This chapter should be cited as follows: This chapter was last updated:
Klinge, C, Rao, C, Glob. libr. women's med.,
(ISSN: 1756-2228) 2008; DOI 10.3843/GLOWM.10281
December 2008

Endocrine biochemistry

The Steroid Hormone Receptors

Carolyn M. Klinge, PhD
Professor, Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky, USA
C. V. Rao, PhD
Professor of Cell Biology, Molecular and Human Genetics, Obstetrics and Gynecology; Director of Reproduction and Development Program, Florida International University College of Medicine, University Park, Miami, Florida, USA

INTRODUCTION

Steroid hormones exert a wide variety of effects on growth, development, and differentiation, including important regulatory and behavioral functions within the reproductive, central nervous system, and adrenal axis. These hormones act through binding to specific intracellular receptor proteins that function as both signal transducers and transcription factors to modulate expression of target genes.1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 Molecular cloning has revealed 48 steroid hormone and nuclear receptor genes in humans (Table 1). Sequence comparison has revealed that steroid hormone receptors belong to a diverse family of ligand-activated gene regulators that share a highly conserved structure and common mechanisms affecting gene transcription.1 The evolutionary relationship among the steroid/nuclear receptors has been deduced by the high conservation in their DNA binding domains and in their less-conserved ligand binding domains and indicates that this large group of proteins arose from a common ancestral molecule.1, 2, 3

The steroid/nuclear hormone receptor superfamily (Table 1) includes 48 receptors for the gonadal and adrenal steroids, nonsteroidal ligands such as thyroid hormones, vitamin D, retinoic acid, and fatty acids, as well as numerous "orphan" receptors whose endogenous ligands, if necessary, are either as yet unknown or being identified.4, 5 Until late 1996, only one ER was thought to mediate the physiological effects of estrogens. However, a second gene encoding a closely related, but distinct, ER, called ERβ, was first identified in rat prostate6 and later in humans.7 The original ER was renamed ERα. ERα and ERβ can form heterodimers as well as homodimers in vitro and in vivo.8 The superfamily also includes the v-erb-A and c-erb-A oncogene proteins that bind to DNA but lack a functional ligand-binding domain,9, 10, 11 and other orphan receptors, e.g., short heterodimer partner (SHP), that lack a DNA binding domain,12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 but have a ligand-binding domain. The steroid receptors are considered class I members of the nuclear receptor superfamily while the other receptors are class II receptors.12 A variety of mechanisms for achieving tissue-specific gene expression in response to steroid hormones has evolved to ensure diversity through the interaction of these receptors with other cellular proteins and gene elements.

In this review, we summarize current information on the steroid/nuclear hormone receptors, with the primary focus on receptors for the sex steroid hormones.

Table 1.  Members of the steroid hormone receptor gene superfamily in mammalian tissues

Receptors with known ligand(s):

ERα32
ERβ7, 8
hAR33
PR34
GR35, 36
MR37
VDR38                           
TRs39
   hTRβ 
   hTRα1
   hTRα2
c-erb A140
Rev-ErbA alpha (Rev-Erb)11
c-erbA beta41
c-erbA beta-242
RARs43
   alpha
   beta
   gamma
RXRs43, 44
   alpha
   beta/ear-2/H-2RIIBP
   gamma
PPARs45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80
   alpha
   beta/delta (NUCI)
   gamma
Orphan receptors
   CAR81, 82, 83, 84, 85
   COUP-TFI/EAR386
   COUP-TFII/ARP-187
   DAX-188, 89, 90, 91, 92, 93, 94
   EAR295
   hERR196, 97, 98, 99, 100
   hERR2101, 102, 103
   GCNF104, 105, 106
   HNF-3107
   HNF-4108, 109
   hSF-1110
   nur77/NGF1-B111
   RTR104, 112
   RZR/ROR104, 113
   RORB/RZRb114
   SHP115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132
   TR4/TAK1133
Orphan receptors with identified ligands
   FXR (farnesoid X receptor, bile)132, 134, 135
   LXR (liver X receptor)61, 136, 137, 138, 139, 140, 141
   PAR/PXR/SXR (human pregnane receptor)142, 143, 144, 145, 146, 147, 148 

 

 

 

STRUCTURE OF THE STEROID HORMONE RECEPTOR PROTEIN

In order to understand how steroid hormone receptors regulate gene function, it is important to know the structure of the receptor proteins as well as the identity and cellular function of the genes that they regulate. Members of the steroid receptor superfamily share direct amino acid homology and a common structure (Fig. 1). Receptors in this superfamily contain several key structural elements which enable them to bind to their respective ligands with high affinity and specificity, recognize and bind to discrete response elements within the DNA sequence of target genes with high affinity and specificity, and regulate gene transcription.13, 14

 

 Fig. 1 Relative lengths of several members of the steroid/nuclear hormone receptor superfamily, shown schematically as linearized proteins with common structural and functional domains. Variability between members of the steroid hormone receptor family is due primarily to differences in the length and amino acid sequence of the amino (N)-terminal domain. Adapted from Wahli W, Martinez E. Superfamily of steroid nuclear receptors: Positive and negative regulators of gene expression. FASEB J 1991;5:2243-2249.

 

 

Molecular cloning of the complementary DNA (cDNA) for each of the major steroid receptors has greatly enhanced our understanding of the structure–function relationships for these molecules. The receptor proteins have five or six domains called A–F from N- to C-terminus, encoded by 8–9 exons.  The receptors contain three major functional domains that have been shown experimentally to operate as independent "cassettes",13 unrestricted as to position within the molecule. The three major functional domains (Fig. 2) of the receptor are:

  1. A variable N-terminus (domains A and B) that confers immunogenicity and modulates transcription in a gene and cell-specific manner through its N-terminal Activation Function-1 (AF-1);
  2. A central DNA-binding domain (DBD, consisting of the C domain), comprised of two functionally distinct zinc fingers through which the receptor physically interacts directly with the DNA helix;
  3. The ligand-binding domain (LBD, domains E and in some receptors F) that contains Activation Function-2 (AF-2).

 

 Fig. 2 Schematic representation of the common structural and functional domains of the steroid hormone receptors. The horizontal lines indicate the domains of the receptor. Adapted from Wahli W, Martinez E. Superfamily of steroid nuclear receptors: Positive and negative regulators of gene expression. FASEB J 1991;5:2243-2249.

 

 

The F domain is thought to play a role in distinguishing estrogen agonists from antagonists, perhaps through interaction with cell-specific factors.15, 16 Domain-swapping experiments in which the DBD of estrogen receptor α (ERα) was switched with that of the glucocorticoid receptor (GR), yielded a chimeric receptor that bound to specific DNA sequences bound by GR, but up-regulated transcription of glucocorticoid-responsive target genes when treated with estrogen,17 thus demonstrating the specificity of the DNA-binding domain in target gene regulation.

The amino (N)-terminal domain is hypervariable (less than 15% homology among steroid receptors) in both size and amino acid sequence, ranging in length from 25 amino acids to 603 amino acids and constituting the major source of size differences between receptors.18, 19 The AF-1 domain in this region is involved in activation of gene transcription, but does not depend on ligand binding. In rat GR, the AF-1 region is called tau 1 or enh2 and constitutes aa 108–317. Tau 1 is necessary for transcriptional activation and repression.20 Deletion of the C-terminal LBD of GR yields constitutive (hormone-independent) transcriptional activation, implying that the N-terminal regions harbor autonomous transcriptional activation functions.21

Some steroid receptors exist as isoforms, encoded by the same gene, but differing in their N-terminus. The progesterone and androgen receptors (PR and AR) exist in two distinct forms, A and B, synthesized from the same mRNA by alternate splicing. The two PR receptor isoforms differ by 128 amino acids in the N-terminal region, yielding PR-A = 90 kDa and PR-B = 120 kDa, that have strikingly differing capacities to regulate transcription.22, 23, 24 In contrast, AR-A and AR-B isoforms show minimal differences in activation of a reporter gene in response to androgen agonists or antagonists in transiently transfected cells.25

The central core or DNA-binding domain (DBD) is highly conserved and shows 60–95% homology among steroid receptors.1 The DBD varies in size from 66 to 70 amino acids, and is hydrophilic due to its high content of basic amino acids.13 The major function of this region is to bind to specific hormone response elements (HREs) of the target gene. DNA-binding is achieved through the tetrahedral coordination of zinc (Zn) by four cysteine residues in each of two extensions, that form two structurally distinct "Zn fingers" (Fig. 3).26 Zn fingers are common among gene regulatory proteins.23 Specificity of HRE binding is determined by the more highly conserved hydrophilic first Zn finger (C1),17 while the second Zn finger (C2) is involved in dimerization and stabilizing DNA binding by ionic interactions with the phosphate backbone of the DNA.18 The D box is involved in HRE half-site spacing recognition. The highly conserved DBD shared by AR, GR, mineralocorticoid receptor (MR), and PR enables them to bind to the same HRE, called the glucocorticoid response element (GRE). The more C-terminal part of the C2 Zn finger and amino acids in the hinge region are involved in receptor dimerization in coordination with amino acids in the hinge region and the LBD. 

 

 

Fig. 3 Schematic diagram of type II zinc finger proteins characteristic of the DNA-binding domain structure of members of the steroid hormone receptor superfamily. Zinc fingers are common features of many transcription factors, allowing proteins to bind to DNA. Each circle represents one amino acid. The CI zinc finger interacts specifically with five base pairs of DNA and determines the DNA sequence recognized by the particular steroid receptor. The three shaded amino acids indicated by the arrows in the knuckle of the CI zinc finger are in the “P box” that allows HRE sequence discrimination between the GR and ERα. The vertically striped aa within the knuckle of the CII zinc finger constitutes the “D box” that is important for dimerization and contacts with the DNA phosphate backbone. Adapted from Tsai M-J, O’Malley BW. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem 1994;63:451-483; Gronemeyer H. Transcription activation by estrogen and progesterone receptors. Annu Rev Genet 1991;25:89-123.

