The Biology and Biochemistry of Steroid Hormones: Advanced Article
The Biology and Biochemistry of Steroid Hormones: Advanced Article
The Biology and Biochemistry of Steroid Hormones: Advanced Article
Advanced Article
Article Contents
Biochemistry of Steroid Hormones Biologic Background of Steroid Hormones Methods for Study of Steroid Hormone Action Molecular Biology/Chemistry of Steroid Hormone Action Summary
Five categories of steroid hormones exist in humans, including androgens, estrogens, glucocorticoids, mineralocorticoids, and progestins. These hormones affect virtually every tissue and organ in the human body and play major roles in the development, differentiation, and homeostasis of normal individuals. Antisteroids usually possess nonsteroidal structures but still block the actions of the steroid hormones and are important tools in endocrine therapies of pathologic conditions. Therefore, how the body regulates where, when, and how much a response to steroids occurs is of major importance. Here we survey what is known about the genomic responses to steroid hormones, each of which is mediated by a unique intracellular receptor protein that interacts with the cellular DNA to modify the rates of gene transcription. These receptors are members of a much larger superfamily of steroid/nuclear receptors, most of which bind either nonsteroidal ligands or no known ligand. Nongenomic (i.e., pathways without initial involvement of genomic DNA) and secondary responses (i.e., changes that require protein synthesis to alter gene transcription) are additional important effects of steroid hormones but are not discussed here. The emphasis is on the biochemistry of the ve classes of steroid hormones, the techniques used to study steroid hormone action, and the basic mechanistic steps by which steroids alter gene expression.
Steroid hormones can increase and decrease the level and/or activity of a large number of proteins in eukaryotes. Steroid hormones were rst discovered in humans, where they play essential roles in development, differentiation, homeostasis, and endocrine therapies. However, current interest in steroid hormones is increasing because they constitute excellent model systems for examining the control of gene expression. Many human pathologies result from the inappropriate expression of protein(s). Thus, to treat disease states, it is critical to understand the normal processes governing how, when, and how much of the information encoded in the DNA of cells is transcribed to mRNAs and eventually into proteins, which perform most of the functions of cells. Steroid hormones provide excellent model systems with which to address these clinically relevant questions.
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not steroids, such as triiodothyronine (T3), retinoic acid, and vitamin D, which is not a steroid although its precursor is a steroid. The receptors for these later ligands are found almost exclusively in the nucleus of cells, in either the presence or the absence of ligand, and are therefore collectively called nuclear receptors. These receptors are discussed in the article entitled the Chemistry of Nuclear Receptors. This article will cover only the receptors of the ve steroid hormones of Fig. 1b.
C 20
17
C B
8
D
15
16
O Cortisol (Glucocorticoid)
O Progesterone (Progestin)
Figure 1 Steroid structures. (a) Basic ring structure and position numbering of steroids with the four rings (ad). (b) Naturally occurring steroids in humans. (c) Common synthetic agonist steroids. (d) Common synthetic antisteroids.
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HO
H3C Diethylstilbesterol [DES] (Estrogen) CH2OH C HO O OH CH3 N N CH3 Deacylcortivazol [DAC] (Glucocorticoid)
H3C
CH2 C O CH3
and DAC in Fig. 1c) (5). These synthetic ligands are all active at lower concentrations than the natural steroids of Fig. 1b, and thus, they exhibit a greater sensitivity, or potency but have equal efcacy. More precisely, full agonists for a given receptor induce (or repress) gene expression to the same level. However, the concentration of these synthetic agonists required for half of the maximal response (=EC50 ) is lower than that of the natural steroids. The synthetic ligands are more stable to metabolic degradation, and thus, they are longer acting, and generally retain more activity when taken orally. They also possess greater specicity than the natural steroids so that there is less interaction with noncognate receptors (5).
agonist steroid. Thus, a molecule with 15% partial agonist activity will be a more effective antagonist than a different compound with 50% partial agonist activity. Some naturally occurring steroids are antisteroids for other receptors, such as progesterone, which is an antagonist for glucocorticoid and mineralocorticoid receptors. Most antisteroids are synthetic and have very different structures (Fig. 1d). RU486 (RU38,486 or mifepristone) is of interest as it is an efcient antagonist for PRs, GRs, and ARs (6) but not MRs (7) or ERs. Unfortunately, it is currently not possible to predict either what kind of activity a new steroid will have or even to which receptor it will bind. This issue will be discussed in greater detail below.
