Nuclear Receptor Minireview Series*

The nuclear receptor superfamily describes a related but diverse array of transcription factors, which include nuclear hormone receptors (NHRs) and orphan nuclear receptors. NHRs are receptors for which hormonal ligands have been identified, whereas orphan receptors are so named because their ligands are unknown, at least at the time the receptor is identified. Unlike hormones for cell surface receptors, lipophilic hormones can traverse the plasma membrane to the cell interiors where NHRs transduce signals from glucocorticoids, mineralocorticoids, the sex steroids (estrogen, progesterone, and androgen), thyroid hormones, and vitamin D3. All of the nuclear receptors have common structural features (Fig. 1), which include a central DNA binding domain (DBD) responsible for targeting the receptor to highly specific DNA sequences comprising a response element (1). The ligand binding domain (LBD) is contained in the C-terminal half of the receptor and recognizes specific hormonal and nonhormonal ligands directing specificity to the biologic response. These receptors contain variable N-terminal and C-terminal domains, as well as a variable length hinge region between the DBD and LBD. Nuclear receptors can exist as homoor heterodimers with each partner binding to specific RE sequences that exist as half-sites separated by variable length nucleotide spacers between direct or inverted half-site repeats. Several years ago Manglesdorf et al. (2) proposed four categories of nuclear receptors in which Class 1 receptors include the known steroid hormone receptors, which function as homodimers binding to half-site RE inverted repeats. Class 2 receptors exist as heterodimers with RXR receptor partners and function in a liganddependent manner. The second two classes include orphan receptors, which function as homodimers binding to direct RE repeats (Class 3) or monomers binding to single site REs (Class 4). Given the widespread relevance of the superfamily of nuclear receptors to almost all aspects of normal human physiology, the role of these receptors in the etiology of many human diseases, and their importance as therapeutic targets for pharmaceuticals, it is obvious that a detailed understanding of these systems has major implications, not only for human biology but also for the understanding and development of new drug treatments. In composing this minireview series, it is quite clear that it is not feasible to comprehensively review any of the separate areas in great detail, and all of the minireviews in this series contain references to more extensive review papers on particular topics. As in all minireviews, the purpose of this series is to highlight major themes and new developments in these areas and to point out common molecular and biochemical principles that broaden our understanding of these complex biological processes. The first article in the series is entitled “Coregulator Codes of Transcriptional Regulation by Nuclear Receptors” authored by Michael G. Rosenfeld and Christopher K. Glass. This review covers the complex and ever-growing network of interactions between coregulatory proteins and nuclear receptors. These regulatory proteins form multicomponent assemblies with the nuclear receptors, and these complexes can serve as coactivators or corepressors. The specific proteins in these complexes can bind to nuclear receptors via specific amino acid sequence motifs in a ligand-dependent or independent manner and can provide enzymatic or scaffolding functions. These coregulators influence chromatin remodeling by histone acetylation/deacetylation, methylation, and possibly other events. In general, ligand binding to nuclear receptors causes an exchange of coactivators for corepressors to facilitate transcription. This review also points out that the coregulatory proteins themselves are subject to biochemical and functional regulation by various signaling pathways. Far more coregulatory molecules have been identified than can bind to a given nuclear receptor, and given recent findings of rapid turnover of these complexes on DNA, it is possible that they work in a combinatorial or sequential manner to exert transcriptional control. Given the tissue specificity of some coregulators, their ability to be modified by various other signaling molecules, and possible combinatorial functions, one can envision that a given nuclear receptor could exert diverse effects depending on the environmental context of a given tissue, cell, or specific promoter. The estrogen receptor (ER) is perhaps the most well defined nuclear receptor system from the point of view of biologic responses and clinical implications. “Multifaceted Mechanisms of Estradiol and Estrogen Receptor Signaling” by Julie M. Hall, John F. Crouse, and Kenneth S. Korach reviews the major features of this important nuclear receptor system. There are two subtypes of the ER (ER and ), which are products of distinct genes but show differences in tissue expression. Although quite similar in structure, the two ER subtypes display structural differences and can mediate overlapping but different sets of biologic functions. This is best exemplified in the ER versus ER knockout mice, which have quite different phenotypes. However, it is also clear that ER can substitute for ER in some biologic pathways. Furthermore, ER can interact with the same ERE as ER , and the two ER subtypes can also form heterodimers, indicating that in cells that express both ER subtypes, the ratio of the two will effect estrogen action. The review provides a discussion of the classical mechanisms of estrogen action mediated through the ER and EREs, as well as nonclassical mechanisms in which ERs can be modulated by ligand independent means. Genomic actions of ERs can also be exerted in the absence of direct DNA binding by mechanisms in which liganded ERs interact directly with other transcription factors such as Fos and Jun, influencing their function at AP-1 sites. To add to the complexity of ER action, it has now been proposed that estrogens can exert nongenomic effects by binding to plasma membrane receptors that directly mediate biologic responses. Finally, this review provides an incisive discussion of the selective estrogen receptor modifier concept, which holds that different ligands form specific three-dimensional structures with receptors that lead to tissueand perhaps cell-specific biologic effects. This concept has already had ramifications on the clinical front, where it has been shown that different selective estrogen receptor modifier compounds (the Type 2 anti-estrogen Raloxifene and the Type 3 antiestrogen, Tamoxifen) exert unique estrogenic effects in a tissuespecific manner. This is an important area of pharmaceutical discovery in which there is hope of developing agents that exert only the beneficial and not the potentially harmful effects of estrogens. Peroxisome proliferator-activated receptors (PPARs) exert diverse effects on fat and carbohydrate metabolism and are major targets for therapeutic agents in metabolic diseases. This has gen* These minireviews will be reprinted in the 2001 Minireview Compendium, which will be available in December, 2001. ‡ To whom correspondence should be addressed. Tel. : 858-534-6651; Fax: 858-534-6653; E-mail: jolefsky@ucsd.edu. 1 The abbreviations used are: NHR, nuclear hormone receptor; DBD, DNA binding domain; LBD, ligand binding domain; ER, estrogen receptor; ERE, estrogen response element; PPAR, peroxisome proliferator-activated receptor; TZD, thiazoladinedione. Minireview Prologue THE JOURNAL OF BIOLOGICAL CHEMISTRY Vol. 276, No. 40, Issue of October 5, pp. 36863–36864, 2001 Printed in U.S.A.