 

The hinge region or D domain is a 40–50 amino acid sequence separating the DNA-binding and ligand-binding domains that contains sequences for receptor dimerization and ligand-dependent and independent nuclear localization sequences (NLSs).27, 28 The hinge region interacts with nuclear corepressor proteins,28 and with L7/SPA, a 27 kDa protein that increases the partial agonist activity of certain antagonist-liganded steroid hormone receptors, i.e., tamoxifen-liganded ERα, RU486-occupied PR, or RU486-occupied GR.29

The carboxy (C)-terminal or ligand-binding domain (LBD) is poorly conserved, ranging in size from 218 to 264 amino acids and is hydrophobic. This region contains the ligand-binding site and dictates hormone binding specificity.30, 31 Greater structural similarity between steroid hormone ligands generally indicates greater amino acid sequence homology in the LBD. Information from the X-ray crystal structures of the LBDs of the retinoic acid receptor (RAR), thyroid hormone receptor (TR), and ERα in the presence or absence of their cognate ligands has shown that the LBD has a compact structure consisting of 12 α-helices with a “pocket” into which the ligand fits.32, 33, 34, 35 Binding of the ligand within the pocket alters the conformation of the LBD with helix 12 forming a “lid” over the pocket, trapping the ligand in a hydrophobic environment and forming a surface on the LDB with which co-activator proteins interact. Helix 12 is indispensable for AF-2 function.36, 37 For ERα, 17β-estradiol (E2) and the antiestrogen, or select ER modulator (SERM), raloxifene form different amino acid contacts within the pocket.38 This results in different positioning of helix 12 in the LBD that is thought to permit interaction with co-activators, e.g., SRC-1, in the presence of E2, but not raloxifene, or by inference antiestrogens, such as tamoxifen.38 

Two human GR isoforms, GRα and GRβ, derived from the same gene by differential splicing at the C-terminus, have been reported.39 While GRα and GRβ share the first eight exons, they differ in their last two exons, i.e., exons 9α or 9β, spliced into the respective mRNA.40 GRβ was reported to localize in the cell nucleus in the absence of ligand and to block hGRα activity.41, 42

Likewise, a novel isoform of ERβ, termed ERβ2, containing an in-frame insertion of an exon of 54 nucleotides, resulting in an insertion of 18 amino acids in the LBD, was recently identified first by screening rat prostate cDNA library, and is also expressed in human cell lines.43 ERβ2 binds E2 with lower affinity (Kd = 8 nM) than ERβ1 (Kd = 1 nM). At least 10 splice variants of ERβ have been identified.44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55

Sequences within the LBD form the binding site for hsp90 that blocks the DBD in the cytosolic, nonliganded GR.40 The CII and CIII regions (Fig. 2) show homology among members of the steroid/nuclear receptor superfamily and are important in forming the ligand binding pocket.56 

The C-terminal AF-2 transactivation domain is highly conserved within the nuclear receptor superfamily36 and is recognized by various transcriptional coregulators, formerly referred to as coactivators or corepressors.57, 58, 59 AF-2 is localized to the most C-terminal end of the E domain. In ERα it constitutes aa 530–553.60 A third transactivation domain called AF-2a or tau2 has been localized to the N-terminal region of the LDB of ERα36 and GR.61 Deletion experiments revealed a role for AF-2a and the DBD in targeting rat GR to the nuclear matrix,62 an interconnected ribonuclear-protein network within the nucleus that is thought to play an important role in transcription of active genes by stabilizing the assembly of the transcriptional machinery.63, 64, 65, 66, 67, 68, 69

Although individual domains of steroid/nuclear receptors can be exchanged70 and function when spliced with nonrelated transcription factors,71 forming chimeric proteins, experiments on ERα72 and GR73 show that these receptors function optimally when intact. Additionally, the N- and C- terminals of the receptor interact with each other to increase transcriptional activation.74

STRUCTURE OF STEROID HORMONE-REGULATED GENES

The transcription of DNA to messenger RNA (mRNA) is the most important process regulated by steroid hormones. All genes share a common basic design (Fig. 4), composed of a structural region in which the DNA encodes the specific amino acids of the protein, and a regulatory region that interacts with various proteins to control the rate of transcription. Several key elements in the regulatory region of the target gene must be activated before mRNA synthesis can occur. These elements, called ‘cis’-acting elements since they are located on the same DNA as the gene itself, are generally located near the 5' end (beginning) of the gene, and consist of four main groups: promoters, hormone-responsive enhancers, silencers, and hormone-independent enhancers.149 The promoter, essential for gene activation, sets the basal rate of transcription and controls the accuracy of transcription initiation.150 The promoter is located closest to the transcription start site and consists of two sub-elements: the TATA box and the upstream promoter. Located further upstream are one or more hormone response elements (HREs), the specific DNA-binding sites to which steroid receptors bind, conferring hormone sensitivity to the gene.151 Silencers are elements that inhibit transcription of adjacent genes in the absence of hormone activation.152 Hormone-independent enhancers are DNA sequences bound by other transcription factors that can further increase the rate of gene expression.28 The synergistic interaction between regulatory cis-acting elements permits fine-tuning of the rates of transcription of target genes in response to the local cellular and hormonal milieu.

 

Fig. 4 Schematic diagram of regulatory and structural regions of a steroid hormone responsive gene. Located upstream from the transcription start site are several regulatory cis-elements that interact with various factors, including steroid hormone receptors that bind to HREs, C/EBP that binds to CCAAT boxes,153 and Sp1 that binds to GC boxes.154 TFIID and the other general transcription factors bind to the TATA box, to control transcription of the target gene.149 The structural region of the gene contains nucleotides encoding the mRNA transcript that will be translated into the protein. Adapted from Tsai M-J, O’Malley BW. Molecular mechanisms of action of steroid/thyroid receptor superfamily members. Annu Rev Biochem 1994;63:451-483.151

 

Hormone response elements (HREs) are consensus 13–15-bp DNA sequences derived from alignment of genes responsive to a particular steroid hormone. HREs have two "half-sites" that each bind the C1 zinc finger of one receptor monomer. Steroid hormone receptors bind DNA as homodimers (or heterodimers, e.g., ERα/ERβ155, 156 with each monomer binding to adjacent major grooves on the same side of the DNA helix.26 Class II nuclear receptors may interact with a different class II nuclear receptor forming a heterodimer, thereby creating a more stable complex with much higher affinity that is thought to enhance transcriptional activity significantly.12 On the basis of sequence homology and functional similarity, there are three classes of hormone response elements within the steroid hormone receptor superfamily (Table 2).

Table 2. Hormone response element (HRE) binding sites for steroid/nuclear receptors. Response elements for the class II nuclear receptors are direct repeats (DR), inverted repeats (IR), or everted repeats (EvR) of the indicated half-site with the letter following the DR or IR indicating the number of nucleotides separating the half-sites, e.g., DR5 is 5’-AGGTCAnnnnnAGGTCA-3’.

 

Steroid/nuclear receptor

Consensus HRE

AR, GR, MR, and PR

ERα/ERβ

Class II NR (PPAR, RAR, RXR, TR, and VDR)

RXR/RAR

RXR/TR

RXR/VDR

RXR/PPAR

GRE: 5’-AGAACAnnnTGTTCT-3’

ERE: 5’-AGGTCAnnnTGACCT-3’

DR: 5’-AGGTCA-3’

 
DR5, DR2, DR1, IR0

DR4, IR0, EvR6

DR3

DR1

 

The response elements for the progesterone, androgen, glucocorticoid, and mineralocorticoid receptors are closely related and are collectively referred to as the glucocorticoid response element (GRE) consisting of a palindromic (symmetrical) sequence 5’-GGTACAnnnTGTTCT-3’, where n = any nucleotide.157 AR, PR, GR, and MR show subtle differences in DNA base contact points to GREs.157 Examples of genes containing one or more GREs whose transcription is up-regulated by glucocorticoids include the much-studied mouse mammary tumor virus (MMTV) promoter158, 159 tyrosine aminotransferase,160 and enzymes involved in gluconeogenesis.161, 162, 163, 164 Examples of genes that are specifically inhibited by glucocorticoids through “negative GREs” include pro-opiomelanocortin,165 interleukin-1beta,166 gonadotropin-releasing hormone (GnRH),167 and prolactin.168

The minimal consensus estrogen response element (ERE) sequence is also palindromic, 5’-GGTCAnnnTGACC-3’,169 and differs in only two bp from the GRE.170 Extension of the length of the ERE palindrome, e.g., 5’-CAGGTCAnnnTGACCTG-3’, and the sequences immediately flanking the ERE, are important in determining the affinity with which ERα binds the ERE.171, 172, 173, 174, 175, 176, 177, 178 Examples of genes whose promoters contain functional EREs include those encoding the much studied Xenopus vitellogenin A1179 and B1 genes;180, 181 and human genes encoding pS2, a marker for human breast cancer diagnostics;182, 183, 184, 185, 186 oxytocin;187 c-fos;188 c-myc;188 TGF-α;189 prolactin;190 progesterone receptor;191 and cathepsin D.192

One of the major advances in the field of transcriptional regulation by ER has been the development of ChIP and the using of tiling arrays to identify ER binding sites throughout the human genome.193, 194, 195, 196, 197, 198, 199, 200 These studies have been performed in MCF-7 human breast cancer cells and demonstrate that with E2 treatment, ERα is recruited not only to the anticipated EREs in the 5’ promoter of known target genes, but to the 3’UTRs and at great distances from established genes in the human genome. Studies have also demonstrated chromatin looping between promoter, intron, and 3’UTR regions of genes are regulated positively and negatively by E2.193, 195

The response elements for the various class II NR, e.g., TR, RAR, RXR, and VDR, are composed of direct repeats of the half-site 5’-AGGTCA-3’ either with no space in between the half sites (DR0), or separated by a gap of 1–5 nucleotides (DR1-DR5).201 The number of nucleotides separating the half-sites determines the specificity of class II NR binding.12 Many class II NR require RXR for hormonal activation of transcription.202 

GENERAL MODEL OF STEROID HORMONE RECEPTOR MECHANISM OF ACTION

(1)   Arrival and entry of steroid hormones into target tissue cells

Steroid hormones are small hydrophobic and lipid-soluble molecules derived from cholesterol. They circulate in blood either free or bound (95%) to plasma carrier protein.203 Sex hormone-binding globulin (SHBG), also known as testosterone-estradiol binding globulin, TeBG, and androgen binding protein (ABP) are encoded by the same gene.204 They differ only in their glycosylation and tissue-specific expression.205 ABP is produced by the Sertoli cells of the testis and SHBG is produced by the liver and is present in the circulatory system.206 SHBG binds most gonadal steroids, and corticosteroid-binding globulin (CBG or transcortin) binds glucocorticoids and progesterone, with differing affinities. When circulating levels of steroid hormones exceed the binding capacity of their respective binding proteins, they can then bind nonspecifically, and with low affinity, to albumin, from which they can readily dissociate and enter target cells.207 The unbound and loosely albumin-bound steroids are generally believed to be the most biologically important fractions since the steroid is free to diffuse (or be actively transported) through the capillary wall and lipid plasma membrane bilayer. Extracellular binding proteins may modulate hormone response by regulating the amount of steroid available to the cell.207 The binding capacity of binding globulins has been shown to be influenced by endocrine status and other factors.203, 208

SHBG binds to a specific cell membrane receptor called sex hormone-binding globulin-receptor (SHBG-R) and activates adenylate cyclase, thus increasing intracellular cAMP.204, 206, 209, 210 Binding of SHBG to SHBG-R also transfers SHBG into the cell as a consequence of receptor-mediated endocytosis.209 The interaction of SHBG with SHBG-R was shown to be inhibited when steroids are bound to SHBG, suggesting that SHBG is an allosteric protein.209 However, if unliganded SHBG is allowed to bind to its receptor on intact cells, and an appropriate steroid hormone then is introduced, adenylate cyclase is activated and intracellular cAMP increases.208 SHBG-R inhibits the E2-induced growth of MCF-7 human breast cancer cells.210 Once the steroid hormone is in the cytoplasm, it is not yet clear whether a transport protein is required for movement of the hydrophobic steroid molecule through the aqueous cytoplasm to the receptor, regardless of whether the receptor is cytoplasmic or nuclear in location. The current model is that the steroid hormone diffuses freely in the cytoplasm. 

