The Nuclear Hormone Receptor Superfamily is a group of proteins which function as transcriptional regulators in a vast array of diverse processes. In mammals, these processes include embryonic development, maintenance of body fluid and electrolyte composition, regulation of energy sources and metabolism, and protection of organ systems from endogenous and exogenous toxic compounds. The nuclear hormone receptors may also be involved in the pathophysiology of diseases such as diabetes, cancer, and atherosclerosis. This chapter begins with a brief overview of general nuclear hormone receptor structure. It then introduces the basic mechanistic concepts underlying transcriptional activation of gene expression by these proteins. In closing, this chapter looks in more detail at specific members of the Nuclear Hormone Receptor Superfamily, and describes their individual roles in the processes introduced above.


Over two decades have passed since the first nuclear hormone receptor (NR) was cloned. Since that time, spectacular growth in the number of recognized NRs has occurred, leading to the identification and characterization of over 40 NRs in vertebrates. Among the many consequences of this rapid growth in characterization of

NRs has been the development of a novel concept known as "reverse endocrinology" in which the characterization of a putative receptor precedes identification of its ligand or study of its physiological function. This approach has succeeded in identifying a number of "orphan receptors" for which a corresponding ligand has not been found. It has also succeeded in underscoring the tremendous number of physiological processes in which NRs play a role. Far from being involved in simply mediating the effects of the steroid hormones, NRs have been shown to be involved in processes ranging from axis patterning and organ morphogenesis in the embryo to lipid homeostasis and xenobiotic metabolism in the adult. NRs are also involved in pathophysiological processes, as roles for NRs have been demonstrated in diseases such as diabetes, cancer, and atherosclerosis. Not surprisingly, given the involvement of this superfamily in processes ranging from development to disease, considerable effort has been spent in attempting to elucidate the mechanisms by which NRs regulate gene expression. However, while a basic understanding of the function of NRs at the promoters of target genes has been garnered through a host of studies, much remains to be understood about NR function.

General Stucture of Nuclear Receptors

Like other transcriptional regulators, NRs possess a modular structure with autonomous functional domains. In many instances, these domains can be interchanged between related receptors with little or no loss of function. Typically, a NR consists of a variable N-terminal domain (Domain A/B), a conserved DNA-

Corresponding Author: Ming-Jer Tsai, Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston Texas 77030, Tel: (713) 798-6253, Fax: (713) 798-8227, E-mail: [email protected]

binding domain (Domain C), a linker or hinge region (Domain D), and a conserved ligand binding domain (Domain E). Many receptors also contain a C-terminal region (Domain F) with unknown function, and it is not uncommon to see this region described as part of a C-terminal E/F domain in combination with the ligand binding domain (Aranda and Pascual, 2001). In addition to distinct domains, the NRs also contain regions within the tertiary structure of the individual receptors which confer functions such as transcriptional activation, dimerization, and nuclear localization upon the fully folded NR polypeptide (see Fig. 16.1) (Aranda and Pascual, 2001).

A: The Hypervariable Region: Domain A/B

The N-terminal A/B region is the most variable domain, both in size and sequence, between all members of the NR superfamily. In some instances, it is also the most variable region between members of a single group of NRs, as many receptor informs generated from a single gene by alternative splicing or alternative promoter usage diverge in their A/B domains (Aranda and Pascual, 2001). Complicating the study of the A/B domain of NRs is the fact that almost no three-dimensional structural information is available for the A/B domain from any member of the NR superfamily (Kumar and Thompson, 1999). Still, molecular genetic analysis has revealed that the A/B domain is important for transcriptional activity of NRs and serves as a target for modulation through phosphorylation (Aranda and Pascual, 2001; Kumar and Thompson, 1999).

Transcriptional activity attributed to the A/B domain is due in large part to a powerful transactivation region within this domain called Activation Function-1 (AF-1). Circular dichroism and nuclear magnetic resonance studies of AF-1 have shown that this region is rich in acidic amino acids, and may be composed of as many as three a-helices (Dahlman-Wright et al., 1995; Folkers et al., 1995). Mutational studies of the AF-1 regions from the Glucocorticoid Receptor have suggested that the ability of AF-1 to transactivate a reporter gene in vivo correlates with the ability of this region to form a-helices in vitro (Dahlman-Wright et al., 1995; McEwan et al., 1993). However, it is not clear how AF-1, or the A/B domain in general, interacts with other components of the transcriptional apparatus to initiate transcription (Kumar and Thompson, 1999).

The A/B domain also shows promoter and cell-specific activity, suggesting that this domain is the target of many NR modulatory mechanisms (Aranda and Pascual, 2001). One such mechanism is phosphorylation. Experiments conducted with a number of different NRs have indicated that phosphorylation may be mediated by kinases such as cyclin-dependent kinases and mitogen-activated protein kinase (MAPK), among others (Juge-Aubry et al., 1999; Shao et al., 1998).

B: The DNA-Binding Domain: Domain C

The DNA-binding domain (DBD) is the most highly conserved domain among members of the NR superfamily (Aranda and Pascual, 2001). This domain confers the ability to recognize specific target sequences and, consequently, the ability to interact with specific promoters to transactivate gene expression. The DBD consists of two interdependent subdomains which are both required for high-affinity DNA binding (Kumar and Thompson, 1999).

The first subdomain of the DBD is composed of an a-helix, designated Helix I, and a zinc-finger motif. In the zinc-finger motif, four invariable cysteines coordinate tetrahedrically with a single zinc ion (Kumar and Thompson, 1999). Helix I, which lies at the base of this first zinc-finger, is involved in the site-specific recognition of the DNA to which the entire NR is bound. This recognition is accomplished by a portion of Helix I composed of 3-4 amino acids and termed the "P-box" (Luisi et al., 1991). During NR binding to DNA, Helix I of the DBD fits into the major groove of the DNA helix, and the amino acids of the P-box make critical contacts with very specific bases in the major groove (Luisi et al., 1991).

Ligand Binding Domain
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