Antisteroids
Not all compounds that bind to a given receptor give full agonist activity, and some give no activity. These agents also antagonize the actions of the above agonist steroids and are therefore called antagonists or antisteroids. The amount of residual agonist activity of an antisteroid, or the partial agonist activity, is expressed as percent of maximal activity of a full
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(d) Antisteroids H H3C F3C N O NC Bicalutamide [Casodex] (Antiandrogen) CH3 N H3C OH CH3 F HO O S O
OH HO S Raloxifene (Antiestrogen)
Figure 1 (continued )
even in organisms. Thus, studies of steroid hormone action are now amenable to many of the more precise experimental manipulations expected by chemists, many of whom have merged with the biologists. Indeed, a complete understanding of steroid hormone action will be achieved only when all components are identied and characterized in the manner of more conventional chemical reactions.
and is the major source of glucocorticoids and mineralocorticoids. Most androgens are secreted from the testes, whereas most estrogens and progestins derive from the ovaries. In postmenopausal women and in men, a variety of sources, such as adipose tissue, are the major source of estrogens, although in much lower amounts (8). The environment contributes many compounds, called xenobiotics and endocrine disrupters, that can compete with the actions of endogenous steroids with often incompletely documented effects (9, 10), whereas plants are the source of phytoestrogens that are ingested both intentionally and unintentionally (11).
Transport of steroids
Almost all steroids reach the target organs through the circulatory system, which is the denition of an endocrine system. A target organ, or cell, for a steroid is one that contains the cognate receptors. Given the hydrophobic properties and relatively low solubility in water of most steroids, their concentration in the circulatory system is increased by their complexation with serum-binding proteins such as corticosteroid binding globulin (CBG). Although these proteins were initially thought to be passive carriers of steroid, evidence now exists that they play
Source of steroids
All steroids are synthesized in humans from cholesterol. The adrenal gland can synthesize all endogenous steroid hormones 4
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a more active role in steroid hormone action (12). In general, steroids enter cells by passive diffusion, although multi-drug resistance transporters can facilitate the depletion of intracellular steroids (13).
DNA. Steroid receptors have been reported in mitochondria (17) and cell membranes, although it is not yet clear whether all of these receptors are the same as the intracellular steroid receptors (16, 1822 vs. 23). Some of the membrane-bound receptors for steroids are G protein-coupled receptors (2427). A recent report suggests that membrane-bound steroid receptors can interact with, and augment the transcriptional activity of, the intracellular receptors (24). Finally, steroids can bind to nonreceptor molecules such as enzymes and transport proteins (see above), which may have yet undiscovered consequences. The nongenomic and nonreceptor responses to steroids will not be covered here. Instead, we will concentrate on the mechanisms by which the classic steroid hormones alter gene transcription via their intracellular cognate receptor protein. We will discuss only the primary effects of steroid hormones, which are those rapid (1530 min) events that lead to changes in gene transcription without any requirement for protein synthesis. It should be remembered that at a sufciently precise level, the mechanism of action of each class of steroid hormone is different from that of the others.
Molybdate
Cell Membrane o RS
Nuclear Membrane
RS
RS
HR E
RS
E HR
Radioactive steroids Western blot, Transient transfection, Immunofluorescence, Fluorescent receptors, Two hybrid, Pulldown, Co-IP
Specific Proteins
mRNA
Figure 2 General steps in steroid hormone action and their assays. The basic model depicts steroid (S) binding to its receptor molecule (R) to form receptorsteroid complexes (RS), which attach to biologically active DNA binding sites (HRE) to eventually produce changes in the levels of specic proteins. Experimental techniques to follow R at various stages in this pathway are indicated at the rst point that each method can detect a signal. Most methods can also be used to detect receptors at any step downstream of the one for which it is rst used. WILEY ENCYCLOPEDIA OF CHEMICAL BIOLOGY 2008, John Wiley & Sons, Inc.