(2)   Intracellular localization of the steroid/nuclear receptors

Early attempts to isolate steroid hormone receptors led to a major controversy regarding their intracellular localization in the unliganded state. Reports published before 1984 suggested that prior to hormone treatment, steroid receptors in target tissues were located predominantly in the cytosolic fraction as large protein complexes of 300–400 kDa.211 Following hormone exposure, receptors were detected primarily in the nuclear fraction.212 It was thus initially proposed that unoccupied and untransformed receptors were located in the cytoplasm until ligand-binding, which caused their translocation into the nucleus.180 The reported presence of ER and PR in cytosol has been considered to be largely artifactual, the result of homogenization and centrifugation processes used to isolate the receptor protein.213 However, other studies demonstrate localization and even movement of ERα and ERβ between nuclear, mitochondrial, and cytoplasmic compartments.214, 215, 216, 217, 218, 219, 220, 221, 222, 223, 224, 225, 226, 227, 228, 229, 230, 231, 232

Although newly synthesized receptor proteins would be expected to contribute a small amount to cytoplasmic levels of receptor, most steroid/nuclear receptors in the unliganded state reside in the nucleus. The exceptions are the glucocorticoid and mineralocorticoid receptors, which in the unliganded state reside in the cytoplasm in association with hsp90, hsp70, and a variety of receptor-associated proteins.233 The hsp90 complex of proteins has chaperonin activity that facilitates hormone binding and subsequent proper folding of the GR.234 Upon activation by hormone-binding, and the release of hsp90 and the other GR-associated proteins, the hormone-receptor monomer is released from the complex, dimerizes, and translocates to the nucleus.235 In contrast to GR, immunohistochemical localization experiments showed that ERα,236 ERβ,6 PR,237 and AR238 are primarily nuclear in the absence of hormone treatment. All class II nuclear receptors are nuclear in the absence of ligand.12

The newly synthesized unliganded receptor is highly unstable and either moves into the nucleus, targeted by its nuclear localization signals, soon after synthesis, or associates with the hsp90 complex of cytoplasmic proteins.234 GR, MR, PR, ERα, and AR have been found in association with hsp90, although hormone-binding has not been shown to be required for translocation of these receptors to the nucleus except for GR and MR.239 Hsp90 is a general molecular chaperone involved in the folding of various proteins.240 The hsp90 dimer is thought to stabilize the receptor, protecting it from protease degradation, to block the DNA-binding domain and the nuclear localization sequence (NLS), and maintain the receptor in an inactive state until ligand-binding occurs (Fig. 5).241, 242 Hsp90 is also required for ligand binding by the steroid receptors. In addition to hsp90, unliganded steroid receptors extracted from animal tissues or mammalian cells showed that GR and PR are complexed with a number of other proteins including hsp70, FKB59, p60, p48 (Hip), and p23.243 These proteins are thought to be required for the assembly and maintenance of ligand-sensitive aporeceptor complexes.

Fig. 5  Schematic diagram of the mechanism of steroid hormone receptor action in a target cell. A target cell contains the steroid hormone receptor(s) required to respond to a given steroid hormone. A. Most steroid hormones that enter the cell travel in the bloodstream either in free state or loosely bound to serum albumins. Estrogens and androgens are bound to steroid hormone binding globulin (SHBG) with high affinity. The cell membrane contains a SHBG receptor linked to adenylate cyclase. Activation of adenylate cyclase by the SHBG receptor or peptide hormones such as LH generate cAMP which activates the protein kinase A (PKA) phosphorylation cascade. As described in the text, PKA can activate ERα and other steroid hormone receptors in the absence of ligand binding.  Most receptors in the steroid/nuclear receptor superfamily reside in the nucleus in the newly synthesized or unliganded state. The exception is the glucocorticoid receptor (GR) which is complexed with the hsp90 chaperonin complex in the cytoplasm. Hsp90 and its accompanying proteins are thought to stabilize the receptor until hormone-binding occurs. Although receptors for progesterone, estrogens, and androgens have also been found in complexes with the primarily cytosolic hsps, the function of these associations is unclear. In the case of estrogens, progestins, and androgens, the hormones freely enter the nucleus and bind to their cognate receptor. Binding of hormone ligand to the receptor “activates” the receptor by inducing alterations in the conformation of the receptor protein. This allows the receptors to form homodimers and bind to specific hormone response elements (HREs, see Table 2 for specific sequences) in the DNA in the regulatory region of the target gene. B. Once bound to the HRE, the liganded steroid hormone receptor induces a DNA bend and, in the presence of agonist ligand, recruits coactivator proteins. The HRE-bound receptor also interacts with other DNA-bound transcription factors, as shown for the interaction of Sp1 with ER. Certain coactivator proteins have histone acetyltransferase (HAT) activity that acetylates lysine residues in histones H3 and H4. This results in a “loosening” of chromatin structure that facilitates the binding and transcriptional activity of RNA polymerase II at the transcription start site. Adapted from Naar AM, Beaurang PA, Robinson KM, Oliner JD, Avizonis D, Scheek S, Zwicker J, Kadonaga JT, Tjian R. Chromatin, TAFs, and a novel multiprotein coactivator are required for synergistic activation by Sp1 and SREBP-1a in vitro. Genes Dev 1998;12:3020-3031;244  Zwijsen RML, Buckle RS, Hijmans EM, Loomans CJM, Bernards R. Ligand-independent recruitment of steroid receptor coactivators to estrogen receptor by cyclin D. Genes Dev 1998;12:3488-3498.245 C. In addition to genomic activity, recent studies have shown that many NR, as reviewed  in the text, including ERα, are located in complexes of proteins in caveolae, including caveolin-1 (Cav-1) and c-src,  in the plasma membrane.246 Binding of E2 to PM-associate ERα or to GPR30, a membrane ER, activates intracellular signaling cascades and cross-talks with EGFR and IGF-R. ERα and ERβ are also present in mitochondria,247 although their roles in this organelle remain to be defined.

 

The role of the hsp90 complex in ER function is not yet clear. Purification of ERα after chemical crosslinking in intact MCF-7 human breast cancer cells revealed one ERα monomer complexed with two molecules of hsp90 and one molecule of p59 (FKBP52), but no hsp70 or 40 kDa cyclophilin.248 Another study showed hsp90 was not required for ligand-dependent transcriptional activation by ERα.249 Although hsp70 was shown to be required for purified, recombinant ERα to bind EREs in vitro,250 other experiments imply that hsp70 targets inappropriately folds nuclear proteins251, 252 and is not required for ERα–ERE binding.253 

(3)   Entry of steroid/nuclear receptors into the nucleus

Steroid hormone receptors within living cells are dynamic.254 They shuttle between the cytoplasm and the nucleus. The hormone receptor enters the nucleus by two processes: passive diffusion through the “ever opened” central channel of the nuclear pore or active transport that is mediated by interaction of the NLSs on the receptor proteins with the NLS receptor–hsp90 complex.255 The NLS-steroid hormone receptor-NLS receptor-hsp90 complex binds to the nuclear pore complex via nucleoporins in an ATP-dependent process.256, 257 The receptor is then trapped by binding to intranuclear components.255 Steroid hormone receptor complexes have been demonstrated in association with nuclear membranes and with chromatin components including histones, nonhistone basic proteins, DNA, and ribonucleoproteins,258 and with nuclear matrix.259, 260

The TR, VDR, RAR, RXR, and other class II nuclear receptors do not form high molecular weight complexes, but are believed to enter the nucleus directly and become tightly associated with chromatin.202 However, recent experiments may cause rethinking of this model. The subcellular localization of human TRβ1 fused at its N-terminus to green fluorescent protein (GFP) was followed in living cells.261 In the absence of thyroid hormone T3, more GFP-TRβ1 was present in the cytoplasm, and when the cells were treated with T3, the GFP-TRβ1 was predominantly localized in the nucleus.261 Since GFP-TRβ1 bound T3 and DNA in a manner identical to wild type TRβ1 and since T3 treatment moved all of the GFP-TRβ1 into the cell nucleus, the authors concluded that their findings reflect the behavior of endogenous TR.261 With the exception of the v-erb A oncogene product and some of the orphan receptors that function constitutively, or are activated by growth factor-mediated phosphorylation, unliganded class II nuclear receptors (NR) are not transcriptionally active until liganded. This is because the class II NR including RAR, RXR, and TR are constitutively bound by corepressor proteins that silence transcription until the appropriate ligand is bound.262, 263, 264 

(4)   Ligand-dependent activation of steroid/nuclear receptors     

The ligand-binding domain of the receptor may act as a repressor of receptor function since deletion of the LBD from the glucocorticoid and progesterone receptors causes constitutive gene activation.265, 266 Ligand-binding to the receptor stimulates dissociation of the receptor-hsp90 complex151 which facilitates conformational changes in the receptor (activation) that exposes the DNA-binding domain and promotes dimerization of the receptor. Binding of the hormone to the receptor may be only one of several factors that activates or transforms the receptor, enabling it to bind as a dimer to specific hormone response elements located adjacent to or sometimes at a distance from the transcription start site of the regulated gene.

It is important to note that Type II nuclear receptors, e.g., TR, VDR, RAR, RXR, and the orphan receptors, do not interact with hsp90. These receptors are bound to DNA in the absence of ligand and are associated with corepressor proteins, e.g., NCoR and SMRT.262, 263, 264 Corepressor proteins NCoR and SMRT are associated with a complex of proteins that have histone deacetylase activity that are believed to repress gene expression by maintaining chromatin in a more condensed conformation.262, 263

Hormone-dependent phosphorylation of steroid hormone receptors may play an important role in binding of the receptor to its specific response element on the gene and subsequent activation of transcription. PR, GR, ERα, and VDR are all phosphorylated after binding to their respective ligands.267

(5)   Ligand-independent activation of steroid hormone receptors

Although steroid and nuclear receptors are classically activated by ligand binding and are subsequently phosphorylated, a second mode of activation in the absence of ligand has been detected for certain receptors. Phosphorylation of certain steroid hormone/nuclear receptors in response to cell-membrane activated signaling cascades activates the receptor in the absence of the cognate ligand.268, 269 Examples of peptide hormones and growth factors that activate steroid receptors by triggering intracellular phosphorylation cascades include dopamine, epidermal growth factor (EGF), insulin, and insulin-like growth factor (IGF).269 Activation of β2-adrenergic receptors by the anti-inflammatory, anti-asthmatic drugs salbutamol and salmeterol was recently demonstrated to activate GR, resulting in nuclear translocation and transactivation of a GRE-driven reporter gene.270 Signal transduction took place through activation of a cAMP-cascade mediated by the cell membrane β2-adrenergic receptor. Likewise activation of the protein kinase A (PKA) pathway stimulated transcription by the MR in a ligand-independent manner.271 Interestingly, PR appears to be refractory to activation induced by phosphorylation cascades.269

ChIP studies have demonstrated that ERα and ERβ are associated with some gene promoters in various cell types in the absence of E2 treatment.196, 272, 273, 274, 275, 276, 277 More recently, proteomic studies of proteins associated with unliganded ERα identified the deleted breast cancer-1 gene product DBC-1 (KIAA1967) to be a direct ligand-independent binding partner of ERα in the nucleus of MCF-7 human breast cancer cells.278 Functional analyses revealed that DBC-1 was a principal determinant of unliganded ER protein levels and survival activity in human breast cancer cells.

