The

steroid PETERJ. Prince

receptor

superfamily:

Institute

of Medical

Research,

Prince

The steroid receptor superfamily of ligand-dependent transcription factors is characterized by marked conservation of both structure and function between the various receptors. Despite their welldocumented extensive similarities, these receptors respond to a diverse range of ligands, which results in an even more impressive diversity of function. A variety of strategies is used at each point in the pathway from ligand binding to gene expression to achieve this diversity. The nature of the ligand is important as are the tissue-specific patterns of receptor gene expression, the presence of binding proteins, and the effects of cell- or tissue-specific ligand-modifying enzymes. Once bound to the receptor, the nature of which may vary as a result of either differential splicing or gene duplication yielding multiple isoforms, the activated receptor may form heteroor homodimers. A complex interplay then occurs between the receptor dimer, other nuclear proteins, the response element, and the promoter complex to regulate gene expression. These elements may vary as a function of the cell type, other stimuli, and the context and sequence of the response element (or elements) in a given gene. By these mechanisms diversity may even be achieved for a given ligand, receptor subtype, gene, or cell. The observations may help to explain certain phenomena in hormone biology that are difficult to reconcile with the previous, simple, univariant model of steroid hormone action. Fuller, P. J. The steroid receptor superfamily: mechanisms of diversity. FASEB 5: 3092-3099; 1991.

J.

THE

steroid

STEROID

receptor

RECEPTOR

transaclivation

SUPERFAMILY

of

DNA

binding

ligand-dependent

transcription factors includes not only the cellular receptors for the steroid hormones, but receptors for a range of other hormonal and nonhormonal molecules (Table 1). After the initial structural characterization of the glucocorticoid, estrogen, and progesterone receptors by conventional methods, the marked similarities within these molecules, and between these receptors and the v-erb A oncogene product, enabled subsequent

studies

to be driven

by reverse

genetics.

The

net

result has been the identification of a superfamily of receptors for hormones, vitamins, and chemical agents as well as a range of receptors, some of which have an identified function but all lack even a putative ligand (Table 1). This latter group has been rather poignantly designated orphan receptOrs (1). Central to the identification of this superfamily has been the remarkable conservation of structure and function between the various receptors. Given the degree of conservation, it is remarkable that such a diverse range of ligands achieves an even more impressive diversity of function. Previous reviews have focused on these similarities (2-6, 6a); this review will focus structural organization observed diversity.

3092

of diversity

FULLER’

Henry’s

ABSTRACT

Key Words:

mechanisms

on the mechanisms by which the basic is variously modified to achieve the

Henry’s

Hospital,

Melbourne,

Victoria,

3004

Australia

BACKGROUND The steroid receptor superfamily is characterized by a unique modular structure (Fig. 1), with receptors classically divided into three main domains and several subdomains or regions. The centrally located, highly conserved DNA binding domain of 66-68 amino acids defines this superfamily. The sequence predicts a zinc finger structure in which the two loops are stabilized by the interaction of the cysteine residues with a zinc atom (Fig. 2) (4). This structure has recently been confirmed by nuclear magnetic resonance (NMR)2 spectroscopy of the glucocorticoid (7) and estrogen (8) receptors. For all receptors across species (Table 1), 18 of 68 residues are invariant, and for human receptors this figure rises to 36 of 68 (Fig. 2). The derivation of this structure and the nature of its interaction with the double helix has been defined in a series of elegant studies (2-5, 9). In common with other DNA-binding transactivators (10), the receptors dimerize with the DNA-binding domain of both molecules contacting the specific response element (3, 4). The second, relatively invariant region is the COOHterminal ligand-binding domain (Fig. 1). Homology between receptors in this domain is most marked for the androgen, glucocorticoid, progesterone, and mineralocorticoid receptors where this sequence conservation has a functional consequence: cross-binding of ligands. The group of receptors that includes thyroid hormone, retinoic acid, and vitamin D does not exhibit cross-binding of ligands nor the same degree of overall homology in this domain. This group nonetheless has two highly conserved subdomains, a central region to which is attributed a dimerization function and a region designated ‘yi [or conserved domain 2(5,12)], which is conserved among all receptors and may play a role in the inactivation of transcription that is relieved by ligand binding (6). A second region of 22 amino acids [conserved domain 3(5,12)], which is also conserved across the vertebrate receptors, lies within the putative dimerization domain. These conserved motifs are more likely to be structural than specificity-conferring; for instance, they may be important in dimerization, transcriptional activation, or in forming the ligand-binding pocket. The NH2-terminal domain is perhaps of more interest in the context of this review, being poorly conserved both in size (vitamin D receptor: 25 amino acids vs. mineralocorticoid receptor: 603 amino acids) and sequence. Even for a given