immunouorescence, gel shift assays, and Western and Northern blots to study steroid receptors. Over the last approximately 10 years, molecular biology has introduced many new techniques that are directed toward detecting receptors at various stages in their mechanism of action (Fig. 2). Two hybrid assays were developed to detect interacting proteins (screening done in yeast) and then to characterize these interactions (usually performed in mammalian cells) (28, 29). Cell-free pulldown assays with one partially puried protein offer more denitive evidence for a direct interaction under cell-free conditions because many potential adapter proteins have been removed. This removal can be accomplished either by attaching an immunogenic or high afnity tag on one protein (30) or, in the case of steroid receptors, using the DNA binding properties of receptors to immobilize the receptor and associated proteins (31). Coimmunoprecipitation (co-IP) assays demonstrate that two or more molecules from intact cells are present in the same complex. Mass spectral identication of copuried proteins (by binding or coIP) offer a more rapid method of identifying a large number of potential associated proteins, but time usually limits the number of subsequently examined proteins to those that seem to be particularly interesting (32). Fluorescent-tagged receptors are excellent for observing the real-time location of receptors, with FLIP and FRAP being methods of determining the rate of protein movement (33). Unfortunately, these methods are not yet sensitive enough to see receptors at a single copy of responsive gene. Chromatin immunoprecipitation (ChIP) assays reveal the presence and kinetics of molecules binding to small regions of responsive genes, like the HREs (34). The advantage of ChIP assays is their ability to interrogate endogenous genes, even if the resolution is low (500 bp). Chromatin conformation capture (CCC) assays detect two separated DNA sequences that are brought together because of the binding of one or more proteins (35). The use of transiently transfected siRNAs in tissue culture cells offers a much simpler method for blocking the expression of selected genes, or at least for reducing the level of translation from the corresponding mRNA, than for preparing gene knockouts in whole animals (36). Microarrays, in which the level of tens of thousands of mRNAs can be determined, offer an unprecedented ability to determine the effects of steroid hormones on essentially the entire genome of a tissue (37). ChIP-on-chip assays use the microarray technology to determine to which regions of the genome receptors (and other proteins) are bound in ChIP assays (37). Systems biology approaches, and the associated model building, provide a powerful method of identifying testable mechanistic hypotheses for which no experimental evidence previously existed (38).
Figure 3 Schematic diagram of functional domains of steroid receptors. The initially labeled domains of AF are also known by the various activities in each segment of the receptor: activation function 1 (AF1) in domains A&B, DNA-binding domain (DBD) in domain C, hinge region (Hinge) in domain D, ligand-binding domain (LBD) and activation function 2 (AF2) in domain E, and a carboxy-terminal domain F.
and is the criterion for superfamily membership because of the high amount of conserved sequence (4). The amino-terminal domain containing the activation function 1 (AF1) displays the greatest variability in length (200 to 600 amino acids) and possesses 15% homology between receptors. A small hinge region separates the DBD from the multifunctional ligand binding domain (LBD) (40), which includes the second activation function (AF2) and is 245 residues long for GRs (41). High amounts of homology exist between the LBDs of several steroid receptors, which accounts for the fact that ligand binding is rarely totally specic (5). Given the large number of biologic activities that are mediated by the LBD (see below and Reference 40), it is not surprising that most mutations are loss of function or neutral. Gain of function mutations that augment receptor properties are rare (42, 43), although many more mutations alter the binding properties of receptors (4446) .
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in a manner that is inuenced by various factors, including the phosphorylation of receptors (54). The biologic consequences of changing the equilibrium position of the shuttling reaction is not yet clear, and all receptors become strongly localized to the nucleus after binding steroid.
Figure 4 X-ray structure of the GR LBD/Dex/TIF2 complex. Two 90-degree views are shown. The bulk of the LBD is shown in yellow with strands in pink. The bound TIF2 peptide is in purple. Regions of the LBD that play major roles in TIF2 binding are shown in red (the AF-2 helix = helix 12) and blue. The bound dexamethasone molecule is in space-lling representation with carbon, oxygen, and hydrogen colored in green, red, and white, respectively. Reprinted from Reference (69) with permission from Elsevier.