(6)   Binding of steroid/nuclear receptors to HREs and DNA bending

The sequences specifically recognized by the various steroid/nuclear receptors were described in Table 2. When steroid/nuclear receptors bind their cognate HRE, the DNA is deformed, causing a bend in the DNA. DNA bending appears to be important in cellular processes mediated by multiprotein complexes, including transcription in both prokaryotes,279 and eukaryotes.280, 281, 282, 283 DNA bending is thought to facilitate interactions between components of the transcription complex bound to different sites and to promote DNA looping to allow single proteins to contact multiple DNA elements. ERα binding to an ERE results in a bend of the DNA toward the major groove.284, 285 Other steroid receptors including GR286 and PR287 also induce DNA bending. Similarly, Class II NR including TR and RXR induce DNA bending.288 More recently, NR-mediated transcriptional activation has been demonstrated to involve “chromatin kissing” in which E2-induced ERα activation induces rapid interchromosomal interactions among subsets of ERα-bound transcription units, with a dramatic reorganization of nuclear territories requiring nuclear actin/myosin-I transport machinery, dynein light chain 1 (DLC1), histone lysine demethylase (LSD1), and a specific subset of transcriptional coactivators and chromatin remodeling complexes.289 

That the topology of DNA is important for steroid hormone receptor recognition of HREs is reinforced by the observation that the nonhistone chromosomal protein HMG-1, which recognizes irregular DNA structure, enhances the binding of PR, ERα, AR, and GR to their respective response elements in vitro, but has no effect on the binding of TR, RAR, RXR, or VDR to their target sequences.287, 288, 290 Moreover, co-expression of HMG-1 or HMG-2 increased PR-mediated transcription in transiently transfected mammalian cells by seven to 10-fold without altering the basal promoter activity of target reporter genes.291 

(7)   Direct regulation of gene transcription by steroid hormone receptors

Initiation of transcription is a complex event occurring through the cooperative interaction of multiple factors at the target gene promoter (Fig. 4). When bound to the specific HRE on the DNA, the hormone-receptor complex interacts with basal transcription factors and with other proteins to stabilize basal transcription factor binding and promote the assembly of the transcription initiation complex. Once the transcription initiation complex is in place, the enzyme RNA polymerase II is recruited to the transcription start site where it begins transcribing the DNA sequence into mRNA. 

(a) Interaction of steroid/nuclear receptors with basal transcription factors

In order for RNA polymerase II to initiate transcription, basal transcription factors TFIIA, TFIIB, TFIID, TFIIE, TRIIF, and TFIIH must assemble on the core promoter and phosphorylate the CTD of RNA pol II.292, 293, 294, 295, 296, 297, 298 TFIID consists of the TATA box binding protein (TBP) and at least eight tightly associated factors (TAFs) of 18–250 kD.299 Since the amount of RNA polymerase II is limited in the nucleus, genes must compete for it by assembling an appropriate set of cis-elements, HREs, and binding sites for sequence-specific transcription factors, such as AP-1,300 CREB,301 TFIIB, and Sp1.302 The net result is the synthesis of new messenger RNAs (mRNAs) which move into the cytoplasm and are translated into new proteins that may alter cell function (acting in an intracrine manner) or may be modified further and secreted by the cell to act as endocrine, autocrine, or paracrine factors.

Steroid receptors interact with basal transcription factors TFIIB, TBP, and various TAFs of TFIID.303 ERα and PR interact directly with TFIIB.304 ERα interacts directly with TBP using both AF-1 and AF-2 as interaction surfaces.305 ERα interacts with human TFIID component TAFII30 through the LBD in a ligand-independent manner. The functional relevance of ERα–hTAFII30 interaction is indicated by the inhibition of ERα-mediated transactivation by monoclonal antibodies to hTAFII30.306 Studies indicate that steroid and nuclear receptors use different domains for interaction with basal transcription factors.303

(b) Interaction of steroid/nuclear receptors with coactivators (coregulators that increase transcriptional activity)

Steroid hormone receptors interact with multiple proteins both when bound to DNA or in solution in vitro. Early experiments showed that overexpression of one type of steroid hormone receptor could inhibit, or “squelch” the activation of transcription mediated by a different steroid hormone receptor, hinting that steroid receptors compete for limited amounts of a factor(s) required for transcription.307 Over the past 4 years, at least 15 different coactivators have been identified (Table 3). These proteins have also been termed receptor interacting proteins (RIPs) and RAPs (receptor associated proteins); however, not all RIPs are coactivators. By definition, coactivators are considered to interact directly with the steroid/nuclear receptor and enhance transcription.308, 309, 310 Thus, the first coactivators for steroid receptors to be discovered, the SWI/SNF proteins,311 may not be strictly coactivators, but instead may serve as bridging factors that interact between coactivators and basal transcription factors. Several coactivators have “general” transcriptional activator function, since they enhance transcription by different types of transcription factors, including steroid receptors.

It is clear that steroid receptors can interact with a number of different coactivators. Some of these coactivators, i.e., SRC-1, CBP, and TIF2, have been demonstrated to play a critical role in ligand-activated transcription.309, 310 Coactivator proteins contain one or more copies of a NR binding motif, also called the NR box, consisting of the aa = LXXLL, which physically interacts with the steroid/nuclear receptors. Steroid receptors show different affinities for the various coactivators312 and use different amino acids to contact the coactivators.313 Coactivators SRC-1, ACTF, and CREB/p300/CBP have histone acetyltransferase (HAT) activity314, 315 providing the mechanism for enhanced transcription.263 Many transcriptional regulatory proteins have intrinsic HAT activity.316, 317 There is a complex ‘histone code’ regulating gene transcription.318, 319 HATs acetylate lysine residues on the N-terminal tails of histones H3 and H4 in chromatin, resulting in a weaker association of histones with DNA, thus altering nucleosomal conformation and stability in a manner that facilitates transcriptional activation by RNA polymerase II.320 SRC-1, CBP/p300, CREB, and other coactivators are believed to form a ternary complex with liganded steroid receptors to increase the rate of hormone-responsive gene transcription.321 Thus, several HAT activities may be tethered to hormone-activated receptors on the promoter, yielding synergistic transactivation. It is important to note that not all genes are affected by histone acetylation, and steroid and nuclear receptors show different affinities of interaction with coactivators.322

The current model suggests that different target cells express different levels of coactivators and corepressors which, along with the amount of receptor protein and ligand, allows fine-tuning of target gene transcription in response to steroid hormones.323 Northern blot analysis confirmed the idea that different rat tissues324 and cell lines325 express different amounts of the mRNA for p300, CBP, SRC-1, RIP140, SMRT, and NCoR.

Table 3.  Examples of coactivator proteins that interact with steroid hormone receptors. These proteins have been identified in yeast and mammalian two hybrid screening, during purification, in immunoprecipitation assays, and by cross-linking studies. Some, but not all, have been shown to stimulate transcription in cell systems309, 310, 326

Names

Interacts with

SR/NR

Effect of SR ligand on direct interaction

Effect of co-expression on transcription

Other information

References

ACTR/

SRC-3/ RAC3/ p/CIP/

AIB1

ERα

RXRα

TR

Requires agonist ligand

Stimulates E2-dependent transcription

·        AIB1 expression elevated in human breast and ovarian cancers327

328, 329

 

 

ARA70 (ELE1α)

 

·        truncated variant ELE1β

AR

ERα

GR

PPAR

Androgens and antiandrogens promote AR-ARA70 interaction – also genistein and RU486330

 

Stimulates AR transcription with DHT or E2

·        No intrinsic HAT activity

·        Interacts with p/CAF that has HAT activity

·        Interacts with TFIIB

·        Highest ELE1α and ERE1β expression in testis

331, 332, 333 

CBP/p300/p270

AR, ERα, GR, PPARg, RAR, RXR, TR, HNF4

Requires agonist ligand, except for AR

·        Stimulates transcription

·        Intrinsic histone acetyltransferase activity

·        Interacts with SRC-1

·        CBP/p300 is also a cofactor for AP-1, c-myb, STAT1, E1A, p53, and Myo-D

·        Helps recruits RNA Pol. II holoenzyme to the promoter

·        CBP interacts with TFIIB

334, 335, 336, 337, 338, 339, 340, 341, 342, 343 

 

RIP140

 

ERα

TR, RXR,

PPARα

PPARγ

Requires agonist ligand; antagonists tamoxifen and ICI 164,384 block interaction with ERα

·        Stimulates ERα-induced transcription

·        Inhibits PPAR and RXR activities

·        Identical to ERAP140344

345, 346, 347, 348

SRC-1/NoA-1

AR, ERα, ERβ1, PR, GR, TR, RARβ, RXRα, PPARγ, HNF4

 

 

·        Requires agonist ligand

·        Antagonist inhibits interaction

Stimulates PR, GR, and ERα-induced transcription

·        Intrinsic HAT activity

·        Interacts with p300/CBP, TBP, and TFIIB

·        Targeted gene disruption resulted in viable and fertile mice, but with decreased growth and development of target organs, e.g., uterus, testis, and mammary gland, and a compensatory  increased expression of TIF2

 

349, 350, 351, 338, 343, 352, 353

 

 

 

 

 

 

SWI/SNF

ER, GR, RAR, HNF-4

 

Stimulates transcription

·        Chromatin remodeling complex in yeast with human homologues

 

354, 355, 356 

TIF1α

ERα, ERβ, PR, RXR, VDR

Requires agonist ligand

Stimulates transcription – requires agonist ligand for ERα, but for ERb 4-OHT acts as an agonist

·        Interacts with heterochromatin proteins, including hSNF2β of the SWI/SNF complex and TIF1β

357, 358, 359, 360, 361, 362 

 

TIF2/GRIP1/
NCoA-2

ERα, GR, AR, PR, RAR, RXR, TR, VDR, HNF4

Requires agonist ligand

Stimulates ERα, AR, PR, TR, RAR, and RXR but not GR, or VDR

·        40% sequence homology to SRC-1

343, 363, 364, 365, 366, 367, 368

 

 
(c) Microarrays have identified hormone-regulated genes in cells and animal tissues


A major advance in the past 8 years, since the initial publication of this chapter, has been the development of microarrays of human, mouse, and rat gene and the identification of genes regulated by steroid hormone action using these assays. Time course assays have identified primary and secondary estrogen target genes regulated by ERα in MCF-7 breast cancer cells369, 370, 371, 372, 373, 374, 375, 376 and by ERα and ERβ in U2OS human osteoblast cells.156, 200, 373, 374, 377, 378, 379

(8)   Indirect regulation of gene transcription by interaction of steroid/nuclear receptors with other transcription factors

Steroid receptors interact directly with different transcription factors and alter target gene transcription without the steroid receptor interacting directly with DNA. The best studied example of this “transcriptional cross-talk” is the interaction of the AP-1 transcription factor with GR.380 Depending on the cell type381 and the composition of the AP-1 complex, GR synergizes with AP-1 (Jun-Jun homodimer) or suppresses the Fos-Jun heterodimer.382 In vitro assays demonstrate that ERα interacts with the Fos-Jun AP1 heterodimer and that raloxifene and tamoxifen are more potent agonists than E2 at AP-1 sites.383

The antiestrogen tamoxifen activates ERα-mediated induction of promoters regulated by AP-1 sites including the human collagenase gene.384 This contrasts with the inability of tamoxifen to activate transcription from promoters bearing classical EREs. Tamoxifen agonism at AP-1 sites is cell type specific, i.e., occurring in cell lines of uterine, but not of breast, origin. The DBD of ERα is required for tamoxifen activation at AP-1 sites. Conversely, the AP-1 components cJun and cFos inhibited E2-dependent ERα-stimulated reporter gene activity in transiently transfected MCF-7 or CV-1 cells transfected with ERα.385 DNA binding experiments revealed that ERα-ERE binding was inhibited by the cJun protein and that ERα inhibited cJun-DNA binding.385

E2 regulates gene transcription in opposite ways through ERα and ERβ from an AP1 site: with ERα, E2 activated transcription, whereas with ERβ, E2 inhibited transcription.386 Moreover, in contrast to ERα, the antiestrogens tamoxifen, raloxifene, and ICI 164,384 were potent transcriptional activators with ERβ at an AP1 site. Thus, the two ERs differ in how they respond to ligand and response element, suggesting that ERα and ERβ may play different roles in gene regulation.386

Another transcription factor with which ERα interacts directly to activate gene transcription is Sp1.387 A number of estrogen-responsive genes are activated by ERα-Sp1 interaction including cathepsin D,388 RARα,389 VEGF,390 and c-fos.391 ERα and Sp1 physically interact in a manner that requires both the N-terminal and C-terminal regions of ERα.392 The interaction of the Sp1 and ERα and the resulting increase in Sp1-DNA binding is observed in the presence or absence of E2, whereas transactivation of promoter-reporter constructs is E2-dependent. These results indicate that transcriptional activation requires more than ERα-Sp1 interaction and increased DNA binding. A likely interpretation is that coactivators are required.

