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J. Biol. Chem., Vol. 276, Issue 40, 36863-36864, October 5, 2001
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From the Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, California 92093 and the Department of Veterans Affairs, San Diego, California 92161
The nuclear receptor superfamily describes a
related but diverse array of transcription factors, which include
nuclear hormone receptors
(NHRs)1 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 homo- or
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 ligand-dependent 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).
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Fig. 1.
Structure/function organization of nuclear
receptors. The six domains (A-F) of nuclear receptors
comprise regions of conserved function and sequence. All of the nuclear
receptors contain a central DBD (region C), which is the
most highly conserved domain and includes two zinc finger modules. A
LBD (region E) is contained in the C-terminal half of the
receptor. Situated between the DBD and LBD is a variable length hinge
domain (region D), and variable N-terminal region
(A/B) contains ampF-I activation function. Most
receptors also contain a variable length C-terminal region
F, the function of which is poorly understood. Many members of the
nuclear receptor family form homo- or heterodimers, and amino acid
sequences important for dimerization are contained within the DBD and
LBD.
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 tissue- and 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 anti-estrogen, Tamoxifen) exert unique estrogenic
effects in a tissue-specific 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 generated enormous
interest in this class of NHRs leading to various molecular,
physiologic, and clinical insights. Evan D. Rosen and Bruce M. Spiegelman provide a review on this topic entitled "PPAR
: a
Nuclear Regulator of Metabolism, Differentiation, and Cell Growth." As suggested by the title, although some discussion of the other PPAR
members, PPAR and PPAR
, is provided, the bulk of this
paper focuses on the PPAR receptor. Although potential endogenous
ligands for this receptor have been proposed, definitive evidence for an endogenously made ligand is still lacking. Nevertheless,
thiazoladinediones (TZDs), as well as other PPAR ligands, are used
clinically as insulin-sensitizing agents, and these pharmacologic
ligands have provided a great deal of knowledge about the biologic
function of the PPAR receptor. This receptor clearly plays a
critical role in adipogenesis, and the complex interactions between
PPAR and other adipogenic transcription factors such as
CCAAT/enhancer-binding protein are explored. Because TZDs
are clinically useful anti-diabetic insulin-sensitizing agents, it is
clear that PPAR is an important factor in the overall regulation of
insulin action, and this area, including the tissue sites of action and
the potential PPAR target genes that mediate insulin sensitization,
are reviewed. Although the effects of PPAR ligands in causing
insulin sensitization are the most well known, two other important
areas of interest are reviewed, i.e. the roles of the
PPAR receptor in atherosclerosis and oncogenesis. Evidence exists
that PPAR receptors can modulate the formation of foam cells in
atherosclerotic plaques and that TZD treatment may be antiatherogenic.
Furthermore, because this receptor promotes differentiation, it is
proposed that it may inhibit oncogenic effects in various cell types.
Consistent with this, mutations and translocations of the PPAR
receptor have been identified in human tumors, and this emerging area
of PPAR biology is examined and put into perspective in the review
by Rosen and Spiegelman.
Cholesterol and sterol homeostasis is another important regulatory system closely controlled by nuclear receptor function, and in this series, Timothy L. Lu, Joyce J. Repa, and David J. Mangelsdorf provide a review on this subject entitled "Orphan Nuclear Receptors as eLiXiRs and FiXeRs of Sterol Metabolism" in which the two major nuclear receptors, LXR and FXR, involved in this regulatory system are reviewed. The role of the LXR nuclear receptor as a cholesterol sensor is discussed, including recent information covering target genes such as SREBP-I and the ATP binding cassette transporters, which facilitate efflux of cholesterol from cells. In the enterocyte, increased function of these ATP binding cassette transporters decreases cholesterol absorption from the gastrointestinal tract, and in macrophages, impaired function of these proteins may promote atherogenesis. The FXR bile acid sensor also plays a key role in overall sterol metabolism by regulating transcription of an array of genes involved in bile acid metabolism. The function of these two nuclear receptors is highly integrated, creating a complex but complementary physiologic network for controlling various facets of cholesterol and sterol metabolism across different tissues. Because of the importance of cholesterol metabolism in the etiology of atherosclerosis, this regulatory system offers a number of potential pharmaceutical targets for the development of new drugs to control hypercholesterolemia and favorably impact the process of atherosclerosis.
The final installment of this series covers another class of transcriptional regulators termed "orphan receptors" belonging to this large superfamily. The orphan nuclear receptors are proteins that share a great deal of structural similarity to NHRs but do not have physiologic ligands that have been identified. At such time that a definitive ligand is identified, then that receptor would lose its orphan status. It is now known that several of these orphan receptors respond to xenobiotics in the environment that includes foreign chemicals such as environmental pollutants and prescription drugs. In response to xenobiotic compounds, these receptors mediate transcription of a variety of detoxifying enzymes that are members of the supergene family of cytochrome P450 (CYP) molecules. As Wen Xie and Ronald M. Evans point out in their review on this topic entitled "Orphan Nuclear Receptors: the Exotics of Xenobiotics," this class of nuclear receptors represents the regulatory interface between the human genome and the external environment. This review discusses the major xenobiotic receptors, SXR, PXR, and CAR and points out that by inducing various CYP family members in response to specific xenobiotics, these receptors dictate our ability to metabolize different pharmaceutical compounds. An understanding of the function of these receptors should provide a mechanistic basis for drug interactions in which one drug alters the metabolism of another. Interestingly, the human SXR receptor and its rodent PXR orthologue display differential sensitivity to various xenobiotic agents, providing the basis for species specificity of xenobiotic responses. These workers go on to discuss a humanized mouse model expressing SXR, which should prove quite useful in preclinical studies of metabolism and toxicology for candidate pharmaceutical agents.
As is clear from the scope of these reviews, nuclear receptors participate in the regulation of almost all biologic processes. Thus, understanding the function of these receptors should be useful to a broad array of basic and clinical scientists.
Because of their diverse biological effects, nuclear receptors have
become major pharmaceutical targets in a host of disease states.
Current pharmaceutical agents include natural hormonal ligands or their
analogs such as glucocorticoids, thyroid hormone, and estrogens, as
well as ligands for the PPAR and - receptors. Undoubtedly, many
more therapeutically useful pharmaceutical agents are on the horizon
and will be entering the clinic in the near future.
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FOOTNOTES |
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* This minireview 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.
Published, JBC Papers in Press, July 17, 2001, DOI 10.1074/jbc.R100047200
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ABBREVIATIONS |
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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.
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| 1. | Bourguet, W., Germain, P., and Gronemeyer, H. (2000) Trends Pharmacol. Sci. 21, 381-388 |
| 2. | Mangelsdorf, D. J., Thummel, C., Beato, M., Herrlich, P., Schültz, G., Umesono, K., Blumberg, B., Kastner, P., Mark, M., Chambon, P., and Evans, R. M. (1995) Cell 83, 835-839 |
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