all show the same basic feature of an -helical sandwich composed of 12 -helices and 2 -sheets (Fig. 4) (68, 69), although the number of -helices (10-13) and -sheets (2-4) can vary across the entire family of steroid/nuclear receptors. Signicant differences were noted between agonist- and antagonist-bound receptors because of induced-t changes in protein structure, but they are not yet predictable (70) because small changes in ligand-binding position can yield much larger effects on receptor structure (71). The rst X-ray structures of ligand-free and ligand-bound receptors were not of the same receptor. Nevertheless, they suggested an attractive model in which the C-terminal helix (helix 12) was triggered (like a mousetrap) to close over the ligand-binding pocket upon steroid binding (68). The generality of this model is unclear, though, because no repositioning of helix 12 was observed in ligand-free and ligand-bound forms of two nuclear receptors [PPAR (72) and PXR (73)] and because residues C-terminal of helix 12 seem to be important for steroid binding to PRs (74), GRs (65), and ARs (75). An alternative path for ligand binding to and dissociation from thyroid receptors (a nuclear receptor) has been proposed to occur through an opening caused by a proline that creates a kink in helix 3 (76). Again, this may not be general as all steroid receptors are lacking the comparable proline residue (68). Thus, multiple binding mechanisms with attending conformational changes may exist.
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that ligand-free steroid receptors can bind to the HREs of regulated genes, albeit with little observable transcriptional activity (77, 78, 79). This nding should be contrasted with the promoter binding of ligand-free nuclear receptors, which usually decrease gene transcription. In all cases, however, agonist steroid binding initiates events that alter gene transcription. Activation for DNA binding is affected by heat, salt, dilution, ATP, RNAse, and high pH (80), and it is blocked by the salts of molybdate, vanadate, and tungstate (81). It is also accompanied by the loss and/or increased rate of dissociation of many associated non-receptor proteins (57). This step is not microscopically reversible, but unactivated GR and PR can be regenerated in an ATP-dependent, reticulocyte lysate system (reviewed in Reference 55).
Gene repression can also occur by preventing other factors from binding to their regulatory sites in responsive genes (100, 101).
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188 C Zn
C 202 pbox
227 dbox
C Zn
237
C C 185 205
C C 221 240
Figure 5 Receptor DBD binding to HRE. (Top) General structure of DBD of steroid receptors. The two zinc ngers, each containing four cysteines coordinating one Zn++ ion, have different functions. The p-box and downstream 8 amino acids participate in binding to the major grove of the HRE, whereas the d-box mediates DBD dimer formation. The numbers correspond to the specic cysteine residues of ER. (Bottom) X-ray structure of ER DBD/ERE complex. Shown is the view looking down the recognition helices of the DBD dimer that contact the major groove of the ERE DNA. Gray spheres are the zinc atoms. The overlap at the top of the structure is the d-box of each ER DBD monomer.
to facilitate transcription initiation, with subsequent rounds occurring in the absence of the initially bound receptorsteroid complex. Alternatively, the entire cycle of receptor binding and regulated gene transcription could be rapid (108).
and x is any amino acid. Corepressor binding to an overlapping, but not identical, region of the receptor involves a related sequence of LxxI/HIxxxI/L (113). This sequence, and region of corepressors, was initially dened from interactions with nuclear receptors but has been conrmed for the steroid receptors (114, 115). However, not all LxxLL or LxxI/HIxxxI/L sequences in coactivators or corepressors (or other molecules) are sufcient for binding to receptors as adjacent residues also make contributions (116, 117). Given the partial overlap of the binding sites, it is not surprising that the association of coactivators and corepressors to a given receptorsteroid complex displays competitive inhibition in a manner that is controlled, at least in part, by the ratio of coactivators to corepressors (114, 118, 119). These receptor-associated cofactors are then thought to recruit a burgeoning array of additional factors, although probably not at the same time (78, 120, 121; see also the articles on Transcriptional Control and on Activators and Repressors of Transcription). The mechanism of action of most of these factors remains poorly understood. Steroid hormones both increase and decrease the levels of gene expression to give induction and repression, respectively. However, it is not yet clear whether all HRE-bound receptoragonist complexes are transcriptionally active (77). A major unanswered question is how supercially similar steps can cause opposite responses. As described, the HREs for gene induction and repression are different. Repression is often achieved via receptors that are tethered to a different DNA-bound protein (97, 98) but see (99) as opposed to the 9