‘Address for correspondence: Prince Henry’s Institute of Medical Research, P.O. Box 118, South Melbourne, Victoria, 3205 Australia. 2Abbreviations: HRE, hormone response elements; GRE, glucocorticoid response element; TRE, thyroid response element; CBG, cortisol-binding globulin; TR, thyroid receptor; RAR, retinoic acid receptor; ERE, estrogen response element; nGREs, negative GREs; POMC, proopiomelanocortin gene; TAF, transactivator function; MMTV-LTR, mouse mammary tumor virus longterminal repeat.

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TABLE

1. Steroid receptor superfamily

MAMMALIAN:

PRERECEPTOR

Known

ligand

Glucocorticoid

(2)

Mineralocorticoid Progesterone (2) Androgen (19)

(2)

Estrogen

(2)

Vitamin

D (2)

Thyroid

a, /31, and

/32 (2, 43, 47)

Retinoic acid a, /3,and ‘y (13, 30, 39) RXRa and /3(40) Peroxisome

proliferators

Orphan

receptors

hERRI

(2)

hERR2 (2) Coup/ear-3 (6,

ear-2/H-2RII

(81)

12) (6, 82)

erbAa 2 and 3 (45-47) Rev-erbAa/ear-I (46, 47) TR2 (82) DROSOPHILIA:

Tailless (Ii) Seven-up (11)

E75A and B (11, 83) EcR/DHR23 (83) Ultraspiracle/XR2C (40) Knirps (11) Knirps-related (11) Embryonic gonad (ii)

conservation

of structure

extends

to

function;

these

receptors are ligand-dependent transcription factors (2), and in common with other transcription factors regulation of gene expression requires DNA binding (9, 10). The DNAbinding domain interacts with hormone response elements (HRE), which are enhancer elements in the regulatory (usually 5’ flanking) region of the specific steroid-induced gene. Such is the conservation of the consensus sequence of the various HREs that in the mouse mammary tumor virus long-terminal repeat (MMTV-LTR) the same HRE is recognized by androgen, progesterone, glucocorticoid, and mineralocorticoid receptors (3, 4). An estrogen response element (ERE) can be converted to a glucocorticoid response element (GRE) by changing just two bases (3, 4), and a thyroid response element (TRE) is a pentadecamer ERE without the nonconserved three middle bases (3, 4, 6). Hormone response elements exhibit diad symmetry, congruent with the demonstration that receptors bind to DNA as dimers, like many other transactivators (10). In

spite

function diversity This has

of the

within

remarkable this

conservation

superfamily,

an

of structure equally

of signals has used this basic effector been achieved by subtle modifications

Prereceptor

enzymatic

activity

similarly

confers

The intracellular localization of the unliganded receptor and the role of the heat shock proteins in cytoplasmic binding of the receptor have been controversial issues (15). Except for the glucocorticoid receptor, steroid receptors appear to be predominantly nuclear (16). The closely related glucocorticoid, androgen, mineralocorticoid, and progesterone receptors have a conserved sequence of eight amino acids just after the DNA-binding domain (Fig. 1) which is homologous to the SV4O T-antigen nuclear localization signal (17) and has been shown to be constituitively active in the progesterone receptor (18); this signal may be masked in the glucocorticoid receptor perhaps by heat-shock protein binding. The 90K heat-shock protein complexes with steroid receptors but not with the thyroid receptor (5, 15); because steroid receptors (with the exception of the glucocorticoid receptor) are nuclear, the physiological relevance of this finding is uncer-

N1 Ugand Binding DNA Binding Dnenzation Transactivation Nuclear Localization hsp9O Binding

and

remarkable framework. at each point

in the pathway from the ligand through its interaction with the receptor to the regulation of gene expression by the activated receptor.

STEROID RECEPTORS

reductase.

