The Nuclear Receptor Superfamily

Many hormones diffuse into the cell and initiate signaling by binding to soluble intracellular receptors that act as transcription factors. 

This mechanism is used by steroid hormones (Table 14—2), thyroid hormone, vitamin D3, and retinoic acid. 

The receptors may be located in the nucleus or cytoplasm of the cell, but they are collectively called the nuclear receptor superfamily because the nucleus is their main site of action. 

The receptors in this family have a similar overall structure with a ligandbinding domain specific for the hormone or vitamin, a DNA-binding domain, and a variable domain that differs among the receptors. 

After formation of the initial ligand-receptor complex, other partner proteins are recruited that complete the active complex. 

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AE Sluder, SW Mathews, D Hough, VP Ym, CV Mama. The nuclear receptor superfamily has undergone extensive proliferation and diversification in nematodes. Genome Res 9 103-120, 1999. 

The thiazolidinediones have also been reported to act as inhibitors of the respiratory chain at high concentrations, and this appears to account for their ability to activate AMGPK in cultured cells. However, the primary target of the thiazolidinediones appears to be the peroxisome proliferator-activated receptor-y ( PPAR-y), a member of the nuclear receptor superfamily expressed in adipocytes. One of the major effects of stimulation of PPAR-y in adipocytes is the release ofthe... 

Gronemeyer H, Gustafsson JA, Laudet V (2004) Principles for modulation of the nuclear receptor superfamily. Nat Rev Drug Discov 3 950-964... 

Mangelsdorf DJ, Thummel C, Beato M et al (1995) The nuclear receptor superfamily the second decade. Cell 83 835-839... 

Peroxisome Proliferator-Activated Receptors. Figure 1 Common structural and functional features of nuclear receptor transcription factors. Consistent with other members of the nuclear receptor superfamily, the PPARs have a modular domain structure consisting of domains A/B, C, D, and E. Each domain is associated with specific functions. 

Moore JT, Collins JL, Pearce KH (2006) The nuclear receptor superfamily and drug discovery. Chem Med Chem 1 504-523... 

Steroid receptors belong to the nuclear receptor superfamily and bind steroid hormones. They are cytoplasmic when inactive and associated with chaperones. 

A comparison of several different steroid receptors with thyroid hormone receptors revealed a remarkable conservation of the amino acid sequence in certain regions, particularly in the DNA-binding domains. This led to the realization that receptors of the steroid or thyroid type are members of a large superfamily of nuclear receptors. Many related members of this family have no known ligand at present and thus are called orphan receptors. The nuclear receptor superfamily plays a critical role in the regulation of gene transcription by hormones, as described in Chapter 43. 

Figure 43-11. The hormone response transcription unit. The hormone response transcription unit is an assembly of DNA elements and bound proteins that interact, through protein-protein interactions, with a number of coactivator or corepressor molecules. An essential component is the hormone response element which binds the ligand (A)-bound receptor (R). Also Important are the accessory factor elements (AFEs) with bound transcription factors. More than two dozen of these accessory factors (AFs), which are often members of the nuclear receptor superfamily, have been linked to hormone effects on transcription. The AFs can interact with each other, with the liganded nuclear receptors, or with coregulators. These components communicate with the basal transcription complex through a coregulator complex that can consist of one or more members of the pi 60, corepressor, mediator-related, or CBP/p300 families (see Table 43-6).

The nuclear receptor superfamily consists of a diverse set of transcription factors that were discovered because of a sequence similarity in their DNA-binding domains. This family, now with more than 50 members, includes the nuclear hormone receptors discussed above, a number of other receptors whose ligands were discovered after the receptors were identified, and many putative or orphan receptors for which a ligand has yet to be discovered. 

As illustrated in Table 43-5, the discovery of the nuclear receptor superfamily has led to an important understanding of how a variety of metabolites and xenobi-otics regulate gene expression and thus the metabolism, detoxification, and elimination of normal body products and exogenous agents such as pharmaceuticals. Not surprisingly, this area is a fertile field for investigation of new therapeutic interventions. 

Nuclear Receptors Nomenclature Committee (1999) A unified nomenclature system for the nuclear receptor superfamily. Cell 97 161-163. 

Fang, H Tong, W.D., Welsh, W.J. and Sheehan, D.M. (2003) QSAR models in receptor-mediated effects the nuclear receptor superfamily. J. Mol. Struct. THEOCHEM, 622 (1-2), 113-125. 

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.

Our observations suggest that Ser-106 and Ser-124 are both required in vivo to fully recruit SRC-1. In addition, when cells were treated with factors known to activate Ras, such as EGF or IGF-1 (data not shown), the in vivo interaction between SRC-1 and ER(3 was also enhanced, thus mimicking the results obtained in the presence of activated Ras. This study demonstrates for the first time that phosphorylation of the AF-1 domain of a member of the nuclear receptor superfamily enhances the recruitment of a steroid receptor coactivator (SRC-1) and provides a molecular basis for ligand-independent activation of ER(3 via the MAPK cascade. 

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