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receptor binding directly to DNA, as observed in induction. Tethering is not per se contraindicated for gene induction, as observed by the ability of GR sequences fused to the GAL4 DBD to bind via the GAL-DBD to a GAL4 upstream activating sequence and still give gene induction that is augmented by added coactivators (31, 122). Also, the coactivators TIF2 and STAMP still augment the activity of GRagonist complexes in both GR-mediated induction and repression (123). Hence, the ability of the same receptoragonist steroid complex to cause increased or decreased gene expression implicates the importance of other processes such as DNA-induced conformational changes (124, 125) and the ability of nearby DNA-bound factors to inuence the recruitment of and/or interaction with additional cofactors (91, 92, 99). The opposite effect of agonist steroids in induction versus repression also causes some confusion regarding the role of coactivators and corepressors. In the absence of precise mechanistic data, we currently must rely on phenomenological descriptions. The original denition of a coactivator was a factor that increases the activity of an agonist steroid (126). Accordingly, a protein that is labeled a coactivator because it increases steroid-regulated induction would be expected to enhance steroid-mediated repression and afford less gene expression (123). Therefore, the apparently opposing effects of a coactivator during induction and repression simply reect the opposite and currently unknown actions of the agonist steroid. Virtually all studies of gene induction involve averages from populations of cells, which led to the assumption that all cells respond equally to the same concentration of steroid. However, starting with the demonstration that two daughter cells can display drastically different levels of response to a common steroid concentration (127), it has become increasingly clear that transcription is a stochastic event for which probabilistic events play an important role (128). The random nature of gene transcription versus receptor binding to the gene was recently described in a real-time, single-cell study of the binding of green uorescent, protein-labeled GRs to an integrated 200-copy tandem array of a reporter gene under the control of the mouse mammary tumor virus promoter (129).
the EC50 for gene repression is often much lower than for gene induction (reviewed in References 119 and 135). The circulating concentrations of steroids (e.g., cortisol 0.4 M, estradiol 0.1 nM, or progesterone 5 nM) are in the region of half-maximal induction of many regulated genes. Consequently, genes with different EC50 s will display different extents of response to the single circulating concentration of each steroid that is present at any one time. In many instances, the levels of steroid change, such as for glucocorticoids during the normal 24-hr cycle and during stress or for estrogens and progestins during the female menstrual cycle and pregnancy. Under these conditions, the transcriptional levels of those genes with EC50 s near the average of the initial and nal steroid concentration will be altered more than the levels of other genes. Antisteroids are widely used in endocrine therapies to block the action of endogenous steroids, such as androgen-dependent prostate cancer and estrogen-dependent breast cancer. A very important parameter under these conditions is the amount of residual agonist activity, or partial agonist activity, of the antisteroid. The expectation from the general model of steroid action that the amount of partial agonist activity of an antisteroid will be the same with all responsive genes has not been experimentally veried. Instead, as above with the EC50 , it was found that the amount of partial agonist activity usually varies with the gene (136, 137). Indeed, for reasons that are not understood, there seems to be an inverse correlation between these two parameters. Thus, for receptor-mediated induction of a given gene, the partial agonist activity of an antisteroid invariably increases when the EC50 of an agonist decreases and vice versa (reviewed in References 119 and 135 and 136). It was then realized that these gene-specic differences in partial agonist activity were desirable and offered a theoretical means of blocking only those genes responsible for the undesired pathology while retaining nearly normal levels of other regulated genes. A prime example is the ability of the antiestrogen raloxifene to block estrogen actions in breast cancer but not in bone (138). In recognition of the importance of having the amount of partial agonist activity of a steroid vary in a gene- and cell-specic manner, the term selective receptor modulator (SRM) is increasingly used instead of antagonist (139, 140). Thus, antiestrogens are often referred to as SERMs (selective estrogen receptor modulators) and so forth. Elucidating the mechanisms driving these changes in EC50 for gene induction, and in partial agonist activity of antisteroids or SRMs, may greatly expand the available therapeutic targets for treatment of a variety of human pathologies. Initial progress has been made with the ndings that these changes can be reproduced by varying the concentration of steroid receptor, coactivator, corepressor, and other transcriptional cofactors such as CBP, pCAF, Ubc9, (reviewed in References 119 and 135) and a new protein STAMP (123). The physiologic relevance of these uctuations is strengthened by the report that the levels of GR mRNA display circadian rhythms in several mouse tissues (141). The EC50 for glucocorticoid killing of thymocytes was lowered 10-fold in transgenic mice containing a 2-fold increase in GR gene dosage (142). Also, increasing the concentration of ER 10-fold in human breast cancer cells increases the percentage of those genes that are induced by ER from 32%
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to 61%, and those that are repressed by ER from 11% to 46%, (52) presumably by lowering the EC50 of the additional genes into the range of estradiol used in the assay. Similarly, in isogenic prostate cancer xenograft models, increased AR protein was the only correlate with androgen insensitivity in prostate tumors and caused both a left-shift in the dose-response curve for gene induction by agonists and increased partial agonist activity for antiandrogens (136). Coactivators and corepressors display competitive equilibrium binding to GRs and probably the other steroid receptors. Therefore, changing the ratio of coactivators to corepressors, and/or the concentrations of other factors, provides a means of adjusting, like with a rheostat, the EC50 , and partial agonist activity, to a continuum of values (114). A recent systems biology approach with model building suggests that many factors and pathways can alter the EC50 , and partial agonist activity, of steroid regulated gene expression under the appropriate conditions (38).