LOCALIZATION

receptor, comparisons across species show little conservation of sequence, in contrast with the DNA and ligand-binding domains that are highly conserved (commonly 100 and >90%, respectively). This

Before entering the cell, ligand access to the receptor is regulated by binding proteins in the plasma [cortisol-binding globulin (CBG), thyroid-binding globulin, etc.]; for retinoic acid, cytoplasmic retinol-binding proteins may similarly modulate access to its receptor (13). Several hormones (thyroxine, vitamin D, testosterone) are processed to an active or more active form by enzymes that are regulated and rate limiting. Although the testosterone receptor appears to be the same in all tissues thus far examined, the sensitivity of a tissue varies depending on whether it contains 5aaldosterone selectivity on the mineralocorticoid (type I corticosteroid) receptor. The native receptor cx vivo binds cortisol with equivalent affinity to aldosterone. Circulating concentrations of cortisol, CBG binding of cortisol notwithstanding, are higher than that of aldosterone; yet in vivo the receptors in mineralocorticoid target tissues are occupied not by cortisol but by aldosterone. Selectivity is conferred at the tissue level by an enzyme (11/3 hydroxysteroid dehydrogenase) that converts cortisol to its inactive metabolite cortisone (14), thereby removing cortisol from the immediate intracellular environment of the mineralocorticoid receptor. In certain tissues (such as the hippocampus) this enzyme is absent, enabling receptor occupancy by cortisol (14).

BP (81)

nur77/NGF1-B/TR3

MODULATION

Figure 1. Schematic representation of a steroid hormone receptor indicating the structural and functional organization. The shaded midportion is the 66-68 amino acid DNA-binding domain (Fig. 2) that defines this superfamily. The COOH terminal shaded region is the ligand-binding domain, which includes the two conserved domains 2 and 3.

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GH

-

D

v’/Zn C

K D I

T C

C

-

-

-

G

conservation of sequence the criticaldivergences that define specificity for a given class of ligand have received little attention. Forman and Samuels (6) have argued that at least for the group of receptors that includes the thyroid hormone, retinoic acid, vitamin D, and certain orphan receptors, broad regions at the amino and carboxyl termini of the ligand-binding domain confer specificity. The region is conserved for a given ligand but not conserved between receptor

-R V G V

A

-

C A CR

-

--

C Zn

G

c”

C K -FFKR---G---Y

‘cK

types,

- -

G II

Figure 2. Schematic representation of the two zinc fingers in the DNA-binding domain. Residues conserved across the human hormone receptors (see Table 1 for references) are shown.

tam

(5, 15), although it appears to be important both for stabilizing the unliganded glucocorticoid receptor and facilitating hormone binding (15, 17). The mechanism whereby the glucocorticoid receptor is different, and the biological implications of this difference, remain to be established. Although the unliganded glucocorticoid receptor binds to GREs in vitro, this does not appear to be the case in vivo; in contrast, thyroid receptors, for example, are bound to the DNA in the absence of ligand (discussed later). Although both estrogen (16) and progesterone (18) receptors are predominantly nuclear, they do not bind response elements in the absence of ligand. In the case of the glucocorticoid receptor it may be disadvantageous to have nuclear interactions between ligand-activated and unliganded glucocorticoid receptors with consequent modulation of the signal when this receptor is responding to stress levels of cortisol; alternatively, its cytoplasmic location may prevent interactions with various nuclear signal-transduction pathways (e.g., fos, jun: see later discussion) until receptor activation has occurred.

LIGAND

BINDING

The crux of the diversity achieved by this superfamily of transcription factors lies in their ability to respond to different signals. The extent of this diversity has expanded from steroid hormone receptors to include the receptors for thyroid hormone and the retinoids. In addition, an increasing number of these receptors (Table 1) have a COOHterminal region homologous to the other receptors but for which no ligand has been identified. These orphan receptors may number as many as 25 (1). O’Malley (1)has postulated that some may respond to intracellular ligands, perhaps the products of metabolic pathways or of hormone/ligand synthesis, a mechanism he has termed intracrine gene regulation. Members of this gene superfamily in Drosop/zilia appear to divide into two groups, those that exhibit the same conservation of sequence in the ligand-bmnding domain and those that lack this homologous COOH-terminal domain (11). It is thus possible that at one extreme of this gene family the molecules remain transactivators, but are no longer liganddependent. The glucocorticoid receptor ligand-binding domain shares only 30% homology with the estrogen receptor and 17% with the thyroid receptor; on the other hand, it exhibits 55, 57, and 50% homology with the progesterone, mineralocorticoid, and androgen receptors in this region (2, 19). Previous analyses have focused on regions of homology such as the conserved domains 2 and 3 (5, 12), but in the regions of non-