NF-kB also interacts directly with ERα, ERβ, and GR and inhibition of NF-kB has been demonstrated to increase ERβ and GR transcriptional activity in cells.393

(9)   Repression of target gene transcription by steroid/nuclear receptors

Binding of the hormone-receptor complex can also repress transcription of target genes, although the precise mechanisms are not as well elucidated as transcriptional activation. One mechanism by which a steroid receptor represses gene transcription is by binding to the same, or an overlapping, DNA binding site as that used by a different activator protein, thus competitively blocking activator binding to DNA. One example of this mechanism is the mutual inhibition by GR and AP-1 on the proliferin gene promoter that contains a composite GRE-AP-1 binding site.382

Competition for limiting amounts of coactivators is another mechanism by which steroid hormones inhibit gene expression. The mutual inhibition of AP-1 and steroid receptor transactivation, including AR, ERα, GR, and PR,380 is that they compete for limiting amounts of the coactivators CBP/p300 in the nucleus.394

Likewise, GR and ERα also block NF-kB-mediated transactivation.380 GR and other steroid receptors interact directly with NF-kB, and NF-kB inhibits GR, ERα, and PR-mediated transcription. GR and NF-kB compete for limited amounts of the coactivators CBP and SRC-1.395

Another mechanism for repression by steroid receptors is by binding to the HRE and recruiting corepressor proteins that quench the activity of activators bound to the promoter. The corepressors N-CoR and SMRT263 were first identified by their binding to unliganded TR, RAR, and RXR (Table 4). Tethering of these corepressors to the DNA by their interaction with the DNA-bound TR, RAR, or RXR recruits other components of the corepressor complex that mediate the actual events of transcriptional silencing.396 Binding of TR or RAR ligands causes dissociation of NCoR, but only when the receptors are bound to DNA. Unlike coactivator complexes that have endogenous HAT activity, corepressors do not appear to have enzymatic activity. Corepressors NCoR and SMRT appear to function by recruiting histone deacetylase (HDAC)-containing multiprotein repression complexes to the promoter.263 Deacetylation of chromatin helps maintain a condensed state of nucleosomal structure that blocks the binding of components of the RNA polymerase II transcription initiation complex.

Table 4. Examples of corepressor proteins that interact with steroid/nuclear receptors. These proteins have been identified in yeast and mammalian two hybrid screening, during purification, in immunoprecipitation assays, and by cross-linking studies.396, 326 In general, interaction of steroid and nuclear receptors with these proteins represses gene transcription in cell systems

 

Name

Interacts with

Effect of SR ligand

 Effect of co-expression on transcription

Other information

References

NCoR

TR, RAR, RXR, PR, ERα

 

 

4-OHT-ERα

·        Increased transcriptional activity of unliganded PR397

·        NCoR expression reduced in TAM-resistant breast cancer cells398

28, 29, 399

 

 

SMRT 

TR, RXR, RAR, ERα

Unliganded class II NR; antagonist-liganded PR

·        Overexpression strongly reduced basal and 4-OHT-stimulated gene expression with no effect on E2 activity400

·        HDAC1 is associated with SMRT

 

397, 401

 
(10)   What is the mechanism of repression of target gene transcription achieved by hormone antagonists? 

A variety of mechanisms is likely to be involved in hormone antagonist action. First, the antagonist activity of an antihormone may depend on the cell or tissue type. For instance, antiestrogen-liganded ERα binds EREs with high affinity,175 but in certain cell types, e.g., MCF-7 human breast cancer cells, transcription is not activated,402 whereas in endometrial cells, tamoxifen stimulates transcription.403 The proposed mechanism for these observations involves the inability of antiestrogen-liganded ERα to interact with co-activator proteins, e.g., SRC-1,404 TIF1α405 that have HAT activity that “loosens” chromatin structure to allow assembly of the transcription initiation complex. Another possibility is that antiestrogen-liganded ERα may recruit corepressor proteins to the promoter, thus inhibiting chromatin changes that promote a “loosening” of nucleosomal structure.323, 406 Indeed, NCoR interacts with the tamoxifen metabolite 4-hydroxytamoxifen (4-OHT)-liganded ER.407 Breast cancer cells that are resistant to tamoxifen-inhibition of cell proliferation show reduced NCoR levels compared to tamoxifen-sensitive cells, suggesting a mechanism whereby cells become resistant to tamoxifen.407 Similarly, NCoR and SMRT repress the agonist activity of antiprogestin RU486-liganded PR or tamoxifen-liganded ERα.408

Actions of NR in the plasma membrane

While most of the effects of steroid hormones are mediated through their interaction with their cognate receptors and subsequent effects on target gene transcription, certain rapid effects of steroid hormones are incompatible with a transcriptional mechanism. Specific binding sites for androgen, estrogen, progesterone, glucocorticoid, and vitamin D receptors have been reported in the plasma membrane of various target cell types.409, 410, 411, 412, 413, 414, 415, 416, 417, 418, 419, 420, 421, 422, 423, 424, 425, 426, 427, 428, 429, 430, 431, 432, 433, 434, 435, 436, 437, 438, 439, 440, 441, 442, 443, 444

Extranuclear activities of GR and MR

GR can bind to cytoskeletal structures445 and glucocorticoids stimulate the rapid-onset of polymerization of actin in a non-genomic manner that involves decreased intracellular cAMP.446 GR has also been found in mitochondria in hepatic cells where it may activate mitochondrial gene expression,447 and in leukemic cells, sensitivity to glucocorticoids-induced apoptosis appears to be regulated by translocation of GR into mitochondria.448 Rapid stress-induced changes in male amphibian reproductive behavior appear to be mediated by corticosteroid receptors within neuronal membranes that may be identical to CBP.447 MRs are also present in limbic neuronal plasma membranes and have been suggested to be important in mediating the initial stress response.449

Membrane PR

One of the membrane steroid receptors that have been well-characterized to date is the membrane progesterone receptor that was initially characterized in amphibian oocytes, fish, and in spermatids.436, 437, 438, 450, 451, 452, 453, 454 There are three subtypes of membrane PR: α, β, and γ, and each has seven transmembrane domains and is a GPCR that is linked to inhibition of adenylate cyclase.436, 437, 455, 456 The bioactivity and roles of mPRs remains controversial since mPRs did not bind progesterone, activate ERK1/2 (MAPK), p38 MAPK, or change Ca+2 signaling in MDA-MB-231 cells.457 In Xenopus, the classical intracellular PR also mediates these rapid, non-genomic responses.458 A novel progesterone receptor that mediates rapid changes in Ca+2 conductance has been demonstrated in human sperm plasma membrane.459 A high affinity progesterone-binding membrane protein of 200 kDa was described in pig liver.460 The single-transmembrane protein PGMRC1 (MW 26–28 kDa) was first purified from pig livers and has subsequently been identified in a variety of other tissues.456 PGMRC1 can bind to other molecules including heme, cholesterol metabolites, and proteins.456 The mechanism by which the synthetic progestin R5020 upregulates c-ErbB2 and c-ErbB3 levels in PR-negative T47D-YB human breast cancer cells involves membrane progesterone receptor and studies have demonstrated that the stimulatory effect of progestins on breast cancer cell proliferation is mediated by activation of MAPK in a transcription-independent manner.461, 462, 463, 464, 465, 466 In addition to membrane progesterone receptor action, metabolites of progesterone and deoxycorticosterone act as positive allosteric modulators of the gamma-aminobutyric acid (GABA) A receptor complex in the cortex of rat brain.467 This means that these hormones bind to an effector site and not the GABA binding site and increase the affinity of GABA binding to the (GABA)A receptor. There is clearly a need for further research to elucidate the roles of membrane PRs in mediating progestin activity in various tissues. 

 

Nongenomic estrogen action

E2 has “nongenomic, extranuclear, or membrane-initiated” effects, i.e., independent of ER-mediated transcription, that occur within minutes after E2 administration.413 Nongenomic estrogen action has been reviewed.223, 421, 468 

The best characterized system for the study of endogenous membrane ERα is the rat GH3/B6 pituitary tumor cell line in which ~10% of ERα was localized in the plasma membrane.415, 419, 469, 470, 471, 472, 473 Exposure of GH3 pituitary cells to E2 elicited a rapid (within 5 minute) release of prolactin (PRL) in a manner that cannot be accounted for by genomic effects of estradiol mediated through nuclear ER. Additionally, binding sites for estrogen with different biochemical properties from the classical nuclear receptor have been reported in the endoplasmic reticulum of uterine tissues.474 

Estradiol appears to have both genomic and nongenomic effects in the brain.475 The cardiovascular protective effects of estradiol are thought to be mediated at least in part by nongenomic ER and involve increased intracellular cAMP,476, 477 inhibition of Ca2+ influx,476, 478 and stimulation of NO release.413, 479, 480, 481, 482, 483 Estradiol has been shown to exert direct beneficial effects on human oocytes during in vitro maturation and these effects are at least partly due to steroid action at the oocyte surface.484 

A comparison of nuclear and membrane localization of recombinant ERα and ERβ in transfected CHO cells (considered to be ER null) showed that both ERα and ERβ were expressed predominantly in the nucleus with ~5% of each ER subtype located in the cell membrane.485 E2 treatment of these transfected CHO cells activated Gαq and Gαs proteins in the membrane and rapidly stimulated corresponding inositol phosphate production and adenylate cyclase activity.485 Interestingly, membrane ERα and ERβ showed a distinct difference in their activities: c-Jun N-terminal kinase activity was stimulated by E2 in ERβ-expressing CHO, but was inhibited in CHO-ERα cells.485 Further studies from this research group have demonstrated that plasma membrane receptors work as dimers,486 that ERα interacts with caveolin-1 (Cav-1) which interacts with G proteins, Src, Grb7, Raf, Ras, MEK, and the EGFR at the plasma membrane of MCF-7 cells, and triggers the release of HB-EGF into the culture medium that, in turn, activates the EGFR and downstream signaling leading to activation of ERK1/2 (MAPK) and PI3K/AKT signaling cascades418, 421 that, in turn, phosphorylate ERα.223 Palmitoylation of ERα is important for its membrane localization.425, 487

In endothelial cells (EC), E2 rapidly increased intracellular cAMP,476 inhibited Ca2+ influx,478 stimulated Ca2+ release from internal stores,488 and stimulated nitric oxide (NO) production.489 In MCF-7 cells, E2 rapidly increased PIP2-phospholipase C activity,490 mobilized intracellular Ca2+, and activated the MAPK488 and PI3K/AKT pathways.491 Immunohistochemical techniques have visualized membrane ERα in pituitary cells.415 Since ERα lacks a transmembrane domain, how it gets to the plasma membrane (PM) has been controversial, but it appears to involve palmitoylation.492 In MCF-7 cells, the adaptor protein Shc shuttles ERα from the nucleus to the PM where ERα  interacts with the IGF-1 receptor (IGF-1R).493 Similarly, another scaffold protein, called MNAR (modulator of nongenomic activity of ER) was reported to mediate ERα-cSrc interaction and MAPK signaling.494, 495, 496 A role for a membrane caveolae-localized ERα variant (ERα46) in rapid NO release via PI3K/Akt activated endothelial nitric oxide synthase (eNOS) in EC has been reported.416, 480, 497, 498