the extent to which those mechanisms observed in isolated cell systems are employed in intact organisms for endogenous genes. System biologists are constructing mathematical models incorporating the burgeoning number of relevant factors in an effort to predict the effects of changing one or more components of the system. Eventually, clinicians will employ this wealth of information to correct selectively numerous pathologic conditions of the endocrine system. It is now clear that the specics of steroid hormone action vary with the gene being regulated. The challenge ahead will be to gather sufcient gene-specic information to limit the effects of steroids to selected target genes and tissues, thereby increasing the desired therapeutic outcomes while reducing the number of unwanted responses.
Acknowledgments
This research was supported by the Intramural Research Program of the NIH and NIDDK. The critical review of this article by John Funder (Prince Henrys Institute of Medical Research, Australia), William Pratt (University of Michican Medical School), Brad Thompson (University of Texas Medical Branch, Galveston), Douglas Forrest (NIH), members of the Steroid Hormones Section, NIDDK/NIH, and the referees is greatly appreciated. We regret that space constraints prevented mentioning many other excellent and informative studies.
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Summary
Much has been learned in the last 40+ years since steroid hormones were found to act via soluble intracellular proteins. This progress has been made under the guise of different labels, each of which is appropriately a discipline of chemical biology. First, better, longer lasting, and more specic steroids were prepared by chemists. Next, biochemists and biologists uncovered the basic steps by which steroid hormones affect the functioning of many cells and tissues of organisms. Biochemists and molecular endocrinologists discovered that the steroid receptors were a small subgroup of a much larger superfamily of related proteins that share many of the same features when inducing or repressing gene transcription. Molecular biologists have uncovered numerous additional factors that participate in steroid receptor regulation of gene transcription. Molecular physiologists are currently using powerful new techniques to determine
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Further Reading
Beato M. Gene regulation by steroid hormones. Cell 1989;56:335344. Freedman LP. Anatomy of the steroid receptor zinc nger region. Endo. Rev. 1992;13:129145. Glass CK, Rose DW, Rosenfeld MG. Nuclear receptor coactivators. Curr. Opin. Cell Biol. 1997;9:222232. Leonhardt SA, Edwards DP. Mechanism of action of progesterone antagonists. Exp. Biol. Med. 2002;227:969980.
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Moriarty K, Kim KH, Bender JR. Estrogen receptor-mediated rapid signaling. Endocrinology 2006;147:55575563. Nuclear Receptor Signaling Atlas. A web sited aimed at developing a comprehensive understanding of the structure, function, and role in disease of nuclear receptors. Available at: http://www.nursa.org/ index.cfm . Robyr D, Wolffe AP, Wahli W. Nuclear hormone receptor coregulators in action: diversity for shared tasks. Mol. Endocrinol. 2000;14:329 347. Tasker JG, Di S, Malcher-Lopes R. Rapid glucocorticoid signaling via membrane-associated receptors. Endocrinology 2006;147:55495556. Xu J, Li Q. Review of the in vivo functions of the p160 steroid receptor coactivator family. Mol. Endocrinol. 2003;17:16811692.
See Also
Steroids, Synthesis of Nuclear Receptors, Chemistry of Chromatin Remodeling Transcriptional Control Transcription, Activators and Repressors of
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WILEY ENCYCLOPEDIA OF CHEMICAL BIOLOGY 2008, John Wiley & Sons, Inc.