which

fits

both

with

the

ligands

being

chemically

Un-

related and with the lack of cross-over binding between members of this disparate group. Most analyses of the ligand-binding domain have used COOH-terminal deletions or insertional mutagenesis with quantitative rather than qualitativeresults(2, 6, 20, 21). Although definitionof the precise details of ligand binding will require crystallographic studies,

some

insights

might

be

gained

from

site-directed

mutagenesis of specific residues or from the naturally occurring mutations in hormone resistance syndromes. Single point mutations causing diminished or absent ligand binding have been reported in patientswith resistanceto cortisol (22), testosterone (19), vitamin D (23), and thyroxine (24, 25). Mutations in highly conserved residues such as the Arg to Gln substitution at position 734 in the androgen receptor of the Tfm rat (26) might result in disruption of a critical structural determinant of ligand binding. Similarly, in two kindred with generalized thyroid hormone resistance,the proline to histidine substitution at position 448 (24) or the glycine to arginine substitution at position 340 (25) of the f3 receptor gene both occur at positions conserved in all the thyroid and retinoid receptors (6), again suggesting an important structural role for these residues. A qualitative change has been reported in a case of complete androgen insensitivity (27) where replacement of valine at position 866 by methionine (as occurs naturally in both corticosteroid receptors) altered ligand specificity. Similarly, in glucocorticoid resistance(22) where asparate at position 641 (which is conserved in all species of glucocorticoid receptor sequenced but not in other types of receptor) is now a valine, the residue mutated may also be an important determinant of specificity. Specificitymight also be conferred on the human glucocorticoid receptor by the cysteine residue at position 638, the site of covalent attachment of dexamethasone mesylate (28);this cysteine isconserved in other species(rat, mouse) but not in other receptors.Cysteine 638 and asparate 641 liewithin a relatively hydrophobic region, which suggests that this region isa likelysiteof receptor ligand interaction (28). Lopez et al. (29) recentlyexplored the abilityof arseniteto react with spacially close thiol groups. The proximity of two other cysteines

to

cysteine

638

is

unique

to

the

glucocorticoid

receptor; it is thus of interest that it is the only receptor where binding isinhibitedby arsenite,supporting an important specificity-conferring role for these cysteine residues in glucocorticoid receptors (29).

NH2-TERMINAL

REGION

The most obvious and perhaps most interesting differences between the members of this highly conserved family reside in the NH2-terminal region. This region varies both in size and sequence, with little conservation of sequence even within the one receptor type across species. The retinoic acid receptors (c and /3) are exceptions, where the mouse and human receptors are 99% identical in their NH2-terminal domains (30). Although this region is no longer classified simply as the immunodomain, its function has not been fully

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elucidated. NH2-terminal deletions or mutations may quantitatively or qualitatively change transactivation activity (2, 20, 21, 31). Activating regions have been classified as being rich in acidic residues, glutamines, or prolines (9); they are not usually susceptible to single-base substitutions but regions can be substituted or exchanged (9). The rat and mouse glucocorticoid receptors and the chicken progesterone receptor contain regions of glutamine/glutamic acid repeats in their NH2-terminal domains. This region is deleted in the glucocorticoid receptors of two glucocorticoid-resistantmouse lymphoma S49 celllinesthat both exhibit reduced ligand-dependent transactivation (20). The human glucocorticoid receptor contains an 82-residue acidic transactivation domain that is not homologous with the enhancement domain in the rat glucocorticoid receptor but is analogous to the activating region of yeast GAL4 (21). This

cross-species

the

conservation

molecule.