Direct interactions between plasma membrane-associated ERα and Gαi have been implicated in eNOS activation and NO production in COS-7 cells transfected with ERα and specific Gαi proteins.2 E2 stimulated the direct interaction of ERα with Gαi2 via ERα-striatin interaction in MCF-7 and other cells.3 Likewise, E2 rapidly activates the G protein-coupled signal cascades in MCF-7 and other breast cancer cell lines.4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14

Estradiol was reported to activate the angiotensin II receptor AT1 in ER-negative SKBr3 breast cancer cells.499

GPR30, a PM protein, was reported to bind E2 with high affinity (Kd = 2.7 nM) resulting in activation of adenylate cyclase.224, 439, 500, 501, 502 Importantly, tamoxifen and ICI 182,780 also bind GPR30 with high affinity and mimic the effects of E2.439 Phytoestrogens, e.g., genistein, and endocrine disruptors, e.g., bisphenol A and nonylphenol, also bound and activated GPR30 with an affinity comparable to E2.441 Overexpression of GFP-tagged GPR30 in COS7 cells revealed the GFP-GPR30 in the plasma membrane and Golgi and endogenous GPR30 had a similar distribution in MCF-7, SKBr, and MDA-MB-231 breast cancer cell.224 Overexpression of FLAG-GPR30 in HeLa cells revealed that physiological concentrations (10 nM–1 μM) of E2 stimulated  FLAG-GPR30 translocation from the plasma membrane to the cytoplasm and that intracellular Ca2+ was elevated within several seconds after the addition of E2 in cells expressing FLAG-GPR30.502 Although the role of GPR30 in MCF-7 and SKBr3 breast cancer cells has been questioned,421 it appears likely that GPR30 may be a novel membrane estrogen receptor in a cell type-specific manner, e.g., thyroid,503 endometrial,504 ovarian,505 and breast506, 507 cancer cells. Indeed, GPR30 expression in primary human breast tumors was recently demonstrated to correlate with Her2/neu expression and metastases, i.e., the opposite of ERαexpression.506, 507  

 

MECHANISMS FOR ASSURING TISSUE-SPECIFICITY OF GENE EXPRESSION

Diversity of tissue responses to steroid hormone action, despite conservation of structure and function, is achieved through a variety of mechanisms. Some receptors are expressed in only a limited number of cell types, e.g., the gonadal steroid receptors, while others are found in a large number of cell types, e.g., the glucocorticoid and thyroid hormone receptors. Other tissue-specific gene regulatory proteins (transcription factors, coactivators, and corepressors) are involved in the modulation of gene transcription by steroid/nuclear receptors. Cell-specific post-translational modification of receptors is another mechanism to assure tissue-diversity of hormone responses.269 Multiple receptor isoforms for hormones may also account for tissue-specific gene expression.508 Receptor isoforms have been shown to arise through alternative splicing of mRNA from a single gene (PR and AR), from multiple genes (ER), or a combination of both (TR).39

Interactions with other transcription factors, coactivators, and corepressors, appear to play a significant role in determining specificity. Thus, even though receptors for several different hormones, i.e., AR, GR, MR, and PR, can bind a common HRE sequence, they may exhibit different interactions with other DNA-bound factors and coactivators, hence achieving different modulation of target gene expression.509

REGULATION OF RECEPTOR NUMBERS

The half-life of steroid hormone receptors ranges from 2–4 h for ERα510, 511 and 4 h for AR,512 to 7–10 h for PR513 and 19 h for GR.514 The relatively long half-life of the steroid hormone receptors strongly suggests that the receptor proteins are recycled before eventual degradation.515

Steroid hormones generally autoregulate their receptor levels.516 Desensitization or down-regulation of receptor numbers, measured by decreased ligand binding capacity, occurs in response to exposure to high levels of ligand, and involves the reduction in receptor mRNA levels, thus decreasing the number of available receptors. The receptor gene may be negatively regulated by the hormonal ligand itself via its receptor protein interacting with specific HREs in the gene.517 Up-regulation or self-priming may occur in an analogous fashion. Additionally, steroid hormones can regulate receptor levels for other hormones, e.g., E2 increases PR levels in estrogen-responsive tissues.518 Progesterone, in return, can not only down-regulate its own receptors, but also ERα519 and ERβ.520 This increase or decrease in receptor levels in homologous or heterologous regulation can be due to alterations in receptor gene transcription and/or decay rates for receptor mRNA and/or protein. Binding of the cytosolic GR complex to very long 3'-untranslated regions of its receptor mRNA has been reported to cause premature degradation.520 

 

 

TARGETED GENE DISRUPTION (GENE "KNOCK-OUT") MOUSE STUDIES

Steroid and nuclear hormone receptors have been detected in virtually every major organ and tissue in the mammalian body, including the brain. Much new information on the location and function of the steroid hormone receptors has been derived from recently developed techniques that allow manipulation of a specific mouse gene in vitro to generate targeted gene disruption of the gene for a given receptor, creating homozygous “gene knockout” mice. The technique disrupts the linear gene by inserting an antibiotic resistance gene, e.g., neomycin, into one coding region (one exon) of the gene. The mutant DNA is inserted into genomic DNA by homologous recombination in mouse embryonic stem cells to generate transgenic mice. Thus, the mRNA for the targeted gene is truncated or nonsensical. This technique has resulted in ERα, ERβ, MR, PR, and GR, "knockout" mice.521

 (1)   ERα knockout mice (ERKO)

To the surprise of the investigators and others, loss of ERα expression was not lethal and had no effects on the ratio of male:female mice born.522 ERKO mice survived to adulthood and developed grossly normal external genitalia, but both sexes were infertile.523 Females have hypoplastic uteri and hyperemic ovaries with no corpora lutea.307 Serum levels of estradiol in the ERKO females are more than 10-fold higher than those in the wild type, consistent with a syndrome of hormone insensitivity.524, 525, 526 ERKO females have 10-fold higher circulating E2 and elevated LH, but not FSH.527 Ovarian histology is abnormal.528 Mammary glands of adult ERKO female mice lack branching and terminal end bud formation.529 Disruption of ERα signaling in ERKO mice leads to an obese phenotype.530, 531 Maternal behavior as measured by retrieving of pups was reduced.525 In some cases, pups were killed by the ERKO females, which was not seen in wild-type animals.527 Aggression toward other females was increased and female-typical lordosis behavior was reduced.527

Adult ERKO males exhibit a number of alterations in reproductive tract histology including atrophied, degenerated seminiferous tubules, and diluted, infertile sperm.532 The mice exhibit decreased sperm counts and significantly lower testicular weight than wild-type (wt) males.527, 528, 529 The reproductive capacity of sperm from ERKO males is significantly compromised in in vitro fertilization experiments. ERKO males appear to have normal mounting behavior toward wt females, but exhibit an almost complete lack of intromission and ejaculation. ERKO males are consistently less aggressive than wt mice.533 These findings indicate that ERα gene expression during development plays a major role in the organization of male-typical aggressive and emotional behaviors in addition to simple sexual behaviors.533, 534, 535, 536, 537 

E2 protected both wild-type and ERKO female mice in response to carotid arterial injury, indicating that ERα may not be required for the protective actions of E2 in the vascular system.538 The rapid effects of E2 on vascular tissue, e.g., rapid changes in vasomotor tone, available nitric oxide, and the resting potential of smooth muscle cells, have been demonstrated to be mediated by a membrane form of ER.421 

There has been one reported human case with an ERα mutation.539 The patient, a male, exhibited severe osteoporosis and insufficient closure of the epiphyseal growth plates. 

(2)   ERβ knockout (BERKO)

Mice lacking ERβ develop normally and are indistinguishable grossly and histologically from their litter mates.524 Breeding experiments with young, sexually mature females show that they are fertile and exhibit normal sexual behavior, but have fewer and smaller litters than wild-type mice. Superovulation experiments indicate that this reduction in fertility is the result of reduced ovarian efficiency. The mutant females have normal mammary gland development and normal lactation. Adult male mice show no overt abnormalities and reproduce normally. Older mutant males display signs of prostate and bladder hyperplasia. The investigators concluded that ERβ is essential for normal ovulation efficiency but is not essential for female or male sexual differentiation, fertility, or lactation.524 BERKO mouse mammary glands showed abnormal epithelial growth, overexpression of Ki67 and severe cystic breast disease as the mice aged.540 BERKO females showed increased anxiety541 and learning deficits.542 Both ERα and ERβ may protect against colorectal cancer in a mouse model.543 

(3)   PR knockout mice (PRKO) 

Mice carrying a null mutation of the progesterone receptor gene exhibit several reproductive abnormalities, including anovulation, attenuated lordotic behavior, uterine hyperplasia, and lack of mammary gland development.544 There were no effects on the viability or sexual differentiation of homozygous PR gene disrupted mice.544 The females homozygous for PR disruption were completely infertile while males exhibited no apparent effects on fertility. Serum LH levels in PRKO mice were found to be elevated by approximately 2-fold over basal (metestrus) values in wild-type mice.545 By contrast, basal FSH levels were not different in PRKO and wild-type mice. Basal levels of E2 and progesterone in serum were likewise similar in the two groups, as were hypothalamic LHRH concentrations. Basal PRL levels were slightly higher in PRKO versus wild-type mice. These results confirm the essential role of progesterone receptors in the regulation of hypothalamic and/or pituitary processes that govern gonadotropin secretion.545 

(4)   GR knockout 

Most of the mice homozygous for disruption of GR die shortly after birth due to severe lung atelectasis.546 Additional defects were found in the adrenals, liver, brain, bone marrow, and thymus as well as in the feedback-regulation of the HPA-axis.547 However, disruption of the ability of GR to dimerize is not lethal.548

(5)   MR knockout 

MR−/− mice, obtained by targeted gene disruption, died between days 8–13 after birth after exhibiting signs of pseudohypoaldosteronism and the pups died from dehydration by renal sodium and water loss.549 The MR−/− mice showed severe dehydration, hyperkalemia, hyponatremia, and high plasma levels of renin, angiotensin II, and aldosterone.550 The MR knockout mice showed significant increases in the expression level of several renal angiotensin system components: renin, angiotensinogen, angiotensin II receptor (AT1), but no alteration in angiotensin-I converting enzyme was detected in the kidney.550

(6)   Androgen receptor insensitivity  

A natural deficiency of androgen receptor occurs in the Tfm mouse551 that has an androgen receptor mutation that results in androgen insensitivity syndrome (AIS) that is an X-linked inherited disease.521 Various mutations in the AR in humans have been shown to cause AIS.552 Tfm mice (the males) exhibit complete infertility.521 

Male androgen receptor knockout (ARKO) mice are phenotypically female with an 80% reduction in testes size, and serum testosterone concentrations are lower than in wild-type (wt) mice.553 The male ARKO mice have reduced spermatogenesis and cancellous bone volumes and the female ARKO have reduced fertility.553 The mice also have specific skeletal muscle defects.554 Interestingly, none of the male or female ARKO mice exposed to N-butyl-N-(4-hydroxybutyl)nitrosamine (BBN) developed bladder cancer, whereas dihydrotestosterone (DHT) treatment of castrated ARKO or wt mice increased bladder cancer incidence by 25 and 50%, thus implicating roles for androgens and AR in the development of bladder cancer.555 Creation of transgenic mice with conditional knockout of AR only in prostate epithelia (pes-ARKO) revealed that these mice lacked external phenotypic differences seen in the ARKO mice, but that they showed increased prostate epithelial cell proliferation.556

