoma. 

PR, AR, GR, MR), thyroid hormone (TRa and j8), and retinoid (RARot, jS, and 7, and RXRa) receptor superfamily of nuclear transcriptional factors (207-210), multiple members of the interleukin cytokine receptor family (211), and subtypes of the glutamate (212) and adenosine (213)receptor families. The importance of access to human cloned receptors continues to be underscored as receptor binding plays an increasingly critical role in modern drug discovery (214). 

Recently, this system was used to identify several factors putatively involved in the mechanism of steroid hormone-mediated gene transcription. In a two-hybrid screen to identify factors that interact with the vitamin D receptor (VDR), we isolated transcription factor IIB (TFIIB) as a VDR-mteractive clone (2). The interaction of VDR, retinoic-acid receptors and other steroid-hormone receptors with TFIIB may represent a fundamental step in the mechanism of transcription mediated by the nuclear-receptor family (3-5) The two-hybrid system has also identified several putative coactivator and corepressor proteins that contact retinoid receptors, thyroid receptors, vitamin D receptors, and other members of the nuclear-receptor family (6-9) Thus, the two-hybrid system is playing an instrumental role in the identification of factors involved in nuclear receptor-mediated gene expression This chapter discusses several procedures and strategies used to establish a two-hybrid system to examine proteins that interact with retinoid receptors, with the VDR, or with nuclear receptors in general. 

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