diversity

of

Androgen

is unexpected,

sequence receptors

particularly

elsewhere contain

in

three

the

given

receptor

potential

trans-

activating regions in their NH2-terminal domain: a stretch of glutamine residues, a run of glycine residues, and a smaller region of proline residues (19). A curious polymorphism has emerged for the human androgen receptors where the lengths of these homopolymeric regions vary with reports of 17 to 20 glutamines and 16, 23, or 27 glycines (19). The generation by alternative splicing of isoforms that differ at their NH2-termini is a feature of several receptors including the progesterone receptor (32), where the shorter A form lacks 128 amino acids including a highly acidic region. Differential regulation of different promoters has been reported for each form (32), which not only suggests a potential point of modulation of progesterone effects via differentialsplicing of the receptor but also underlines the importance of this region in these receptors. Studies using both chimeric receptors and deletion mutants indicate that the effects of the NH2-terminal region can be not only promoter-specific but also cell-specific (33-35). Analysis of the hormone response motifs suggests a lack of specificity at this level (e.g., the MMTV promoter). Specificity may thus be conferred by the NH2-terminal region, the context of the response element, and the cell type. Intrinsic to their role as transactivators is the concept that these receptors interact with other nuclear factors to regulate gene expression. Such factors can be functionally limiting, at least under experimental conditions, so that one class of receptor may inhibit activationby a separate classof receptor (36). Competition by transactivators for a pool of limiting soluble factors has been termed the transcriptional interference phenomenon or squelching (37). Whereas the NH2terminal domain clearly contains transactivating regions, there is also a region within the ligand-binding domain that has the ability to transactivate independent of possible effects of ligand binding, nuclear localization, and dimerization (6, 31, 33). Tasset et al.(31) have analyzed the patterns of activation for various receptor regions and transactivation domains

of other

nuclear

factors

by comparing

their

ability

to

compete for other limiting nuclear factors (squelching). Their data indicate that classes of transactivators can be defined by their ability to interact with different nuclear factors and that transactivator domains may be composed of two different functional classes of transactivator.

ISO FORM

S

The thyroid (TR) and retinoic acid receptors achieved greater diversity both by alternate

(RAR) splicing

have of a

given transcript mone receptor chromosomes

and by gene duplication. Two thyroid horloci (a and j3) have been identified on human 17 and 3, respectively (24, 25). Linked to

these, due presumably to an earlier preceding gene duplication event, are the a and /3loci for the retinoic acid receptor (38). In addition the RAR has a third locus (RARy) on

chromosome 12 (39) and a further, but nevertheless retinoic acid-binding The effect of this molecular diversity

more distantly related species, RXR (40). is reflected in different

tissue-specific

for

patterns

of expression

each

locus

(38).

In

addition, the binding affinities of the RAR genes differ with the 3 and -y genes having 10-fold higher affinities for retinoic acid an

than

the

expanded

important

a

gene

range

(39).

if target

concentration bryo (13).

The

This

of ligand

tissues

gradients concept

may

enable

concentrations

are

which

to respond

of retinoids of receptors

responses

over may

differentially

be

to

in the developing emresponding to different

segments of an expanded concentration range may also apply to the binding of cortisol to the type I and type II corticosteroid receptors (14). In addition, divergence of the NH2-terminal

sequence

between

genes

may

enable

specific

patterns of interaction with other transactivating factors. RARa, RAR/3, and RAR-y all have multiple isoforms that differ in their 5-untranslated regions and NH2-terminal amino

3A)

also

acid sequences (39, 41, 42). Differential occurs at the thyroid receptor loci;

splicing (Fig. so that in addi-

tion to the principal peripheral thyroid hormone receptor (TRI31), the TR/3 locus yields a pituitary-specific /32 isoform (43). Like the RAR, progesterone, and also the estrogen (44) receptors, this effect on TR expression reflects differential activity of alternate promoters, in turn yielding different first

CHROMOSOME 11q21

B. Rev-ErbAa (earl Figure

3. Schematic

representation

of the two principal

patterns

of

that generate diversity. A) The estrogen, progesterone, RAR, and TR/3 genes all exhibit alternate splicing of 5’ exons with the use of different promoters to yield receptors that differ at their 5’ termini. B) The TRa locus exhibits a complex pattern of differential splicing of 3’ exons to yield multiple isoforms including the two shown, TRa1 being the authentic receptor. This transcription unit on human chromosome 17q21 overlaps at its 3’ end with the Rev-erbAa (earl) transcription unit. differential

splicing

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exons and NH2-terminal sequences that differ in size and sequence (Fig. 3A). At leasttwo TRa isoforms (Fig. 3B) result from alternate splicing of the last exon so that the COOH terminus differs (45-47), with only TRal binding thyroid hormone. The a2 and a3 non-ligand-binding isoforms demonstrate a further level of modulation in this receptor system analogous in many ways to the v-erb A oncogene (2, 48), inasmuch as these molecules retain the abilityto bind to DNA and thus serve as molecular antagonists competing for binding of the TRE by the

authentic

receptor

(45).