METHODS FOR THE MEASUREMENT OF RECEPTORS IN TISSUES

Steroid hormone receptors are present in relatively low numbers in target tissues. Their instability when isolated from cells and tendency to adhere to the surfaces of test tubes requires special consideration in handling under experimental and clinical conditions. The basic principles of measurement of nuclear hormone receptors are the same as for plasma membrane receptors.557 Multi-point titration and sucrose density gradient analyses are commonly used for measurement of steroid hormone receptors in tissue samples.558 Tissue homogenates containing receptors are incubated with increasing amounts of radioactively labeled steroids of high specific activity in the presence and absence of corresponding excess unlabeled steroid or incubating with a fixed concentration of labeled steroid and increasing amount of corresponding unlabeled steroid.559 Tritiated or radioiodinated steroids are most commonly used because they are available in high specific activities. The binding in the presence of corresponding excess unlabeled steroid hormone is nonspecific binding, which is unsaturable and generally represents binding to nonreceptor sites. Nonspecific binding is subtracted from total binding (the amount bound in the absence of unlabeled steroid) to obtain saturable and high-affinity specific binding. By appropriately varying the incubation conditions, kinetic and equilibrium binding constants, specificity of binding, and other properties can be determined by titration analysis. Receptor-bound and free hormones are separated by dextran-coated charcoal559 or precipitation of steroid-receptor complex with protamine sulfate560 or absorption to hydroxyapatite561 followed by centrifugation and scintillation counting. For clinical samples, ER and PR status in breast tumor samples are quantitated by monoclonal antibody-based methods using a commercially available kit from Abbott Laboratories.562 One important clinical application of this method is the use of ERα and PR status as an indication for antiestrogen therapy.563

Scatchard analysis is the most universal method for calculating binding affinity (KD) and number (binding capacity) of steroid hormone receptors.564 The shape of Scatchard plots can be linear or curvilinear with upward or downward concavity. The interpretation and calculation of binding constants is the same as for membrane receptors.557

Ligand binding affinity and specificity for steroid hormone receptors

The apparent dissociation constants for steroid hormones binding to their cognate receptors is in the range of 10-11 to 10-9 M, which is close to circulating steroid hormone concentrations. The affinity of nonrelated steroid hormones to the receptor is generally about 100 times lower than the appropriate steroid hormone. However, if the levels of these nonrelated hormones are greatly elevated due to some physiological or pathological process, then significant binding and biological response to them can be expected.

Ligand binding specificity is also influenced by interaction with coactivators.  In the presence of coactivator ARA70, E2 bound to the AR and induced AR-responsive transcriptional activity more than 30-fold in DU145 human prostate cancer cells.331 In contrast, the synthetic estrogen diethylstilbestrol (DES) had no effect. The significance of this newly discovered ability of E2 to activate AR is strengthened by finding patients with Reifenstein partial-androgen-insensitive syndrome with a single mutation in the AR that makes the receptor nonresponsive to E2-stimulation in the presence of ARA70. These data suggest that testosterone/dihydrotestosterone are not the only ligands for the AR.565

 

MOLECULAR BIOLOGY TECHNIQUES FOR STUDY OF STEROID HORMONE RECEPTORS

Prior to the development of cloning techniques, steroid hormone receptor structures were analyzed by painstaking methods of classical protein chemistry. Protein purification required processing of large amounts of tissues and sequencing was laborious and slow. Ligand-binding characteristics were described by Scatchard analysis and binding displacement curves, as described above. 

Molecular biological techniques have revolutionized the study of hormone receptor biology, providing a wealth of information regarding the structure and mechanism of action of the steroid and nuclear hormone receptors. Common techniques used by molecular biologists include Southern, northern, and western blotting, used to detect the presence and size of specific DNA, RNA, and protein sequences, respectively.566 Molecular cloning of DNA provides a technique whereby a single segment of DNA can be isolated from a large population of genes, purified to homogeneity and amplified to produce sufficient quantities for structural and functional analysis. Receptors are now routinely cloned from RNA extracted from small amounts of hormone-responsive tissues or cells. When it is possible to predict a certain degree of homology of DNA sequence of the hormone receptor with other known proteins, specific DNA segments can be amplified using polymerase chain reaction (PCR), with the cDNA as template and highly conserved sequences from related proteins as primers.567 Alternatively, specific enzymes may be used to copy, cut and splice together pieces of DNA that are inserted into circular plasmid DNA or bacteriophage viruses, introduced into bacteria and allowed to divide many times. The greatly amplified DNA is then isolated, purified and the nucleotide sequence of the cloned DNA segment is determined. The cDNA clone can be transcribed into mRNA and used to confirm biological activity in in vivo and in vitro functional expression systems and the amino acid sequence of the encoded protein can be readily determined. The cDNA can be tagged with radioactivity or a fluorescent marker and used to detect the presence or describe the distribution of receptor mRNA in various tissues and endocrine states using solution hybridization and in situ hybridization methods.

Once the molecular structure of the receptor protein is known, the structure-function relationships of certain amino acid sequences relative to those of other receptors in the steroid hormone receptor family are investigated using domain-swapping and site-directed mutagenesis methods. In domain-swapping experiments, hybrid mRNA transcripts can be produced from a receptor cDNA in which a key functional element, such as the ligand-binding domain, is replaced with the nucleotide sequence from the same region of another closely related receptor.568 With this technique, it has been possible to determine the functional significance and specificity of the various regions of the steroid receptor proteins.568 Site-directed mutagenesis has been used to determine the identity of amino acid residues that are important for DNA and ligand binding of ERα.569

The electrophoretic mobility shift assay (EMSA), also called gel mobility shift assay, is the most common technique to examine the binding of a given steroid/nuclear receptor to DNA.570 For EMSA, a preparation of a particular steroid/nuclear receptor is incubated with a short (20–400 bp) fragment of [32P]-labeled double-stranded DNA. The DNA may be a synthetic construct of a particular HRE or a fragment from the promoter of a particular gene that is thought to contain a HRE. The protein-DNA reaction mixture is then separated by a nondenaturing polyacrylamide gel electrophoresis. The free [32P]-labeled DNA migrates to the bottom of the gel, while the migration of the [32P]-labeled DNA that is bound by the receptor is slowed. The gel is dried and exposed to X-ray film or placed in a Phosphorimager cassette to detect where the [32P] is located. The free, unbound [32P]-labeled DNA appears at the bottom and the receptor-bound DNA is located toward the middle or top of the gel. Addition of a 50–200-fold molar excess of cold competitor DNA is used to determine the specificity of the receptor-DNA complex. Addition of an antibody to a particular steroid/nuclear receptor is used to confirm the identity of the protein in the protein-DNA complex. The antibody may either block the receptor-DNA binding, leaving an empty spot on the autoradiograph; “supershift” the receptor-DNA complex by binding stably to it and thus further retarding its mobility in the electrophoretic field; or have no effect, indicating that the epitope recognized by the antibody is not available under the assay conditions. EMSA is useful to compare the relative binding affinities of a given receptor for various HREs in vitro.177

Chromatin immunoprecipitation (ChIP) is used to examine the association of specific proteins with specific regions of the genome by using specific antibodies that recognize a specific protein or a specific modification, e.g., phosphorylation or acetylation, of a protein. ChIP is used in molecular endocrinology research to examine the time or ligand-dependency of direct interaction of NR with a region of DNA in a cell or tissue.571, 572 This technique is primarily used to examine the binding of a NR to a known region containing a HRE in cultured cells. For ChIP analysis of NR-DNA interaction in cells, the cells are treated with vehicle versus ligand for a short period of time (20–60 min) followed by cross-linking of protein-protein and protein-DNA in live cells with formaldehyde. After cross-linking, the cells are lysed and whole cell extracts are sonicated to shear the DNA to ~500 bp lengths. The proteins together with cross-linked DNA are subsequently immunoprecipitated with specific antibodies, e.g., to ERα.272, 273, 403, 572, 573, 574, 575, 576, 577, 578, 579 The protein-DNA cross-links in the immunoprecipitated extract are reversed by heating and the DNA fragments are purified and PCR amplified using primers flanking the region of interest and a nonspecific region, e.g., far upstream of the promoter or ERE-containing region.580 “Re-ChIP” is used to identify proteins that simultaneously interact with the first protein/gene region.156, 277, 581, 582, 583, 584 

To examine how a particular ligand, steroid receptor, and HRE affect transcription, transient transfection experiments are performed in cultured mammalian cell.402 For these experiments, the cell must either contain the steroid receptor of interest or the receptor must be introduced into the cell by means of an expression vector encoding the cDNA of the receptor with a strong viral promoter, e.g., CMV or RSV, to ensure its expression. The reporter vector contains a reporter gene not expressed in normal mammalian cells. Examples of reporter genes are chloramphenicol acetyltransferase (CAT),585 luciferase,402 and green fluorescent protein (GFP).586 The reporter and hormone receptor expression plasmids are transfected into the mammalian cells using calcium phosphate co-precipitation, electroporation, or by means of lipid-mediated transfer, e.g., Lipofectamine.402 Following a recovery period, the cells are treated with hormone for 12–48 h. The cells are then lysed and reporter gene activity is measured. As a control, cells are usually co-transfected with a β-galactosidase or Renilla reporters as an indication of the percent efficiency with which the cells have taken up the plasmid DNA.587 This technique allows quantitation of how different ligands and DNA sequences affect the transcriptional response of a given steroid receptor. In addition, co-transfection of the cells with expression plasmids for coactivators or corepressors allows determination of the functional consequence of these proteins.588

EFFECTS OF STEROID HORMONES ON BEHAVIOR

Effects of steroid hormones on behavior

Steroid hormones exert profound effects on mood, mental state, and memory by acting on both "classical" monoamine and neuropeptide transmitter mechanisms in the brain.589, 590 In women, estrogen is thought to protect against depression and delay the onset of schizophrenia,591, 592, 593 and Alzheimer's disease,594, 595, 596, 597, 598, 599 although other studies indicate that estrogens may increase the risk of the development of dementia.600 Estradiol has been implicated in the physiologic control of eating in laboratory animals and thus may play a role in anorexia nervosa, bulimia, and other eating disorders.601 Estrogens and progestins have been shown to regulate the synthesis and release of brain neurotransmitters including norepinephrine, dopamine, serotonin, gonadotropin releasing hormone, beta-endorphin, corticotropin releasing factor, and prolactin.589 A comparison of pre- and postmenopausal women to “stress reactivity to math and speech tasks” showed a higher elevation in systolic blood pressure in postmenopausal women compared with premenopausal women in response to the stressor, indicating that estrogens “blunt” the stress response, thus offering a hypothesis for the increased risk of cardiovascular disease in postmenopausal women.602, 603 Estrogens have proven mood-elevating and antidepressant properties and prior to the termination of the Women’s Health Initiative (WHI) hormone replacement therapy (HRT) trials,604, 605 HRT was commonly used to treat these and other menopausal symptoms.606 

Estrogens607 and progestins608 play a key role in female rodent sexual receptivity609 and in behavior.610, 611, 612 Studies with ER and PR knockout (ERKO and PRKO) mice showed that the female mice exhibited reduced521, 533, 608, 613, 614 or exhibited no lordosis,521 respectively, and that PR-regulation of dopamine synthesis in the brain is involved in this lack of responsiveness to male advances.609 PRKO male mice showed reduced mount frequencies compared to wild-type mice, indicating a role for progestins in regulating male sexual response.615, 616

The sexual orientation of homosexual (gay) men is a biological variation of human sexuality/sexual preference that has been postulated to be dictated by testosterone action on the prenatal and possibly postnatal brain.617 Whether homosexual males are “hyper-masculinized” by high or “under-masculinized” by low prenatal testosterone remains uncertain.618 Likewise, the etiology of female (lesbian) homosexuality is undefined, but appears to involve prenatal and/or postnatal hormone exposure, at least in “butch” lesbians.618 Differences in auditory system responses of lesbian and bisexual females compared to heterosexual women were suggested to be caused by alterations in brain structures that had been partially masculinized by exposure to high levels of prenatal androgen.619 Correlations of auditory responses with sexual orientation in males and females were most often consistent with the hypothesis that male homosexuals were undermasculinized and female homosexuals overmasculinized, presumably due to prenatal testosterone exposure.620 Experiments in female zebra finches showed that early estrogen treatment or injection with an estrogen synthesis inhibitor resulted in a preference for females over males as mates.621 These results suggest that sexual partner preference may result from hormone actions in the developing brain of these birds, but the implications on human sexual orientation are uncertain.