For

the

avian

erythroblastosis

virus this provides a block to thyroid hormone-induced erythroid differentiation, allowing proliferation under the influence of its second oncogene v-erbB at the erythroblast stage (48). For TRa2, the ratio of its expression to that of TRal will determine the ability of a given tissue to respond to thyroid hormone (45). Further complexity is provided by a third transcript (Rev-TRa), which is transcribed off the opposite ture with

stand

to TRal/a2

but does not that of TRa2,

(46,

47).

It also

has

bind thyroid hormone. Its i.e., the two genes overlap

a TR-like

struc-

exon 8 overlaps at their 3’ ends

(Fig. 3B). It has been suggested that expression of TRa2 may be regulated by competition with Rev for the transcription unit; alternatively, regulation of splicing which dictates whether a 1 or a2 is produced may also determine whether Rev is produced (46).

DIMERS Many transactivatingfactors,including the steroidhormone receptors, bind DNA as dimers; in addition, various members of a given family may form heterodimers, with a consequent diversity of response (10). The region for steroid hormone receptor dimer formation appears to lie within (6, 18) or overlap the ligand-binding domain (49). Both direct and indirect evidence indicates that homodimer formation is a general feature of this family (6, 18, 49-51). The thyroid and retinoic acid receptors exhibit heterodimer formation as seen for other families of transactivators (10) and the TREs of several genes respond not only to TR homodimers, but to both RAR homodimers (52, 53) and TR-RAR heterodimers (54). Glass et al. (54) have demonstrated that RARa-TRf3 heterodimers may either enhance or repress transcription, depending on the particular TRE. If the other isoforms of RAR and TR can diversity of response

form may

heterodimers, be generated

then a substantial that will be defined

by the isoform (or isoforms) expressed, of cell, and the specific gene (response

RESPONSE

their ratios, element).

the type

ELEMENTS

Hormone receptors activate specific genes by binding to HREs (reviewed recently in refs 3 and 4). Four classes of HRE have been characterized; the GRE, which has a consensus sequence GTACA nnn TUTTCT, has been studied the most extensively. Androgen, progesterone, and mineralocorticoid receptors can also act via this GRE. The estrogen response element (ERE) consensus sequence AGGTCA nnn TGACCT can be converted to a functional GRE by just changing two bases (55), whereas the TRE, which also binds the RAR (52, 53) [as does the vitamin D response element (56)], is the same as the ERE except that it lacks the intervening three variable bases. The orphan receptor COUP binds

may

3096

to

the

represent

Vol. 5

sequence

a fourth

December

GTGTCAA

class

1991

AGGTCA

of response

elements

(12),

which

(6). The

sequences are imperfect palindromes to which the receptor dimers bind. As for the receptors, there is once more a pattern of extraordinary conservation of sequence between HREs, at apparent odds with both the diversity and the specificity

of the

hormonal

responses

observed.

Several mechanisms increase the diversity both of classic HREs (34) and HREs responsible for delayed and negative effects. The context, relative position, and number of HREs all modulate the response. The first dilemma to address, however, is the apparent identity of the response elements for the glucocorticoid, mineralocorticoid, androgen, and progesterone receptors despite very different profiles of hormone response. In part this is achieved by tissue- and cellspecific

patterns

of receptor

expression,

although

glucocorti-

coid receptors are essentially ubiquitous. In addition, the model of a simple GRE, such as that in the MMTV-LTR where only activated receptor is required to increase transcription, is probably an oversimplification and may represent a viral HRE that may have evolved to promiscuity. In physiological systems the context of the HRE is probably particularly important, as is seen for the negative response elements (see later discussion). Finally, adequate examples of physiologically relevant HREs for androgens, progesterone, and especially mineralocorticoids are limited or absent. The assumption that HREs are the same for all four classes of steroids ments

must therefore from physiologically

await

description of response eleregulated genes for androgens,

progesterones, and aldosterone. Indeed, various lines of evidence suggest that the interaction of the various receptors with the MMTV-LTR differs subtly between the progesterone, androgen, and glucocorticoid receptors (57). The TRE also appears promiscuous, binding both thyroid and retinoid receptors (52, 53). This, however, must be viewed

in the

context

heterodimers,

and

of the of the

ability recent

of these report

receptors

to form

of specific

retinoid

response elements that do not bind the thyroid hormone vitamin D receptors (58). The response element sequences described previously consensus sequences; it is possible that variations from consensus may either increase (59) or decrease (34) affinity

of

the

response

element

for

the

activated

or are the the

liganded

receptor complex. A further levelof diversityisconferred by the particular cell, in which other factors may variously compete for or interact with the receptor dimer (31, 33, 34, 60-62); one such factor is the COUP transcription factor, which itself is an orphan member of the steroid receptor superfamily (12). Additional diversity is generated for the specific

gene

by the

presence/proximity

of DNA

binding

sites

for various factors that contribute to or modify the response (34, 36, 63, 64); the presence of other hormone response elements (65) or multiple copies of the same response element (63, 66-68) clearly confers a synergistic increase in transcriptional efficiency. By implication, the magnitude of the response is determined by the number of response elements (69). Such synergism is also seen with sets of imperfect response elements (66, 70, 71), which individually may have a reduced

affinity

so that

synergism

is required

for functional

binding of the receptor dimer (or dimers). In addition, these imperfect response elements often overlap with other recognition sequences (34). A response element (or elements) tend to be linked closely to the promoter in experimental constructs, but in the genome they often lie several kilobases upstream (70-72), or even downstream (73), of the promoter. In many cases there are multiple potential response elements (69, 70, 72, 74), and the transcriptionalenhancement provided by the synergism

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between response elements may be required to overcome the distance. Marked separation of the response elements from the promoter may also attenuate the response, and may enable a greater variety of other factors to interpose and thus modulate expression of the gene.

NEGATIVE

RESPONSE

ELEMENTS

with CREB binding. In contrast, when positive response elements are removed from the rat prolactin gene, the estrogen receptor interacts with the transactivator protein pitl to inhibit expression (77). A 63-amino-acid domain adjacent to the DNA-binding domain of the estrogen receptor is required but functional DNA binding is not (77), so the effect involves an analogous protein: protein interaction to that seen with glucocorticoid receptors and fos/jun. Recent evidence

Whereas these hormone receptors are classicallyviewed as activators,a further diversificationis theirabilityto also act as repressors in that some genes have been identified as being negatively regulated by hormones. The mechanism of this negative regulation is not readily explained by the classic model described in the previous section.Recent studieshave not only explored this phenomenon, but offer insightsinto what may be the more general mechanism of action of this class of DNA-binding molecules. Negative GREs (nGREs) are the best characterized of such effectors (3). They differ from the classic GRE not only in sequence [though only two base changes in the prolactin nGRE convert it to a classic GRE (34)], but between each other so that no clear consensus exists (3). They also bind receptor with a lower affinity than the classic GRE. In several genes the nGRE may be negative in some tissues and act as a positive response element in others. Diamond et al. (34)

have

characterized

the

nGRE

from

the

mouse

proliferin

gene which overlaps with an AP-1 binding site.The element alone isan enhancer by virtue of itsbinding of fos-junheterodimers or jun homodimers. The response to activated glucocorticoid receptor is further activation in the presence of the jun homodimer (itself a weak enhancer) or repression in the presence of fos-jun heterodimers, so that the net response depends on the ratio of fos to jun in a given cell. The converse appears to hold for the osteocalcingene, where the response element mediates up-regulation by both vitamin D and retinoic acid, with inhibition in response to junfos heterodimers (56). Several groups (60-62, 75) have recently reported transrepression by the glucocorticoid receptor and the AP-l complex of their respective response elements. The AP-1 response element of the collagenase I gene, in contrast to the proliferin gene, neither contains nor overlaps a glucocorticoid response element, and the glucocorticoid receptor does not bind to the DNA (60-62). The transrepression is mediated via a direct protein: protein interaction between the DNA-binding domain of the glucocorticoid receptor and the DNA-binding region (which includes the leucine zipper) of the jun monomer (62). Lucibello et al. (75) have also reported that reciprocal transrepression of the glucocorticoid receptor by fos requires a region of fos that is not conserved among fos-related proteins and for which no previous function has been defined. Other nGREs appear to overlap AP-2 sites which bind the cyclic AMP signal transducer protein CREB (76). Diamond et al. (34) have characterized such nGREs as composite GREs and postulated that they be more common than the simple GRE. They argue that their demonstration that the glucocorticoid receptor interacts both with c-jun and DNA indicates that negative regulation is not simply competition between DNA-binding proteins for overlapping response elements but involves a more complex interplay with the other factors. Conversely, Oro et al. (76) found that transrepression of the glycoprotein hormone common a-subunit gene was dependent mains but not nus;