It is still unclear to what extent cross-gender identity (transsexuals) is due to pre- and perinatal organizing effects of sex hormones on the brain.622 A study of early onset, adult male-to-female (MTF) and female-to-male (FTM) transsexuals, who were not yet hormonally treated, showed pronounced gender differences, and that both transsexual groups occupied a position in between the two control groups, indicating a pattern of performance away from their biological sex.623 Prenatal androgen exposure has been implicated in transsexualism and the ratio of the 2nd to the 4th (2D:4D) digit lengths has been suggested to be negatively correlated to prenatal androgen exposure.624 A recent study reported that the right-hand 2D:4D in MFT is higher than in control males but similar to that observed in control females, but no differences were seen in FMT relative to control females.624 The authors concluded that these data support a biological etiology of male-to-female transsexualism, implicating decreased prenatal androgen exposure in MFT.624

In animal models, androgens play a critical role in engendering neural sexual dimorphism by masculinizing the nervous system of males.625 Usually, the androgen must act early in life, often during the fetal period, to masculinize the nervous system and behavior.625 Interestingly, androgens appear to work by being converted to estrogens and binding to ER, since ERKO male mice show reduced masculinization535 and aromatase knockout (ArKO) mice have decreased fertility and deficits in male sexual behavior including mount, intromission, and ejaculation.626 In aging men, decreased testosterone has been associated with symptoms including depression, anxiety, irritability, insomnia, weakness, diminished libido, impotence, poor memory, reduced muscle and bone mass, and diminished sexual body hair.627 However, there is great interindividual variability, and the connection between serum testosterone levels and clinical psychiatric signs and symptoms is not clear-cut, since other hormonal changes are implicated as well.627 Previous studies suggested that postmenopausal women have “androgen deficiency” resulting in decreased sexual desire, and that administration of testosterone improves a number of parameters of sexuality in the testosterone-treated postmenopausal women.628 However, more recent results indicate no benefit of testosterone therapy, highlighting the concern that conversion of androgens to estrogens may increase breast cancer risk.629

 

STEROID HORMONE RECEPTORS IN DISEASE STATES

Clinical manifestations of abnormal steroid hormone receptor function have been demonstrated to involve variation in receptor numbers and the ability to stimulate transcription of certain genes. Hormone resistance, the failure of tissues to respond to normal circulating hormone levels, has been shown in a variety of endocrine systems to be due to the genetic lack or functional defect in steroid hormone receptors. The gene for the human androgen receptor has been isolated, cloned, and mapped to a locus on the X chromosome.630 Deletions in all or part of this gene have been shown in several individuals with complete androgen insensitivity.631, 632 The lack of functional androgen receptors results in testicular feminization.633 Hypocalcemic (Type II) rickets results from a single gene mutation in the steroid hormone binding domain of the human vitamin D receptor gene.634, 635

Sex steroid hormones have been implicated in the pathogenesis of breast, uterine, ovarian, prostate, thyroid, and other cancers. Expression of mutant forms of ERα may be an important factor in some cases of breast cancer.636 Determination of steroid hormone receptor expression, i.e., ERα and PR, in breast tumors, is critical to the selection of appropriate therapy. Hormone-dependent tumors tend to have elevated levels of steroid hormone receptors.637 One study found that 50% of the 60 breast tumors sampled expressed both ERa and ERβ, and that the ERα+/ERβ+ phenotype was associated with node positive status.638 It has long been established that elevated levels of ERα and ERβ are highly associated with poor histological differentiation in breast cancer and may serve as a predictor of responsiveness to endocrine therapy as well as a prognostic indicator of metastatic disease.637 The combined presence of ER and PR in a breast tumor provides an additional indication of the probability of prolonged survival following antiestrogen therapy.639, 640, 641, 642 

Association between single-nucleotide polymorphisms (SNPs) in ER genes and disease have been demonstrated in several cases.643

Steroid hormone receptor analysis has limited value in the selection of patients with endometrial cancer for endocrine therapy because both normal and malignant uterine tissues contain significant levels of both estrogen and progesterone receptors.644 Although the results of different studies disagree, progesterone receptor expression appears a better prognostic indicator than ERα expression in ovarian cancer.645 At present, the relationship between steroid-receptor status and response to endocrine therapy in ovarian cancer remains to be established. 

Glucocorticoid resistance results from an inability of glucocorticoids to exert their effects in their target tissues.646 Glucocorticoid resistance is associated with elevated ACTH and cortisol, with an attendant increase in  adrenal androgens and steroids with salt-retaining activity. Clinical manifestations of glucocorticoid resistance vary from asymptomatic to different degrees of hypertension and/or hypokalemic alkalosis and/or hyperandrogenism. In women, the excess androgens can result in acne, hirsutism, male type baldness, menstrual irregularities, oligoanovulation, and infertility; in men, it may lead to infertility; and in children to precocious puberty. Different molecular defects in the GR gene, resulting in various defects in the receptor protein, alter the functional characteristics and/or concentrations of GR and cause glucocorticoid resistance.647 It is postulated that acquired tissue-specific glucocorticoid resistance may play a role in the origin and pathogenesis of depression, steroid-resistant asthma, autoimmune disorders, and AIDS.648, 649 Glucocorticoid receptor mutations have been suggested to play a role in the pathogenesis of leukemia, hereditary glucocorticoid resistance, and Nelson's syndrome.648 Corticosteroid-resistant asthma has recently been found associated with decreased GR and increased AP-1-DNA binding in peripheral blood mononuclear cells as compared to corticosteroid-sensitive asthma.650 These findings indicate that variations in the GR may play a central role in a wide variety of diseases.651

Hypertension and pseudohypoaldosteronism are associated with diminished or complete loss of high-affinity aldosterone receptors in select target tissues in some, but not all patients.652 MR induces the transcription of specific genes which regulate apical amiloride-sensitive epithelial sodium channels located in the apical membrane of epithelial cells from the distal colon and kidney collecting duct.653

Estrogens play a central role in the immune response and immune-mediated diseases and cells involved in the immune response, namely thymocytes, macrophages, and endothelial cells, express ERα.654 Certain pathological states are characterized by the production of abnormal levels of antibodies to steroid hormone receptors. Although the autoimmune disorder systemic lupus erythematosus (SLE) was postulated to result from anti-estrogen receptor action,655 and one study showed that men with autoimmune disorders, including SLE, or related diseases such as mixed connective disease and Sjogren's syndrome, had increased serum levels of antibodies to estrogen receptors compared to women,656 another report showed that peripheral blood monocytes of SLE patients showed a similar Kd and number of specific [3H]E2 binding sites compared to normal values.657 Hormonal regulation of B cell function was recently reviewed.658 Similarly, ERα variants do not appear to play a role in SLE.659 

ENDOCRINE DISRUPTORS

Endocrine disruptors (ED) are chemicals present in the environment that are thought to disrupt endogenous hormone action by acting either as hormone agonists or antagonists in vivo. ED have been postulated to play a role in the increased incidence of breast cancer in the US since 1940660, 661 and decreased sperm counts662 as well as reproductive tract abnormalities in wildlife species.663 In the years following World War II, the production and use of a variety of hydrocarbons as pesticides, herbicides, food preservatives, and plastics has increased.664 A growing body of evidence indicates that some of these compounds, whether as food or aquatic contaminants, mimic, antagonize, or indirectly alter the activity of estrogens in vivo.665, 666, 667, 668 Such compounds are collectively referred to as “environmental estrogens” (EE) or “xenoestrogens”. Amongst the chemicals thought to be xenoestrogens are various organochloride pesticides, e.g., dieldrin; polychlorinated biphenyls (PCBs), a family of 209 related compounds widely used as industrial coolants; alkylphenolic polyethoxylates (APEOs: 4-nonylphenol [NP] and 4-octylphenol [OP]), used as nonionic surfactants in detergents, paints, herbicides, and pesticides; bisphenol A, used in manufacturing plastics; and the heavy metal cadmium.669 EE are also natural dietary components, e.g., the phytoestrogen coumestrol.433 Because they are lipophilic, EE can enter the human body by ingestion or adsorption through the skin and mucosal membranes. Certain EE, e.g., OP and NP,670 are present in water from sewage treatment plants and bioaccumulate in aquatic species and in animal fat.660 Bisphenol A is a contaminate in canned foods671 and was found in human saliva after dental work.672 However, the level of human exposure to these agents and whether these levels are sufficient to cause harmful effects remains controversial.142, 673, 674, 675, 676, 677, 678, 679, 680 Long-term exposure to exogenous estrogens is thought to increase the relative risk of not only breast, but also liver, ovarian, and uterine tumors.681, 682, 683, 684, 685 Because EE lack structural similarity to natural estrogens, i.e., estradiol (E2), having in common only a phenol ring,686 it is not immediately obvious which compounds have estrogenic or antiestrogenic activity. Although all EE stimulate cell proliferation, not all EE induce estrogen target genes, indicating a divergence in the molecular pathways regulating cell proliferation and estrogen end-product induction. The US Environmental Protection Agency (EPA) is currently funding considerable research on endocrine disruptors. 

SUMMARY

The past 20 years have seen remarkable progress in our understanding of the mechanism of action of steroid hormones and receptor function. The development of molecular cloning, targeted gene disruption, microarrays, and ChIP analysis of NR-chromatin interaction has greatly facilitated the molecular understanding of steroid receptor action. We know that steroid hormones and other ligands mediate their biological activities by binding to a superfamily of related receptors that share a common modular structure. The steroid receptor superfamily includes not just receptors for steroid hormones and thyroid hormones, but also a diverse set of other gene regulators, some of which are called orphan receptors and whose ligand, if necessary, is, at present, unknown. Tremendous progress has been made in understanding the way hormone-liganded-steroid receptors interact with specific binding sites in hormone-regulated genes and the role of receptor interaction with other nuclear transcription factors in the regulation of hormone target gene transcription. Another significant advance is the identification of coactivators and corepressors as proteins that interact directly with steroid/nuclear receptors, but not with DNA, that aid the receptors in modulating target gene expression. The nucleosome remodeling activity of these coactivators and corepressors and their associated proteins has revealed the importance of chromatin structure in hormone-induced gene transcription. The importance of multiple levels of “cross-talk” between cell-membrane-bound receptors, acting via second messenger phosphorylation cascades, and nuclear hormone receptors, and between different classes of transcriptional enhancer proteins, indicates the overall complexity involved in specific gene regulation. Finally, recent developments in the analysis of abnormal receptor structure and function have enhanced our potential for clinical diagnosis and treatment of numerous endocrine disorders.

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