they

further

only on the

on the DNA and activation domains

demonstrated

that

the

ligand-binding of the NH2 role

of the

dotermi-

carboxyl-

terminal region was largely one of sterichindrance, possibly

suggests

that

the

estrogen

receptor

can

indeed

interact

with fos-c-jun in this manner (78). Several other genes, in addition to the rat prolactin gene, contain both negative and positive response elements, allowing a further level of complexity in the transregulation mechanism. In some cases of negative regulation such as glucocorticoids and the proopiomelanocortin gene (POMC) or thyroid hormone and the /3 subunit of TSH, the repression was thought to be mediated via interaction with elements of the proximal promoter and a consequent interferencewith basal transcription factors(79, 80). One might postulate that for the negative feedback regulation of POMC by glucocorticoid, or TSHI3 by thyroid hormone, a distinct noncompetitive direct interaction with the promoter may be important. In view of the above findings the glucocorticoid receptor may be interacting with some component of the stimulatory second-messenger pathways such

as CREB

or AP-1.

Thyroid

mechanism for regulation, bind response elements however, ments

compete (53).

for either

There

are,

receptors

exhibit

a further

as the unliganded receptor can but cannot transactivate; it can, positive

therefore,

or negative several

response

means

ele-

by which

ac-

tivated receptors may act as transrepressors,enabling both cell-specific modulation of gene expression and dynamic modulation within the same cell. The nonsteroidal anti-estrogen tamoxifen offers a fascinating and clinically relevant insight into many of these mechanisms

of

diversity.

Tamoxifen

is

a

partial

estrogen

agonist in certain tissues of some species. In a given cell line the activity can range from fully estrogenic to totally antiestrogenic for the induction of various genes (33). Berry et al. (33) recently showed that hydroxytamoxifen binding to the receptor enables the constitutively active transactivator function (TAF-1), which is located within the NH2-terminal domain, to function. It does not, however, activate TAF-2, which lies within the ligand-binding domain. Tissue and gene differential activity appears, therefore, to be determined tivity

by whether is required.

both This

TAF-l

and

TAF-2,

requirement

or just

is defined

TAF-l, both

by

acthe

context of the estrogen response element in the given gene, and by the extent to which other transactivators or transrepressors are expressed in a given cell or cell line (31, 33).

CONCLUSION The fundamental mechanism of gene regulation by this receptor superfamily involvesligand-dependent activationof the receptor with subsequent dimer formation and DNA binding. Transactivation then follows from the interaction of this complex with the promoter elements of the target gene. A diverse range of hormones use this basic mechanism to achieve a very diverse range of responses. In this review the various mechanisms for generating diversity and specificity at each step in the process have been identified(Table 2): the ligand may be modified or itsaccess to the receptor regulated; different forms of the receptor occur, reflectingboth alternativesplicingand gene duplication; some receptor forms may be nonbinding antagonists at response

elements;

receptors

may

form

heterodimers,

3097 STEROID RECEPTORS ww.fasebj.org by UNIVERSITY OF TOLEDO LIBRARIES (18.218.56.169) on September 27, 2018. The FASEB Journal Vol. ${article.issue.getVolume()}, No. ${article.issue.getIssueNumb

2. Mechanisms of diversity

TABLE Ligand

Agonist,

Target

tissue

14.

antagonist

Receptor gene expression Activating and/or inactivating Binding

Receptor

proteins

Cytoplasmic

Dimers

Heterofactors

(extra-

vs.

Isoforms

Nuclear

13.

15.

enzymes

or intracellular) 16.

nuclear

-

differential

-

gene

splicing;

duplication

Regal. 1, 291-299 17.

or homodimerization

Antagonist

isoforms 18.

“Squelching” Response

Element

Consensus

Simple, Number Position

vs. nonconsensus

complex (imperfect), of copies

Proximity

Transactivation

of other

Gene-specific Cell-specific

response

or negative 19.

elements

20.

factors factors

21.

thereby altering their specificity; activity and direction of response elements may vary as a resultof differentpatterns of interaction with other nuclear factors;and, finally,each cellby virtue of these factors, together with its specific profile of the expression of other nuclear factors, may alter the observed response. The author wishes to thank Jeana Thomas, Sue Smith, and Sue Panckridge for preparation of the manuscript and Professor John Funder and Cris Keightley for their critical reading of the manuscript.

The

author

is a Weilcome

Australian

Senior

Fellow and the work was supported by the National Medical Research Council of Australia.

22.

23.

Research

Health

2. 3. 4.

and 25.

5.

6.

6a.

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26.

335-344

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